Indian Patents. 269841:HETEROARYL SUBSTITUTED PYRROLO[2,3-B] PYRIDINES AND PYRROLO[2,3-B] PYRIMIDINES AS JANUS KINASE INHIBITORS

Title of Invention	HETEROARYL SUBSTITUTED PYRROLO[2,3-B] PYRIDINES AND PYRROLO[2,3-B] PYRIMIDINES AS JANUS KINASE INHIBITORS
Abstract	The present invention provides heteroaryl substituted pyrrolo[2,3-b]pyridines (I) and heteroaryl substituted pyrrolo[2,3-b]pyrim- idines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

Full Text	HETEROARYL. SUBSTITUTED PYRROLO[2,3-b]PYKIDINES AND PYRROLO[2,3-b]PYRDMIDINES AS JANUS KINASE INHIBITORS FIELD OF THE INVENTION The present invention provides heteroaryl substituted pyrrolo[2,3-b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases. BACKGROUND OF THE INVENTION Protein kinases (PKs) are a group of enzymes that regulate diverse, important biological processes including cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration, among others. Protein kinases exert their physiological functions through catalyzing the phosphorylation of proteins (or substrates) and thereby modulating the cellular activities of the substrates in various biological contexts. In addition to the functions in normal tissues/organs, many protein kinases also play more specialized roles in a host of human diseases including cancer. A subset of protein kinases (also referred to as oncogenic protein kinases), when dysregulated, can cause tumor formation and growth, and further contribute to tumor maintenance and progression (Blume-Jensen P et al, Nature 2001, 411(6835):355-365). Thus far, oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for cancer intervention and drug development. Protein kinases can be categorized as receptor type and non-receptor type. Receptor tyrosine kinases (RTKs) have an extracellular portion, a transmembrane domain, and an intracellular portion, while non-receptor tyrosine kinases are entirely intracellular. RTK mediated signal transduction is typically initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response such as cell division, differentiation, metabolic effects, and changes in the extracellular microenvironment At present, at least nineteen (19) distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, includes EGFR, HER2, HER3 and HER4, and bind such ligands as epithelial growth factor (EGF), TGF-, amphiregulin, HB-EGF, betacellulin and heregulin. A second family of RTKs, designated theiuisulin subfamily, includes the INS-R, the IGF-1R and the IR-R. A third family, the "PDGF" subfamily, includes the RDGF alpha and beta receptors, CSFIR, c- kit and FJJfC-H. Another subfamily of RTKs, referred to as the FLK subfamily, encompasses the Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fins-like tyrosine kinase 1 (flt-1). Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-Met, Ron and Sea). For a detailed discussion of protein kinases, see for example, Blume-Jensen, P. et ah, Nature. 2001, 411(6835):355-365, and Manning, G. et al., Science. 2002, 298(5600): 1912-1934. The non-receptor type of tyrosine kinases is also composed of numerous subfamilies, including Src, Btk, Abl, Fak, and Jak. Each of these subfamilies can be further subdivided into multiple members that have been frequently linked to oncogenesis. The Src family, for example, is the largest and includes Src, Fyn, Lck and Fgr among others. For a detailed discussion of these kinases, see Bolen JB. Nonreceptor tyrosine protein kinases. Oncogene. 1993, 8(8):2025-31. A significant number of tyrosine kinases (both receptor and nonreceptor) are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem. 2004, 37(7):618-35.)- Clinical studies suggest that overexpression or dysregulation of tyrosine kinases may also be of prognostic value. For example, members of the HER family of RTKs have been associated with poor prognosis in breast, colorectal, head and neck and lung cancer. Mutation of c-Kit tyrosine kinase is associated with decreased survival in gastrointestinal stromal tumors. In acute myelogenous leukemia, Flt-3 mutation predicts shorter disease free survival. VEGFR expression, which is important for tumor angiogenesis, is associated with a lower survival rate in lung cancer. Tie-1 kinase expression inversely correlates with survival in gastric cancer. BCR-Abl expression is an important predictor of response in chronic myelogenous leukemia and Src tyrosine kinase is an indicator of poor prognosis in all stages of colorectal cancer. The immune system responds to injury and threats from pathogens. Cytokines are low- molecular weight polypeptides or glycoproteins that stimulate biological responses in virtually all cell types. For example, cytokines regulate many of the pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and they can modulate both proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Binding of a cytokine to its cell surface receptor initiates intracellular signaling cascades that transduce the extracellular signal to the nucleus, ultimately leading to changes in gene expression. The pathway involving the Janus kinase family of protein tyrosine kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) is engaged in the signaling of a wide range of cytokines. Generally, cytokine receptors do not have intrinsic tyrosine kinase activity, and thus require receptor- associated kinases to propagate a phosphorylation cascade. JAKs fulfill this function. Cytokines bind to their receptors, causing receptor dimerization, and this enables JAKs to phosphorylate each other as well as specific tyrosine motifs within the cytokine receptors. STATs that recognize these phosphotyrosine motifs are recruited to the receptor, and are then themselves activated by a JAK- dependent tyrosine phosphorylation event. Upon activation, STATs dissociate from the receptors, dimerize, and translocate to the nucleus to bind to specific DNA sites and alter transcription (Scott, M. J., C. J. Godshall, et al. (2002). "Jaks, STATs, Cytokines, and Sepsis." Clin Diagn Lab Immunol 9(6): 1153-9). The JAK family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. Currently, there are four known mammalian JAK family members: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3) and TYK2 (also known as protein-tyrosine kinase 2). The JAK proteins range in size from 120 to 140 kDa and comprise seven conserved JAK homology (JH) domains; one of these is a functional catalytic kinase domain, and another is a pseudokinase domain potentially serving a regulatory function and/or serving as a docking site for STATs (Scott, Godshall et al. 2002, supra). While JAK1, JAK2 and TYK2 are ubiquitously expressed, JAK3 is reported to be preferentially expressed in natural killer (NK) cells and not resting T cells, suggesting a role in lymphoid activation (Kawamura, M., D. W. McVicar, et al. (1994). "Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes." Proc Natl Acad Sci USA 91(14): 6374-8). Not only do the cytokine-stimulated immune and inflammatory responses contribute to normal host defense, they also play roles in the pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from hypoactivity and suppression of the immune system, and a hyperactive or inappropriate immune / inflammatory response contributes to the pathology of autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroiditis, immunoglobulin nephropathies, myocarditis as well as illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). "Janus kinases and signal transducers and activators of transcription: their roles in cytokine signaling, development and immunoregulation." Arthritis Res 2(1): 16-32). Furthermore, syndromes with a mixed presentation of autoimmune and immunodeficiency disease are quite common (Candotti, F., L. Notarangelo, et at. (2002). "Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways." J Clin Invest 109(10): 1261-9). Thus, therapeutic agents are typically aimed at augmentation or suppression of the immune and inflammatory pathways, accordingly. Deficiencies in expression of JAK family members are associated with disease states. Jakl-/- mice are runted at birth, fail to nurse, and die perinatally (Rodig, S. J., M. A. Meraz, et al. (1998). "Disruption of the Jakl gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine- induced biologic responses." Cell 93(3): 373-83). Jak2-/- mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive erythropoiesis. JAK2-deficient fibroblasts do not respond to IFN gamma, although responses to IFNalpha/beta and IL-6 are unaffected. JAK2 functions in signal transduction of a specific group of cytokine receptors required in definitive erythropoiesis (Neubauer, H., A. Cumano, et al. (1998). Cell 93(3): 397-409; Parganas, E., D. Wang, et al. (1998). Cell 93(3): 385-95.)- JAK3 appears to play a role in normal development and function of B and T lymphocytes. Mutations of JAK3 are reported to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans (Candotti, F., S. A. Oakes, et al. (1997). "Structural and functional basis for JAK3-deficient severe combined immunodeficiency." Blood 90(10): 3996- 4003). The JAK/STAT pathway, and in particular all four members of the JAK family, are believed to play a role in the pathogenesis of the asthmatic response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. For instance, the inappropriate immune responses that characterize asthma are orchestrated by a subset of CD4+ T helper cells termed T helper 2 (Th2) cells. Signaling through the cytokine receptor JX-4 stimulates JAK1 and JAK3 to activate STAT6, and signaling through IL-12 stimulates activation of JAK2 and TYK2, and subsequent phosphorylation of STAT4. STAT4 and STAT6 control multiple aspects of CD4+ T helper cell differentiation (Pernis, A. B. and P. B. Rothman (2002). "JAK-STAT signaling in asthma." J Clin Invest 109(10): 1279-83). Furthermore, TYK2-deficient mice were found to have enhanced Th2 cell-mediated allergic airway inflammation (Seto, Y., H. Nakajima, et al. (2003). "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice." J Immunol 170(2): 1077-83). Moreover, multiple cytokines that signal through JAK kinases have been linked to inflammatory diseases or conditions of the upper respiratory tract such as those affecting the nose and sinuses {e.g. rhinitis, sinusitis) whether classically allergic reactions or not. The JAK/STAT pathway has also been implicated to play a role in inflammatory diseases/conditions of the eye including, but not limited to, iritis, uveitis, scleritis, conjunctivitis, as well as chronic allergic responses. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases. The JAK/STAT pathway, and in particular, JAK3, also plays a role in cancers of the immune system. In adult T cell leukemia/lymphoma (ATLL), human CD4+ T cells acquire a transformed phenotype, an event that correlates with acquisition of constitutive phosphorylation of JAKs and STATs. Furthermore, an association between JAK3 and STAT-1, STAT-3, and STAT-5 activation and cell-cycle progression was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four ATLL patients tested. These results imply that JAK/STAT activation is associated with replication of leukemic cells and that therapeutic approaches aimed at JAK/STAT inhibition may be considered to halt neoplastic growth (Takemoto, S., J. C. Mulloy, et al. (1997). "Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins." Proc Natl Acad Sci USA 94(25): 13897-902). Blocking signal transduction at the level of the JAK kinases holds promise for developing treatments for hitman cancers. Cytokines of the interleukin 6 (IL-6) family, which activate the signal transducer gp130, are major survival and growth factors for human multiple myeloma (MM) cells. The signal transduction of gp130 is believed to involve JAK1, JAK2 and Tyk2 and the downstream effectors STAT3 and the mitogen-activated protein kinase (MAPK) pathways. In IL-6-dependent MM cell lines treated with the JAK2 inhibitor tyrphostin AG490, JAK2 kinase activity and ERK2 and STAT3 phosphorylation were inhibited. Furthermore, cell proliferation was suppressed and apoptosis was induced (De Vos, J., M. Jourdan, et al. (2000). "JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells." Br J Haematol 109(4): 823- 8). However, in some cases, AG490 can induce dormancy of tumor cells and actually then protect them from death. Activation of JAK/STAT in cancers may occur by multiple mechanisms including cytokine stimulation (e.g. IL-6 or GM-CSF) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT) (Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002). Importantly, activation of STAT signaling, as well as other pathways downstream of JAKs (e.g. Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Moreover, elevated levels of circulating cytokines that signal through JAK/STAT may adversely impact patient health as they are thought to play a causal role in cachexia and/or chronic fatigue. As such, JAK inhibition may be therapeutic for the treatment of cancer patients for reasons that extend beyond potential anti-tumor activity. The cachexia indication may gain further mechanistic support with realization that the satiety factor leptin signals through JAKs. Pharmacological targeting of Janus kinase 3 (JAK3) has been employed successfully to control allograft rejection and graft versus host disease (GVHD). In addition to its involvement in signaling of cytokine receptors, JAK3 is also engaged in the CD40 signaling pathway of peripheral blood monocytes. During CD40-induced maturation of myeloid dendritic cells (DCs), JAK3 activity is induced, and increases in costimulatory molecule expression, IL-12 production, and potent allogeneic stimulatory capacity are observed. A rationally designed JAK3 inhibitor WHI-P-154 prevented these effects arresting the DCs at an immature level, suggesting that immunosuppressive therapies targeting the tyrosine kinase JAK3 may also affect the function of myeloid cells (Saemann, M. D., C. Diakos, et al. (2003). "Prevention of CD40-triggered dendritic cell maturation and induction of T-cell hyporeactivity by targeting of Janus kinase 3." Am J Transplant 3(11): 1341-9). In the mouse model system, JAK3 was also shown to be an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor JANEX-1 exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M., A. L. Dragt, et al. (2003). "Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice." Clin Immunol 106(3): 213-25). It has been suggested that inhibition of JAK2 tyrosine kinase can be beneficial for patients with myeloproliferative disorder. (Levin, et al, Cancer Cell, vol. 7, 2005: 387-397) Myeloproliferative disorder (MPD) includes polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES) and systemic mast cell disease (SMCD). Although the myeloproliferative disorder (such as PV, ET and MMM) are thought to be caused by acquired somatic mutation in hematopoietic progenitors, the genetic basis for these diseases has not been known. However, it has been reported that hematopoietic cells from a majority of patients with PV and a significant number of patients with ET and MMM possess a recurrent somatic activating mutation in the JAK2 tyrosine kinase. It has also been reported that inhibition of the JAK2V617F kinase with a small molecule inhibitor leads to inhibition of proliferation of hematopoietic cells, suggesting that the JAK2 tyrosine kinase is a potential target for pharmacologic inhibition in patients with PV, ET and MMM. Inhibition of the JAK kinases is also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization. In psoriasis vulgaris, the most common form of psoriasis, it has been generally accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques (Gottlieb, A.B., et al, Nat Rev Drug Disc, 4:19-34). Psoriatic plaques contain a significant immune infiltrate, including leukocytes and monocytes, as well as multiple epidermal layers with increased keratinocyte proliferation. While the initial activation of immune cells in psoriasis occurs by an ill defined mechanism, the maintenance is believed to be dependent on a number of inflammatory cytokines, in addition to various chemokines and growth factors (JCI, 113:1664-1675). Many of these, including interleukins -2, -4, -6, -7, -12, -15, -18, and -23 as well as GM-CSF and EFNg, signal through the Janus (JAK) kinases (Adv Pharmacol. 2000;47:113-74). As such, blocking signal transduction at the level of JAK kinases may result in therapeutic benefits in patients suffering from psoriasis or other immune disorders of the skin. It has been known that certain therapeutics can cause immune reactions such as skin rash or diarrhea in some patients. For instance, administration of some of the new targeted anti-cancer agents such as Iressa, Erbitux, and Tarceva has induced acneiform rash with some patients. Another example is that some therapeutics used topically induce skin irritation, skin rash, contact dermatitis or allergic contact sensitization. For some patients, these immune reactions may be bothersome, but for others, the immune reactions such as rash or diarrhea may result in inability to continue the treatment. Although the driving force behind these immune reactions has not been elucidated completely at the present time, these immune reactions are likely linked to immune infiltrate. Inhibitors of Janus kinases or related kinases are widely sought and several publications report effective classes of compounds. For example, certain inhibitors are reported in WO 99/65909, US 2004/0198737; WO 2004/099204; WO 2004/099205; and WO 01/42246. Heteroaryl substituted pyrroles and other compounds are reported in WO 2004/72063 and WO 99/62908. Thus, new or improved agents which inhibit kinases such as Janus kinases are continually needed that act as immunosuppressive agents for organ transpiants, as well as agents for the prevention and treatment of autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, Crohn's disease, autoimmune thyroid disorders, Alzheimer's disease), diseases involving a hyperactive inflammatory response (e.g., eczema), allergies, cancer (e.g., prostate, leukemia, multiple myeloma), and some immune reactions (e.g., skin rash or contact dermatitis or diarrhea) caused by other therapeutics, to name a few. The compounds, compositions and methods described herein are directed toward these needs and other ends. SUMMARY OF THE INVENTION The present invention provides compounds of Formula I: or pharmaceutically acceptable salt forms or prodrugs thereof, wherein constituent members are defined herein. The present invention further provides compositions comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention further provides methods of modulating an activity of JAK comprising contacting JAK with a compound of Formula I, or pharmaceutically acceptable salt thereof. The present invention further provides methods of treating a disease in a patient, wherein the disease is associated with JAK activity, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof. The present invention further provides compounds of Formula I for use in therapy. The present invention further provides compounds of Formula I for the preparation of a medicament for use in therapy. DETAILED DESCRIPTION The present invention provides, inter alia, compounds that modulate the activity of one or more JAKs and are useful, for example, in the treatment of diseases associated with JAK expression or activity. The compounds of the invention have Formula I: including phannaceutically acceptable salt forms or prodrugs thereof, wherein: A1 and A2 are independently selected from C and N; T, U, and V are independently selected from O, S, N, CR5, and NR6; wherein the 5-membered ring formed by A1, A2, U, T, and V is aromatic; X is Nor CR4; Y is C1-8 alkylene, C2_8 alkenylene, C2-8 alkynylene, (CR11R12)p-(C3-10cycloalkylene)- (CR1 'R12)q, (CRlIR12)p-(arylene)-(CR11R12)q, (CR11R12)p-(C1-10 heterocycloalkylene)-(CR"RI2)qj (CR11R12)p (heteroarylene)-(CR11R12)q, (CR11R12)p O(CR11R12)q, (CR11R12)p SCR11R12)q) (CR11RI2)PC(O)(CR11R12)p , (CR11R12)pC(O)NRC(CR11R12)q (CR11RI2)PC(O)O(CR11Rl2)q, (CR11R12)p 0C(O)(CR11R12)p , (CR11R12)pOC(O)NRc(CR11R12)q, (CR11R12)P NRC(CR11R12)Q , (CR11R12)p NRcC(O)NRd(CR11R12)q, (CR11R12)pS(O)(CR1 'R12),, (CR11R12)q S(O)NRC(CR11R21),,, (CR11R12)Q(O)2(CR11R12)Q, or (CR11R12)p S(O)2NRc(CR11R12)p , wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D1D2D3-D4; Z is H, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4 hydroxyalkyl, C1-4 cyanoalkyl, =C-Rf, =N-R!, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd5 NRcRd, NRcC(O)Rb, NR'C(O)NRCRD, NRcC(O)ORa, C(=NR1)NRcRd,NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NReS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl,C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR", SR", C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NR°Rd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(0)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl))Rb, and S(O)2NRcRd; wherein when Z is H, n is 1; or the -(Y)n-Z moiety is taken together with i) A2 to which the moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which the R5 or R6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2,3,4, or 5 substituents independently selected from -(W)m-Q; W is C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, O, S, C(O), C(O)NRC', C(O)O, OC(O), OC(O)NRC', NRC', NRcC(O)NRd", S(O), S(O)NRC', S(O)2, or S(O)2NRC'; Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C1-4 alkyl, C2.4 alkenyl, C2.4 alkynyl,C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl. Cy2, CN, NO2, OR"', SRa', C(O)Rb, C(O)NRc'Rd', C(O)ORa', OC(O)Rb>, OC(O)NRcRd',NRcRd",NRcC(O)Rb',NRcC(O)NRc'Rd",NRC>C(O)OR"', S(O)Rb>, S(O)NRc'Rd', S(O)2Rb>, NRc'S(O)2Rb\ and S(O)2NRcRd'; Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-4alkyl,C2-4 alkenyl, C2.4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl. CN, NO2, ORa", SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", 0C(O)Rb", OC(O)NRC "Rd", NRc'Rd",NRc"C(O)Rb",NRc"C(O)ORa",NRc"S(O)Rb",NRc"S(O)2Rb", S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd"; R1, R2, R3, and R4 are independently selected from H, halo, C1-4 alkyl, C2.4 alkenyl,C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2> OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR9R10,NR9C(O)R8, NRCC(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10; R5 is H, halo,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)N9R10; R6 is H, C1-4 alkyl,C1-4alkenyl, C2-4 alkynyl,C1-4 haloalkyl, OR7, C(O)R8, C(O)NR9R10, C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, or S(O)2NR9R10; R7 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R8 is H, C1-6 alkyl, C1-4 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R9 and R10 are independently selected from H, C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R9 and R10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; R" and R12 are independently selected from H and -E1-E2-E3-E4; D1 and E1 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO2 N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and C2-8 dialkylamino; D2 and E2 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, (C1-6 alkylene)r-O-( C1-6 alkylene)s, (C1-6 alkylene)r-S-(C1-6alkylene)S) (C1-6 alkylene)r-NRe-(C1-6 alkylene)s,(C1-6 alkylene)r-CO-(C1-6 alkylene)s, (C1-6 alkylene)r-COO-(C1-6 alkylene)s, (C1-6 alkylene)r-CONRe-(C1-6 alkylene)s, (C1-6alkylene)r-SO-(C1-6 alkylene)s, (C1-6 alkylene)r-SO2-(C1-6 alkylene)s, (C1-6 alkylene)r-SONRe-(C1-6 alkylene)s, and (C1-6alkylene)r- NReCONRf-(C1-6 alkylene)s, wherein each of the C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2_8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and C2-8 dialkylamino; D3 and E3 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-4 alkylamino, and C2-8 dialkylamino; D4 and E4 are independently selected from H, halo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy', CN, NO2, ORa, SRa, C(O)Rb, C(O)NR0Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NR°Rd, NRCC(O)OR°, C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O02Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl)Rb, and S(O)2NR°Rd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1,2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR", SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C,.fi alkyl))Rb, and S(O)2NRcRd; Rq is H, Cy1, -(C1-6 alkyl)-Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaiyl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy1, -(C1-6 alkyl)-Cy', C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R8> and Ra' are independently selected from H, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb' and Rb" are independently selected from H, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc and Ra are independently selected from H, Cy1, -(C1-6 alkyl)-Cy', C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, is optionally substituted with 1,2, or 3 substituents independently selected from Cy1, -(C1-6 alkyl)-Cy1, OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6 haloalkyl,and halosulfanyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently selected from Cy1, -(C1-6 alkyl)-Cy', OH, CN, amino, halo, d.6alkyl, d.6haloalkyl, C1-6 haloalkyl, and halosulfanyl; Rc and Rd are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, CC1-6 haloalkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc" and Rd' together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, ammo, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroaiylalkyl, cycloalkyl and heterocycloalkyl; Rc and Rd are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R! is H, CN, NO2, or C1-6alkyl; Re and Rf are independently selected from H and C1-6 alkyl; R' is H.CN.or NO2; m is 0 or 1; n is 0 or 1; pis 0,1, 2, 3,4, 5, or6; q is O, 1,2, 3,4, 5 or 6; r is 0 or 1; and s is O or 1. In some embodiments, when X is N, n is 1, and the moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula: then Y is other than (CR11R12)qC(O)NR(CR11R12)q. In some embodiments, when X is N, the 5-membered ring formed by A1, A2, U, T, and V is other than pyrrolyl. In some embodiments, when X is CH, n is 1, and the moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula: then -(Y)n-Z is other than COOH. In some embodiments, when X is CH or C-halo, R1, R2, and R3 are each H, n is 1, and the moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula: then Y is other than (CR11R12)pC(O)NRc(CR11R12)q or (CR11R12)p C(O)(CR11Rl2)q. In some embodiments, when X is CH or C-halo, R1, R2, and R3 are each H, n is 0, and the moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula: then Z is other than CN, halo, or C1-4 alkyl. In some embodiments, when X is CH or C-halo, R1, R2, and R3 are each H, n is 1, and the moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula: then Y is other than (CR11R12)pC(O)NRc(CR11R12)p or (CR11R12)pC(O)(CR11R12)q. In some embodiments, when X is CH or C-halo, R1, R2, and R3 are each H, n is 1, and the moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula: then Y is other than (CR11'R12)qNR(CR11R12)q. In some embodiments, when X is CH or C-halo and R1, R2, and R3 are each H, then the moiety formed by A1, A2, U, T, V, and —(Y)n-Z has a formula other than: In some embodiments: Z is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NReRd, C(O)OR°, OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR8, C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd; Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4 haloalkyl,C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy2, CN, NO2, ORa', SR" C(O)Rb', C(O)NRcRd\ C(O)ORa', OC(O)Rb', OC(O)NRcRd', NRc'Rd>, NRcC(O)Rb', NRcC(O)NRcRd', NRc'C(O)ORa', S(O)Rb", S(O)NRcRd", S(O)2Rb', NRc'S(O)2Rb', and S(O)2NRcRd'; Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocyclo- alkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo,C1-4 alkyl, C2-4 alkenyl,C1-4 alkynyl,C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, CN, NO2, ORa", SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", OC(O)Rb>, OC(O)NRc"Rd'\NRc"Rd",NRc"C(O)Rb", NRc"C(O)ORa", NRc"S(O)Rb", NRc"S(O)2Rb", S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd"; R1, R2, R3, and R4 are independently selected from H, halo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NRCC(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10; R5 is H, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R83 NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)2NR9R10; R6 is H,C1-4 alkyl,C1-4 alkenyl,C1-4 alkynyl, C1-4 haloalkyl, OR7, C(O)R8, C(O)NR9R10, C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, or S(O)2NR9R10; R7 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R8 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R9 and R10 are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R9 and R10 together with the N atom to which, they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; R" and R12 are independently selected from H, halo, OH, CN, C1-6 alkyl,C1-4haloalkyl, C1-4 alkenyl, C2-4 alkynyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R°, Ra', and Ra' are independently selected from H, C1-4 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb, Rb' and Rb" are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1.6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-8 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc and Rd are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc' and Rd' are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, hetero- aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc and Rd are independently selected from H, C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; and or R° and R together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-4haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl. In some embodiments, X is N. In some embodiments, X is CR4. In some embodiments, A1 is C. In some embodiments, A1 is N. In some embodiments, A2 is C. In some embodiments, A2 is N. In some embodiments, at least one of A1, A2, U, T, and V is N. In some embodiments, the 5-membered ring formed by A1, A2, U, T, and V is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or oxadiazolyl. In some embodiments, the 5-membered ring formed by A1, A2, U, T, and V is selected from: wherein: a designates the site of attachment of moiety -(Y)n-Z; b designates the site of attachment to the core moiety: c and c' designate the two sites of attachment of the fused 4- to 20-membered aryl, cycloalkyl, heteroaiyl, or heterocycloalkyl ring. In some embodiments, the 5-membered ring formed by A1, A2, U, T, and V is selected from: wherein: a designates the site of attachment of moiety -(Y)n-Z; b designates the site of attachment to the core moiety: wnerein: a designates the site of attachment of moiety -(Y)n-Z; b designates the site of attachment to the core moiety: In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 1 and Y is C1-8 alkylene, C2-8 alkenylene, (CR11RI2)PC(O)(CR"RI:2)()> (CR11R12)pC(O)NRc(CR11R12)q, (CR11R12)pC(O)O(CR11R12)q) (CRllRl2)pOC(O)(CR11R12)q, wherein said C1-8 alkylene or C2-8 alkenylene, is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, C1-6alkylamino, or C2-8 dialkylamino. In some embodiments, n is 1 and Y is C1-8 alkylene, (CR11R12)pC(O)(CR11R12)p , (CR11R12)qC(O)NRc(CRnRI2)q, (CR11R12)qC(O)O(CR11R12)p , wherein said C1-8 alkylene is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, C1-4 alkylamino, or C2-6 dialkylamino. In some embodiments, n is 1 and Y is C1-8 alkylene optionally substituted with 1, 2, or 3 halo, OH, CN, amino, C1-4 alkylamino, or C2-8 dialkylamino. In some embodiments, n is 1 and Y is ethylene optionally substituted with 1,2, or 3 halo, OH, CN, amino,C1-4alkylamino, or C2-8 dialkylamino. In some embodiments, n is 1 and Y is (CRllRl2)pC(O)(CRI1RI2)q (CR11R12)pC(O)NR°- (CR11R12)q, or (CR11R12)qC(O)O(CR11R12)q. In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R12)q-(C3-10 cycloalkyleneX(CR11R12)q, (CR11R12)p-(arylene)-(CR11R12)q, (CR11R12q(C)(C1-10 heterocycloalkylene)- (CR11R12)q, (CR11R12)q-(heteroarylene)-(CR11R12)q, (CR11R12)qO(CR11R12)p , or (CR11R12)qS(CR11R12)qi wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1,2, or 3 substituents independently selected from -D'-D2-D3-D4. In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R12)q-(C3-10 cycloalkylene)-(CR11R12)q, (CR11R12)p -(arylene)-(CR11R12)q, (CR11R12)q-(C1-10 heterocycloalkylene)- (CR11R12)q> (CR11R12)q-(heteroarylene)-(CR11R12)q, (CR11R12)q O(CR11R12)Q, or (CR11R12)pS(CR11R12)p ) wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from D4. In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, or (CR11R12)p-(C3. 10 cycloalkylene)-(CR11R12)q, wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, or cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D1- D2-D3-D4. In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, or (CR11R12)q-(C3. 10 cycloalkylene)-(CR11R12)p , wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, or cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from D4. In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, or C2-6 alkynylene, each optionally substituted with 1, 2, or 3 substituents independently selected from -D1-D2-D3D4. In some embodiments, Y is C1-8 alkylene optionally substituted with 1, 2, or 3 substituents independently selected from -D1-D2-D3-D4. In some embodiments, Y is C1-8 alkylene optionally substituted with 1,2, or 3 substituents independently selected from D4. In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-6 alkynylene, (CR11R12)qO- (CR11R12)p , (CR11R12)pS(CR11R12)p , (CR11Rl2)pC(O)(CR11R12)q, (CR11R12)pC(O)NR0(CR11R12)q, (CR11R12)qC(O)O(CR11R12)p , (CR11R12)qOC(O)(CR11R12)q, (CR11R12)pOC(O)NRC(CR11R12)q, (CR11R12)qNRC (CR11R12)Qi (CR11R12)pNRcC(O)NRd(CR11R12)q, (CR11R12)qSCO)(CR11R12)Q, (CR11R12)p S(O)NRc(CR11R12)p , (CR11R12)pS(O)2(CR11R12)q, or (CR11R12)qS(O)2NRc(CR11R12)p , wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, amino,C1-4alkylaraino, and C2-8 dialkylamino. In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R12)q-(C3-10 cycloalkylene)-(CR11R12)q,(CR11RI2)p-(arylene)-(CRllR12)q,(CRllR12)p-(C1-10 heterocycloalkylene)- (CR11R12)q, (CR11R12)q-(heteroarylene)-(CR11R12)q, (CR11R12)qO(CR11R12)q, (CR11R12)qS(CR11R12)q, (CR11R12)qC(O)(CRllR12)q,(CR11R12)qC(O)NRc(CR11R12)q, (CR11R12)qC(O)O(CR11R12)q, (CR11R12)qOC(O)(CR11R12)q, (CR11R12)qOC(O)NRC(CR11R12)q, (CR11R12)qNRC(CR11R12)Q, (CR11R12)p NRcC(O)NRd(CR11R12)q, (CR11R12)qSCO)(CR11R12)q, (CR11R12)q,S(O)NRc(CR11R12)q, (CR11R12)qS(O)2(CR11R12)q, or (CR11R12)pS(O)2NRc(CR11R12)q, wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, amino, C1-4 alkylamino, and C2-8 dialkylamino. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, one of p and q is 0 and the other of p and q is 1, 2, or 3. In some embodiments, Z is H, halo,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN,NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)OR°, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NReRdl, NRcC(O)ORa, C(=NRi)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NR'CCONRcRd, NRcC(O)ORa, C(=NR1)NRcRd,NRcC(=NRi)NReRd) S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl))Rb, and S(O)2NRcRd. In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR0, SR\ C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR°, C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NReS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1,2, 3, 4, 5, or 6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy\ CN, NO2> ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NRi)NRcRd, MReC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR", SRa, C(O)Rb, C(O)NcRd, C(O)ORa, OC(0)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NR°C(=NRl)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NR°Rd. In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3,4,5, or 6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2 ORa SRa, C(O)Rb, C(O)NRcRd, C(O)OR°, OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)NR°Rd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, SC(O)2R1", NRcS(O)2Rb, and SC(O)2NRcRd. In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NR°C(O)NReRd, NRcC(O)ORa, C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NReRd. In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl,C1-4alkenyl, C2-6 alkynyl, C1-4 haloalkyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)OR°, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NR°Rd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is phenyl optionally substituted with 1, 2, 3,4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, CCO)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd,NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NReRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)RD, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NR°Rd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NR°Rd, S(O)Rb, S(O)NR'R4, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NReRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycioheptyl, each optionally substituted with 1, 2, 3,4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NReRd, NRcRd, NRcC(O)Rb, NReC(O)NRBRd,NRcC(O)ORa, C(=NR1)NRcR NRcS(O)aRb and S(O)2NRCd. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRCRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4 haloalkyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa SRa C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NR°C(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy', CN, NO2, OR", SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl,C1-4alkynyl,C1-4haloalkyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NReRd, C(O)OR\ OC(O)Rb, OC(O)NR°Rd, NR°Rd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR", SR", C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NR°Rd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR", S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4alkenyl, C2-6 , alkynyl, C1-4 haloalkyl, C1-6 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C:.4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)ORB, S(O)R°, S(O)NRcRd, S(O)2Rb, NRCS(O)2R\ and S(O)2NRcRd. In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SR", C(O)Rb, C(O)NRcRd, C(O)ORa, 0C(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and SCO)2NRcRd. In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NR°Rd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NR°Rd, NR'R", NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)Ra, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NR°Rd. In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,C1-4 hydroxyalkyl, C1-6 cyanoalkyl, Cy1, CN, NO2, OR", SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyi, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(0)Rb, OC(O)NRcRd, NRTRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyi, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and'S(O)2NRcRd. In some embodiments, Z is C1-8 alkyl, C2_8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo,C1-4alkyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2, OR", C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, and S(O)2Rb. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3,4,5, or 6 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl,C1-4hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2, OR", C(O)NReRd, C(O)ORa, NRcRd, NReC(O)Rb, and S(O)2Rb. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo,C1-4alkyl,C1-4haloalkyl, halosulfanyl, C1-4 hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, and S(O)2Rb. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl,C1-4haloalkyl,C1-4hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, and S(O)2Rb. In some embodiments, Z is substituted with at least one substituent comprising at least one CN group. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with at least one CN orC1-4cyanoalkyl and optionally substituted with 1,2, 3, 4, or 5 further substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)OR°, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR3, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with at least one CN orC1-4cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents selected from halo,C1-4alkyl,C2-4alkenyl, C2-4 , alkynyl,C1-4haloalkyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NOz, OR\ SRa, C(O)Rb, C(O)NRTR.d, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR% S(O)Rb, S(O)NRcRd, S(O)2Rb,NRcS(O)2Rb, and S(O)2NRCRd. In some embodiments, wherein the -(Y)o-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1,2, 3, 4, or 5 substituents independently selected from —(W)m-Q. In some embodiments, wherein the -(Y)n-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of either T or V is attached to form a 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1,2, 3, 4, or 5 substituents independently selected from -(W)m-Q. In some embodiments, the -(Y)n-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said Rs or R6 of either T or V is attached to form a 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5- membered ring formed by A1, A2, U, T, and V, wherein said 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted by 1, 2 or 3 CN. In some embodiments, Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, CN, NO2, ORa", SRa", C(O)Rb", C(O)NRc"Rd"\ C(O)ORa", OC(O)Rb", OC(O)NRc"Rd", NRc"Rd", NRc"C(O)Rb",NRc"C(O)ORa", S(O)Rb", S(O)NRcRd'", S(O)2Rb", and S(O)2NRc"Rd". In some embodiments, Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1,2, 3,4 or 5 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN, NO2, OR"", SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", OC(O)Rb", OC(O)NRc"Rd", NRc"Rd", NR°"C(O)Rb", NRc"C(O)ORa", S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd". In some embodiments, Cy1 and Cy2 are independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN, NO2, OR"", SRa", C(O)Rb", C(O)NRt"Rd", C(O)ORa",OC(O)Rb", OC(O)NRc"Rd",NRc"Rd",NRc"C(O)Rb",NRc"C(O)ORa", S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd". In some embodiments, Cy1 and Cy2 are independently selected from cycloalkyl optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2. 4 alkynyl, C1-4 haloalkyl, CN, NO2) OR8", SRa", C(O)Rb", C(O)NRc"Rd", C(O)OR°", OC(O)Rb", OC(O)NRc"Rd", NRc"Rd", NRc"C(O)Rb", NRc"C(O)ORa", S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd". In some embodiments, R1, R2, R3, and R4 are independently selected from H, halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NRCC(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10. In some embodiments, R1, R2, R3, and R4 are independently selected from H, halo, andC1-4alkyl. In some embodiments, R1, R2, R3, and R4 are each H. In some embodiments, R1 is H, halo, orC1-4alkyl. In some embodiments, R5 is H, halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR'R'0, NR9C(O)R8, NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)2NR9R10. In some embodiments, R5 is H, halo, C1-4 alkyl,C1-4haloalkyl, halosulfanyl, CN, or NR9R10. In some embodiments, Rs is H, halo, C1-6 alkyl,C1-4haloalkyl, CN, orNR9RID. In some embodiments, R5 is H. In some embodiments, R6 is H or C1-4 alkyl. In some embodiments, R6 is H. In some embodiments, R11 and R12 are independently selected from H, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-6 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRCRD, NRCRD, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NR°Rd, NR°C(=-NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2 ORa, SRa, C(O)Rb, C(O)NRcRd, C(0)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR°, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NR°Rd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl))Rb, and S(O)2NRcRd. In some embodiments, R11 and R12 are independently selected from H, halo, OH, CN,C1-4 alkyl, C1-4 haloalkyl, halosulfanyl, SCN,C2-4 alkenyl, C2-4alkynyl,C1-4hydroxyalkyl,C1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, R11 and R12 are independently selected from H, halo, OH, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the compound has Formula la or Ib: At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. At various places in the present specification, linking substituents are described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CRR")n- includes both NR(CR'R")n and -(CR'R")nNR Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively. The term "n-membered" where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. A linking alkyl group is referred to herein as "alkylene." As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. A linking alkenyl group is referred to herein as "alkenylene." As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. A linking alkynyl group is referred to herein as "alkynylene." As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF3, C2F5, CHF2, CC13, CHC12, C2C15, and the like. As used herein, "halosulfanyl" refers to a sulfur group having one or more halogen substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SF5. As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. A linking aryl group is referred to herein as "arylene." As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Cycloalkyl groups also include cycloalkylidenes. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. A linking cycloalkyl group is referred to herein as "cycloalkylene." As used herein, "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fury], quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. A linking heteroaryl group is referred to herein as "heteroarylene." As used herein, "heterocycloalkyl" refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems as well as spirocycles. Example "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3- dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. The heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double or triple bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double or triple bonds. A linking heterocycloalkyl group is referred to herein as "heterocycloalkylene." As used herein, "halo' or "halogen" includes fluoro, chloro, bromo, and iodo. As used herein, "arylalkyl" refers to alkyl substituted by aryl and "cycloalkylalkyl" refers to alkyl substituted by cycloalkyl. An example arylalkyl group is benzyl. As used herein, "heteroarylalkyl" refers to alkyl substituted by heteroaryl and "heterocycloalkylalkyl" refers to alkyl substituted by heterocycloalkyl. As used herein, "amino" refers to NH2. As used herein, "alkylamino" refers to an amino group substituted by an alkyl group. As used herein, "dialkylamino" refers to an amino group substituted by two alkyl groups. As used herein, "hydroxylalkyl" refers to an alkyl group substituted by hydroxyl. As used herein, "cyanoalkyl" refers to an alkyl group substituted by cyano. The carbon of the cyano group is typically not counted if a carbon count precedes the term. For example, cyanomethyl is considered herein to be a Ci cyanoalkyl group. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as (3-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methyl- benzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone — enol pairs, amide - imidic acid pairs, lactam — lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the invention further include hydrates and solvates, as well as anhydrous and non-solvated forms. Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which is was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art. The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. The present invention also includes prodrugs of the compounds described herein. As used herein, "prodrugs" refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety. Synthesis Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., H or 13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. Compounds of the invention can be prepared according to numerous preparatory routes known in the literature. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below. As shown in Scheme 1, pyrazole-containing cores 1-9 and 1-6 can be synthesized starting with pyrrolo[2,3-b]pyridine or pyrrolo[2,3-b]pyrimidine 1-1. The compound 1-1 can be converted to an active species such as an N-oxide analog (1-2) by using an oxidant such as m-CPBA. The N-oxide 1-2 can be halogenated with a halogenating agent such as a combination of tetramethylammonium bromide and methanesulfonic anhydride to form a 4-halo compound 1-3 such as a 4-bromo compound while the N-oxide is reduced at the same time. The amine group of the compound 1-3 can be protected by a suitable amine protecting group to afford the protected compound 1-7, which subsequently undergoes a Suzuki coupling with a boric acid 1-8 to afford the pyrazole-containing cores l-9a which can be further reacted with reagent L-(Y)n-Z (where L is a leaving group) to give compounds of the invention l-9b. Alternatively, the N-oxide 1-2 can be halogenated with a halogenating agent such as MeSO2Cl to form a 4-halo compound 1-4 such as a 4-chloro compound while the N-oxide is reduced at the same time. The 4-halo compound 1-4 can be coupled to a bromo- substituted pyrazole compound 1-5 under suitable conditions such as heating to afford the pyrazole- containing core 1-6, which may contain some functional groups such as bromo or cyano suitable for further chemical modification. Similarly, an imidazole core 1-11 can be synthesized by coupling of the 4-halo compound 1-4 to an imidazole derivative 1-10 under suitable conditions such as heating to afford the imidazole- containing core 1-11, which may contain some functional groups such as bromo or cyano suitable for further chemical modification. As shown in Scheme 2, pyrazole-containmg cores 2-3, 2-5 and 2-6 can be synthesized starting with a bromo-substituted pyrazole derivative 2-1 (a compound 1-6 in Scheme 1 wherein one of R5 is Br). The bromo-substituted pyrazole derivative 2-1 can be coupled to boron-containing aromatic species such as an aromatic boric acid 2-2 using Suzuki coupling wherein Ar is aryl or heteroaryl, each of which can be optionally substituted by one or more substituents such as alky, aryl, CN, nitro, alkoxy, etc. Alternatively, an alkene- or alkyne-containing compound such as an alkene-containing 2- 5 can be obtained by coupling the bromo-substituted pyrazole derivative 2-1 to an unsaturated compound such as an alkene 2-4 in the presence of a metal catalyst such as bis(triphenylphcs- phine)palladium (IT) chloride wherein t can be 0, 1, 2, and the like; and R can be a substituent such as alkyl, aryl, CN, nitro, alkoxy, etc. The alkene group of compound 2-5 can be reduced by hydrogenation to afford the corresponding compound 2-6. As shown in Scheme 3, imidazole-containing cores 3-7 can be synthesized starting with an N- protected 4-bromo-pyrrolo[2,3-b]pyridine or an N-protected 4-bromo-pvrrolo[2,3-b]pyrimidine 3-1 wherein P is a suitable amine protecting group such as {[2-(trimethylsilyl)ethoxy]methyl} (SEM). Compound 3-1 can be reacted with a Grignard reagent such as isopropyl magnesium chloride to generate an aromatic anion through ion exchange. The subsequent addition of a chloroacetyl- containing compound such as 2-chloro-N-methoxy-N-methylacetarnide 3-2 to the anion will typically afford the chloroacetyl derivative 3-3. The derivative 3-3 can be reacted with an organic acid salt such as a cesium salt R5CO2Cs to afford a compound 3-4. In the presence of a suitable ammonia source such as ammonium acetate, the compound 3-4 can react with ammonia under suitable conditions such as at a high temperature to form the imidazole ring of the compound 3-5. The free amine nitrogen of the imidazole derivative 3-5 can undergo further modification such as reacting with a compound X-(Y)n-Z where X is a leaving group such as chloro, bromo or iodo so as to afford compound 3-6. The protecting group of compound 3-6 can be removed by an appropriate method according to the nature of the protecting group to yield compound 3-7. It should be noted that if there are functional groups present within the R, R5, and —(Y)n-Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to an alcohol, which in turn can be further modified. One skilled in the art will recognize appropriate further modifications. As shown in scheme 4, thiazole-contammg cores 4-3 can be synthesized starting with an N- protected chloroacetyl derivative 4-1 wherein P is a suitable amine protecting group such as SEM. Compound 4-1 can be reacted with a thioamide 4-2 to form the thiazole ring, followed by deprotection of the amine nitrogen of the pyrrole ring by removal of the P group to afford the compound 4-3. Various thioureas 4-5 (equivalent to compound 4-2 wherein — (Y)n-Z is NR'R"; and R* and R" are H, alkyl, aryl or the like; or R' and R" together with the N atom to which they are attached form a heterocycloalkyl) useful in preparing the thiazole compounds 4-3 can be made from secondary amines 4-4. A secondary amine 4-4 can be reacted with 1,1 '-thiocarbonyldiimidazole; and the resulting intermediate can further be reacted with ammonia to afford a thiourea 4-S. As shown in Scheme 5, thiazole-containing cores 5-5 can be synthesized starting with a thiazole compound 5-1. The compound 5-1 can be reacted with a metal alkyl such as n-butyl lithium via ion exchange to generate an aromatic anion in situ. The subsequent addition of boric acid trimethyl ester followed by hydrolysis will typically afford the boric acid 5-2. The boric acid 5-2 can undergo Suzuki coupling with an N-protected 4-bromo-pyrrolo[2,3-b]pyridine or an N-protected 4- bromo-pyrrolo[2,3-b]pyrimidine 5-3 wherein P is a suitable amine protecting group such as SEM. The protecting group P of the coupling product 5-4 can be removed by an appropriate method according to the nature of the protecting group to yield the compound of the invention 5-5. As shown in Scheme 6, pyrazole-containing compounds 6-1 can further be modified by substitution on the pyrazole NH group with appropriate reagents. For example, a compound 6-1 wherein P is a suitable amine protecting group such as SEM can be reacted with L-(Y)n-Z where L represents a leaving group such as halo, triflate or the like to afford compound 6-2 under basic condition. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol. One skilled in the art will recognize the further modifications if appropriate. Additionally, compound 6-1 can be reacted with alkene 6-3 (wherein R' and R" can be H, alkyl, cycloalkyl and the like; and Z' can be an electron withdrawing group such as an ester or CN) to afford the compound 6-4. Further, substitution can be made on alkene 6-3 at the alpha position (alpha to Z') to generate a substituted derivatives of product, 6-4 (see, e.g., Example 68). Compounds 6-2 and 6-4 can be deprotected by appropriate methods according to the nature of the protecting group used to afford their corresponding de-protected counterpart. As shown in Scheme 7, bromo pyrazole containing compounds 7-1 can be further modified by metallation with reagents like butyl lithium and reaction with electrophiles like aldehydes to give the alcohol containing compounds 7-2 which can be deprotected to yield compounds of the invention having formula 7-3. One skilled in the art will recognize the further modifications where appropriate. As shown in Scheme 8, pyrazole-containing compounds 8-4 and 8-5 can be prepared by reaction of the N-protected bromo compound 8-1 with hydrazine in an appropriate solvent such as iV;Af-dimethylformamide (DMF) to give the hydrazine intermediate 8-2. The hydrazino intermediate 8-2 is reacted with an appropriately substituted 1,3 bis-aldehyde like 8-3 to give the pyrazole containing compound 8-4. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol. One skilled in the art will recognize further potential modifications. As shown in Scheme 9, the 1,2,4-oxadiazole compound 9-6 can prepared from the N- protected bromo compound 9-1 by treatment with zinc cyanide in DMF in the presence of a catalyst like bis(tributyl) palladium to give the N-protected cyano compound 9-2. The N-hydroxy carbox- imidamide compound 9-3 can be prepared by heating the N-protected cyano compound 9-2 with hydroxylamine hydrochloride in an appropriate solvent like ethanol and a base like potassium carbonate at a temperature below the boiling point of the solvent. The N-protected 1,2,4-oxadiazole compound can be prepared by treating the N-hydroxy carboximidamide compound 9-3 with an appropriately substituted acid chloride compound 9-4 in a solvent like pyridine at a sufficient temperature to complete the ring closure. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to an ester, which in turn can be further reduced to alcohol. One skilled in the art will recognize further modifications where appropriate. As shown in Scheme 10, the 3- and 4-arylpyrazolo compounds 10-9 can be prepared by reaction of the respective 3-arylpyrazolo compound 10-4 or 4-aryl pyrazolo compound 10-7 with an appropriately substituted bromo compound 10-8 as previously described. The 3-aryl pyrazolo compound 10-4 can be prepared by reacting an appropriately substituted aryl group containing a halogen like bromo or a triflate with the N-protected boronic acid or boronic acid ester pyrazole compound 10-2 under Suzuki-like conditions known in the literature. The N-protecting group of 10-3 can be removed by conditions previously described and known in the literature for removing groups like SEM. The 4-arylpyrazolo compounds 10-7 can be prepared by reacting the appropriately substituted acetophenone compound 10-5 with DMF acetal in DMF at elevated temperatures to give the dimethylamino compound 10-6. The 4-arylpyrazolo compounds 10-7 can be prepared by treating the dimethylamino compound 10-6 with hydrazine in a solvent such as ethanol. As shown in Scheme 11 the substituted pyrazole compound 11-5 can be prepared by a variety of methods, such as by removing the protecting group e.g., SEM from compound 11-4 under conditions previously described. For example the substituted pyrazole N-protected compound 11-4 can be prepared by reaction of the intermediate pyrazole N-protected compound 11-3 with an appropriately substituted alkyl halide, benzyl halide, alkyl sulfonates, e.g., mesylate or tosylate, or other suitable leaving group L, in an appropriate solvent such as MeCN, DMF or tetrahydrofuran (THF), in the presence of a base such a sodium hydride or cesium carbonate. The N-aryl pyrazole 11- 4 (wherein Y is aromatic) may be prepared by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl boronic acid in a solvent such as dichloromethane (DCM) with copper acetate and pyridine. Alternatively the N-aryl pyrazole 11-4 (wherein Y is aromatic) can be prepared by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl-fluoride in a solvent such as DMF at elevated temperature. Or, the substituted pyrazole compounds 11-4 (wherein Z is a group such as nitrile or ester and Y is at least two carbons) can be prepared by the reaction of intermediate pyrazole 11-3 with an appropriately substituted acrylate, acrylonitrile or other Michael- like acceptors in a solvent such as DMF in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylamine (TEA) and at a temperature below the boiling point of the solvent. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol. One skilled in the art will recognize the further modifications if appropriate. As shown in Scheme 12, pyrazole 12-1 wherein P is a suitable amine protecting group such as SEM can be reacted with an alkyne-containing conjugate acceptor such as 12-2, wherein Z is an electron-withdrawing group (for example, -CN) optionally in the presence of a base (DBU or K2CO3 and the like) in a solvent such as DMF or MeCN for variable lengths of time to provide olefin- containing adducts 12-3. Compounds represented by the formula 12-3 can be deprotected by appropriate methods according to the nature of the protecting group used to afford compounds of the invention 12-4. As shown in Scheme 13, oxazole- or thiazole-containing compounds 13-6 can be prepared starting with N-protected 4-chloro-pyrrolo[2,3-b]pyrimidine 13-1 wherein P is a suitable amine protecting group such as SEM. Oxazole- or thiazole-containing products of formula 13-2 can be prepared by palladium-catalyzed coupling of 13-1 with oxazole or thiazole. The compound 13-2 can be reacted with a metal alkyl such as n-butyllithium to generate the aromatic anion in situ to which can be added at low temperatures (preferably between -78°C and 0°C) derivatives of carboxylic acids 13-3 (wherein W = N(Me)(OMe) when X1=S; and W = Cl when X'=O), in the presence of other additives such as zinc chloride and copper(I) iodide when X1=O, in a suitable solvent such as THF to generate a variety of ketones 13-4. Ketones 13-4 can be caused to react with a variety of reagents such as diethyl (cyanomethyl)phosphonate or triethylphosphonoacetate in the presence of a base like potassium tert-butoxide followed by reduction (including hydrogenation or a copper-hydride catalyzed conjugate reduction), or with reagents such as tosylmethyl isocyanide to provide products of formula 13-5 wherein Z is an electron-withdrawing group such as ester or -CN. If there are functional groups present within the R group or encompassed by the Z group, further modification can be made, and such appropriate further modifications will be recognized by one skilled in the art. Compounds 13-5 can be deprotected by appropriate methods according to the nature of the protecting group used to afford their corresponding deprotected counterparts 13-6. As shown in Scheme 14, aminothiazole-containing cores 14-5 can be synthesized starting with thiazole-containing core 14-1 wherein P is a suitable amine protecting group such as SEM. The compound 14-1 can be treated with a metal alkyl such as n-butyllithium to generate the aromatic anion in situ to which can be added a suitable source of electrophilic halogen such as carbon tetrabromide to afford the halogenated derivative 14-2. The protecting group P of 14-2 can be removed by an appropriate method according to the nature of the protecting group to yield product 14-3. The compound 14-3 can be reacted with amines 14-4 at elevated temperatures in a suitable solvent such as DMF to afford the compound of the invention, 14-5. As shown in Scheme 15, pyrrole-containing cores 15-4 can be synthesized starting with N- protected 4-chloro-pyrrolo[2,3-b]pyrimidine 15-1 wherein P is a suitable amine protecting group such as DEM (diethoxymethyl). The compound 15-1 can be reacted with l-(triisopropylsilyl)pyrrole-3- boronic acid under Suzuki coupling conditions to afford the simultaneously pyrrole-deprotected core 15-2. Pyrrole-containing compounds 15-2 can be reacted with alkenes 15-3 containing an electron- withdrawing group Z (such as —CN) in the presence of an appropriate base (such as DBU) at various temperatures (e.g., between room temperature and 40° C) followed by an in situ or separate deprotection step that is suitable for the selected protecting group to afford compounds of the invention 15-4. As shown in Scheme 16, a substituted pyrazole compound containing a sultone or sulfoxide functionality as in 16-6 can be prepared by a variety of methods, such as starting with an appropriately substituted bromo thiophenyl ether 16-2. Thioether 16-2 may be readily prepared by alkylation of the thiophenol 16-1 with an alkyl halide, mesylate or the like using a base like DBU, potassium carbonate or sodium hydride. The cinnamyl nitrile 16-3 may be prepared by Heck chemistry and the like, using palladium acetate and triphenylphosphine in DMF at an appropriate temperature with acrylonitrile. The SEM protected intermediate 16-4 may be prepared by methods previously described for performing the Michael like addition of the pyrazole core to an appropriately substituted — unsaturated nitrile like 16-3. The sulfoxide 16-5, where n=l, and sulfone 16-5, where n=2, may be prepared by methods well known in the literature for the oxidation of the thio ether 16-4 like m-chloroperbenzoic acid (MCPBA) in DCM. The final compounds 16-6, where n= 0, 1 or 2, may be prepared by methods previously described for the removal of the SEM protecting group. Alternatively, the sulfur oxidation may be performed on compounds 16-2 or 16-3 depending on the compatibility of the substitution in the synthetic scheme. Also, as shown in Scheme 17, substituted pyrazole compounds containing a sulfonamide functionality, such as 17-6 can be prepared by a variety of methods. For example, one may start with an appropriately substituted bromo phenyl sulfonamide 17-2, where Rc and Rd are suitable substituents. A compound 17-2 may be readily prepared by reaction of the bromo phenyl sulfonyl chloride 17-1 and an appropriately substituted amine such as an aniline, or a primary or secondary amine in a suitable solvent such as DCM, THF or pyridine. The cinnamyl nitrile 17-3 may be prepared by Heck chemistry or the like, using palladium acetate and triphenylphosphine in DMF at an appropriate temperature with acrylonitrile. The final compounds 17-6 where Rc and Rd are part of the sulfonamide functional group may be prepared by methods analogous to those described in Scheme 16 starting with the cinnamyl nitrile 17-3. Also, as shown in Scheme 18, substituted pyrazole compounds containing an alpha- allyl cyclopentylmethylene functionality, such as 18-8, can be prepared by, for example, reacting a pyrazole 18-3, wherein P is a suitable amine protecting group such as SEM and X is N or C, with a cyclopentylacrylate ester 18-4 to form the ester 18-5. The ester 18-5 may then be reduced to the corresponding aldehyde, 18-6, for example, by the two-step procedure of reducing to the alcohol and selectively oxidizing the intermediate alcohol to the aldehyde, e.g., via a Swern oxidation.. The aldehyde, 18-6, may then be converted to the corresponding olefin, 18-7, for example by reaction with a Wittig reagent. The olefin 18-7, may then be deprotected, as described earlier, to produce the formula 18-7 compound. The intermediate, 18-4, may be prepared, for example as shown in Scheme 18, stearting with cyclopentylaldehyde. Also, as shown in Scheme 19, the cyanoguanidine derivative 19-6 can be prepared starting from substituted pyrazole compounds such as pyrazole 18-3, wherein P is a suitable protecting group such as SEM and X is N or C. A compound 18-3 may, for example, be reacted with olefin 19-1, prepared by Horner-Wadsworth Emmons reaction of the corresponding Boc-protected piperidone, in the presence of a suitable basic catalyst, in a suitable solvent, to form 19-2. The intermediate 19-2 is deprotected using a suitable deprotection reaction, to provide the amine compound 19-3, which then reacts selectively with a cyanoimidocarbonate reagent such as 19-4, in a polar solvent at a suitable temperature, for example, about 20 °C to give a cyanoimidocarbamate such as 19-5, which can then be reacted with any of a variety of amines at elevated temperature to give product 19-6. The intermediate compounds 20-5 and 20-6 may be prepared by a variety of methods in the literature, for example, methods such as are outlined in Scheme 20. The intermediate compound 20-3 may be prepared by reaction of the aldehyde compound 20-1 with an appropriately substituted Wittig reagent or Horner Emmons reagents to give the a-p unsubstituted ester 20-3. Alternatively, 20-3 may be prepared by a Heck-like reaction with an appropriately substituted aryl bromide 20-2 and an acrylic ester in the presence of a palladium reagent at elevated temperatures. The compound 20-4 may be prepared by methods previously described for the Michael-like addition of an appropriately substituted pyrrole 18-3 on the a-p unsaturated ester compound 20-3. The aldehyde compound 20-5 may be prepared by reduction of the ester compound 20-4 with reagents such as diisobutyl aluminium hydride at low temperatures such as about -78 °C in an appropriate solvent. The aldehyde compound 20-5 can be further reduced to the corresponding alcohol compound 20-6 with reagents such as sodium borohydride in methanol. Alternatively the alcohol compound 20-6 may be prepared directly by reduction of the ester 20-4 with reagents such as lithium aluminium hydride in appropriate solvent and at appropriate temperatures. The compounds 21-2 and 21-3 may be prepared by using a variety of methods in the literature, such as, for example, methods outlined in Scheme 21. The olefin compound 21-1 may be prepared by the reaction of aldehyde compound 20-5 with an appropriately substituted Wittig reagent or Homer Emmons reagents using a base such as sodium hydride or potassium t-butoxide in an appropriate solvent and conducted at temperature. The olefin compound compound 21-1 may be reduced to the saturated compound 21-2, for example, using hydrogenation conditions well known in the literature, e.g., hydrogen in the presence of palladium on carbon in a solvent such as methanol. The acetylenic compound 21-3 may be prepared by methods previously described, or by reaction of the aldehyde 20-5 with Bestmann-Ohira reagent (E. Quesada et al, Tetrahedron, 62 (2006) 6673- 6680) as described in the literature. Alternatively the alcohol compound 20-6 in Scheme 20 may be oxidized to the aldehyde 20-5 with methods well known in the literature, e.g., Swem oxidation conditions, followed by reaction with the Bestmann-Ohira reagent, wherein this reaction sequence may be carried out either as a one pot two-step reaction sequence, or in two separate reaction steps. . The compounds 22-1 and 22-3 may be prepared by using a variety of methods in the literature, for example, via methods outlined in Scheme 22. The oxygen-substituted compound 22-1 may be prepared, for example, by reaction of an appropriately substituted alcohol 20-6 (in Scheme 20), wherein X is N or C, and P is a protecting group, with a base such as sodium hydride and an appropriate agent such as an alkyl iodide, carbonate, or isocyanate, carried out in a suitable solvent and at a suitable temperature. Alternatively, the alcohol group on the compound 20-6 may be converted to a leaving group LG, as in compound 22-2, where the leaving group can be, for example, bromide or mesylate. The compound 22-2 serves as a substrate for subsequent reaction with a nucleophile, such as, for example, sodium ethoxide (Nuc = ethoxy). It should noted that in all of the Schemes described herein, if there are functional groups present on a substituent group such as Y, Z, R, R1, R2, R5, etc., further modification can be made if appropriate and desired. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be reduced to an alcohol, which in turn can be further modified. In another example, an OH group can be converted into a better leaving group such as mesylate, which in turn is suitable for nucleophilic substitution, such as by CN. One skilled in the art will recognize such further modifications. Methods Compounds of the invention can modulate activity of one or more Janus kinases (JAKs). The term "modulate" is meant to refer to an ability to increase or decrease the activity of one or more members of the JAK family of kinases. Accordingly, compounds of the invention can be used in methods of modulating a JAK by contacting the JAK with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as inhibitors of one or more JAKs. In some embodiments, compounds of the present invention can act to stimulate the activity of one or more JAKs. In further embodiments, the compounds of the invention can be used to modulate activity of a JAK in an individual in need of modulation of the receptor by administering a modulating amount of a compound of Formula la, Ib, or Ic. JAKs to which the present compounds bind and/or modulate include any member of the JAK family. In some embodiments, the JAK is JAK1, JAK2, JAK3 or TYK2. In some embodiments, the JAK is JAK1 or JAK2. In some embodiments, the JAK is JAK2. In some embodiments, the JAK is JAK3. The compounds of the invention can be selective. By "selective" is meant that the compound binds to or inhibits a JAK with greater affinity or potency, respectively, compared to at least one other JAK. In some embodiments, the compounds of the invention are selective inhibitors of JAK 1 or JAK2 over JAK3 and/or TYK2. In some embodiments, the compounds of the invention are selective inhibitors of JAK2 (e.g., over JAK1, JAK3 and TYK2). Without wishing to be bound by theory, because inhibitors of JAK3 can lead to immunosuppressive effects, a compound which is selective for JAK2 over JAK3 and which is useful in the treatment of cancer (such as multiple myeloma, for example) can offer the additional advantage of having fewer immunosuppressive side effects. Selectivity can be at least about 5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity can be tested at the Km of each enzyme. In some embodiments, selectivity of compounds of the invention for JAK2 over JAK3 can be determined by the cellular ATP concentration. Another aspect of the present invention pertains to methods of treating a JAK-associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. A JAK-associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the JAK, including over- expression and/or abnormal activity levels. A JAK-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating JAK activity. Examples of JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host disease). Further examples of JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, autoimmune thyroid disorders, and the like. In some embodiments, the autoimmune disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP). Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, atopic dermatitis and rhinitis. Further examples of JAK-associated diseases include viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV). Further examples of JAK-associated diseases or conditions include skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances including some Pharmaceuticals when topically applied can cause skin sensitization. In some embodiments, co-administration or sequential administration of at least one JAK inhibitor of the invention together with the agent causing unwanted sensitization can be helpful in treating such unwanted sensitization or dermatitis. In some embodiments, the skin disorder is treated by topical administration of at least one JAK inhibitor of the invention. In further embodiments, the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, melanoma etc.), hematological cancers (e.g, lymphoma, leukemia such as acute lymphoblastic leukemia, or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Example cutaneous T-cell lymphomas include Sezary syndrome and mycosis fungoides. JAK-associated diseases can further include those characterized by expression of a mutant JAK2 such as those having at least one mutation in the pseudo-kinase domain (e.g., JAK2V617F). JAK-associated diseases can further include myeloproliferative disorders (MPDs) such as polycythemia vera (PV)» essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like. Further JAK-associated diseases include inflammation and inflammatory diseases. Example inflammatory diseases include inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis, conjunctivitis, or related disease), inflammatory diseases of the respiratory tract (e.g., the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy such as myocarditis, and other inflammatory diseases. The JAK inhibitors described herein can further be used to treat ischemia reperfusion injuries or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest. The JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as that resulting from or associated with cancer. The JAK inhibitors described herein can further be used to treat restenosis, sclerodermitis, or fibrosis. The JAK inhibitors described herein can further be used to treat conditions associated with hypoxia or astrogliosis such as, for example, diabetic retinopathy, cancer, or neurodegeneration. See, e.g., Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427-36 and Sriram, K. et al. J. Biol. Ckem. 2004, 279(19):19936-47. Epub 2004 Mar 2. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a JAK with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a JAK, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the JAK. As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder {i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder {i.e., reversing the pathology and/or symptomatology). Combination Therapies One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti- inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors such as, for example, those described in WO 2006/056399, or other agents can be used in combination with the compounds of the present invention for treatment of JAK-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially. Example chemotherapeutic include proteosome inhibitors {e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, cannustine, and the like. Example steroids include coriticosteroids such as dexamethasone or prednisone. Example Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, EP2005/009967, EP2005/010408, and U.S. Ser. No. 60/578,491. Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120. Example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444. Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402. In some embodiments, one or more JAK inhibitors of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma, for example, can include, without- limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of the present invention with an additional agent. Furthermore, resistance of multiple myeloma cells to agents such as dexamethasone may be reversible upon treatment with a JAK inhibitor of the present invention. The agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with at least one JAK inhibitor where the dexamethasone is administered intermittently as opposed to continuously. In some further embodiments, combinations of one or more JAK inhibitors of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant. Pharmaceutical Formulations and Dosage Forms When employed as Pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be "i necessary or desirable. Coated condoms, gloves and the like may also be useful. This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers (excipients). In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner. The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 jag/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove. Labeled Compounds and Assay Methods Another aspect of the present invention relates to labeled compounds of the invention (radio- labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating JAK in tissue samples, including human, and for identifying JAK ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes JAK assays that contain such labeled compounds. The present invention further includes isotopically-labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), "C, 13C, 14C, 13N, 15N, I5O, 17O, 18O, I8F, 35S, 36C1, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and I31I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro metalloprotease labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, I25I, I31I, 35S or will generally be most useful. For radio- imaging applications nC, 18F, I25I, I23I, I241,1311,75Br, 76Br or 77Br will generally be most useful. It is understood that a "radio-labeled " or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3H, I4C, 1251,35S and 82Br. The present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention. A labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a JAK by monitoring its concentration variation when contacting with the JAK, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of smother compound which is known to bind to a JAK (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the JAK directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained. Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of JAK-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples have been found to be JAK inhibitors according to at least one assay described herein. Step 1. lH-Pyrrolo[2,3-b]pyridine 7-oxide To a solution of lH-pyrrolo[2,3-b]pyridme (4.90 g, 0.0415 mol) in ethyl acetate (41 mL, 0.42 mol) was added a solution of meta-chloroperbenzoic acid (MCPBA; 9.3 g, 0.054 mol) in ethyl acetate (27 mL, 0.28 mol) at 0 °C. The reaction mixture was solidified when -20 mL solution of MCPBA was added. An additional ~10 mL of ethyl acetate was added so that a solution resulted. The reaction mixture was allowed to warm to room temperature (rt) and stirred overnight, then was cooled at 0 °C, filtered and washed with ethyl acetate three times to give 10.94 g wet solid. The wet solid (8.45 g) was then suspended in water (35 mL), and to the suspension was added 13 mL of sat. Na2CO3 dropwise, and the resulting mixture was stirred at room temperature overnight. The mixture was then cooled at 0° C, filtered and washed with water (x4) to give 3.55 g of pale purple solid which was dried at 40° C overnight to give the desired product (2.47 g, 44.4% yield). 'H NMR (400 MHz, CD3OD): 5 8.2 (1H, d); 7.95 (1H, d); 7.5 (1H, d); 7.2 (1H, m); 6.65 (1H, d). MS (M+H)+: 136. Step 2. 4-Chloro-lH-pyrrolo[2,3-b]pyridine To a pink solution of 1H-pyrrolo[2.3-b]pyridine 7-oxide (2.47 g, 0.0184 mol) in dimethylformamide (DMF) (13.3 mL, 0.172 mol) was added methanesulfonyl chloride (4.0 mL, 0.052 mol) at 50 °C, and the pink color changed to orange. The reaction mixture was heated at 73 °C for 2h, then cooled to 40 °C. Water (35 mL) was added, and the resulting suspension was cooled at 0 °C. NaOH was added to adjust the pH of the mixture to about 7. The mixture was filtered and washed with water (x3) to give 3.8 g of a wet pale orange solid that was dried at 40 °C overnight to give the product (2.35 g, 82.2% yield). 1H NMR (400 MHz, CDC13): 6 10.8 (1H, br); 8.21 (1H, d); 7.41(1H, d); 7.18 (1H, d); 6.61 (1H, d). MS (M+H)+: 153. A mixture of 4-chloro-lH-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) and 4-bromo-3- methyl-lH-pyrazole (0.10 g, 0.00066 mol) was heated at 130 °C overnight. The reaction mixture then was subjected to column chromatography (eluting with 5% MeOH/DCM, 0.5% NH4OH, on silica gel) to give 80 mg pale yellow solid which was triturated with MeOH (1.5 mL) to yield the product as a pale yellow solid (44 mg, 44% yield). 1H NMR (400 MHz, CD3OD): 5 8.32 (1H, s); 8.25 (1H, d); 7.6 (1H, s); 7.45 (1H, d); 7.37 (1H, d); 6.96 (1H, d); 2.4 (3H, s). MS (M+H)+: 276. Step 4. 3-[3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]benzonitrile A mixture of 4-(4-bromo-3-methyl-lH-pyrazol-l-yl)-lH-pyrrolo[2,3-b]pyridine (0.032 g, 0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodium carbonate (0.032 g, 0.00030 mol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in 1,2- dimethoxyethane (0.3 mL, 0.003 mol) and water (0.3 mL, 0.02 mol) was heated at 130 °C (a liquid resulted, but with two layers) for 4 h. The reaction mixture then was cooled to room temperature (rt), filtered and was washed with water (x2) and dimethyl ether (DME) (x2) to give the product as a pale orange solid (15 mg, 44% yield). 'H NMR (400 MHz, CD3OD): 5 8.57 (1H, s); 8.31 (1H, d); 7.8 (2H, m); 7.75 (2H, m); 7.55 (1H, s); 7.45 (2H, m); 7.01 (1H, d); 2.6 (3H, s). MS (M+H)+: 299. Example 2: (2E)-3-[3-Methyl-l-(lH-pyrrolo[2^-b]pyridin-4-yl)-lH-pyrazol-4-yl]acrylonitrile trifluoroacetate salt Step 1. 4-Bromo-lH-pyrrolo[2,3-b]pyridine To a solution of lH-pyrrolo[2,3-b]pyridine 7-oxide (8.0 g, 0.060 mol), prepared by the procedure outlined in Example 1, Step 1 in DMF (100 mL, 1 mol) was added methanesulphonic anhydride (20.8 g, 0.119 mol, in four portions) at 0 °C. The mixture was stirred at 0 °C for an additional 20 min followed by an addition of tetramethylammoniuni bromide (23.0 g, 0.149 mol). The resulting mixture was stirred overnight. Water (0.1 L) was added, and a slight exotherm was observed. A solution of sodium hydroxide in water (12.5 M, 12 mL) was added to adjust the pH of the mixture to about 8, followed by an addition of ~0.25 L of water. The resulting mixture was stirred for additional 2 h then filtered. The solid obtained was washed with water x3 to give 6.72 g of a reddish solid which was dried at 50 °C over a weekend to give the product (5.75 g, 49% yield). 'HNMR (400 MHz, CDC13): 510.8 (1H, br); 8.2 (1H, d); 7.41 (1H, d); 7.19 (1H, d); 6.61 (1H, d). MS (M+H)+: 196. Step 2. 4-Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine To a solution of 4-bromo-lH-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol) and [/3- (trimethylsilyl)ethoxy]methyl chloride (6.7 mL, 0.038 mol) in DMF (62 mL, 0.80 mol) was added sodium hydride (1.5 g, 0.038 mol) at 0 °C, and the resulting solution turned opaque. The mixture was stirred for additional 4 h, then diluted with methyl tert-butyl ether (MTBE). The organic layer was separated and washed with water (x2) and brine aqueous solution successively. The organic phase was dried and concentrated in vacuo to give 14.1 g of a product as a pale orange oil. The oil was purified by column chromatography eluting with 5-20% ethyl acctate/hexanes to give the purified product as a colorless oil (9.66 g , 94% yield). 'H NMR (400 MHz, CDCL,): 8 8.2 (1H, d); 7.49 (1H, d); 7.19 (1H, d); 6.62 (1H, d); 5.78 (2H, s); 3.6 (2H, t); 0.98 (2H, t); 0.0 (9H, s). MS (M+H)+: 326. Step 3. (2E)-3-[3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4~yl)-lH-pyrazol-4-yl]acrylonitrile A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo-3-methyHH-pyra2ol-l-yl>lH-pyrrolo[2,3-b]pyridine (0.036 g, 0.00013 mol), and tetraethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019 mol) was microwaved at 120 °C for 2 h. The solution was then diluted with ethyl acetate and washed with water (x2) and brine successively. The organic phase was dried and concentrated in vacuo to give 62 mg of the product as an orange solid. The orange solid was purified by prep-LCMS to give 12 mg of an off-white solid as a trifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL) to provide the purified product as a pale green solid, (dried at 60 °C for 4 h, 9 mg , 28% yield). 1HNMR (400 MHz, CD3OD): 2 :1 of trans : cis isomers. For trans: 8 8.95 (NH.1H, s); 7.75 (olefin, 1H, d); 6.1 (olefin, 1H, d); 2.45 (Me, 3H, s). MS (M+H)+: 249. A mixture of (2E)-3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]acrylo- nitrile, TFA salt, (0.0050 g, 0.000020 mol, prepared according to Example 2) and palladium (5.8 mg, 0.0000054 mol) in methanol (1 mL, 0.02 mol) and 1,2-dichloroethane (1 mL, 0.01 mol) was degassed and then was stirred under an atmosphere of hydrogen for 3 h. The reaction mixture then was filtered and the filtrate was concentrated in vacuo to give 8 mg of the product as an off-white solid. The crude material was purified by prep-LCMS to give 5.1 mg of a white solid as a TFA salt which was triturated with MTB (1 mL) to give the product as a white solid (1.7 mg, 34% yield). 'H NMR (400 MHz, CD3OD): 5 8.52 (1H, s); 8.35 (1H, d); 7.72(1H, d); 7.6 (1H, s); 7.38 (1H, d); 6.96 (1H, d); 2.7-2.9 (4H, m); 2.4 (3H, s). MS (M+H)+: 251. A melt oi 4-chloro-lH-pyrroIo[2,3-b]pyridine (0.050 g, 0.00033 mol) in 4-pnenyl-1H- imidazole (0.24 g, 0.0016 mol) was heated at 200 °C overnight. The reaction was partitioned between ethyl acetate and saturated NaHCO3, separated and the organic phase was washed with brine. The organic layer was then dried and evaporated to give 250 mg of an orange oil. The oil was chromatographed with 7% MeOH/DCM, 0.7% NH4OH, sample in solvent system. Collected 74 mg of the product as an orange glass. The glass was triturated with hot DCE (1.5 mL) to give 51 mg of a brown solid which was dried at 60 °C for 4 h to afford the desired product (50 mg, 59 yield). 1H NMR (400 MHz, dimethylsulxoxide (DMSO)): 8 12.5 (1H, s); 8.5 (1H, s); 8.4 (1H, s); 8.38 (1H, d); 7.8 (2H, m); 7.62 (1H, d); 7.4 (3H, m); 7.3 (1H, m); 6.81 (1H, d). MS (M+H)+: 260 Step 1. 3-Methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazole- 4-carboxylic acid To a -70 °C solution of 4-(4-bromo-3-methyl-lH-pyrazol-l-yl)-l-[2-(trimethylsilyl)ethoxy]- methyHH-pyrrolo[2,3-b]pyridine (0.107 g, 0.000263 mol) in THF (1 mL, 0.01 mol), and n- butyllithium in hexane (0.23 mL of 1.6M), 0.5g of CO2 solid was added. After 15 min, the reaction was quenched with NH4CI. Ethyl acetate and water were added. The organic phase was washed with brine, and was evaporated to give 84 mg of an off-white glass/solid. The solid was chromatographed with 50% ethyl acetate/hexanes, 0.5% AcOH, sample on silica gel to give 40 mg of a purified product as a white solid (37% yield). 'H NMR (400 MHz, CDC13): 5 8.5 (1H, d); 7.45 (1H, d); 7.25 (1H, d); 7.02 (1H, s); 6.6 (1H, d); 5.75 (2H, s); 3.6 (2H, t); 2.48 (3H, s); 0.98 (3H, t); 0.0 (9H, s). MS (M+H)+: 372. Step 2. 4-[3-Methyl-4-(piperidin-l-ylcarbonyl)-lH-pyrazol-l-yl]-l-[2-(trimethylsilyl)ethoxy]methyl- 1 H-pyrrolo[2,3-bJpyridine A solution of 3-methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)- lH-pyrazole-4-carboxylic acid (0.040 g, 0.00011 mol) (1:1 of AcOH) and N,N-carbonyldiimidazole (0.035 g, 0.00021 mol) in THF (1 mL, 0.01 mol) was stirred for 1.2h, after which time piperidine (32 uL, 0.00032 mol) was added. After another 2h, another portion of piperidine (15 L) was added and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water, and washed sequentially with sat. NaHCO3 and brine. The organic phase was dried and evaporated to give 49 mg of the crude product as an orange oil/glass. The crude product was chromatographed with 75-100% ethyl acetate/hexanes, sample in DCM. Collected 25 mg of the purified product as a colorless glass/oil (50% yield). 1H NMR (400 MHz, CDCl3): 5 8.45 (1H, d); 8.23 (1H, s); 7.5 (1H, d); 7.4 (1H, d); 7.05 (1H, d); 5.8 (2H, s); 3.7 (4H, br); 3.6 (2H, t); 2.55 (3H, s); 1.7 (6H, br); 1.0 (3H, t); 0.0 (9H, s). MS (M+H)+: 439. Step 3. 3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-piperidin-l-yl-methanone A solution of 4-[3-methyl-4-(piperidin-l-ylcarbonyl)-lH-pyrazol-l-yl]-l-[2-(trimethylsilyl)- ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.025 g, 0.000057 mol) in TFA (1 mL, 0.01 mol) was stirred for 1.5 h. The reaction mixture was then concentrated and partitioned between DCM and sat. NaHCO3 x2, and brine. The organic layer was then dried and concentrated to give 28 mg of the product as a white foam. The foam was dissolved in methanol (1 mL, 0.02 mol) and treated with ammonium hydroxide in water (8.0M, 1 mL) for 1.5h. The reaction was concentrated using a rotary evaporator to give 24 mg of a pale yellow glass. The glass was triturated with methyl t-butyl ether (MTBE) to give 13 mg of a white solid which was dried at rt over a weekend. A total of 8 mg of the product was obtained after drying (45% yield). 1H NMR (400 MHz, CDC13): 5 9.7 (1H, s); 8.4 (1H, d); 8.2 (1H, s); 7.42 (1H, d); 7.4 (1H, d); 6.99 (1H, d); 3.4-3.8 (4H, br); 2.47 (3H, s); 1.5-1.8 (6H, br). MS (M+H)+: 309. Step 1. 3-Methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin~4-yl)-lH-pyrazole- 4'Carbaldehyde To a -70 °C solution of 4-(4-bromo-3-methyl-lH-pyrazol-l-yl)-l-[2-(trimethylsilyl)ethoxy]- methyl-lH-pyrrolo[2,3-b]pyridine (0.25 g, 0.00061 mol) in THF (2 mL, 0.03 mol), 1.6 M n- butyllithium in hexane (0.54 mL). After 10 min, DMF (120 L, 0.0015 mol) was added. The reaction was allowed to warm to rt and stirred overnight. The reaction was then quenched with NH4CI. Ethyl acetate/water was added. The organic phase was separated and washed with brine, then dried and concentrated to give 180 mg of an orange oil. The crude product was chromatographed with 25% ethyl acetate/hexanes, sample in DCM. Collected 40 mg of a pale yellow oil (18% yield). 1H NMR (400 MHz, CDC13): 8 10.15 (1H, s); 8.7 (1H, s); 8.47 (1H, d); 7.58 (1H, d); 7.5 (1H, d); 7.05 (1H, d); 5.8 (2H, s); 3.63 (2H, t); 2.7 (3H, s); 0.98 (3H, t); 0.0 (9H, s). MS (M+H)+: 356. Step 2.N-[3-Methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- pyrazol-4-yl] methylaniline A solution of 3-methyl-l-(l-[2-(trimethylsiIyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)- lH-pyrazole-4-carbaldehyde (0.025 g, 0.000070 mol) and aniline (1M in DCM, 0.070 mL), in DCM (1 mL, 0.02 mol) was stirred for 1 min. Acetic acid (20 L, 0.0004 mol), aniline (1M in DCM, 140 L) and sodium triacetoxyborohydride (0.022 g, 0.00010 mol) were added. The reaction was stirred overnight and partitioned between DCM and sat. NaHCO3, washed with brine. The organic phase was dried and evaporated to give 21 mg of a product as a pale orange glass (70% yield). 'H NMR (400 MHz, CDC13): 5 8.4 (1H, d); 8.15 (1H, s); 7.65 (1H, d); 7.35 (3H, m); 7.09 (1H, d); 6.82 (1H, m); 6.89 (2H, m); 5.8 (2H, s); 4.35 (2H, s); 3.6 (2H, t); 2.5 (3H, s); 0.99 (3H, t); 0.0 (9H, s). MS (M+H)+: 433. Step 3. [3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-ylmethyl]-phenyl-amine Deprotection of N-[3-methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin- 4-yl)-lH-pyrazol-4-yl]methylaniline was carried out according to the procedures of Example 14, Step 3 to give the desired product (58% yield). 1H NMR (400 MHz, CDC13): 5 9.9 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.4 (1H, d); 7.35 (1H, d); 7.3 (2H, m); 7.0 (1H, d); 6.79 (1H, m); 6.77 (2H, m); 4.25 (2H, s); 3.81 (1H, s); 2.41 (3H, s). MS rM+H)+: 303. To a -75 °C solution of 4-(4-bromo-3-methyl-lH-pyrazol-l-yl)-l-[2-(trimethylsilyl)ethoxy]- methyl-lH-pyrrolo[2,3-b]pyridine (0.11 g, 0.00027 mol) in THF (1.5 mL, 0.018 mol) was added 1.6 M n-butyllithium in hexane (0.22 mL). The reaction mixture turned dark orange. After ~10 min, 1.0 M magnesium dibromide in ether (0.35 mL) was added. After another 50 min, a solution of 3-ethoxy- 2-cyclohexen-l-one (41.5 L, 0.000308 mol) in THF (-0.3 mL) was added. The resulting mixture was warmed to -40 °C over ~lh and quenched with NH4CI. Then ethyl acetate/water was added. The organic phase was washed with brine, and concentrated to give 145 mg of an orange oil. The crude product was chromatographed with 0-50% ethyl acetate/hexane gradient, sample in DCM. Collected 35 mg of the produce as an oil (30% yield). 1H NMR (400 MHz, CDC13): 5 8.49 (1H, d); 8.38 (1H, s); 7.55 (1H, d); 7.4 (1H, d); 7.1 (1H, d); 6.0 (2H, s); 3.6 (2H, t); 2.81 (2H, m); 2.62 (3H, s); 2.58 (2H, m); 2.27 (2H, m); 1.0 (3H, t); 0.0 (9H, s). MS (M+H)+: 422. Step 2. 3-[3-Methyl-l-(l-[2-(trimeihylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- pyrazol-4-yl] cyclohexanol A mixture of 3-[3-methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4- yl)-lH-pyrazol-4-yl]cyclohex-2-en-l-one (0.019 g, 0.000045 mol) and palladium on carbon (Pd/C) (0.018 g, 0.000017 mol) in methanol (2 mL, 0.05 mol) was degassed and was stirred under a hydrogen atmosphere overnight. An additional 48 mg of 10% Pd/C was added and stirred under a hydrogen atmosphere for 8h. The palladium was filtered and the filtrate was stirred with sodium tetrahydroborate (0.032 g, 0.00084 mol) for 5h. The reaction was purified by prep-HPLC to give 5 mg of the desired product. MS (M+H)+: 426. Step 3. 3-[3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-cyclohexanol Deprotection of 3-[3-methyl-l -(1 -[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin- 4-yl)-lH-pyrazol-4-yl]cyclohexanol was carried out according to the procedures of Example 14, Step 3 to give the desired product (40% yield). 'H NMR (400 MHz, CDC13): 5 9.72 (1H, s); 8.35 (1H, d); 7.95 (1H, s); 7.41 (1H, d); 7.35 (1H, d); 7.02 (1H, d); 3.78 (1H, m); 2.6 (1H, m); 2.4 (3H, s); 1.2-2.4 (8H, m). MS (M+H)+: 296. Step 1. 4-[l-(3-Methoxy-l-methylpropyl)-lH-pyrazoJ-4-yl]-l-[2-(trimethylsilyl)ethoxy]-methyl-lH- pyrrolo[2,3-bJpyridine To a 0 °C solution of 3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4- yl)-lH-pyrazol-l-yl]butan-l-ol (the alcohol was made by DIBAL reduction of the ester in Example 58) (0.056 g, 0.00014 mol)) in DMF (1 mL, 0.01 mol), was added sodium hydride (0.0107 g, 0.000268 mol). After 5 min, methyl iodide (18 L, 0.00029 mol) was added and the resulting mixture was stirred over a weekend. The mixture was then partitioned between ethyl acetate and water, separated and the organic phase was washed with brine. The organic phase was concentrated to give a pale orange oil. 'H NMR (400 MHz, CDC13): 5 8.4 (1H, d); 8.3 (1H, s); 8.0 (1H, s); 7.65 (1H, d); 7.27 (1H, d); 6.8 (1H, d); 5.8 (2H, s); 4.7 (1H, m); 3.63 (2H, t); 3.2-3.4 (2H, m); 3.38 (3H, s); 2.1-2.3 (2H, m); 1.7 (3H, d); 1.0 (2H, t); 0.0 (9H, s). MS (M+H)+: 400. Step 2. 4-[l -(3-Methoxy-l-methyl-propyl)- lH-pyrazol-4-yl]-lH-pyrrolo[2,3-bJpyridine Deprotection of 4-[l -(3-methoxy-l -methylpropyl)-lH-pyrazol-4-yl]-l -[2-(trimethylsilyl)- ethoxy]-methyl-lH-pyrrolo[2,3-b]pyridine was carried out according to the procedures of Example 14, Step 3 to give the desired product (25% yield). 'H NMR (400 MHz, CDC13): 5 10.0 (1H, s); 8.35 (1H, d); 8.18 (1H, s); 7.95 (1H, s); 7.41 (1H, d); 7.21 (1H, d); 6.75 (1H, d); 4.63 (1H, m); 3.15-3.4 (2H, m); 3.35 (3H, s); 2.21-2.05 (2H, m); 1.6 (3H, d). MS (M+H)+: 270. Step 1. 4-l-[l-Methyl-3-(lH-pyrazol-l-yl)propyl]-lH-pyrazol-4-yl-l-[2-(trimelhylsilyl)ethoxy]methyl- lH-pyrrolo[2,3-bJpyridine To a 0 °C solution of 3-[4-(l-[2-(trimethylsayl)ethoxy]methyl-lH-pyiTolo[2,3-b]pyridin-4- yl)-lH-pyrazol-l-yl]butyl methanesulfonate (prepared by raesylation of the alcohol as in Example 59, Step 1) (0.055 g, 0.00012 mol) and lH-pyrazole (0.025 g, 0.00036 mol) in DMF (1 mL, 0.01 mol) was added sodium hydride (0.014 g, 0.00036 mol). The resulting solution was stirred overnight and then partitioned between ethyl acetate and 0.1 N HC1, water, the organic phase was separated and washed with brine. The organic layer was then concentrated to give 49 mg of a pale orange glass (87% yield). 1H MMR (400 MHz, CDCl3): S 8.4 (1H, d); 8.18 (1H, s); 7.99 (1H, s); 7.6 (1H, t); 7.5 (1H, d); 7.4 (1H, t); 7.27 (1H, d); 6.8 (1H, d); 6.3 (1H, m); 5.8 (2H, s); 4.2 (1H, m); 4.0-4.2 (2H, m); 3.61 (2H, t); 2.58 (2H, m); 1.65 (3H, d); 1.0 (2H, t); 0.0 (9H, s). MS (M+H)+: 436. Step 2. 4-[l-(l-Methyl-3-pyrazol-l-yl-propyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine Deprotection of 4-l-[l-methyl-3-(lH-pyrazol-l-yl)propyl]-lH-pyrazol-4-yl-l-[2-(trimethyl- .silyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine was carried out according to the procedures of Example 14, Step 3 to give the desired product (38% yield). 1H NMR (400 MHz, CDC13): 8 9.7 (IH, s); 8.38 (1H, d); 8.1 (1H, s); 7.7(1H, s); 7.59 (1H, t); 7.4 (1H, d); 7.35 (1H, t); 7.21 (IH, d); 6.75 (IH, d); 6.25 (IH, m); 4.4 (1H, m); 3.9-4.15 (2H, m); 2.55 (2H, m); 1.63 (3H, d). MS (M+H)+: 306. The following compounds in Table 1 were made by methods analogous to the procedures above as indicated. "Purification A" indicates that the product following deprotection was purified by preparative-HPLC under the following conditions: C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH. Step 1. 4-(2-tert-butyl-lH-imidazol-5-yl)-l-[2-(tnmetoylsilyl)ethoxy]methyl-IH-pyrrolol2J- bjpyridine To a solution of trimethylacetic acid (0.169 mL, 0.00147 mol) in ethanol (6 mL, 0.1 mol) was added cesium carbonate (0.24 g, 0.00073 mol), and the resulting mixture was stirred for 2 hours. The solvent was removed in vacuo to afford cesium pivalate. To a solution of 2-chloro-l-(l-[2-(trimethylsiIyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4- yl)ethanone (prepared, e.g., as in Ex. 50, Step 1) (0.054 g, 0.00017 mol) in DMF (1.8 mL, 0.023 mol) was added cesium pivalate (0.0389 g, 0.000166 mol) and the reaction was stirred at room temperature for 16 hours. Ammonium acetate (0.45 g, 0.0058 mol) was added, and the reaction was heated in the microwave to 170 °C for 5 minutes. Water was added and the product was extracted with MTBE. The combined organic extracts were dried over sodium sulfate, then filtered and concentrated. The crude residue was purified by flash column chromatography (2.5% MeOH/DCM) to yield 4-(2-tert-butyl- lH-imidazol-5-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (32 mg, 52%). 'H NMR (400 MHz, CDC13): § 8.31 (d, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 7.37 (d, 1H), 6.94 (d, 1H), 5.69 (s, 2H), 3.52 (dd, 2H), 1.46 (s, 9H), 0.90 (dd, 2H), -0.08 (s, 9H); MS(ES):371(M+1). Step 2. 4-(2-tert-butyl-l-methyl-lH-imidazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo- [2,3-bJpyridine To a mixture of 4-(2-tert-butyl-lH-imidazol-5-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH- pyrrolo[2,3-b]pyridine (0.019 g, 0.000051 mol) and potassium carbonate (0.15 g, 0.0011 mol) in DMF (3 mL, 0.04 mol) was added methyl iodide (0.01 mL, 0.00015 mol) in two portions over 48 hours. Water was then added and the product was extracted with MTBE. The combined extracts were dried with sodium sulfate, filtered, and concentrated in vacuo, then purified by silica gel chromatography (20% ethyl acetate/hexanes) to afford 4-(2-tert-butyl-l-methyl-lH-imidazol-4-yl)-l- [2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (10 mg, 51%). 1H NMR (400 MHz, CDC13): § 8.37 (d, 1H), 7.54 (d, 1H), 7.44-7.22 (m, 2H), 7.19 (d, 1H), 5.78 (s, 2H), 3.93 (s, 3H), 3.60 (dd, 2H), 1.61 (s, 9H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):385(M+1). Step 3. A solution of . 4-(2-tert-butyl-l-methyl-lH-imidazol-4-yl)-l-[2-(trimethylsilyl)-ethoxy]- methyl-lH-pyrrolo[2,3-b]pyridine (0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2 hours. Then the excess TFA was evaporated and the residue was stirred in methanol (3 mL, 0.07 mol) and NH4OH (1 mL) for 16 hours. The solvents were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-(2- tert-butyl-l-methyl-lH-imidazol-4-yl)-lH-pyrrolo[2,3-b]pyridine, trifluoroacetate salt (9 mg, 90%). 'H NMR (400 MHz, de-DMSO): § 12.24 (s, 1H), 8.38 (br s, 1H), 8.24 (s, 1H), 7.70-7.63 (m, 2H), 7.08 (br s, 1H), 2.55 (s, 3H), 1.51 (s, 9H); MS(ES):255(M+1). Additional analogs were prepared as shown in Table 2 using analogous procedures to those described in Example 46 with different starting materials such as alternative carboxylic acids in Step 1. When the analogs were obtained as the free base, the product was obtained by preparative-HPLC (Cl 8 eluting with a gradient of ACN/H2O containing 0.15% NH4OH). The results are summarized in Step 1. 2-Chloro-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)ethanone To a solution of 4-bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (2.05 g, 0.00626 mol) in THF (10 mL, 0.123 mol) at 0 °C was added dropwise a solution of isopropylmagnesium chloride in ether (2.0 M, 9.4 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. This mixture was then transferred via cannula to a solution of 2- chloro-N-methoxy-N-methylacetamide (2.84 g, 0.0207 mol) in THF (10 ml). After 30 minutes reaction time, the solution was quenched by the addition of saturated ammonium chloride aqueous solution. The product was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (0-20% ethyl acetate/hexanes) to afford 2-chloro-l-(l-[2-(trimethylsilyl)- ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)ethanone (711 mg, 35%). 1H NMR (400 MHz, CDC13): 5 8.56 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H), 0.98 (dd, 2H), 0.01 (s, 9H); MS(ES):325(M+1). Step 2. 4-(2-Phenyl-l,3-thiazol-4-yl)-lH-pyrrolo[2,3-b]pyridine trifluoroacetate salt A solution of 2-chloro-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridbi-4-yl)- ethanone (0.050 g, 0.00015 mol) and benzenecarbothioamide (0.031 g, 0.00022 mol) in ethanol (2 mL, 0.03 mol) was heated to reflux for I hour. The solvent was removed in vacuo. Ethyl acetate was added, and the resulting solid was isolated by filtration. The crude solid was stirred with TFA for 1 hour, then excess TFA was removed in vacuo. The crude residue was then stirred with aq. NH4OH and MeOH for 16 hours. The solvent was removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-(2-phenyl-l,3-thiazol-4- yl)-lH-pyrrolo[2,3-b]pyridine as the trifluoroacetate salt (11 mg, 18%). 'H NMR (400 MHz, d6- DMSO): q 12.01 (s, 1H), 8.58 (s, 1H), 8.39 (br s, 1H), 8.13-8.07 (m, 2H), 7.81 (d, 1H), 7.67-7.64 (m, 1H), 7.62-7.52 (m, 3H), 7.22 (d, 1H); MS(ES):278(M+1). Step 1. N-Methyl-N-propylthiourea N-Methyl-N-propylamine (0.501 mL, 0.00488 mol) was added to a solution of 1,1'- thiocarbonyldiimidazole (0.957 g, 0.00537 mol) in THF (9 mL, 0.1 mol), and the resulting solution was stirred for 16 hours. The intermediate from the reaction mixture was isolated by silica gel chromatography (5% MeOH in DCM) and this intermediate was stirred with ammonia (7M solution in MeOH) (6 mL) for 48 hours. The solvent was removed in vacua. N-methyl-N-propylthiourea was obtained after flash column chromatography (4% MeOH in DCM). Step 2. A solution of 2-chloro-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)- ethanone (0.050 g, 0.00015 mol) and N-methyl-N-propylthiourea (0.030 g, 0.00022 mol) in ethanol (2 mL, 0.03 mol) was heated to reflux for 2 hours. Then, the ethanol was removed in vacuo and the residue was dissolved in 2 mL TFA and stirred for 40 minutes. The excess TFA was removed in vacuo and the residue was dissolved in 3 mL of MeOH. To this was added 0.5 mL of NH4OH and 100 uL of ethylenediamine, and the resulting solution was stirred for 16 hours. Solvent was removed, then water was added to give a white precipitate which was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford N-methyl-N-propyl-4-(lH-pyrrolo[2,3- b]pyridin-4-yl)-l,3-thiazol-2-amine as the trifluoroacetate salt (39 mg, 67%). H NMR (300 MHz, CD3OD): § 8.46-8.12 (br s, 1H), 7.92 (br s, 1H), 7.72 (s, 1H), 7.63 (d, 1H), 7.45 (br s, 1H), 3.56 (t, 2H), 3.20 (s, 3H), 1.78 (dq, 2H), 1.00 (t, 3H); MS(ES):273(M+1). Additional aminothiazole analogs were prepared by procedures analogous to those described in Example 51, using different starting materials such as alternative thioureas in Step 2. In Examples 52 and 53, the white precipitate obtained by the procedure of Example 51 was isolated by filtration, washed with water and dried under high vacuum to afford the analogs as the free amine. The results are summarized in Table 3 according to the following structure: Step 1. (2-Phenyl-l,3-thiazol-5-yl)boronic acid To a solution of n-butyllithium in hexane (1.6 M, 2.1 mL) in ether (20 mL) at -78 °C, a solution of 2-phenyl-l,3-thiazole (449 mg, 0.00278 mol) in ether (5 mL) was added dropwise. The mixture was stirred for one hour at -78 °C followed by the addition of boric acid trimethyl ester (0.949 mL, 0.00835 mol). The mixture was stirred at -78 °C for 15 minutes, then was allowed to warm to room temperature and stirred for an additional 40 minutes. Saturated NH4CI aqueous solution was added, followed by 1.0 N aqueous HC1. The acidified mixture was stirred for 15 minutes, and the desired product was extracted with four portions of DCM containing 15% isopropanol. The combined organic extracts were dried over sodium sulfate and concentrated to give 566 mg of a white solid containing the desired (2-phenyl-l,3-thiazol-5-yl)boronic acid as a mixture with 2-phenyl-l ,3- thiazole. This mixture was used in Step 2 without further purification. MS(ES):206(M+l). Step 2. To a mixture of (2-phenyl-l,3-thiazol-5-yl)boronic acid (75.0 mg, 0.000366 mol) and 4- bromo-l-[2-(trimethyIsilyl)ethoxy]methyl-lH-pynrolo[2,3-b]pyridine (80 mg, 0.000244 mol) in DMF (4 mL, 0.0516 mol) was added a solution of potassium carbonate (101 mg, 0.000732 mol) in water (1 mL, 0.0555 mol). The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(triphenylphospbine)palladium(0) (20 mg, 0,000018 mol) was added and the resulting mixture was heated to 125 °C for 30 minutes. The product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 12 mg of a yellow solid containing the desired product as the major component. The mixture was stirred in TFA (1 mL) for 1 hour. Then excess TFA was removed in vacuo and the resulting residue was stirred with 2 mL MeOH, 0.5 mL NH4OH and 100 uL ethylenediamine for 16 hours. The product was isolated by preparative- HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-(2-phenyl-l ,3- thiazol-5-yl)-lH-pyrrolo[2,3-b]pyridine trifluoroacetate salt (5 mg, 5%). 1H NMR (400 MHz, CD3OD): 5 8.64 (s, 1H), 8.34 (d, 1H), 8.10-8.04 (m, 2H), 7.73 (d, 1H), 7.71 (d, 1H), 7.56-7.51 (m, 3H), 7.14 (d, 1H); MS(ES):278(M+1). 4-(lH-Pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pvridine (60 mg, 0.00019 mol) was dissolved in DMF (1.5 mL), and the solution was cooled to 0 °C with a cold bath. Sodium hydride (15 mg, 0.00038 mol) was added. After stirring for 10 min, 2-bromo-2-methyl- propanoic acid ethyl ester (42 L, 0.00028 mol) was added. The cold bath was then removed and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution. More water was added, and the product was extracted with MTBE. The combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 2 mL TFA and stirred for 1 h. Then excess TFA was removed in vacuo and the resulting residue was stirred in 2 mL EtOH containing 0.6 mL NH4OH solution for 16 hours. Volatiles were removed, and purification of the mixture was carried out via preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) afforded ethyl 2- methyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yI]propanoate trifluoroacetate salt (13 mg, 17%): 'HNMR (300 MHz, dVDMSO): 5 12.03 (s, 1H), 8.67 (s, 1H), 8.31-8.19 (m, 2H), 7.59 (t, 1H), 7.48 (d, 1H), 6.98 (br s, 1H), 4.10 (q, 2H), 1.84 (s, 6H), 1.12 (t, 3H); MS(ES):299(M+1) and 2- methyl-2-[4-(lH-pyrrolot2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanoic acid (27 mg, 53%): 'H NMR (300 MHz, de-DMSO): 5 12.04 (s, 1H), 8.64 (s, 1H), 8.26 (s, 2H), 7.59 (br s, 1H), 7.48 (d, 1H), 6.99 (br s, 1H), 1.83 (s, 6H); MS(ES):271(M+H). A mixture of 2-methyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanoic acid (23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CD1) (21 mg, 0.00013 mol) in 2 mL of DMF was stirred for 3 hours. An excess of solid NH4CI and TEA was added to the mixture and this was stirred for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) followed by re-purification via preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford 2-methyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanamide (6 mg, 26%). 'H NMR (400 MHz, d6-DMSO): § 11.63 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS(ES):270(M+l). 4-(lH-Pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (220 mg, 0.0006996 mol) and 3-methyl-2-butenoic acid ethyl ester (292 L, 0.00210 mol) were dissolved in DMF (10 mL). Cesium carbonate (912 mg, 0.00280 mol) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the product was extracted with MTBE several times. The combined extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography (0-60% EtOAc/Hexanes) to afford ethyl 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2>3- b]pyridin-4-yl)-lH-pyrazol-l-yl]butanoate (244 mg, 79%). 1H NMR (300 MHz, CDCl3): §8.37 (d, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H), 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):443(M+1). Step 2. Ethyl 3-meAyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- pyrazol-l-yl]butanoate (20 mg, 0.0000452 mol) was stirred in 1 mL TFA for 1 hour. Then excess TFA was removed in vacuo. The residue was stirred for 16 hours in 2 mL MeOH containing 0.5 mL NH4OH. Evaporation of the volatiles was followed by purification by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford ethyl 3-methyl-3-[4-(lH-pyrrolo[2,3-b]- pyridin-4-yl)-lH-pyrazol-l-yl]butanoate, trifluoroacetate salt (5 mg, 26%). 1H NMR (400 MHz, d6- DMSO): § 12.19 (s, 1H), 8.61 (br s, 1H), 8.34-8.22 (br m, 2H), 7.62 (br s, 1H), 7.51 (br d, 1H), 7.02 (br s, 1H), 3.91 (q, 2H), 2.96 (s, 2H), 1.70 (s, 6H), 1.02 (t, 3H); MS(ES):313(M+1). To a solution of ethyl 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]- pyridin-4-yl)-lH-pyrazol-l-yl]butanoate (213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at -78 °C was added diisobutylaluminum hydride in DCM (1.00 M, 1.1 mL) dropwise. The reaction mixture was stirred for 3 hours during which time the reaction slowly wanned to -10 °C. To the mixture at -10 °C was carefully added K/Na tartrate tetrahydrate in water. The mixture was stirred for 2 hours, then was extracted with three portions of ethyl acetate. The combined organic extracts were washed with two portions of water and one portion of brine, then dried over sodium sulfate, filtered and concentrated to afford 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]- pyridin-4-yl)-lH-pyrazol-l-yl]butan-l-ol (185 mg, 96%), which was used without further purification. A portion of the alcohol so obtained (15 mg, 0.000037 tnol) was stirred in TFA (1 mL) for 2 hours. The TFA was removed in vacuo and the residue was stirred with 2 mL MeOH containing 0.5 mL NH4OH for 16 hours. Volatiles were removed and the product was purified by preparative- HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 3-methyl-3-[4-(lH- pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butan-l-ol as the trifluoroacetate salt (8.0 mg, 57%). 'H NMR (300 MHz, de-DMSO): § 12.17 (s, 1H), 8.58 (br s, 1H), 8.32-8.22 (br m, 2H), 7.62 (br s, 1H), 7.53 (br d, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 2H), 1.62 (s, 6H); MS(ES):271(M+1). Step 1. 4-Methyl-4-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- pyrazol-1 -yljpentanenitrile TEA (38.0 L, 0.000273 mol) and methanesulfonyl chloride (21.1 L, 0.000273 mol) were added sequentially to a solution of 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3- b]pyridin-4-yl)-lH-pyrazol-l-yl]butan-l-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in DCM (4 mL, 0.05 mol) at 0° C. The reaction mixture was held at this temperature for 1.5 hours, then was quenched by the addition of water. The reaction mixture was extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude 3-methyl- 3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butyl methanesulfonate (87 mg). MS(ES):479(M+1). A mixture of 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4- yl)-lH-pyrazol-l-yl]butyl methanesulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg, 0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30 min at 125 °C followed by additional 30 min at 135 °C. The mixture was then diluted with water, and the product was extracted with three portions of MTBE. The combined extracts were dried over sodium sulfate, filtered and concentrated to give 61 mg of crude 4-methyl-4-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo- [2,3-b]pyridin-4-yl)-lH-pvrazol-l-yl]pentanenitrile, which was used without further purification. MS(ES):410(M+l). Step 2. 4-MethyM-[4-(l-[2-(1ximethylsilyl)ethoxy]methyl-lH-pyirolo[2,3-b]pyridin-4-yl)-lH- pyrazol-l-yl]pentanenitrile (57 mg, 0.00014 mol) was stirred in DCM (4 ml) and TFA (1 mL) for 2 hours. The solvents were removed in vacuo and the residue was stirred in 2 mL MeOH containing 0.2 mL ethylenediamine for 16 hours. The volatiles were evaporated and the product was isolated from .... the reaction mixture by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) affording 4-methyl-4-[4-(lH-pyrrolo[2]3-b]pyridin-4-yl)-lH-pyrazol-l-yl]pentanenitri]e as the trifluoroacetate salt (10 mg, 18%). 1HNMR (400 MHz, ds-DMSO): 5. 12.09 (s, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 8.25 (d, 1H), 7.60 (t, 1H), 7.48 (d, 1H), 7.00 (br s, 1H), 2.33-2.21 (m, 4H), 1.61 (s, 6H); MS(ES):280(M+l). The crude 4-methyl-4-[4-(l-[2-(trimethylsilyl)ethoxylmethyl-lH-pyrrolo[23-b]pyridin-4-yl)- lH-pyrazol-l-yl]pentanenitrile (36 mg, 0.000088 mol, see preparation in Example 59), was stirred in TFA (2 mL) for 1 hour. The mixture was concentrated to remove excess TFA, and the resulting residue was stirred in 2 mL methanol containing 0.5 mL NH4OH for 16 hours. The product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-methyl-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pvrazol-l-yl]pentanamide as the trifluoro- acetate salt (21 mg, 58%). lH NMR (400 MHz, da-DMSO): 5 12.18 (s, 1H), 8.60 (s, 1H), 8.33-8.21 (m, 2H), 7.62 (br s, 1H), 7.53 (d, 1H), 7.22 (br s, 1H), 7.04 (br s, 1H), 6.71 (br s, 1H), 2.14-2.07 (m, 2H), 1.86-1.79 (m, 2H), 1.58 (s, 6H); MS(ES):298(M+1). Example 61: (3S)-3-[4-(lH-PyrroIo[2r3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile trifluoro- acetate salt, AND (3R)-3-[4-(lH-Pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile trifluoroacetate salt To a solution of 4-(lH-pyrazoI-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolot2,3- b]pyridine (0.050 g, 0.00016 mol) in ACN were added 2-butenenitrile (0.014 mL, 0.00017 mol) and DBU (0.029 mL, 0.00020 mol). The resulting mixture was stirred for 16 hours. Then the volatiles were evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed successively with 1.0 N HC1, water, and brine, then was dried over sodium sulfate, filtered and concentrated. To obtain the enantiomers in substantially pure form, Method A (vide infra) was used. The crude residue was dissolved in TFA (7 mL, 0.09 mol) and the solution was stirred for 1 hour. Then excess TFA was evaporated and the residue was then stirred with ethylenediamine (0.1 mL, 0.001 mol) in methanol (4 mL, 0.09 mol) for 16 hours. The mixture was concentrated, and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile trifluoroacetate salt (35 mg, 61%). 'H NMR (300 MHz, d6-DMSO): 8 12.16 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 8.28 (d, 1H), 7.65-7.61 (m, 1H), 7.48 (d, 1H), 6.99 (d, 1H), 4.86 (q, 1H), 3.17 (d, 2H), 1.57 (d, 3H); MS(ES):252(M+1). Additional analogs were prepared by procedures analogous to those described in Example 61 using different starting materials for alleviation of the pyrazole ring. For example, the ,-unsaturated nitriles were prepared by procedures analogous to the following, illustrated for (2E)- and (2Z)- hexenenitrile: To a solution of 1.00 M potassium tert-butoxide in THF at 0 °C (24.2 mL) was added a solution of diethyl cyanomethylphosphonate (4.10 mL, 0.025 mol) in THF (30 mL) dropwise. The bath was removed and the solution was allowed to warm to room temperature. After reaching room temperature, the solution was re-cooled to 0° C and a solution of butanal (2.00 mL, 0.023 mol) in THF (7 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. This afforded 1.6 g of a crude mixture containing both (2E)- and (2Z)-hexenenitrile, which was used without further purification in the subsequent alkylation step. 1H NMR (400 MHz, CDC13): § 6.72 (dt, 1H trans olefin), 6.48 (dt, 1H cis olefin), 5.34 (dt, 1H trans olefin), 5.31-5.30 (m, 1H cis olefm). Where it was desirable to obtain the enantiomers in substantially pure form, chiral separation was performed by one of the following methods: A) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with 15% ethanol in hexanes); B) The separation was performed on the deprotected free base by preparative chiral HPLC (OD-H column, eluting with 15% ethanol in hexanes); C) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with 10% ethanol in hexanes); D) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with 15% ethanol in hexanes); E) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with 20% ethanol in hexanes; or F) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with 30% ethanol in hexanes. An OD-H column refers to Chiralcel OD-H from Chiral Technologies, Inc 3x25 cm, 5 m. An AD-H column refers to ChiralPak AD-H from Chiral Technologies, Inc. 2x25 cm, 5 m. The results are summarized for compounds in Table 4 below. Step 1. 4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloropyrrolo[2,3-d]pyrimidine (0.86 g, 0.0056 mol) in DMF (20 mL, 0.2 mol) at 0 °C was added sodium hydride (0.27 g, 0.0067 mol) in several portions. The reaction mixture was stirred for an additional 45 minutes followed by a dropwise addition of -(trimethylsilyl)ethoxy]- methyl chloride (1.2 mL, 0.0067 mol). The resulting reaction mixture was stirred at 0 °C for 45 min, then was quenched with water and extracted with ethyl acetate. The organic extract was washed with water, brine, dried over sodium sulfate, filtered and concentrated to give an oil. The crude residue was purified by flash column chromatography (0-15% ethyl acetate/hexanes) to yield 4-chloro-7-[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pvrimidine (1.40 g, 88%). 1HNMR (400 MHz, CDC13): § 8.71 (s, 1H), 7.46 (d, 1H), 6.72 (d, 1H), 5.71 (s, 2H), 3.59 (dd, 2H), 0.97 (dd, 2H), 0.00 (s, 9H); MS(ES):284(M+1). Step 2. 4-(lH-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine To a mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4-(4>4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.4 g, 0.0074 mol) in DMF (40 mL} 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water. The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(triphenyl- phosphine)palladium(O) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125 °C for 30 min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to give a solution in a small volume of DMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na2SO4, and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[233- d]pyrimidine as a white powder which was dried under vacuum (lg, 60%). 1H NMR (300 MHz, CDC13): 5 10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):316(M+1). Step 3. To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine (0.050 g, 0.00016 mol) in ACN (1 mL, 0.02 mol) was added hex-2-enenitrile (0.100 g, 0.00105 mol) (as a mixture of cis and trans isomers), followed by DBU(60 L, 0.0004 mol). The resulting mixture was stirred at room temperature for 16 hours. The ACN was removed in vacuo. The crude residue was dissolved in ethyl acetate, and was washed with 1.0 N HC1, brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (0-70% EtOAc/Hexane) to afford 56 mg of product, which was stirred with 1:1 TFA/DCM for 1 hour and the solvents were evaporated. The resulting product was stirred with methanol (4 mL, 0.1 raol) containing ethylenediamine (0.1 mL, 0.001 mol) overnight. The solvent was evaporated and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]hexanenitrile as the trifluroacetate salt. Where desired, the enantiomers were isolated in substantially pure form by Method A described above for Example 61. 'H NMR (300 MHz, CD3OD): 8 8.93 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.85 (d, 1H), 7.28 (d, 1H), 4.87-4.77 (m, 1H), 3.26-3.05 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.86 (m, 1H), 1.40-1.10 (m, 2H), 0.95 (t, 3H); MS(ES):281(M+1). Example 67: (3R-) and (3S)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- 1 -yl\|propanenitrile step i. (2E)- ana (22)-3-Cyclopentylacrylonitnle To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0 °C was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath was removed and the reaction was warmed to room temperature followed by recooling to 0 °C, at which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water, the aqueous was extracted with three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture containing 24.4 g of olefin isomers which was used without further purification (89%). 1H NMR (400 MHz, CDC13): 8 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98- 1.26 (m, 16H). Step 2. (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethyIsilyl)ethoxy]methyl-7H-pyiTolo[2,3-d]- pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added 3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HC1. The organic layer was back- extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93%). The enantiomers were separated by preparative-HPLC, (OD-H, 15% ethanol/hexanes) and used separately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors; however, the final product stemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer. 1H NMR (300 MHz, CDC13): 5 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H), 1.80- 1.15 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):437 (M+l). Step 3. To a solution of 3-cycIopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated above) in DCM (40 mL) was added TFA (16 mL) and this was stirred for 6 hours. The solvent and TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary evaporator two further times to remove as much as possible of the TFA. Following this, the residue was stirred with ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. The solvent was removed in vacuo, water was added and the product was extracted into three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford the crude product which was purified by flash column chromatography (eluting with a gradient of methanol/DCM). The resulting mixture was further purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford product (2.68 g, 58%). 1H NMR (400 MHz, D6-dmso): 5 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS(ES):307(M+l). Additional analogs provided in the following Tables were prepared by procedures analogous to those described in, for example, Examples 61 and 65, using different starting materials such as different ,-unsaturated nitriles in Step 3. Isolation of the enantiomers in substantially pure form was achieved by the indicated chiral separation method described above (A-F) preceding Table 4. Where the product was isolated as the free amine, the product following deprotection was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) instead of preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA). This is referred to as "modification G". The results are summarized in Table 5 according to the following structure: A solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyirolo[2,3-d]- pyrimidine (0.050 g, 0.00016 mol) in DMF (2 mL, 0.02 mol) was cooled in an ice bath and to this was added sodium hydride (0.013 g, 0.00032 mol). The resulting mixture was stirred for 10 minutes, followed by an addition of 2-bromopentane (0.030 mL, 0.00024 mol). The cooling bath was then removed and the reaction was stirred at room temperature for 3 hours, at which time a further portion of 2-bromopentane (0.015 mL, 0.00012 mol) was added. After 45 minutes, water was added and the reaction mixture was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was stirred with TFA (3 mL, 0.04 mol) and DCM (3 mL, 0.05 mol) for 3.5 hours, then the solvent was removed in vacuo. The residue was then stirred with NH4OH (1.5 mL) in MeOH (4 mL) for 16 hours. The solvent was evaporated and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-[l-(l-methylbutyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3- d]pyrimidine as the trifluoroacetate salt (25 mg, 44%). 'H NMR (300 MHz, CD3OD): 5 8.83 (s, 1H), 8.75 (s, 1H), 8.43 (s, 1H), 7.77 (d, 1H), 7.24 (d, 1H), 4.63-4.50 (m, 1H), 2.07-1.91 (m, 1H), 1.88-1.74 (m, 1H), 1.58 (d, 3H), 1.38-1.09 (m, 2H), 0.93 (t, 3H); MS(ES):256(M+1). Isolation of the enantiomers in substantially pure form was achieved by separation of the racemic free base (isolated by flash column chromatography after deprotection, eluting with a MeOH/DCM gradient) using HPLC (OD-H, eluting with 5% isopropanol/hexanes). Step 1. Ethyl 3-methy!-3-f4-(7-f2-(trimethylsilyl)etho^Jmethyl-7H-pyrrolof2,3d]pyrimidin-4-yl)-lH- pyrazol-l-yl]butanoate A solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (12.1 g, 0.0384 mol), 2-butenoic acid, 3-methyl-, ethyl ester (16.0 mL, 0.115 mol) and DBU (14.3 mL, 0.0959 mol) in ACN (100 mL) was heated at reflux for 3.5 hours. The solvent was removed in vacuo. The residue was diluted with water, extracted with ethyl acetate, and the combined organic extracts were washed with saturated-ammonium chloride, dried over sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (15.5 g, 91%). 1H NMR (400 MHz, CDC13): 5. 8.83 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 7.37 (d, 1H), 6.80 (d, 1H), 5.66 (s, 2H), 4.03 (q, 2H), 3.54 (dd, 2H), 2.98 (s, 2H), 1.80 (s, 6H), 1.13 (t, 3H), 0.91 (dd, 2H), -0.07 (s, 9H); MS(ES):444(M+1). Step 2. 3-Methyl-3-[4-(7-[2-(trimelhylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]butan-l-ol To a solution of ethyl 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]butanoate (15.4 g, 0.0347 mol) in THF (151 mL) at -78 °C was added 1.00 M diisobutylaluminum hydride in DCM (84.5 mL) dropwise. The reaction was stirred for 2 hours with slow wanning to -10 0C. The mixture was quenched with water, then was treated with potassium sodium tartrate tetrahydrate and water. The mixture was stirred for 1 hour, then was extracted with ethyl acetate. The extracts were washed with water and brine, then dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (13.8 g, 99%). 'H NMR (300 MHz, CDC13): 8 8.83 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.38 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 3.65 (dd, 2H), 3.54 (dd, 2H), 2.21 (t, 2H), 1.72 (s, 6H), 0.91 (dd, 2H), -0.07 (s, 9H); MS(ES):402(M+l). Step 3. 3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butan-l-ol A solution of 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrTolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl]butan-l-ol (13.8 g, 0.0344 mol) in TFA (20 mL) was stirred for 1 hour. The mixture was then concentrated in vacuo and the residue was stirred for 2 hours in a mixture of methanol (30 mL), ammonium hydroxide (30 mL), and ethylenediamine (8 mL). The mixture was then concentrated, and the residue was diluted with water and extracted with several portions of 15% IPA/CH2CI2. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give 20 g of white solid. The solid was triturated with ether and the product was isolated by filtration to give the product as a white solid (7.75 g, 83%). 'H NMR (400 MHz, CDC13): 5. 9.99 (s, 1H), 8.83 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.38 (dd, 1H), 6.80 (dd, 1H), 3.66 (t, 2H), 2.72 (br s, 1H), 2.22 (t, 2H), 1.74 (s, 6H); MS(ES):272(M+1). Step 4. 3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-I-ylJbutyl methanesulfonate A solution of 3-methyl-3-[4-(7H-pyrroIo[2J3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]butan-l-ol (6.61 g, 0.0244 mol) in DCM (300 mL) at 0 °C was treated with TEA (3.74 mL, 0.0268 mol), followed by methanesulfonyl chloride (2.07 mL, 0.0268 mol). The reaction was stirred for 1 hour, and was then concentrated in vacuo. The crude residue was purified by flash column chromatography to afford the desired product (4.9 g, 57%). 1H NMR (400 MHz, ds-dmso): 5. 12.45 (s, 1H), 9.50 (s, 1H), 9.35 (s, !H), 8.83 (s, 1H), 7.79 (dd, 1H), 7.11 (dd, 1H), 4.75 (t, 1H), 3.30 (s, 3H), 2.85 (t, 1H), 1.75 (s, 6H); MS(ES):254(M-CH3SO3H+1). Step 5: 4-Methyl-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile 3-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]butyl methanesulfonate (2.97 g, 8.50 mmol), DMF (120 mL) and sodium cyanide (6.21 g, 0.127 mol) were distributed evenly into six 20 mL microwavable vessels, each of which was heated in the microwave reactor for 4000 seconds at 125 °C. The contents of the vials were combined and were diluted with 400 mL water and extracted with five 150 mL portions of ethyl acetate. The combined extracts were dried over sodium sulfate, and the solvent was removed in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.40 g, 59%). 'H NMR (400 MHz, CDC13): 6 9.52 (br s, 1H), 8.83 (s, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 7.39 (dd, 1H), 6.81 (dd, 1H), 2.38 (dd, 2H), 2.16 (dd, 2H), 1.73 (s, 6H); MS(ES):281(M+1). The analogs in Table 5a were prepared according to the above method described for Example 69a. For Example 69b, a conjugate acceptor was used and prepared as described in Perkin Trans. 1, 2000, (77), 2968-2976, and Steps 4&5 were performed before Step 3. Step 1. Senecionitrile To a solution of 1.0 M potassium tert-butoxide in THF (2.0 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (0.33 mL, 2.06 mmol) in THF (4 mL) dropwise. The cold bath was removed and the reaction was wanned to room temperature. The reaction was then re-cooled to 0 °C and acetone (0.20 mL, 2.81 mmol) was added dropwise. The cooling bath was then removed and the reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted with water, the layers separated, and the aqueous extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was used without further purification (339 mg, 67%). 1H NMR (300 MHz, CDC13): 5. 5.10 (br s, 1H), 2.05 (s, 3H), 1.92 (s, 3H). Step 2. 3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljbutanenitrile To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]niethyl-7H-pvrrolo[2,3-d]- pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 L, 0.002 mol) and the resulting mixture was heated to 60 °C for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HC1 and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. 'H NMR (300 MHz, d6-dmso): 5 8.83 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), 5.66 (s, 2H), 3.54 (dd, 2H), 3.08 (s, 2H), 1.84 (s, 6H), 0.91 (dd, 2H), -0.07 (s, 9H); MS(ES):397(M+1). To a solution of this product in DCM at 0 °C was added TFA sufficient to comprise 20% of the total volume. The solution was stirred at this temperature for 30 min, then at ambient temperature for 2 hours and 15 minutes. The solvents were removed in vacuo and the residue was stirred with methanol (10 mL) and ethylenediamine (0.4 mL, 0.006 mol) overnight. The solvent was evaporated arid the product was purified by preparative-HPLCAMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% MH4OH) to afford the product (25 mg, 14%). 1HNMR (300 MHz, ds-dmso): $ 12.08 (s, 1H), 8.68 (s, 2H), 8.39 (s, 1H), 7.59 (d, 1H), 7.05 (d, 1H), 3.32 (s, 2H), 1.73 (s, 6H); MS(ES):267(M+1). Examples 69e and 69f in Table 5b were prepared by a method analogous to that described above for Example 69d, with unsaturated nitriles prepared either according to published literature procedures, or by the method in Step 1. Additional analogs were prepared by procedures analogous to those described in Example 69, using different starting materials such as alternative bromide or mesylate compounds for the nucleophilic substitution step. Where the free amine was obtained as the product, the product was purified after deprotection either by silica gel chromatography (eluting with 5% methanol in DCM) or by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH). The results are summarized for compounds listed in Table 6. Step 1. 3-Cyclopentylprop-2-ynenitrile To a solution of cyclopentylacetylene (0.50 g, 5.3 mmol) in THF (5 mL) at -78 °C was added 2.5 M n-butyllithium in hexane (2.23 mL). The mixture was stirred for 15 min followed by the dropwise addition of phenyl cyanate (0.70 g, 5.8 mmol) in THF (3 mL). The reaction was wanned to room temperature. Into the reaction mixture was poured 6 N NaOH, and the mixture was stirred for 5 minutes. The product was extracted with diethyl ether. The extracts were washed with 6 N NaOH and with brine, then dried over sodium sulfate, decanted and the solvent was removed in vacuo to afford product (600 mg, 95%). 'H NMR (300 MHz, CDC13): 5 2.81-2.68 (m, 1H), 2.07-1.54 (m, 8H). Step 2. (2Z)-3-Cyclopentyl-3-[4-(7-[2~(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4- yl)-lH-pyrazol-l-yl]acrylonitrile To a mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (0.40 g, 1.2 mmol) and 3-cyclopentylprop-2-ynenitrile (0.30 g, 2.5 mmol) in DMF (8 mL) was added potassium carbonate (0.09 g, 0.6 mmol). The mixture was stirred for 35 min. The reaction was diluted with ethyl acetate and brine, and the aqueous portion extracted with three volumes of ethyl acetate. The combined organic extracts were washed with brine again, then were dried over sodium sulfate, decanted and concentrated in vacua. The crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (290 mg, 53%). 'H NMR (400 MHz, CDC13): 5. 8.98 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 7.42 (d, 1H), 6.84 (d, 1H), 5.67 (s, 2H), 5.21 (s, 1H), 3.64-3.55 (m, 1H), 3.53 (t, 2H), 2.13-2.01 (m, 2H), 1.83-1.66 (m, 4H), 1.57-1.46 (m, 2H), 0.91 (t, 2H), -0.07 (s, 9H); MS(ES):435(M+1). Step 3. (2Z)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]actylonitrile A solution of (2Z)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]acrylomtrile (0.030 g, 0.069 mol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were removed in vacuo and the product was stirred with THF (1.5 mL), sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) for 2 hours. The reaction mixture was neutralized by the dropwise addition of cone. HC1. The product was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (16 mg, 76%). 'H NMR (400 MHz, d6-dmso): 5 9.08 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 7.66 (d, 1H), 7.05 (d, 1H), 5.82 (d, 1H), 3.62-3.54 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.48 (m, 6H); MS(ES):305(M+l). Example 75 : 3-Cyclopentylidene-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile Step 1. 3-Cyclopentylidene-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-l H-pyrazol-1 -yljpropanenitrile To a suspension of 3-cyclopentylprop-2-ynenitrile (0.4 g, 0.003 mol) in ACN (10 mL) was added 4-(lH-pyraz»l-4-yl)-7-[2-(timethylsilyl)ethoxy]methyl-7H-pyn"olo[2,3-d]pyriinidine (0.53 g, 1.7 mmol) and DBU (0.33 mL, 2.2 mmol). This mixture was stirred at room temperature for 50 minutes. The reaction mixture was partitioned between ethyl acetate and dilute HC1. The aqueous portion was separated and extracted with ethyl acetate. The combined organic extracts were washed with dilute HC1 and brine, were dried over sodium sulfate, filtered and concentrated in vacuo. The erode residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (540 mg, 74%). 1H NMR (300 MHz, CDC13): 8. 8.85 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.40 (d, 1H), 6.78 (d, 1H), 5.67 (s, 2H), 3.70 (s, 2H), 3.54 (dd, 2H), 2.55 (t, 2H), 2.45 (t, 2h), 1.85 (dddd, 2H), 1.73 (dddd, 2H), 0.91 (dd, 2H), -0.06 (s, 9H); MS(ES):435(M+1). Step 2. 3-Cyclopentylidene-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile A solution of 3-cyclopentylid6ne-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (0.030 g, 0.069 mmol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were evaporated in vacuo and the product was stirred with sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) and THF (1.5 mL) for 2 hours. The reaction mixture was neutralized by dropwise addition of concentrated HC1. The product was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (7 mg, 33%). 1H NMR (400 MHz, d6-dmso): 5. 12.23-12.01 (br s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 7.60 (d, 1H), 7.04 (d, 1H), 3.95 (s, 2H), 2.53 (t, 2H), 2.42 (t, 2H), 1.76 (dddd, 2H), 1.65 (dddd, 2H); MS(ES):305(M+l). Step 1. 4- (1,3-Thiazol-S-yl)- 7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidine 4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 0.0106 mol), and 1,3-thiazole (7.50 mL, 0.106 mol) were dissolved in N,N-dimethylacetamide (40.0 mL). The solution was distributed in equal portions into four 20 mL microwavable vessels. Into each reaction vessel was then added potassium acetate (0.777 g, 7.93 mmol) followed by tetrakis(triphenyl- phosphine)palladium(0) (0.60 g, 2.1 mmol). Each reaction vessel was heated at 200 °C in the microwave reactor for 30 minutes. The reactions were combined and most of the solvent was removed in vacuo. The residue was diluted with DCM, filtered and concentrated. Purification by flash column chromatosranhv (ethvl acetate/hexanesi afforded the desired nroduct (1.15 e. 64%). 1H NMR (300 MHz, CDCI3): 8 8.99 (s, 1H), 8.90 (s, 1H), 8.72 (s, 1H), 7.49 (d, 1H), 6.91 (d, 1H), 5.70 (s, 2H), 3.56 (dd, 2H), 0.93 (dd, 2H), -0.05 (s, 9H); MS(ES):333(M+1). Step 2. 4-(2-Bromo-l,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine 2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a -78 °C solution of 4- (ls3-thiazoi-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2)3-d]pyrimidine (550 nag, 0.0016 mol) in THF (20 mL). The mixture was stirred for 30 minutes at -78 °C, followed by the slow addition of carbon tetrabromide (658 mg, 0.00198 mol) as a solution in THF (10 mL). After 30 minutes, the mixture was quenched with a small amount of saturated ammonium chloride, diluted with ether, and dried over sodium sulfate. The residue obtained after filtration and concentration was purified by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (387 mg, 57%). 1H NMR (300 MHz, CDCl3): 5 8.85 (s, 1H), 8.33 (s, 1H), 7.49 (d, 1H), 6.83 (d, 1H), 5.69 (s, 2H), 3.55 (dd, 2H), 0.92 (dd, 2H), -0.05 (s, 9H); MS(ES):411, 413(M+1). Step 3. 4-(2-Bromo-l,3-thiazol-5-yl)-7H-pyrrolo[2,3-dJpyrimidine A solution of 4-(2-bromo-l,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo- [2,3-d]pyrimidine (370 mg, 0.90 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at room temperature for 7 hours. The mixture was then concentrated, re-dissolved in methanol (2 mL), and ethylenediamine (0.5 mL) was added. The mixture was stirred for 6 hours at room temperature. The mixture was diluted with DCM (10 mL), and the precipitate was isolated by filtration and washed with a small amount of DCM to afford desired product (182 mg, 72%). 'H NMR (300 MHz, dVdmso): 8.8.74 (s, 1H), 8.70 (s, 1H), 7.76 (d, 1H), 7.15 (d, 1H); MS(ES):281,283(M+1). Step 4. 3-Methyl[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l, 3-thiazol-2-yl]aminopropanenitrile A solution of 4-(2-bromo-l,3-thiazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (31 mg, 0.11 mmol) and 3-(methylamino)propionitrile (103 L, 0.00110 mol) in DMF (1.0 mL, 0.013 mol) was stirred at 90 °C for 2 hours. The crude reaction mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) and again by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.1% TFA) to yield the desired product as the trifluoroacetate salt (30 mg, 68%). 1H NMR (300 MHz, d6-DMSO): 8. 12.25 (s, 1H)5 8.60 (s, 1H), 8.31 (s, 1H), 7.60 (dd, 1H), 7.00 (dd, 1H), 3.89 (t, 2H), 3.20 (s, 3H), 2.94 (t, 2H); MS(ES):285(M+1). Example 77: (3S)- and (3R)-3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]hexane- nitrile Step 1. N-Methoxy-N-methylbutanamide To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydro- chloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-l-yloxytris(dimethylamino)- phosphonium hexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). The mixture was stirred overnight at room temperature. The solution was then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column chromatography (ether/hexanes). The solvent was removed (235 mbar/40 °C) to afford the product (1.33g, 88%). lH NMR (300 MHz, CDC13): 8. 3.68 (s, 3H), 3.18 (s, 3H), 2.40 (t, 2H), 1.74-1.59 (m, 2H), 0.96 (t, 3H). Step 2. l-[5-(7-[2-(Trimethylsilyl)ethoxy]methyI- 7H-pyrrolo[2,3-dJpyrimidin-4-yl)-J, 3-thiazol~2-yl]- butan-1-one 2.5 M n-Butyllithium in hexane (878 uL) was added slowly dropwise to a -78 °C solution of 4-(l,3-thiazol-5-yl)-7-[2-(trimethyIsilyl)ethoxy]memyl-7H-pyirrolo[2,3-d]pyrimidine (501 mg, 1.37 mmol) in THF (20 mL). After 45 minutes, N-methoxy-N-methylbutanamide (0.360 g, 2.74 mmol) was added. The reaction was continued at -78 °C for 30 man, and was then allowed to reach room temperature. The reaction was quenched with saturated ammonium chloride, and was extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography (ethyl acetate/hexanes) afforded the product (235 mg, 42%). 1H NMR (300 MHz, CDC13): 8 8.93 (s, 1H), 8.76 (s, 1H), 7.52 (d, 1H), 6.92 (d, 1H), 5.71 (s, 2H), 3.56 (dd, 2H), 3.19 (t, 2H), 1.92-1.77 (m, 2H), 1.05 (t, 3H), 0.93 (dd, 2H), -0.05 (s, 9H); MS(ES):403(M+l). Step 3. (2E)- and (2Z)-3-[5-(7-[2-(Trimethylsilyl)eth(^]methyl-7H-pyrrolo[2,3-dJpynmidin-4-yl)- l,3-thiazol-2-yl]hex-2-enenitrile To a solution of 1.0 M potassium tert-butoxide in THF (0.605 mL) in THF (4,0 mL) at 0° C was added diethyl cyanomethylphosphonate (0.102 mL, 0.634 mmol) dropwise. The cooling bath was removed and the reaction was wanned to room temperature. After 30 minutes, a solution of l-[5- (7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyiTolo[23-d]pyrimidih-4-yl)-l,3-thiazol-2-yl]butan.-l-one (232 mg, 0.576 mmol) in THF (3.0 mL) was added dropwise. The reaction was stirred for 2 hours, and the crude mixture was then adsorbed onto silica gel'and purified by flash column chromatography (ethyl acetate/hexanes) to afford the product as a mixture of olefin isomers (225 mg, 92%). 'H NMR (300 MHz, CDC13), major isomer: £ 8.89 (s, 1H), 8.65 (s, 1H), 7.52 (d, 1H), 6.89 (d, 1H), 6.35 (s, 1H), 5.70 (s, 2H), 3.56 (dd, 2H), 2.96 (t, 2H), 1.88-1.72 (m, 2H), 1.08 (t, 3H), 0.93 (dd, 2H), - 0.07 (s, 9H); MS(ES):426(M+1). Step 4. (3SJ- and (3R)-3-[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2.3-d]pyrimidin-4-yl)- 1,3-thiazol-2-yl]hexanenitrile Cupric acetate, monohydrate (0.7 mg, 0.004 mmol) and (oxydi-2,l-phenylene)bis(diphenyl- phosphine) (2 mg, 0.004 mol) was mixed in toluene (0.24 mL). PMHS (30 L) was added. The mixture was stirred for 25 minutes at room temperature followed by the addition of (2E)-3-[5-(7-[2- (trimethylsilyl)ethoxy]methyI-7H-pyrrolo[2,3-d]pyrirnidin-4-yl)-l,3-thiazol-2-yl]hex-2-enenitrile (51 mg, 0.12 mol) in toluene (0.24 mL) and finally, tert-butyl alcohol (0.043 mL). The resulting mixture was stirred overnight. The crude mixture was purified directly by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (39 mg, 76%). 'H NMR (300 MHz, CDC13): 8. 8.87 (s, 1H), 8.52 (s, 1H), 7.48 (d, 1H), 6.87 (d, 1H), 5.69 (s, 2H), 3.60-3.46 (m, 3H), 2.99-2.82 (m, 2H), 2.05-1.89 (m, 2H), 1.50-1.34 (m, 2H), 0.97 (t, 3H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):428(M+1). Step 5. (3S)~ and (3R)-3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1.3-thiazol-2-yl]hexanenitrile TFA (1.0 mL) was added to a solution of 3-[5~(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]hexanenitrile (36 mg, 0.084 mmol) in DCM (4.0 mL) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated, and re- dissolved in methanol (3 mL), to which ethylenediamine (0.1 mL) was added. After 2 hours reaction time, the mixture was concentrated and directly purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (10 mg, 40%). 1H NMR (300 MHz, CDC13): 5 9.96 (br s, 1H), 8.87 (s, 1H), 8.54 (s, 1H), 7.51-7.45 (m, 1H), 6.90-6.86 (m, 1H), 3.59-3.44 (m, 1H), 3.01-2.82 (m, 2H), 2.06-1.87 (m, 2H), 1.51-1.34 (m, 2H), 0.98 (t, 3H); MS(ES):298(M+1). Example 78: (3R)- and (3S)-3-Cyclopentyl-3-l5-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-l,3-thiazoI-2- yllpropanenitrile To a solution of (2E)- and (2Z)-3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrirnidin-4-yl)-l,3-thiazol-2-yl]acrylonitrile (199 mg, 0.440 mmol) (prepared, for example, as in Example 77, steps 1 through 3) in a mixture of ethanol (10 mL) and ethyl acetate (10 mL) was added a catalytic amount of 10% palladium on carbon. The mixture was stirred at room temperature under one atmosphere of hydrogen overnight. It was then subjected to 50 PSIH2 until the reaction was complete. Filtration and removal of solvent afforded an oil which was dissolved in DCM (4 mL) and TFA (1 mL). The solution was stirred until starting material was consumed and the mixture was then concentrated and re-dissolved in methanol (3 mL), to which ethylenediamine (0.4 mL) was added. The solution was stirred at room temperature for one hour, and was concentrated in vacuo. The crude mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (36 mg, 25%). 1H NMR (400 MHz, CDC13): 8 10.44 (br s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 7.50 (dd, 1H), 6.89 (dd, 1H), 3.34 (dt, 1H), 2.98 (dd, 1H), 2.89 (dd, 1H), 2.44-2.31 (m, 1H), 2.07-1.96 (m, 1H), 1.80-1.52 (m, 5H), 1.40-1.24 (m, 2H); MS(ES):324(M+1). The following compounds of Table 5c were prepared (as racemic mixtures) as described by Example 77, 78 or 86, as indicated in the following table, by using different Weinreb amides (as prepared in Example 77, Step 1): Step 1. (2S)- and (2R)-2-[5-(7-[2-(Trimethylsifyl)ethoxy]methyl-7H-pyrrolo[2,3-dJpyrimidin-4-yl)- 1 r3-thiazol-2-yl]pentanenitrile To a mixture of l-fS-Cy-P-CtrimethylsUyOethoxyjmethyl-TH-pyrrolop^-dJpyrimidin^-yl)- l,3-thiazol-2-yl]butan-l-one (prepared as in Example 77) (101 mg, 0.251 mmol) and p-tolylsulfonyl- methyl isocyanide (147 mg, 0.753 mmol) in a mixture of DMSO (5.0 mL) and ethanol (61 \|jL) was added 1.0 M potassium tert-butoxide in THF (753 \\L). The mixture was then heated to 45 °C for 2 hours. Upon cooling to room temperature, the mixture was quenched by the addition of saturated ammonium chloride, followed by water. The product was extracted with ether, and the extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacua. Flash column chromatography (ethyl acetate/hexanes) afforded the product (39 mg, 25%). 'H NMR (400 MHz, CDC13): 5 8.88 (s, 1H), 8.52 (s, 1H), 7.50 (d, 1H), 6.87 (d, 1H), 5.70 (s, 2H), 4.32 (dd, 1H), 3.55 (dd, 2H), 2.20-2.11 (m, 2H), 1.71-1.57 (m, 2H), 1.03 (t, 3H), 0.93 (dd, 2H); MS(ES):414(M+1). Step 2. (2S)- and (2R)-2-[5-(7H-PyrroJo[2l3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]pentanenitrile A solution of 2-[5-(7-[2-(trimethyIsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3- thiazol-2-yl]pentanenitrile (59 mg, 0.093 mmol) in DCM (3 mL) and TFA (0.5 mL) was stirred at room temperature for 4 hours. The mixture was then concentrated, and the residue was then dissolved in methanol (3 mL) to which ethylenediamine (0.3 mL) was then added. The solution was stirred at room temperature for 40 minutes. The solvent was removed in vacuo, and the crude mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH,OH) to afford the desired product (20 mg, 76%). 'H NMR (400 MHz, CDC13): 8. 9.66 (br s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 7.49 (dd, 1H), 6.88 (dd, 1H), 4.33 (dd, 1H), 2.23-2.12 (m, 2H), 1.75-1.60 (m, 2H), 1.04 (t, 3H); MS(ES):284(M+1). Example 85: (4S)- and (4R)-4-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl>l^-ttiiazol-2-yl]heptane- nitrile To a solution of triethyl phosphonoacetate (188 nig, 0.838 mmol) in THF (6.0 mL) at 0 °C was added 1.0 M potassium tert-butoxide in THF (840 L). The mixture was then allowed to warm to room temperature followed by re-cooling to 0 °C, at which time l-[5-(7-[2-(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]butan-l-one (prepared as in Example 77) (225 mg, 0.559 mmol) in THF (4.0 mL) was added. The mixture was stirred at room temperature for 1.5 hours, at which time it was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacua. Flash column chromatography afforded the product as a mixture of olefin isomers (222 mg, 84%). MSQES):473(M+1). Ethyl 3-[5-(7-[2-(trimethylsilyl)emoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol- 2-yl]hex-2-enoate as a mixture of (2E)- and (2Z)- isomers (222 mg, 0.470 mmol) was dissolved in ethanol (10 mL), and a catalytic amount of 10% Pd-C was added. The mixture was stirred under an atmosphere of hydrogen, provided by a balloon, for 16 hours. Filtration and concentration in vacuo afforded the desired product (201 mg, 90%). MS(ES):475(M+1). To a solution of ethyl 3-t5-(7-[2-(trimethylsiIyI)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-l,3-thiazol-2-yl]hexanoate (201 mg, 0.423 mmol) in THF (5.0 mL) at -78 °C was added 1.00 M diisobutylaluminum hydride in DCM (1.06 mL). The mixture was allowed to warm to -10 °C slowly over 1.5 hours, followed by the addition of potassium sodium tartrate tetrahydrate, water, and ether. The mixture was stirred for 1 hour, then layers were separated, and the aqueous layer was extracted further with ethyl acetate. The organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to afford desired product (176 mg, 96%). MS(ES):433(M+1). A solution of 3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3- thiazol-2-yl]hexan-l-ol (88 mg, 0.20 mmol) in TFA (2 mL) was stirred for 30 minutes. The TFA was then evaporated and the residue was stirred in methanol (2 mL) containing ethylenediamine (0.2 mL) and a drop of water for 30 minutes. Purification via preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) afforded the desired product (36 mg, 58%). MS(ES):303(M+l). To a mixture of 3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]hexan-l-ol (36 mg, 0.12 mmol) and TEA (19.9 L, 0.143 mmol) in DCM (5 mL) at 0 °C was added methanesulfonyl chloride (11.0 L, 0.143 mmol). After stirring for 10 minutes, the solution was concentrated and dissolved in DMSO (1.6 mL) and sodium cyanide (23 mg, 0.48 mmol) was added. The mixture was then heated at 125 °C in the microwave for 30 minutes. The mixture was then purified directly using preparative-HPLC/MS (CIS eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (10 mg, 27%). 1H NMR (400 MHz, CDC13): 5. 9.37 (br s, 1H), 8.86 (s, 1H), 8.52 (s, IH), 7.46 (dd, 1H), 6.88 (dd, 1H), 3.34-3.25 (m, 1H), 2.47-2.30 (m, 2H), 2.22-2.12 (m, 2H), 1.95-1.71 (m, 2H), 1.44-1.31 (m, 2H), 0.94 (t, 3H); MS(ES):312(M+1). Step 1. N-Methoxy-2-[(4-methoxybenzyl)oxy]-N-methylacetamide To a mixture of [(4-methoxybenzyl)oxy]acetic acid (Bioorganic and Medicinal Chemistry Letters, 2001, pp. 2837-2841) (6.86 g, 0.0350 mol) and N,O-dimethylhydroxylamine hydrochloride (3.41 g, 0.0350 mol) in DCM (100 mL) was added benzotriazol-l-yloxytris(dimethylamino)- phosphonium hexafluorophosphate (17 g, 0.038 mol) foEowed by TEA (9.7 mL, 0.070 mol). The resulting mixture was stirred overnight at room temperature. The solution was then washed with water, 0.5 M HC1, saturated NaHCO3, and brine, then was dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ether/hexanes) afforded the desired product (5.75 g, 69%). Step 2. 2-[(4-MethoxybenzyI)oxy]-l-[5-(7-[2-(trimethytsilyt)ethoxy]methyl-7H-pyrrolo[213-d]- pyrimidin-4-yl)-l,3-thiazol-2-yl]ethanone To a solution of 4-(l,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (2.12 g, 6.38 mmol) in THF (70 mL) at -78 °C was added 2.5 M n-butyllithium in hexane (3.06 mL) slowly dropwise. After stirring for 30 minutes, N-methoxy-2-[(4-methoxybenzyl)oxy]-N- methylacetamide (2.29 g, 9.56 mmol) was added. The reaction was continued for 30 minutes following the addition, at -78 °C, then the cooling bath was removed and the reaction was quenched with saturated ammonium chloride and extracted with ether. The extracts were dried with sodium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (ethyl acetate/hexanes) to afford desired product (2.16 g, 66%). 1H NMR (300 MHz, CDC13): 5. 8.93 (s, 1H), 8.72 (s, 1H), 7.53 (d, 1H), 7.37 (d, 2H), 6.91 (d, 2H), 6.89 (d, 1H), 5.70 (s, 2H), 5.00 (s, 2H), 4.70 (s, 2H), 3.81 (s, 3H), 3.56 (dd, 2h), 0.93 (dd, 2H), -0.05 (s, 9H); MS(ES):511(M+1). Step 3. (2E)- and (2Z)^-[(4-Methoxyberizyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H~ pyrrolo[2,3-dJpyrimidin-4-yl)-l,3-thiazol-2-yl]but-2-enenitrile To a solution of 1 M potassium tert-butoxide in THF (4.44 mL) in THF (30 mL) at 0° C was added diethyl cyanomethylphosphonate (820 mg, 0.0046 mol) dropwise. The bath was removed and the reaction was wanned to room temperature. After 30 minutes, a solution of 2-[(4-methoxybenzyl)- oxy]-l-[5-(7-[2-trimethylsayl)emoxy]methyl-7H-pyrrolo[2,3-d]pyrmidin-4-yl)-l,3-thiazol-2-yl]- ethanone (2.16 g, 0.00423 mol) in THF (20 mL) was added dropwise. The reaction was stirred for 1 hour, and was then quenched with a small amount of saturated ammonium chloride, diluted with ether, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography, eluting with a gradient of 0-35% ethyl acetate/hexanes afforded the desired product as a mixture of olefin isomers in nearly equal amounts (1.76 g, 78%). 1HNMR (400 MHz, CDC13): 8 8.90 (s, 1H), 8.88 (s, 1H), 8.71 (s, 1H), 8.67 (s, 1H), 7.50 (d, 2H), 7.35 (dd, 2H), 7.31 (dd, 2H), 6.92 (dd, 2H), 6.90 (dd, 2H), 6.86 (d3 2H), 6.62 (s, 1H), 6.10 (t, 1H), 5.70 (s, 4H), 4.75 (s, 2H), 4.72 (d, 2H), 4.64 (s, 4H), 3.82 (s, 3H), 3.81 (s, 3H), 3.56 (dd, 2H), 3.55 (dd, 2H), 0.96-0.90 (m, 4H), -0.05 (s, 9H), -0.054 (s, 9H); MS(ES):534(M+1). Step 4. 4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-l,3-thiazol-2-yl]butanenitrile (2E)- and (2Z)-4-[(4-Methoxyben2yl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d3pyrimidin-4-yl)-l,3-thiazol-2-yl]but-2-enenitri]e (880 mg, 1.6 mmol) was dissolved in a mixture of ethanol (20 mL) and ethyl acetate (20 mL). A catalytic amount of 10% Pd-C was added. The mixture was shaken under 50 PSI of hydrogen. The mixture was filtered and concentrated in vacuo to afford the desired product (0.85 g, 99%). MS(ES):536(M+1). Step 5. 3-[5-(7H-PyrroIo[2,3-d]pyrimidin-4-yl)-lt3-thiazol-2-yl]pentanedinUrile 4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-l,3-thiazol-2-yl]butanenitrile (251 mg, 0.468 mmol) in DCM (10 mL) was treated with dichlorodicyanoquinone (DDQ) (434 mg, 1.87 mmol), followed by water (376 L). After 1.5 hours, saturated sodium bicarbonate and water were added, and the reaction was extracted with ethyl acetate three times. The extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product which was used without further purification. A solution of the above prepared 4-hydroxy-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]butanenitrile in DCM (12 mL) at 0 °C was treated sequentially with TEA (130 L, 0.94 mmol) and methanesulfonyl chloride (73 L, 0.94 mmol). After 1 hour reaction time, the mixture was diluted with water and extracted with ethyl acetate three times. The extracts were washed with water and brine, dried over sodium sulfete, filtered and concentrated in vacuo. The residue was then dissolved in DMSO (5 mL) and sodium cyanide (110 mg, 2.3 mmol) was added. After 30 minutes, the mixture was diluted with water, extracted with ether, washed with water, brine and dried over sodium sulfate. Concentration and purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (14 mg, 7%). MS(ES):425(M+1). A solution of 3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3- thiazol-2-yl]pentanedinitrile (14 mg, 0.033 mmol) in DCM (3 mL) containing TFA (0.6 mL) was stirred for 4 hours. The mixture was then concentrated and the residue was redissolved in methanol (2 mL) to which ethylenediamine (0.4 mL) was then added. After 1 hour reaction time, the product was purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O containing 0.15% NK4OH) to afford the desired product (6 mg, 62%). 1H NMR (400 MHz, d6-dmso): 5 12.27 (br s, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 7.75 (d, 1H), 7.14 (d, 1H), 4.14 (m, 1H), 3.17 (d, 4H); MS(ES):295(M+1). Example 87: (3R)-3-CycIopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-oxazol-2-ylI- propanenitrile, and (3S)3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-l,3-oxazol-2-yl]propanenitrile Step I. 4-(l,3-Oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.440 g, 1.55 mmol), 1,3-oxazole (0.306 mL, 4.65 mmol), potassium acetate (0.456 g, 4.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.179 g, 0.155 mmol) in N,N-dirnethylacetamide (8.0 mL) was heated to 200 °C in the microwave reactor for 30 minutes. Most of the solvent was removed in vacuo. The resulting residue was diluted with DCM, and was filtered and concentrated. Flash column chromatography (ethyl acetate/hexanes) afforded the product (330 mg, 67%). 1H NMR (400 MHz, CDCI3): 6 8.96 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.54 (d, 1H), 7.08 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):317(M+1). Step 2. Cyclopentyl[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3~ oxazol-2-yl] methanone n-Butyllithium in hexane (1.6 M, 0.30 mL) was added slowly dropwise to a -78 °C solution of 4-(13-oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrinudine (140.0 mg, 0.44 mmol) in THF (10.0 mL). After 20 minutes, 1.0 M zinc dichloride in ether (0.53 mL) was added. The reaction mixture was then stirred for 60 min at 0 °C. Following this, copper© iodide (84 mg, 0.44 mmol) was added, and this mixture was allowed to stir for 10 minutes. Cyclopentanecarbonyl chloride (108 L, 0.885 mmol) was then added. The reaction was stirred at 0 °C for a further 1 hour, at which time it was allowed to warm to room temperature. The reaction was quenched by the addition of saturated NH4CI solution, and was extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ethyl acetate/hexanes) afforded the product (97 mg, 53%). 1H NMR (400 MHz, CDC13): 5 8.96 (s, 1H), 8.21 (s, 1H), 7.56 (d, 1H), 7.22 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.56 (t, 1H), 2.23-1.56 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):413(M+1). Step 3. (3R)- and (3S)-3-Cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4~yl)'l,3-oxazol-2-yl]propanenitrile To a solution of 1.0 M potassium tert-butoxide in THF (0.355 mL) and THF (3 mL) at 0° C was added diethyl cyanomethylphosphonate (66 mg, 0.37 mmol) dropwise. The cold bath was removed and the reaction was warmed to room temperature. After 30 minutes, a solution of cyclopentyl[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-oxazol-2- yl]methanone (1.40E2 mg, 0.338 mmol) in THF (2.0 mL) was added dropwise. After 3 hours reaction time, the mixture was adsorbed onto silica gel, and flash column chromatography (ethyl acetate/hexanes) afforded the desired product as a mixture of olefin isomers (89 mg, 60%). MS(ES):436(M+1). To a mixture of cupric acetate, monohydrate (4.0 mg, 0.020 mmol) and (oxydi-2,1- phenylene)bis(diphenylphosphine) (11 mg, 0.020 mmol) in toluene (0.40 mL, 0.0038 raol) was added PMHS (50 jiL). The resulting mixture was stirred for 25 minutes at room temperature, followed by the addition of (2E)- and (2Z)-3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-l,3-oxazol-2-yl]acrylonitrile (88 mg, 0.20 mmol) in toluene (0.40 mL), and then tert-butyl alcohol (0.072 mL). After failure to react at room temperature over 16 hours, additional cupric acetate, monohydrate and (oxydi-2,l-phenylene)bis(diphenylphosphine) (0.10 mol equivalent each) were added and the reaction mixture was heated at 60 °C for 16 hours. The crude mixture was subjected to flash column chromatography (ethyl acetate/hexanes) to afford the desired product (21 mg, 23%). 1H NMR (400 MHz, CDC13): 8 8.96 (s, 1H), 8.02 (s, 1H), 7.56 (d, 1H), 7.10 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.38-3.30 (m, 1H), 3.03 (dd, 1H), 2.95 (dd, 1H), 2.60-2.40 (m, 1H), 2.10-2.00 (m, 1H), 1.85-1.15 (m, 7H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):438(M+1). Step 4. (3R)- and (3S)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-oxazol-2-yl]- propanenitrile A solution of 3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyn-olo[2,3-d)- pyrimidin-4-yl)-l,3-oxazol-2-yl]propanenitrile (20.0 mg, 0.0457 mmol) was stirred with TFA (0.1 mL) in DCM (0.2 mL) for 6 hours. The solvent was removed, and the resulting residue was stirred overnight with ethylenediamine (0.1 mL) in methanol (0.2 mL). The solvent was removed in vacuo. The desired product was obtained via preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) (5.3 mg, 38%). 'H NMR (400 MHz, CDC13): 5 10.25 (br s, 1H), 8.90 (s, 1H), 8.00 (s, 1H), 7.50 (d, 1H), 7.06 (d, 1H), 3.36-3.28 (m, 1H), 2.98 (dd, 1H), 2.90 (dd, 1H), 2.51-2.38 (m, 1H), 2.08-1.96 (m, 1H), 1.80-1.51 (m, 5H), 1.44-1.30 (m, 2H); MS(ES):308(M+l). The following compound of Table 5d was also prepared as a racemic mixture, according to the procedure of the above Example 87. Step 1. (2E)-5-(Methyltyio)pent-2-enenitrile To a 0 °C mixture of [chloro(triphenyl)phosphoranyl]ACN (2.5 g, 0.0073 mol) in THF (10 mL, 0.1 mol) was added TEA (2.0 mL, 0.014 mol), and the resulting mixture was stirred for 30 min. The ice bath was removed for 30 min, then the mixture was re-cooled back to 0 °C, A solution of 3- (methylthio)-propanol (0.68 mL, 0.0072 mol) in THF (1 mL, 0.02 mol) was added and the mixture was stirred overnight. Water was added and the mixture was filtered. The filtrate was washed with water x3 and brine. The organic phase was dried and the solvent was removed by rotary evaporation to give 2.1 g of an off-white solid. The solid was triturated with MTBE and was filtered. The filtrate was washed with IN HC1, water, sat. NaHCO3 and brine. The organic phase was dried and was concentrated using a rotary evaporator to give 0.62 g orange oil (44% yield, trans : cis ~ 2 : 1). 1H NMR for trans (400 MHz, CDC13): 5 6.68 (1H, m); 5.14 (1H, d); 2.6 (2H, m); 2.55 (2H, t); 2.1 (3H, s). Step 2. 5-(Methylthio)-3-[4-(7-[2-(trimethyhilyl)ethoxy]methyl-7H-pyrrolo[2t3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]pentanenitrile A mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (0.30 g, 0.00095 mol), (2E)-5-(methylfhio)pent-2-enenitrile (0.28 g, 0.0016 mol) and DBU (45 L, 0.00030 mol) in ACN (3 mL, 0.06 mol) was stirred at rt for 5 days. The solvent was removed by rotary evaporation to give an orange oil. The crude oil was chromatographed with 30-70 ethyl acetate/hex, to give 0.35 g of a colorless oil (83% yield). 1H NMR (400 MHz, CDC13): 5 8.95 (1H, s); 8.41 (1H, s); 8.4 (1H, s); 7.48 (1H, d); 6.84 (IH, d); 5.75 (2H, s); 4.95 (IH, br); 3.6 (2H, t); 3.1 (2H, m); 2.58 (2H, m); 2.28 (2H, m); 2.1 (3H, s); 1.99 (2H, t); 0.0 (9H, s). MS (M+H): 443. Step 3. 5-(Methylthio)-3'[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrlle A solution of 5-(methylthio)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile (0.35 g, 0.00079 mol) in THF (4 mL, 0.05 mol) and 3.0 M HCI (HC1) in water (4 mL) was heated to reflux overnight. The solvent was removed by rotary evaporation to give a pale orange oil. The oil was stirred in ethanol (3 mL, 0.05 mol) and 8.0 M ammonium hydroxide in water (1 mL) overnight. The reaction was concentrated and purified by prep LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give 125 mg of a white foam. The white foam was triturated with MTBE (~ 1.5 mL). The resulting solid was filtered, washed and dried to give 80 mg of the product (32% yield). 1H NMR (400 MHz, CDCI3): 5 10.38 (1H, s); 8.88 (1H, s); 8.39 (1H, s); 8.38 (1H, s): 7.44 (1H, d); 6.8 (1H, d); 5.75 (2H, s); 4.9 (1H, br); 3.05 (2H, m); 2.5 (2H, m); 2.23 (2H, d); 2.1 (3H, s). MS (M+H): 313. A solution of 5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- pentanenitrile (0.065 g, 0.00021 mol) and hydrogen peroxide (0.022 mL, 0.00023 mol) in ACN (1 mL, 0.02 mol) was stirred overnight. The reaction was concentrated and purified by HPLC to give 21 mg of a solid. The solid was triturated with MTBE (1 mL)/DCM (10 drops). The solid was filtered and washed to give 13 mg of a white solid (20% yield) which was dried rt to 50 °C for 2 h. 1H NMR (400 MHz, CDCl3): 5 9.95 (1H, s); 8.85 (1H, s); 8.4 (2H, m); 7.4 (1H, d); 6.8 (1H, s); 4.9 (1H, br); 3.15 (2H, m); 3.0 (2H, m); 2.8-2.5 (2H, m); 2.6 (3H, s). MS (M+H): 329. Example 92: 5-(Methylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yI]- pentanenitrile A solution of 5-(Jnethylthio)-3-[4-(7H-pyrrolo[2,3-d]pynmidin-4-yl)-lH-pyrazol-l-yl]- pentanenitrile (0.040 g, 0.00013 mol) and hydrogen peroxide (0.5 mL, 0.005 mol) in ACN (1 mL, 0.02 mol) was refluxed overnight. The reaction was purified by HPLC to give 16 mg of a white glass/solid which was triturated with EtOH (~0.8 mL) to give 13 mg of a white solid (30% yield). 1HNMR (400 MHz, CDC13): 8 8.75 (1H, s); 8.48 (1H, d); 8.4 (1H, d); 7.43 (1H, d); 6.8 (1H, s); 5.0 (1H, br); 3.4 (2H, m); 3.2-3.0 (2H, m); 2.8-2.5 (2H, m); 2.95 (3H, s). MS (M+H): 345. Step 1. 4,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- IH-pyrazol-l-ylJbutanenitrile A mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (6.9 g, 0.022 mol), (2E)-4,4,4-trifluorobut-2-enenitrile (2.8 g, 0.023 mol) and DBU (0.18 mL, 0.0012 mol) in ACN (70 mL, 1 mol) was stirred for 20 min. The reaction was filtered and filtrate was removed by rotary evaporation to give an orange oil. The crude oil was chromatographed with 20-50% ethyl acetate/hex to give to give 9.1 g of a solid/oil (96% yield). A single enantiomer (peak 2) was separated by chiral column chromatography (OD-H column, 30%EtOH/hex) as a greenish solid/glass (3.3 g, 32% yield). lHNMR(400 MHz, CDC13): 5 8.93 (1H, s); 8.46 (1H, s); 8.45 (1H, s); 7.5 (1H, d); 6.85 (1H, d); 5.75 (2H, s); 5.2 (1H, m); 3.6 (2H, t); 3.7-3.3 (2H, m); 1.99 (2H, t); 0.0 (9H, s). MS (M+H): 438. Step 2. 4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-l-ylJ-butyronitrile A solution of 4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyra2X)l-l-yl]butanenitrile (3.1 g, 0.0071 mol) from Step 1 in THF (35 mL, 0.43 mol) and 3.0 M HC1 in water (35 mL) was heated to reflux overnight. The solvent was removed by rotary evaporation to give a greenish orange oil/glass. The oil was stirred with ethyl acetate and sat. NaHCO3 (50 mL). The aqueous phase was extracted with ethyl acetate. The organic layers were washed with brine and reduced by rotary evaporation to give an oil/glass residue. The residue was stirred in ethanol (20 mL, 0.3 mol) and 8.0 M ammonium hydroxide in water (10 mL) over a weekend. The solvent was removed by rotary evaporation to give a pale orange foam/solid. The crude was chromatographed with 0-7% MeOH/DCM, O-O.7% NH4OH to give 3 g of a pale orange paste/solid. The solid was recrystallized from EtOH to give 1.6 g of an off-white crystals (74% yield). Step 1: 3-(Dimethoxymethyl)cyclopentanecarbaldehyde. Into a 3-neck round bottom flask 2-norbomene (5.500 g, 0.05841 mol) was dissolved in DCM (198.0 mL,) and raethanol (38.5 mL) and was cooled at -78 °C. Ozone was passed through the reaction until it turned blue and was stirred at -78 °C for 30 minutes. Then nitrogen was passed through for 20 minutes and p-toluenesulfonic acid (0.95 g, 0.0055 mol) was added The reaction was allowed to warm at 20 °C and was stirred for 90 minutes. Into the reaction was added sodium bicarbonate (1.67 g, 0.0199 mol) and the resulting mixture was stirred at 20 °C for 30 minutes and dimethyl sulfide (9.4 mL, 0.13 mol) was added. The reaction was stirred for 16 hours and was reduced by rotary evaporation to ~50 mL The reaction was extracted with DCM and the organic extracts were washed with water and brine, dried (MgSO4), and stripped in vacuo. The reaction was distilled at 135 °C (bath temperature) at high pump vacuum to give the product (7.5,g) as a ~2:1 mixture of diastereomers. 1HNMR (300 MHz, CDC13): 9.64 & 9.62 (d, 1H), 4.i5 & 4.12 (s, 1H), 3.35 & 3.34 (s, 6H), 2.77 m, 1H), 2.34 (m, 1H), 1.35-2.00 (m, 6H). Step 2. (2E,Z)-3-[3-(Dirnethoxymethyl)cyclopentyl]acrylonitrile. Into a flask containing a 0 °C solution of t-BuOK in THF (1.0 M, 6,10 mL) was added a solution of diethyl cyanomethylphosphonate (1.1 g, 6.4 mmol) in THF (8 mL). The cooling bath was removed and the reaction was warmed to ambient temperature, then a solution of 3-(dimethoxy- methyl)cyclopentanecarbaldehyde (1.00 g, 5.81 mmol) in THF (2 mL) was added dropwise. Shortly after completion of the addition orange gel-like particulates began to form, after approximately 1 hour the reaction was gelatinous. The reaction was held with stirring at ambient temperature for 16 hours at which time tic indicated complete reaction. The reaction was partitioned between water and EtOAc and the aqueous phase was washed with additional EtOAc. The combined organic phase was washed with water, then satd NaCl, and then was dried over MgSO4 and reduced in vacuo, and the resulting residue was purified by column chromatography with 6:1 hexanes:EtOAc +1% TEA to obtain the product as a 1:1 mixture of E/Z isomers (760 mg, 61%). 1H NMR (400 MHz, CDC13): 8 vinylic protons at 6.69 (m, 0.5H), 6.37 (m, 0.5H), 5.32 (m, 0.5H), 5.23 (m, 0.5H), acetal methine proton at 4.14 (m, 1H), methyl protons at 3.34 (s, 6H). Step 3. 3-[3-(Dimethoxyrnethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile. To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyI-7H-pyrrolo[2,3- d]pyrimidine (230 mg, 0.74 mmol) in ACN (5 mL) was added (2E,Z)-3-[3-(dimethoxymethyl)cyclo- pentyl]acrylonitrile (289 mg, 1.48 mmol), followed by DBU (300 L, 2.0 mmol). The mixture was stirred at ambient temperature for 16 hours, at which point LCMS and TLC indicated complete reaction. The reaction was reduced to dryness in vacuo, and the residue was purified by column chromatography to obtain the product as a mixture of diastereomers (293 mg, 77%). 1HNMR (400 MHz, CDC13): 8 8.85 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.28 (m, 1H), 4.11 (m, 1H), 3.54 (t, 2H), 3.36 (s, 1.5H), 3.34 (s, 1.5H), 3.30 (s, 1.5H), 3.26 (s, 1.5H), 3.12 (m, 1H), 2.94 (m, 1H), 2.65 (m, 1H), 2.34 (m, 1H), 2.0-1.0 (m, 6H), 0.92 (t, 2H), -0.56 (s, 9H). MS (El) m/z = 511.3 (M+H). Step 4. 3-(3-Formylcyclopentyl)-3-[4-(7-[2-(trimethyIsilyl)ethaxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile. To a solution of 3-[3-(dimethoxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3-d]pyrimidinr4-yl)-lH-pyrazol-l-yl]propanenitrile (293 mg, 0.574 mmol) in THF (4.5 mL) was added aqueous HC1 (1.0 M, 1.5 mL). The reaction was held at ambient temperature for 2.5 hours at which point TLC and LCMS indicated complete deprotection to the corresponding aldehyde. The reaction was partitioned between water and EtOAc and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then sat'd NaHCO3, then sat'd NaCl, and then was dried over MgSO4 and filtered and stripped to dryness to leave the crude product as a mixture of diastereomers. 'H NMR (400 MHz, CDC13): 5 9.69 (d, 0.5H), 9.64 (d, 0.5H), 8.85 (s, 0.5H), 8.84 (s, 0.5H), 8.35 (s, 0.5H), 8.34 (s, 0.5H), 8.32 (s, 0.5H), 8.30 (s, 0.5H), 7.41 (d, 0.5H), 7.40 (d, 0.5H), 6.80 (d, 0.5H), 6.79 (d, 0.5H), 5.68 (s, 1H), 5.67 (s, 1H), 4.32 (m, 1H), 3.54 (m, 2H), 3.14 (m, 1H), 2.96 (m, 2H), 2.76 (m, 1H), 2.1-1.1 (m, 6H), 0.92 (m, 2H), -0.058 (s, 9H). MS (El) m/z = 465.1 (M+H). Step 5. 3-3-f(E, Z)-(Hydroxyimino)methyl]cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljpropanenitrile. To a solution of 3-(3-formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yljpropanenitrile (336 mg, 0.000723 mol) in CH3OH (5.0 mL, 0.12 mol) was added hydroxylamine hydrochloride (60 mg, 0.00087 mol) and KHCO3 (110 mg, 0.0011 mol) and the reaction was held at ambient temperature for 16 hours, at which point LCMS indicated complete reaction. The reaction was reduced to dryness in vacuo and the residue was partitioned between water and EtOAc, and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then sat'd NaCl, then was dried over MgSO4 and concentrated to leave the crude product, which was carried forward to the subsequent reaction without purification. NMR indicated disappearance of aldehydic protons. MS (El) m/z = 480.2 (M+H). Step 6. 3-(2-Cyano-l -[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]ethyl)cyclopentanecarbonitrile. To a solution of 3-3-[(E,Z)-(hydroxyimino)methyl]cyclopentyl-3-[4-(7-[2-(trimethylsiIyI)- ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (324 rag, 0.67 mmoJ) in pyridine (1.2 mL), was added methanesulfonyl chloride (210 L, 2.7 mmol) dropwise. The reaction was heated to 60 °C for 2.5 hours, at which point LCMS indicated complete reaction. The reaction was partitioned between water and EtOAc, and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then 0.1N HC1, then sat'd NaCl, and then was dried over MgSO4. The crude product was purified by column chromatography to obtain the product as a mixture of diastereomers (164 mg, 52%). The diastereomers were then separated by chiral HPLC to provide four distinct diastereomers, which were taken directly on to the deprotection step. MS (El) m/z = 462.1 (M+H). Step 7. 3-(2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)-cyclopentane- carbonitrile trifluoroacetate. The four diastereomers were then separately deprotected in this representative manner. To 3- 2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]ethylcyclopentanecarbonitrile (35 mg, 0.076 mmol) dissolved in CH2C12 (2.0 mL) was added TFA (1.0 mL) and the reaction was stirred for 2 hours at ambient temperature at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (40 uL, 0.61 mmol), the reaction was stirred for 16 hours at which point LCMS indicated complete reaction. The solvent was removed and the residue was purified by preparative LCMS to provide the product as a TFA salt. NOE experiments confirm that all isomers have cis geometry on cyclopentyl ring. Isomers 1 and 2: 'H NMR (400 MHz, CD3OD): 5 8.95 (s, 1H), 8.89 (s, 1H), 8.54 (s, 1H), 7.86 (d, 1H), 7.29 (d, 1H), 4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 2.95 (m, 1H), 2.72 (m, 1H), 2.2-1.9 (m, 4H), 1.67 (m, 2H). Isomers 3 and 4: "H NMR (400 MHz, CD3OD): 5 8.95 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.85 (d, 1H), 7.28 (d, 1H), 4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 2.05 (m, 1H), 1.92 (m, 1H), 1.72 (m, 1H), 1.58 (m, 2H).MS (El) m/z = 332.2 (M+H). Example 98: 3-[3-(Hydroxymcthy0cycIopentyll-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]propanenitrile Step 1: 3-[3-(Hydroxymethyt)cyclopentyl]-3-(4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile A solution of 3--3-fonnylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (50.0 mg, 0.108 mmol) in methanol (280 L) was cooled to 0 °C, then sodium tetrahydroborate (14 mg, 0.37 mmol) was added. The reaction was held at 0 °C for 10 minutes, at which point LCMS and TLC indicated complete reaction. The reaction was quenched by cautious addition of IN HC1 (3 drops) and methanol (1 mL), followed by addition of aqueous NaHCO3 and CHC13. The phases were separated and the aqueous phase was washed with additional CHC13. The combined organic phase was washed with sat'd NaCl, dried over MgSO4 and reduced to dryness. The residue was purified by column chromatography to obtain the product as a mixture of diastereomers (37.4 mg, 74%). 1HNMR (400 MHz, CDC13): 5 8.84 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, 1H), 3.53 (m, 1H), 3.53 (t, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.68 (m, 1H), 2.2-1.0 (m, 9H), 0.92 (t, 2H), -0.059 (s, 9H). MS (El) m/z = 467.2 (M+H). Step 2. 3-[3-(Hydroxymethyl)cyclopentyl]-3'[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH--pyrazol-l - yljpropanenitrile To 3-[3-(hydroxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (60.4 mg, 0.129 mmol) dissolved in CH2C12 (2.0 mL) was added TFA (1.0 mL) and the reaction was stirred for 1 hour at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate (m/z = 367). The trifluoroacetate ester of the hydroxymethyl of the cyclopentyl ring was also observed (m/z = 463). The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (80 uL, 1.19 mmol). The resulting mixture was stirred for 16 hours at which point LCMS indicated complete reaction to the desired product. The solvent was removed and the residue was purified by chiral HPLC to provide four distinct diastereomers (20.2 mg total of four isomers, 46%). NOE experiments suggest that all isomers have cis geometry on the cyclopentyl ring. Isomers 1 and 2: 1H NMR (400 MHz, CD3OD): 8 8.65 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.40 (m, 2H), 3.22 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.82 (m, 1H), 1.6-1.4 (m, 3H), 1.03 (m, 1H). Isomers 3 and 4: 'H NMR (400 MHz, CD3OD): S 8.66 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.09 (m, 1H), 1.71 (m, 1H), 1.55-1.25 (m, 3H),' 1.04 (m, 1H). MS (EI)m/z = 337.1(M+H). 4-Bromo-lH-pyrrolo[2,3-b]pyridine (0.078 g, 0.00040 mol) and lH-indazole (0.283 g, 0.00240 mol) was heated neat in a sealed tube at 200 °C (an oil bath) overnight with stirring. The reaction was allowed to cool to it and the crude product was purified by prep LC-MS on a C-18 column during with a water/ACN gradient containing 0.2% TFA to give the title compound (0.015 gm, 15%), as an amorphous white solid, LC /MS (M+H)+ 235, 'H NMR (DMSO-cfe) 8 12.01 (bs, 1H), 9.17(s, 1H), 8.31(s, 1H), 7.73(d, 1H, J=9.0), 7.67(m, 2H), 7.58(m, 1H), 7.28(m, 1H), 7.07(m, 2H). 4-Bromo-l-t2-(trimethyIsilyl)ethoxy]methyl-lH-pyrroloE2,3-b]pyridine (0.300 g, 0.000917 mol) was dissolved in DMF (6.5 mL, 0.084 mol) and then zinc cyanide (0.30 g, 0.0026 mol) was added. The solution was degassed with nitrogen and then bis(tri-t-butylphosphine)palladium (0.1 g, 0.0002 mol) was added. The reaction was sealed and heated in the microwave to 100 °C for 30 minutes. The reaction was allowed to cool to rt, taken up in ethyl acetate and washed with water saturated sodium carbonate, brine, dried over magnesium sulfate and concentrated to give an oil. The crude product was purified by flash column chromatography (FCC) on silica gel, eluting with a hexane: ethyl acetate gradient to give the product (0.25 gin) as a colorless oil. LC/M S (M+H)+ 274, lH NMR (CDC13) 5 8.22 (d, 1H), 7.53(d, 1H), 7.40(d, 1H), 6.73(d, 1H), 5.65(s, 2H), 3.50(m, 2H), 0.90(m, 2H), 0.0(s, 9H). l-[2-(Trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.05 g, 0.0002 mol) was dissolved in ethanol (2.0 mL, 0.034 mol), and then hydroxylamine hydrochloride (0.023 g, 0.00033 mol) and potassium carbonate (0.10 g, 0.00073 mol) were added. The reaction was heated to reflux for 5 h, and the reaction was then allowed to cool to rt and filtered to remove the solids. The filtrate was concentrated to give the product 0.06 g as yellow oily residue, LC/MS (M+H)+ 307. Step3.3-[3-(l-[2-(Trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxadiazol-5- yl] benzonitrile The crude product N-hydroxy-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine- 4-carboximidamide (0.06 gm, 0.0002 mol) was dissolved in pyridine (1.0 mL, 0.012 mol) and then 3- cyanobenzoyl chloride (0.040 g, 0.00024 mol) was added at rt. This mixture was stirred for 1 h and heated to 80 °C in an oil bath. After heating for 18 h the reaction was allowed to cool to rt and then diluted with ACN and concentrated in vacuo to give 3-[3-(l-[2-(trimethylsilyl)ethoxy]methyl-lH- pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxadiazol-5-yl]benzonitrile 0.08 gm as an off white residue, LC/M S(M+H)+ 418. Step4.3-[3-(lH-Pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxadiazol-5-yl]benzonitrile Thecmde 3-[3-l-t2^trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxa- diazol-5-yl]benzonitrile (0.08 g, 0.0002 mol) was dissolved in TFA (3.0 mL, 0.039 mol) under nitrogen and then heated to 60 °C. After heating for 2 h the reaction was allowed to cool to rt and concentrated in vacuo. The resulting residue was taken up in methanol and concentrated to remove as much of the TFA as possible. The residue was taken up in methanol (2.0 mL, 0.049 mol) and ammonium hydroxide (I mL). This mixture was stirred at rt for 2 h and the reaction was then complete. The reaction was concentrated in vacuo to give the crude product which was purified by prep HPLC on a C-18 column eluting with a ACNiwater gradient with 0.2% TFA to give the title compound (0.025 gm, 43%) (M+H)= 288. 1H NMR (DMSOd6) 8 12.1 (bs, 1H), 8.65(s, 1H), 8.48(d, 1H,J=6.4), 8.39(d, 1H, J=4.8), 8.16(d, 1H, J=6.4), 7.84(t, 1H, J=6.4), 7.75(d, 1H, J=4.8), 7.68(m, 1H), 6.99 (m, 1H). l-Benzothien-2-ylboronic acid (0.05 g, 0.0003 mol) and 4-bromo-l -[2-(trimethylsilyl)- ethoxy]methyl-lH-pyrroIo[2,3-b]pyridine (0.10 g, 0.00031 mol) were combined in toluene (3.0 mL, 0.028 mol) and ethanol (1.0 mL, 0.017 mol). Potassium carbonate (0.085 g, 0.00062 mol) dissolved in water (1.0 mL) then was added and the reaction was degassed with nitrogen. Then tetrakis(triphenylpnosphine)palladhim(0) (0.05 g, 0.00004 mol) was added and the reaction was heated to 120 °C in a sealed tube in the microwave for 60 minutes. This was allowed to cool to rt, taken up in ethyl acetate and washed with water 2X, brine, dried over magnesium sulfate and concentrated to give 4-(l-benzothien-2-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]- pyridine (0.10 gm) as an oil, LC /MS (M+H)+ 381. Step 2. 4-(l-Benzothien-2-yl)-lH-pyrrolo[2,3-b]pyridine Using a procedure analogous to Example 106, Step 4, but using 4-(l-benzothien-27yl)-l-[2- (trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was prepared as a yellow powder (0.015 g, 18%), LC /MS (M+H)+: 251, 1H NMR (DMSO-d6) 5 11.95 (bs, 1H), 8.28(d, 1H, J=5.4), 8.l5(s, 1H), 8.03(m, 1H), 7.96(m, 1H), 7.64(m, 1H), 7.42(m, 2H), 7.39(d, 1H, J=5.4), 6.95(m, 1H). 4-Bromo-lH-pyrrolo[2,3-b]pyridine (0.050 g, 0.00025 mol) and 4-fluoro-2-(lH-pyrazol-3- yl)phenol (0.150 g, 0.000842 mol) were heated neat to 160 °C for 5 h. The reaction was allowed to cool to rt and the residue was purified by prep LC-MS on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give the title compound, (0.052 g, 20%, as an amorphous white solid, LC IMS (M+H)+ 295, 'H NMR (DMSO-d6) 5 12.01 (bs, 1H), 10.25(bs, 1H), 8.81(s,lH), 8.35(d, 1H, J= 5.5), 7.77(d, 1H, J=9.5), 7.64(m, 1H), 7.59(d, 1H, J=5.5), 7.32(s, 1H), 7.09(m, 1H), 7.05(m, 1H), 7.01(m, 1H). l-[5-(Trifluoromethyl)phenyl]ethanone (0.20 mL, 0.0013 mol) and l,l-dimethoxy-N,N- dimethylmethanamine (0.17 mL, 0.0013 mol) were combined in a sealed tube and heated in a microwave to 120 °C for 15 minutes, the reaction was allowed to cool and was concentrated to remove the residual DMF acetal, to give (2E)-3-(dimethylamino)-l-[3-(trifluoromethyl)phenyl]prop- 2-en-l-one, 0.32 gm, as a red oil, LC /MS (M+H)+: 244. The (2E)-3-(dimethylamino)-l-[3-(trifluoromethyl)phenyl]prop-2-en-l-one (0.32 g, 0.0013 mol) was dissolved in ethanol (10.0 mL, 0.171 mol) and hydrazine (0.24 mL, 0.0078 mol) under nitrogen and heated to reflux. The reaction was monitored by HPLC and was complete almost immediately. The mixture was allowed to cool to rt and concentrated to give the crude product as an oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to give 3-[3-(trifluoromethyl)phenyl]-lH-pyrazole as an oil (0.25 g, 89% ), LC /MS (M+H)+: 213, 'H NMR (CDC13) 5 8.06 (s, 1H), 7.99(d, 1H, J=7.5), 7.66(d, 1H, J= 2.4), 7.57(m, 1H), 7.55(d, 1H, J=7.5), 6.69(d, 1H, J= 2.4). Step 3. 4-3-[3-(Trifluoromethyl)phenyl]-lH-pyrazol-l-yl-lH-pyrrolo[2,3-b]pyridine 4-Bromo-lH-pyrrolo[2,3-b]pyridine (0.028 g, 0.00014 mol) and 3-[3-(trifluoromethyl)- phenyl]-lH-pyrazole (0.03 g, 0.0001 mol) were combined neat. The reaction was heated in a sealed tube in an oil bath to 175 °C for 20 to produce a crude product that was a black viscous gum. The crude product was purified by HPLC on a C-18 column eluting with a waterACN gradient with 0.2% TFA to give the title product (0.025 gm, 50%) as a white amorphous solid, LC /MS (M+H)+: 329, 'H NMR (DMSO-rf6) 5 11.95 (bs, 1H), 8.83(d, 1H, J=2.7), 8.31(m, 3H), 7.75(m, 2H), 7.60(m, 2H), 7.35(d, 1H, J=2.7), 7.14(m, 1H). Example 128: 3-[l-(lH-Pyrrolo[2,3-blpyridin-4-yl)-lH-pyrazol-3-yl]benzonitrile Step 1. 3-[(2E)-3-(Dimethylamino)prop-2-enoyl]benzonitrile 3-AcetylbenzonitriIe (0.435 g, 0.00300 mol) and l,l-dimethoxy-N,N-dimethylmethanamine (0.400 mL, 0.00301 mol) were combined and heated in sealed tube to 120 °C in the microwave for 15 min. The reaction was then allowed to cool to rt giving the 3-[(2E)-3-(dimethylamino)prop-2-enoyl]- benzonitrile as a red-orange crystalline material, LC /MS (M+H)+: 201. Step 2. 3-(lH-Pyrazol-3-yl)benzonitrile The 3-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile (0.600 g, 0.00300 mol) was dissolved in ethanol (20.0 mL, 0.342 mol) and hydrazine (0.56 mL, 0.018 mol) under an atmosphere of nitrogen was stirred at room temperature for 1.5 h. The reaction was concentrated in vacuo to give a dark product which was purified by FCC on silica gel, eluting with ethyl acetate-hexane 1:1 to give 3-(lH-pyrazol-3-yl)benzonitrile as an oil (0.430g, 84%), LC /MS (M+H)+: 170. Step 3. 3-[l-(lH-Pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yl]benzonitrile 4-Bromo-lH-pyrrolo[2,3-b]pyridine (0.075 g, 0.00038 mol) and 3-(lH-pyrazol-3-yl)benzo- nitrile (0.161 g, 0.000952 mol) were heated in sealed tube to 160 °C for 18 h. The resulting product, dark viscous gum, was purified by HPLC on a C-l 8 column eluting with a water:ACN gradient with 0.2% TFA to give the title product (0.030 g, 27%) as a white amorphous solid, LC /MS (M+H)+: 286, 'H NMR (DMSO-d6) 6 11.95 (bs, 1H), 8.76(s, 1H), 8.36(s, 1H), 8.29(d, 1H, J=7.5), 8.25(d, 1H, J=5.0), 7.79(d, 1H, J= 7.5), 7.62(t, 1H, J= 7.5), 7.53(m, 2H), 7.25(s, 1H), 7.1 l(m, 1H). Stepl.4-(4A,5,S-Tetramethyl-l,3,2-(Uoxaborolan-2-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH- pyrazole A solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyra2ole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0 °C. Sodium hydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture was stirred for 10 min. [/3-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the resulting mixture was stirred for 20 min at 0° C and 2 h at room temperature. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrazole as a crude material. LC/MS (M+H)+: 325, 1H NMR (CDC13) 6 7.85 (s, 1H), 7.80(s, 1H), 5.45(s, 2H), 3.55(t, 2H), 1.35(s, 12H), 0.95(t, 2H), 0.0(s, 9H). Step 2. 3-(l-[2-(Trimethylsilyl)ethoxy]methyl-lH-pyrazol-4-yl)benzonitrile A mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-[2-(trimethylsilyl)ethoxy]- methyl-lH-pyrazole (150.0 mg, 0.0004625 mol) and 3-bromobenzonitrile (0.10 g, 0.00056 mol) in toluene (2.0 mL, 0.019 mol) and ethanol (0.3 mL, 0.005 mol) was treated with sodium carbonate (98 mg, 0.00092 mol) in water (0.5 mL, 0.03 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.000046 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a microwave at 80 °C for 30 min, then allowed to cool to it and taken up in water and ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to give a crude product, which was purified by FCC on silica gel, eluting with EtOAc/Hexanes (1:5) to give 3-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrazol-4-yl)benzonitrile, as an oil, LC /MS (M+H)+: 300. A solution of 3-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrazol-4-yl)benzonitrile (110.0 mg, 0.0003673 mol) was taken up in TFA (3.0 mL, 0.039 mol) and the mixture was heated in microwave at 120 °C for 3 min. The reaction mixture was allowed to cool to rt, and then concentrated to give a crude residue. The product was purified by HPLC on a C-l 8 column eluting with a water/ACN gradient containing 0.2% TFA to give 3-(lH-pyrazol-4-yl)benzonitrile trifluoroacetate as an amorphous white solid, LC /MS (M+H)+: 170. Step 4. 3-[l-(lH-Pyrrolo[2,3-b]pyridin-4-yl)~lH-pyrazol-4-yl]benzonitrile A mixture of 4-bromo-lH-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol) and 3-(lH- pyrazol-4-yl)benzonitrile trifluoroacetate (23.6 mg, 0.0000833 mol) was heated at 180 °C, neat overnight. The crude residue was purified by HPLC on a C-18 column eluting with a water; ACN gradient containing 0.2% TFA to give the title compound as an amorphous white solid, LC/MS (M+H)+: 286, 'H NMR (DMSCW6) 5 11.85 (bs, 1H), 9.18(s, 1H), 8.42(s, 1H), 8.28(s, 1H), 8.25(d, 1H, J=5.0), 8.07(d, 1H, J=7.0), 7.64(d, 1H, J=7.0), 7.56(t, 1H, J= 7.0), 7.51(m, 1H), 7.47(d, IH, J=5.0), 7.03(m,lH). To 4-bromo-l-t2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (1.98 g, 0.00605 mol) was added hydrazine (11.0 mL, 0.350 mol) followed by addition of methanol (1.0 mL, 0.025 mol) (to improve solubility). The reaction mixture was heated in a sealed tube at 97 °C (an oil bath) for 18 h. The reaction mixture was cooled to rt and formed an off-white solid precipitate. The solid was filtered off and rinsed with cold water and dried to give 4-hydrazino-l-[2-(trimethylsilyl)ethoxy]- methyl-lH-pyrrolo[2,3-b]pyridine (1.55gm) as a light yellow solid, LC/MS (M+H)+:279, 1H NMR (DMSO-d6) 8 7.98(d, 1H), 7.91(s, IH), 7.28(d, IH), 6.69(s, 1H), 6.61(d, IH), 5.58(s, 2H), 4.37(s, 2H), 3.56(t, 2H), 0.90(t, 2H), 0.0(s, 9H). Step 2. 2-[l-(l-[2-(Trimethylsilyl)elhoyy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]- 1,3-benzoxazole To 4-hydrazino-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.083 g, 0.00030 mol) 3782-117-1 and l.S-benzoxazol^-ylmalonaldehyde (0.056 g, 0.00030 mol) in toluene (1.5 mL, 0.014 mol) was added molecular sieves. The mixture was heated in a sealed tube at 70 °C (an oil bath) with stirring for 2 h. The solvent was removed in vacuo and the crude product was purified by FCC on silica using ethyl acetate:hexanes 3:7 to give 2-[l-(l-[2-(trimethylsilyl)ethoxy]- methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-l,3-benzoxazole (0.090gm) as an oil, LC/MS (M+H)+: 432. Step 3. Using a procedure analogous to Example 106, Step 4, but using 2-[l-(l-[2-(trimethylsilyl)- ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-l,3-benzoxazole, the title compound was prepared as a white amorphous powder (0.015 gm, 18%), LC /MS (M+H)+:302, 1H NMR (DMSO-d6) 5 11.85 (bs, 1H), 9.45(s,lH), 8.53(s, 1H), 8.36(bs, 1H), 7.7-7.6(m, 2H), 7.65(d, 1H), 7.56(bs, 1H), 7.38-7.34(m, 2H),7.01(d,lH). A mixture of 4-bromo-lH-pyrrolo[2,3-bJpyridine (1.10 g, 0.00558 mol) and 4-broroo-lH- pyrazole (1.2 g, 0.0084 mol) was heated neat to 150 °C for 2 h. DMF was added to dissolve the crude residue. This residue was taken up in EtOAc and washed with IN NaOH. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a crude 4-(4-bromo-lH- pyrazol-l-yl)-lH-pyrrolo[2,3-b]pyridine residue, LC /MS (M+H)+: 263,265. A solution of 4-(4-bmma-lH-pyrazol-l--yl]-l-[2-(trimethylsiiyl)ethoxy]methyl chloride (1.4 mL, 0.0079 mol) was added and stirred for 20 min at 0 °C. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the crude material. The product was purified by FCC on silica gel (EtOAc/Hexanes, 1/10) to give 4-(4-bromo-lH-pyrazol-l-yl)-l-[2-(triinethyIsilyl)ethoxy]methyl-lH-pyrro/o/2,5-67]yarirfine as a solid product, LC /MS (M+H)+: 393, 394, 1HNMR (CDC13) 8 8.47(d, 1H, J=7.0), 8.27(s, 1H), 7.88(s, 1H), 7.52(d, 1H, J=4.5), 7.39(d, 1H, J=7.0), 7.069(d, 1H, J=4.5), 5.80(s, 2H), 3.6(t, 2H), 1.95(t, 2H), 0.0(s, 9H). Step 3. CyclohexyI[l-(l-[2-(trimethylsilyl)ethoty]methyI-lH-pyrrolo[2J-b]pyridin-4-yl)-1H-pyrazol 4-ylfmethanol A mixture of 4-(4-bromo-lH-pyrazol-l-y])-l-[2-(trimethylsilyl)ethoxy]inethyl-lH- pyrrolo[2>3-b]pyridine (50.0 mg, 0.000127 mol) in THF (2.0 mL, 0.025 mol) under a nitrogen atmosphere was cooled to -78 °C and 1.6 M n-butyllithium in water (1.00 mL, 0.0555 mol). The mixture was stirred for 3 rain. The reaction was partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give the cyclohexyl[l-(l:5) to give 4-yl)- lH-pyrazol-4-yl]methanol as a crude residue, LC /MS (M+H)+: 417. Step 4. Cyclohexyl[l-phenylvinyl)-lH-pyrazol-4-yl]methanol Using a procedure analogous to Example 106, Step 4, but using cyclohexyl[l-(l-[2- (trimethylsilyl)ethoxy]methyI-lH-pyrroIo[2)3-b]pyridine, the title compound was prepared as a white amorphous powder (0.015 gm, 18%), LC /MS (M+H)+: 297. 1H NMR (DMSO-d6) S 11.85 (bs, 1H), 8.44(s, 1H), 7.74(s, 1H), 7.50(m, 1H), 7.44(d, 1H, J=6.5.70(s, 1H), 5.37(s, 1H). A mixture of (l-phenylvinyl)boronic acid (24.0 mg, 0.000162 mol) and 4-(4-bromo-l H- pyrazol-l-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol) in toluene (2.00 mL, 0.0188 mol) and ethanol (0.50 mL, 0.0086 mol) was treated with potassium 5 carbonate (35 mg, 0.00025 mol) in water (1.00 mL, 0.0555 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(triphenylphosphine)palladiiim(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a sealed tube in the microwave at 100 °C for 30 min. The reaction was allowed to cool to it and partitioned between ethyl acetate and water. The combined organic layer was dried over MgSO4 filtered and concentrated to give the crude material The crude product was purified by FCC on silica gel eluting with EtOAc/Hexanes (1:5) to give 4-[4^1-phenylvnyl)-lH-pyrazol-l-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]- pyridine as a solid residue, LC /MS (M+H)+: 417. Step 2. Using a procedure analogous to Example 106, Step 4, but using 4-[4-(l-phenylvinyl)- 1H- pyrazol-l-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was prepared as an white amorphous powder (0.015 gm, 31%), LC /MS (M+H)+: 287, 'H NMR (DMSO- d6) 8 11.85 (bs, 1H), 8.63(s, 1H), 7.99(s, 1H), 7.55(bs, 1H), 7.48(m, 2H), 7.43-7.37(m, 5H), 7.01(m,lH), 5.70(s, 1H), 5.37(s, 1H). 4-Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyn-olo[2>3-b]pyridine (0.100 g, 0.000306 mol) was combined with l-benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.113 g, 0.000398 mol) in toluene (3.0 mL, 0.028 mol) and ethanol (0.5 mL, 0.008 mol). Potassium carbonate (0.084 g, 0.00061 mol) dissolved in water (1.0 mL, 0.056 mol) was added and the reaction mixture was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.000069 mol) was added, and again the mixture was degassed with nitrogen for 5 min. The reaction was heated in sealed tube to 100 °C in a microwave for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a crude residue. The product was purified by FCC on silica gel using ethyl acetate:hexane 3:7, to give 4-(l-benzyl-lH-pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH- pyrrolo[2,3-b]pyridine 0.092g as a semisolid residue, LC /MS (M+H)+: 405. Step 2. 4-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine Using a procedure analogous to Example 106, Step 4, but using 4-(l-benzyl-lH-pyrazol-4- yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was prepared as a white amorphous powder (0.054 gm), LC /MS (M+H)+: 275, 'H NMR (DMSO-rf6) 5 12.21 (bs, 1H), 8.80(s, 1H), 8.25(vbs, 1H), 8.23(s, 1H), 7.63(s, 1H), 7.49(bs, 1H), 7.4-7.2(m, 5H), 6.99(s, 1H), 5.42(s, 2H). Step 1. l-(2-Naphthylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole The 4-(4J4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.10 g, 0.00052 mol) was combined with naphthalene, 2-(bromomethyl)- (0.12 g, 0.00057 mol) in ACN (3.0 mL, 0.057 mol) under nitrogen at rt. Then cesium carbonate (0.50 g, 0.0015 mol) was added and the reaction was complete after stirring for 1 h. This was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give l-(2- naphthylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole 0.17 gm, as an oil, LC/MS (M+H)+: 335, 'H NMR (CDC13) 5 7.89 (s, 1H), 7.79-7.84(m, 3H), 7.69(bs, 2H), 7.49-7.4(m, 2H), 7.46-7.33(m, 1H), 5.47(s, 2H), 1.31(s, 12H). 4-Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.06 g, 0.0002 mol) and l-(2-naphthylmethyl)-4-(4,4,5,5-tetramethyl-l)3)2-dioxaborolan-2-yl)-lH-pyrazole (0.074 g, 0.00022 mol) were combined in toluene (2.0 mL, 0.019 mol) and ethanol (1.0 mL, 0.017 mol), and then potassium carbonate (0.063 g, 0.00046 mol, in 1 mL water) was added. The reaction mixture was degassed with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol) was added, sealed in a tube and heated to 120 °C in a microwave for 30 minutes. This was allowed to cool and then partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and concentrated to give 4-[l-(2-naphthylmethyl)-lH-pyrazol-4-yl]-l-[2- (trimethylsilyl)ethoxy]methyl-lH-pyrroIo[2,3-b]pyridine 0.08 g, as an oily residue, LC /MS (M+H)+: 455. Step 3 Using a procedure analogous to Example 106, Step 4, but using 4-[l-(2-naphthylmethyl)-lH- pyrazol-4-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was prepared as a white amorphous powder (0.053 g, 88%), LC /MS (M+H)+: 325, 1H NMR (DMSO-D6) 5 • 12.0(bs, 1H), 8.79(s, 1H), 8.24(s, 1H), 8.19(d, 1H, J=5.7), 7.82(m, 4H), 7.56(m, 1H), 7.43(m, 4H), 6.92(m, 1H), 5.54(s, 2H). Step 1. l-phenyl-4-(4,4,5,5-Tetramethyl-l,3.2-dioxaborolan-2-yl)-lH-pyrazole 4-(4,4,575-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.07 g, 0.0003 mol) and phenylboronic acid (0.083 g, 0.00068 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(Il) diacetate (0.010 g, 0.000055 mol) and pyridine (0.069 mL, 0.00085 mol) were added. The reaction was heated in an open tube to 80 °C for 40 minutes. The reaction was complete by HPLC, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give l-phenyl-4-(4,4,5,5-tetramethyl-l,332-dioxaborolan-2-yl)-lH-pyrazo, 0.09 gm as an oily residue, LC/MS (M+H)+: 271. Step 2. 4-(l-Phenyl-lH-pyrazol-4-yl)-l-f2-(trimethylsilyl)ethojty]methyl-lH-pyrrolof2,3-b]pyridine Using a procedure analogous to Example 201, Steps B and C, but using 1 -phenyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)~lH-pyrazo, the title compound was prepared as an white amorphous powder (0.015 gm, 18%), LC/MS (M+H)+: 261, 1H NMR (DMSO-d6) 5 12.05 (bs, 1H), 9.23(s, IH), 8.53(s, 1H), 8.31(m, 1H), 8.01(m, 2H), 7.63(m, 1H), 7.57-7.52 (m, 3H>, 7.36(m, 1H), 7.13(m, IH). 4-Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.20 g, 0.00061 mol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.15 g, 0.00079 mol) were combined in DMF (5.0 mL, 0.064 mol) and then potassium carbonate (0.25 g, 0.0018 mol) in 1 mL water was added. The reaction was degassed with nitrogen, then tetrakis(triphenylphosphine)- palladium(O) (0.08 g, 0.00007 mol) was added and in a sealed tube the reaction was heated to 120 °C oil bath. The reaction was heated for 30 minutes, allowed to cool and then taken up in ethyl acetate. The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated to give an oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to give 4-(lH-pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.13 gm, 70%) as a crystalline white powder, LC /MS (M+H)+: 315, 1H NMR (DMSO-d6) 8 13.35 (bs, IH), 8.59(bs, IH), 8.32(d, 1H, J=8.5), 8.26(bs, IH), 7.76(d, IH, J=6.0), 7.45(d, 1H, J=8.5), 7.01 (d, IH, J=6.0), 5.73(s, 2H), 3.6l(t, 2H), 0.92(t, 2H), 0.0(s, 9H). Step2.3-[4-(l-[2-(Trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l- yljbenzonitrile 4-(lH-Pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyirolo[2,3-b]pyridine (0.025 g, 0.000080 mol) and (3-cyanophenyl)boronic acid (0.023 g, 0.00016 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(H) diacetate (0.002 g, 0.00001 mol) and pyridine (0.019 mL, 0.00024 mol) were added. The reaction was heated in an open tube to 125 °C for 40 minutes, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]- benzonitrile (0.025 gm, 92%) as an oily residue, LC /MS (M+H)+: 316. Step 3 Using a procedure analogous to Example 106, Step 4, but using 3-[4-(l-[2-(trhnethylsilyl)- ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile, the title compound was prepared as an white crystalline powder (0.012 gm, 60%), LC/MS (M+H)+: 286, 1H NMR (DMSO- d6) 5 12.05 (bs, 1H), 9.32(s, 1H), 8.59(m, 1H), 8.55(m, 1H), 8.36(m, 1H), 8.30(d, 1H, J=5.2), 7.83(m, 1H), 7.75(m, 1H), 7.63(m, 1H), 7.51(d, 1H, J=5.2), 7.12(m, 1H). 4-(lH-Pyra2zol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyirolo[2,3-b]pyridine (50 mg, 0.0002 mol) (see, Example 231, Step 1) was dissolved in DMF (2 mL, 0.02 mol) and cooled at 0 °C. This solution was treated with sodium hydride (7.0 mg, 0.00029 mol) (60% in oil) and stirred for 15 min. The mixture was then treated with 2-bromopentane (40 mg, 0.0002 mol) and was stirred for 5 h. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product 4-[l-(l-methylutyl)-lH- pyrazol-4-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine as an oil, LC/MS (M+H)+: 286. Step 2. 4-[l-(l-Methylbutyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine Using a procedure analogous to Example 106, Step 4, but using 4-[l-(l-methylbutyl)-lH- pyrazol-4-yl]-l-[2-(trimethylsiIyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was prepared as an white amorphous powder (0.025 gm, 60%), LC /MS (M+H)+: 255, 1H NMR (DMSO- d6) S 12.21 (bs, 1H), 8.66(s, 1H), 8.27(bs, 1H), 8.25(s, 1H), 7.62(m, 1H), 7.49(m, 1H), 7.02(m, 1H), 4.46(m, 1H), 1.9-1.8(m, 1H), 1.7-1.6(m, 1H), 1.47(d, 3H), 1.2-1.0(m, 2H), 0.83(t, 3H). Step 3. Separation of Enantiomers The separation of the enantiomers of 4-[l-(l-methylbutyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3- b]pyridine from Step 2 was performed by chiral column preparative HPLC separation using an OD-H column eluting with an isopropanokhexane gradient to give the title compounds as amorphous white residues, LC /MS (M+H)+: 255, 1H NMR (DMSO-d6) 6 12.21 (bs, 1H), 8.66(s, 1H), 8.27(bs, 1H), 8.25(s, 1H), 7.62(m, 1H), 7.49(m, 1H), 7.02(m, 1H), 4.46(m, 1H), 1.9-1.8(m, 1H), 1.7-1.6(m, 1H), 1.47(d, 3H), 1.2-1.0(m, 2H), 0.83(t, 3H). To a mixture of 4-(lH-pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]- pyridine (0.050 g, 0.00016 mol) (see, Example 231, Step 1) and cesium carbonate (0.10 g, 0.00032 mol) in dry DMF (1.0 mL, 0.013 mol) was added 3-fluoro-4-methylbenzonitrile (0.043 g, 0.00032 mol). The reaction mixture was heated in sealed tube to 120 °C for 5.5 hours. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give 4-methyl-3-[4-(l-[2- (trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile as a crude product, LC /MS (M+H)+: 430. Step 2. 4-Methyl-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile Using a procedure analogous to Example 106, Step 4, but using 4-methyl-3-[4-(l-[2- (trimethyIsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-l-yl]benzonitrile, the title compound was prepared as a white amorphous powder (0.037 gm, 88%), LC /MS (M+H)+: 300, 'H NMR (DMSO-d6) 8 12.19 (bs, 1H), 8.98(s, 1H), 8.57(s, 1H), 8.31(d, 1H, J=7.0), 8.08(s, 1H), 7.89(d, 1H, J=10), 7.66(d, 1H, J=10), 7.63(m, 1H), 7.55(d, 1H), 7.07(m, 1H), 2.4(s, 3H). Further example compounds of the invention are provided in Tables 7, 8,9,10, and 11 below. The compounds listed in Tables 7, 8, 9, 10 and 11 are racemic unless the enantiomers are indicated separately. Step 1: Dimethyl 3~[4-(7-{[2-(tnmetkylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]pentanedioate 4^1H-PyrazoM-yl)-7-t2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (31.0 g, 0.0983 mol) was suspended in ACN (620 mL, 12 mol), and DBU (9.3 mL, 0.062 mol) was added under nitrogen. The reaction was heated to 65 °C and dimethyl (2E)-pent-2-enedioate (16 mL, 0.12 mol) was added in 5 mL portions over 2 h. After stirring overnight, the reaction was complete. The reaction was allowed to cool to room temperature and was concentrated in vacuo to give a dark oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with 1.0 N HC1, brine, dried over magnesium sulfate, and then concentrated to give a dark oil. The viscous oil was-triturated with ethyl ether 3X 500 mL to give a dark precipitate. The oil was taken up in ethyl acetate to form a solid. The solids were collected, washed with ethyl ether and dried to give dimethyl 3-[4-(7-{[2-(trimemylsilyl)ethoxy3methyl}-7H-pvrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]pentanedioate as a white powder (29.5 gm, 64%), LC /MS (M+H)+: 474, 'H NMR (DMSO-d6) 8 9.1 (s,lH), 9.02 (s,lH), 8.65 (s, 1H), 8.11 (d, 1H), 7.42(d, 1H), 5.78(s, 2H), 5.27(m, 1H), 3.65(m, 8H), 3.15(m, 4H), 0.95(t, 2H), 0.1(s, 9H). Step 2: 3-[4-(7-[2-(Trimetf^lsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-dJpyrimidin-4-yl)-lH-pyrazol-J-ylJ- pentanedioic acid Dimethyl 3-[4 pyrazol-l-yl]pentanedioate (43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol) and lithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125 mL) was added. The reaction was stirred at rt for 2 h. The methanol was removed in vacuo and a resulting aqueous layer was cooled in an ice bath. The solution was made acidic pH~4 with IN HC1 to give a white precipitate. The solid precipitate was collected, washed with water, dried to give 3-[4-(7-[2- (trimethylsilyl)ethoxy3methyl-7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yljpentanedioic acid as a white crystalline powder (31.8 gm, 80%), LC /MS (M+H)+: 446, 'H NMR (DMSO-d6) 5 8.85s 1H), 8.75(s, 1H), 8.42(s, 1H), 7.85(d, 1H), 7.17(d, 1H), 5.71(s, 2H), 5.18(m,lH), 3.65(t, 2H), 3.05(m,4H), 0.92(t,2H),0.1(s,9H). Step 3: 3-[4-(7-[2-(Trimethylsilyl)ethoy]methyl-7H-pyrrolo[2,3-d]pyHmidin-4-yl)-lH-pyrazol-l-yl]- pentanediamide 3-[4 yl]pentanedioic acid (31.80 g, 0.07137 mol) was dissolved in DMF (636 mL, 8.21 mol) under nitrogen cooled in an ice bath and CDI (34.7 g, 0.214 mol) was added. This mixture was allowed to stir for 30 minutes and then allowed to warm to rt. After stirring for 2 h ammonia (12.2 g, 0.714 mol) was bubbled through the solution for 30 minutes giving a cloudy suspension. The reaction mixture was concentrated to remove some of the DMF (~200 mL) and then water was added slowly to give a white precipitate. This mixture was cooled in an ice bath and the solid precipitate was collected, washed with water and dried in vacuo to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pvrazol-l-yl]pentanediamide as a white powder (29.0 gm, 91%), LC /MS (M+H)+: 444, 'H NMR (DMS0-d6) 8 8.85(s, 1H), 8.59(s, 1H), 8.40(s, 1H), 7.87(d,lH), 7.75(s,2H), 7.15(d, 1H), 6.95(s, 2H), 5.73(s, 2H), 5.29(m,lH), 3.63(t, 2H), 2.82(m, 2H), 2.73(m, 2H), 0.90(t,2H),0.1(s,9H). Step 4: 3-[4-(7-[2-(Trimethylsilyl)etho^]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- pentanedinitrile 3-[4-(7,[2-9Trimethylsllyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]pentanediamide (29.0 g, 0.0654 mol) was partially dissolved in DMF (200 mL, 2 mol), DCM (200 mL, 3 mol) and TEA (36 mL, 0.26 mol) and. cooled in an ice bath under nitrogen atmosphere. The trichloroacetyl chloride (IS mL, 0.14 mol) was added dropwise turning the reaction to a dark solution. This was stirred at 0 °C for 1/2 h. The reaction was then concentrated to remove the DCM and the resulting DMF solution was diluted with water to precipitate the product. The solid precipitate was collected and washed with water to give a dark solid. The solid was then dissolved in DCM and washed with brine, dried over magnesium sulfate and concentrated to give a very dark oily residue. The residue was taken up in DCM, and hexane was added until the solution became slightly cloudy. This was stirred at it to precipitate 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanedinitrile as white needle-like crystals (22.7 gm, 85%), LC /MS (M+H)+: 408, 'H NMR (DMSO-4;) 8 9.07(s, 1H), 8.87(s, 1H), 8.59(s, 1H), 7.88(d, 1H), 7.19(d, 1H), 5.75(s, 2H), 5.30(m,lH), 3.62(t, 2H), 3.40(m, 4H), 0.91(t, 2H), 0.10(s, 9H). Step 5: 3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanedinitrile 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l- yl]pentanedinitrile (10.0 g, 0.0245 mol) was dissolved in ACN (200 mL, 3.83 mol) and water (20 g, 1.1 mol) at rt. To this lithium tetrafluoroborate (23.0 g, 0.245 mol) was added giving a cloudy solution. The reaction was heated to reflux and monitored by HPLC. After heating for 24 h the reaction was allowed to cool to rt and then cooled in an ice bath. To this, ammonium hydroxide (23 mL, 0.59 mol) was added slowly. The reaction was allowed to warm to rt. After stirring for 18 hs the reaction was diluted with water and concentrated in vacuo to remove the ACN, giving a precipitate. The solids were collected, washed with water and dried to give the title compound as an off-white solid (6. 2 gm, 91%), LC /MS (M+H)+: 278, 'H NMR (DMSO-d6) S 8.9(s, 1H), 8.72(s,lH), 8.43(s, 1H), 7.59(d, 1H), 6.92(d, 1H), 5.21(m,lH), 3.25(m, 4H). Example 421: 5-{2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]etnyl}- pyridine-2-carbonitrile trifluoroacetate Step J: 3-(6-Chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile 3-(6-Chloropyridin-3-yl)-3-[4-(7-[2-(trimethylsi!yl)ethoxy]methyI-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yI]propanenitrile (prepared by methods analogous to those described for Example 61) (0.070 g, 0.00014 mol) in TFA (3.0 mL, 0.039 mol) and DCM (3.0 mL, 0.047 mol) was stirred at room temperature for 1 hour. Solvent was removed in vacuo, and the residue was dissolved in methanol (4.0 mL, 0.099 mol) and ethylenediamine (0.07 mL, 0.001 mol). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo, the crude product was purified by preparative HPLC eluting with an ACN; water gradient buffered with ammonium hydroxide to pH=10, to give 3-(6-chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH- pyrazol-l-yl]propanenitrile as a white powder (35mg,69%), LCMS (M+l)+:350, 'H NMR (DMSO-d6) 6 12.21 (b,lH), 9.00 (s,lH), 8.78 (s,lH), 8.62 (s,lH), 8.58 (s,lH), 8.00(m,lH), 7.70(m,2H), 7.00(s,lH), 6.22(m,lH), 3.90(m,lH), 3.78(m,lH) Step 2: 5-2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin~4-yl)-lH-pyrazol-l-yl]ethylpyridine-2-carbo- nitrite trifluoroacetate A mixture of 3-(6-cchloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]propanenitrile (0.025 g, 0.000071 mol) and zinc cyanide (0.08 g, 0.0007 mol) in DMF (1.0 mL, 0.013 mol) was degassed with nitrogen. To this mixture, tetralds(triphenylphosphine)palladium(0) (0.04 g, 0.00004 mol) was added and the resulting mixture degassed again with dinitrogen. The reaction mixture was heated in a sealed tube at 170 °C for 15 minutes in a microwave (Personal Chemistry). After cooling to room temperature, the solids were filtered, rinsed with DMF and the combined solvent was concentrated in vacuo. The residue was triturated with hexanes (3x), and hexanes washes were discarded. The crude product was purified by preparative HPLC eluting with an ACN; water gradient containing 0.2% TFA to give the title compound as. a white powder (16 mg, 49.27%), LCMS (M+l)+: 341, 1H NMR (DMSO-d6) 5 12.50(b,lH), 9.05(s,lH), 8,89(s,lH), 8,80(s,lH), 8.58(s,lH), 8.18(m,2H), 7.78(s,lH), 7.05(s,lH), 6.20(m,lH), 3.90(m,lH), 3.77(m,lH). Example 428: 4-[4-(7H-PyrroloI2^-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]heptanedinitrile Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yllpentane-l ,5-diol Diethyl 3-[4-(7-[2-(1ximethylsilyl)ethoxy]methyl-7H-pynrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]pentanedioate, prepared substantially as described in Example 407 (0.80 g, 0.0016 mol), was dissolved in THF (40 mL, 0.49 mol) and cooled in an ice bath under a nitrogen atmosphere. To this mixture, 1.0 M lithium tetrahydroaluminate in THF (3.2 mL) was added slowly. The reaction was stirred for lh, quenched with ice and partitioned between ethyl acetate and 1 N HC1. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give an amber oil. The product was purified by FCC on silica gel eluting with an ethyl acetate: methanol gradient to give 3-[4-(7-[2-(tiimethylsilyl)ethoxy]methyl-7H-pyn:olo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentane- 1,5-diol as a clear viscous oil (0.51 gm, 76%), LC /MS (M+H)+: 418, 1H NMR (DMSO-ds) 5, 8.85(s, 1H), 8.41(s, 1H), 8.37(s, 1H), 7.45(d,lH), 6.83(d, 1H), 5.73(s, 2H),4.91(m, 1H), 3.75(m,2H), 3.59(m, 2H), 3.45(m,2H), 2.18(m, 4H), 0.95(m,2H), 0.1(s, 9H). Step 2: 3~[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- ylJpentane-J, 5-diyl dimethanesulfonate A mixture of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]pentane-l,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0 °C. To this mixture, TEA (50 \xL, 0.0004 mol) was added. The reaction was stirred for 15 minutes. Methanesulfonyl chloride (23 L, 0.00030 mol) was added and the resulting mixture was stirred for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-[4-(7-[2 pentane-1,5-diyl dimethanesulfonate (57 mg, 80 %) as an oil. MS(ES): 574 (M+l). Step 3: 4-[4-(7-[2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]heptanedinitrile To a mixture of S-[4-(7-[2-(trimethylsilyl)ethoxylmethyl-7H-pyrrolo[2,3-dlpyriraidin^4-yl)- lH-pyrazol-l-yl]pentane-l,5-diyl dimethanesulfonate (57 mg, 0.000099 mol) in DMSO (1 mL, 0.01 mol), sodium cyanide (10 mg, 0.0003 mol) was added and the mixture was stirred for 2 hours. The mixture was heated at 60 °C for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]heptanedinitrile (40 mg, 90 %) as an oil. MS(ES): 436 (M+l). Step 4: 4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]heptanedinitrile Using a procedure analogous to Example 61 for the removal of the SEM protecting group, the title compound was prepared as a white amorphous solid, (17 mg, 60%) 1H NMR (400 MHz, DMSO): 5. 8.75 (s, 1H), 8.65 (s, 1H), 8.4 (s, 1H), 7.6 (d, 1H), 7.0 (d, 1H), 4.5 (m, 1H), 2.35 (m, 4 H), 2.2 (m, 4H). MS(ES): 306 (M+l). Example 429: 3-(5-Bromopyridin-3-yl)-3-[4-(7H-pyrroIo[2,3-dlpyrimidin-4-yl)-lH-pyrazol-l- yi]propaneni trite To a mixture of 1.0 M potassium tert-butoxide in THF (2.7 mL) at 0 °C (water-ice bath, under an atmosphere of nitrogen) was added diethyl cyanomethylphosphonate (0.48 mL, 0.0030 mol) in THF (4.0 mL, 0.049 mol), dropwise. The reaction mixture was wanned to room temperature, and then was cooled to 0 °C, followed by dropwise addition of 5-bromonicotinaldehyde (0.5 g, 0.003 mol) in THF (1.0 mL, 0.012 mol). After stirring at room temperature for 20 hours, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a crude product as a dark oil. The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 3:7 as eluent to give a mixture of cis and trans isomers (2)-3-(5-bromopyridin-3-yl)acrylonitrile as an off- white solid (268 mg, 47.69%). LCMS (M+l)+: 209,211, 1H NMR (400 MHz, CDC13): 5. 8.75(s,lH), 8.62(s,lH), 7.90(s,lH), 7.40(d,lH), 6.00(d, 1H). Step 2: 3-(5-Bromopyridin-3-yl)-3-[4-(7-[2-(tnmethylsilyl)ethooy]rmthyl-7H-pyrrolo[2,3-d]pyr- imidin-4-yl)-lH-pyrazol-l-yl]propanenitrile To 4-(lH-pyrazol-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pjmrolo[2,3--di]pyrimidine (0.200 g, 0.000634 mol) in 1.0 mL of dry ACN was added DBU (0.10 mL, 0.00067 mol), followed by the addition of (2Z&E)-3-(5-bromopyridin-3-yl)actylonitrile (0.234 g, 0.00112 mol) in 1.0 mL of ACN. The reaction mixture was stirred at 67 °C for 4 hours. Upon cooling, the mixture was partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate : hexanes (7:3) to give 3-(5- bromopyridin-3-yl]-3-[4-7-[2-(trimethylsilyl)-ethoxy]-methyl-7H-pyrrolo[2,3-d]pyriniidin-4-yl)-1H- pyrazol-l-yl]propanenitrile as an off-white solid (225 mg, 67.66%). LCMS (M+l)+:524,526: 'H NMR (400 MHz, CDC13): § 8.90(s, 1H), 8.80(s, 1H), 8.70(s, 1H), 8.42(s, 1H), 8.40(s, 1H), 8.00(s, 1H), 7.50(d, 1H), 6.82(d, 1H), 5.81(m, 1H), 5.75(s, 2H), 3.70(m,lH), 3.60(m, 2H), 3.42(m, 1H), 1.00(m,2H),0.08(s,9H). Step 3: 3-(5-Bromopyridin-3-yl)-3'[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-ylJpropane- nitrite The 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (0.220 g, 0.000419 mol) in DCM (9.0 mL, 0.14 mol) and TFA (9.0 mL, 0.12 mol) was- stirred at room temperature for 1 hour. The reaction was concentrated in to give a residue. This crude intermediate was dissolved in methanol (12 mL, 0.30 mol) and ethylenediamine (0.2 mL, 0.003 mol) and was stirred overnight at room temperature. The reaction was concentrated in vacuo to give the crude product which was purified by preparative HPLC eluting with a water : ACN gradient buffered with ammonium hydroxide (pH=10) to give 3- (5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]propanenitrile as an amorphous white powder (118 mg, 71.36%). LCMS (M+l)+:394,396, H NMR (400 MHz, DMSO- d6): 5. 12.05(bs,lH), 8.98(s, 1H), 7.0(s, 1H), 6.50(m, 2H), 8.50(s, 1H), 8.10(s, 1H), 7.80(s, 1H), 6.98(s, 1H), 6.21(m, 1H), 3.90(m, 1H), 3.70(m, 1H). Example 430: 3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentane-l,5-diol Using a procedure analogous to Example 61 for the removal of the SEM protecting group but using 3-[4-(7-[2-(trimethylsilyI)ethoxy]methyl-7H-pyn-olo[2,3Hl]pyrimidin-4-yl)-lH-pyrazol-l-yl]- pentane-l,5-diol from Example 428, the title compound was prepared as a white amorphous solid, (25 mg, 70%) 1HNMR (400 MHz, DMSO): 5. 8.65 (s, 1H), 8.6 (s, 1H), 8.25 (s, 1H), 7.6 (d, 1H), 6.0 (d, 1H), 4.6 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 2.1 (m, 2H), 1.9_(m, 2H). MS(ES): 288 (M+l). Example 431: 5-(2-Cyano-l-[4-(7H-pyrrolo[2^-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)- nicotinonitrile bis(trifluoroacetate) A slurry of 3-(5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l- yl]propanenitrile (0.050 g, 0.00013 mol) (from Example 429), DMF (2.0 mL, 0.026 mol) and zinc cyanide (0.1 g, 0.001 mol) was degassed by purging with nitrogen. Then tetrakis(triphenyl- phosphine)palladium(O) (0.07 g, 0.00006 mol) was added and the resulting slurry again was degassed with nitrogen. The reaction was sealed and heated at 170 °C for 15 minutes in a microwave (Personal Chemistry). The reaction was allowed to cool and the solids were filtered off. The combined DMF fractions were concentrated in vacuo. The residue was triturated with ethyl acetate-hexanes 2:8, then with ethyl ether to removed by-products. The crude product,was purified by preparative HPLC eluting with a water : acetontrile gradient containing 0.2% TFA to give the racemic title compound (43 mg, 59.65%). LCMS (M+l)+:341, 1HNMR(400 MHz, DMSO-d6): 6. 12.60(bs, 1H), 9.10(s, 1H), 8.90(s, 1H), 8.80(s, 1H), 8.50(s, 1H), 8.42(s, 1H), 7.78(s, 1H), 7.10(s, 1H), 630(m, 1H), 3.90(m, 1H), 3.70(m, 1H). Example 431R and Example 431S The enantiomers R-5-(2-cyano-I -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]- ethyl)nicotinonitrile and S-5-(2-cyano-l -[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl] - ethyl)nicotinonitrile were separated by chiral column HPLC. Example 467: 3-(3-Aminophenyl)-3-14-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l-yl]- propanenitrile bis(trifluoroacetate) Stepl: 3-(3-Nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl] 1H-pyrazol-J-ylJpropanenitrile To 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL, 0.0016 mol) followed by addition of (2Z)-3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction mixture was heated at 67 °C for 18 hours. This was cooled to room temperature, and the mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 6:4, to give 3- (3-nitropheny])-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-1 -yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+l)+:490 Step 2. 3-(3-Aminophenyl)-3-(4-7-[2-(trimethylsilyl)etho7y]-7H-pyrrolo[2,3-d]pyrimidin-4-yl-lH- pyrazol-l-yl)propanenitrile The 3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl]propanenitrile (0.630 g, 0.00129 mol) was dissolved in ethanol (65 mL, 1.1 mol), degassed with nitrogen, and then palladium (0.55 g, 0.0052 mol) (10% on carbon) was added. The reaction mixture was again purged with nitrogen, and it was then charged at 50 psi hydrogen in a Parr shaker for 60 minutes. The reaction mixture was filtered and concentrated to give 3-(3-amino- phenyl)0-(4-7-[2-(trimethylsilyl)ethoxy]-7H-pyn-olo[2,3wi]pyrimidin--4-yl-lH-pyrazol-l-yl)propane- nitrile as a colorless oil (550 mg, 95.92%), LCMS (M+l)+=460, Step 3. 3-(3-Aminophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljpropanertitrile his(trifluoroacetate) Using a procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was prepared as a white amorphous solid (18 mg, 38%), LCMS (M+l)+=329: 1H NMDR. (DMSO-d6) 6 12.61 (b,lH), 9.00 (s,lH), 8.80 (s,lH), 8.50 (s,lH),7.78 (m,lH), 7.25( m,lH), 7.18(m,lH), 6.85(m,2H), 6.02 (m.lH), 3.78(m,lH), 3.60 (m,lH). Step 1 -(3-2-Cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]ethylphenyl)acetamide To 3-(3-aminophenyl)-3-[4^7-[2-(trimethylsllyl)ethoxy]memyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl]propanenitrile (0.070 g, 0.00015 mol) (from Example 467) in dry DCM (1.0 mL, 0.016 mol) was added TEA (0.042 mL, 0.00030 mol). The reaction was cooled in an ice bath and acetyl chloride (0.016 mL, 0.00023 mol) was added. The reaction mixture stirred for 30 minutes and was diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N-(3-2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pvrimidin-4-yl)-lH-pyrazol-l-yl]ethylphenyl)acetamide as a colorless oil, (65 mg, 85.08%), LCMS(M+l)+= 502. Step 2 N-(3-2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylphenyl)acetamide trifluoroacetate Using a procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was prepared as a white amorphous solid (40 mg, 68.9%), LCMS(M+l)+=372, 1H NMR (DMSO-ds) 5 12.61 (b.lH), 9.05 (s.lH), 8.79 (s,lH), 8.44 (s,lH): (s,lH), 7.55 (s,lH), 7.48 (d,lH), 7.24 (m,lH), 7.10 (m,2H)), 6.05 (m,lH), 3.70 (m,lH), 3.48 (m 1.98 (s,3H). Example 470: 4-(2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI]ethyl)- thiophene-2-carbonitrile trifluoroacetate Step 1 4-Bromo-2-(diethoxymethyl)thiophene A mixture of 4-bromothiophene-2-carbaldehyde (1.2 g, 0.0063 mol) in ethanol (10 mL, 0.2 mol) was treated with ammonium chloride (0.42 g, 0.0078 mol) and ethyl orthoformate (1.2 g, 0.0078 mol). The mixture was stirred at 60 °C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-bromo-2-(diethoxymethyl)thio- phene as an oil (1.3 g, 81% ). 1H NMR (400 MHz, CDCI3): 5 7.22 (s, 1H), 6.99 (s, 1H), 5.68 (s, 1H), 3.63 (q,4H) 1.24 (t,6H). Step 2 5-(Diethoyymelhyl)thiophene-3-carbaldehyde A solution of 4-bromo-2-(diethoxymethyl)thiophene (500 mg, 0.002 mol) in ether (5 mL, 0.05 mol) was cooled at -78 °C. To this solution, 2.5 M n-butyllithium in hexane (0.83 mL) was added dropwise. The reaction was stirred at -78 °C for 1 hour. To the reaction was added DMF (0.4 g, 0.006 mol) at -78 °C and the mixture was stirred for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the 5-(diethoxymethyl)thiophene-3-carbaldehyde as an oil (170 mg, 42.0%). By lH NMR two different regioisomers of aldehydes were formed and were not separated; (note: NMR shifts are for the major isomer only) ]H NMR (400 MHz, CDC13): § 9.85 (s, 1H), 8.05,7.7 (s, 1H), 7.45, 7.15 (s, 1H), 5.7 (s, 1H), 3.65 (m, 2H), 1.25 (m, 2H). Step 3 (2E)-3-[5-(Diethoxymethyl)-3-thienyl]acrylonitrile To a solution of diethyl cyanomethylphosphonate (100 mg, 0.0008 mol) in THF (2 mL, 0.02 mol) cooled at 0 °C and 1.0 M potassium tert-butoxide in THF (0.8 mL) was added dropwise. The bath was removed and the reaction was warmed to room temperature for 30 minutes. The reaction was cooled to 0 °C and a solution of 5-(diethoxymethyl)thiophene-3-carbaldehyde (170 mg, 0.00079 mol) in THF (2 mL, 0.02 mol) was added drop wise. The reaction was stirred overnight at room temperature. The reaction was partitioned between water and ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (ethyl acetate:hexane, 1:5) to give (2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile as an oil (160 mg, 84.9%). 'H NMR (300 MHz, CDC13): 8 7.4-7.0 (m, 3H), 5.65 (m 1H), 4.2 (m, 1H), 3.65 (m, 4H), 1.25 (m, 6H). Step 4 3-[5-(Diethoxymethyl)-3-thienylJ-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4~yl)-lH-pyrazol-l-yl]propanenitrile To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (200 mg, 0.0007 mol) in ACN (2 mL, 0.04 mol) and (2E)-3-[5-(diethoxymethyl)-3- thienyl]acrylonitrile (160 mg, 0.00067 mol) (mixture of regioisomers) DBU (80 uL, 0.0005 mol) was added. The reaction was stirred overnight than water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (50% EtOAc/Hexane) to give 3-[5-(diethoxymethyl)-3-thienyl]- 3-[4-(7-[2-(trimethylsilyl)ethoxy]memyl-7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile (160 mg, 43%). 1H NMR (400 MHz, CDC13): 5 8.92 (s, 1H), 8.41 (s, 1H), 8.29 (b, 1H), 7.45(d, 1H), 7.41(d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.82 (m, 1H), 5.74 (d, 2H), 3.74 (m, 2H), 3.71 (m, 8H), 3.59 (m, 1H), 1.32 (m, 4H), 0.95 (m, 2H), -0.08 (s, 9H); MS(ES):553 (M+l). Step 5 3-(5-Formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-dJpyrimidin- 4-yl)-lH-pyrazol-l-yl]propanenitrile A solution of 3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (70 mg, 0.0001 mol) in THF (1 mL, 0.01 mol) was treated with 1 M HC1 in water (400 uL). The reaction was stirred at room temperature. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-foimyl-3-thienyl)-3-[4-(7-[2-(trunethylsilyl)ethoxy]m yl)-lH-pyrazol-l-yl]propanenitrile as a semisolid residue (60 mg, 98%). 1H NMR (400 MHz, CDC13): 8. 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, 1H), 3.73-3.43 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+l). Step 6: 5-[(E)~(Hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethyhilyl)ethoxyJmethyl- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile A solution of 3-(5-formyl-3-thienyl)-3-[4-(7-(2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (65 mg, 0.00014 mol) in methanol (2 mL, 0.05 mol) was treated with hydroxylarnine hydrochloride (11 mg, 0.00016 mol) and potassium bicarbonate (23 mg, 0.00023 mol). The reaction was stirred at room temperature for 4 hours. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-5-[(E)- (hydroxyimino)methy]]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yi)-lH-pyrazol-l-yl]propanenitrile as a semisolid oil (60 mg, 89.5%). (The crude product contained both isomers of oxime and also both regioisomers of thiophene). MS (ES): 494 (M+l). Step 7: 4-(2-Cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]ethyl)thiophene-2-carbonitrile To a mixture of 3-5-[(E)-(hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]- methyl-7H-pyn-olo[2,3-d]pyrknidin-4-yl)-lH-pyra2»l-l-yl]propanenitriIe (70 mg, 0.0001 mol) in pyridine (1 mL, 0.01 mol), methanesulfonyl chloride (100 L, 0.001 mol) was added. The mixture was stirred at 60 °C for 2 hours. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with 0.1 N HC1, brine, dried over magnesium sulfate, filtered and concentrated to give 4-(2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pvrimidin-4-yl)-lH-pyra2ol-l-yl]ethyl)thiophene-2-carbonitrile as a crude product (30 mg, 44%). MS (ES): 476 (M+l). Step 8: 4-(2-Cyano~l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)thiophene-2- carbonitrile trifluoroacetate A mixture of 4-(2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrroio[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)thiophene-2-carbonitrile (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) and TFA (1 mL, 0.01 mol) was stirred for 1 hour. The starting material was consumed and the desired methyl hydroxy compound was formed. The mixture was concentrated in vacuo to remove TFA. The crude intermediate was dissolved in methanol (3 mL, 0.07 mol) and was treated with ethylenediamine (1 mL, 0.01 mol). The mixture was stirred overnight and concentrated in vacuo. The products were purified by preparative HPLC eluting with ACN: water with 0.2% TFA to give two regioisomers, the title compound as an amorphous white solid (30 mg, 60 %). 1H NMR (500 MHz, DMSO): $ 8.95 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.70 (d, 1H), 7.05 (d, 1H), 6.25 (m, 1H), 3.80-3.60 (m, 2H); MS (ES): 346 (M+l). Isolated as the second regioisomer from Example 470, the title compound was isolated as an amorphous white solid (4 mg, 8%). 1H NMR (500 MHz, DMSO): 8. 9.0 (s, 1H0, 8.75 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.0 (d, 1H), 6.45 (m, 1H), 3.8 (dd, 2 H); MS (ES): 346 (M+l). Example 472 : 3-[3-(Morpholin-4-yIcarbonyl)phenyll-3-[4-(7H-pyrrolo[2^-d]pyrimidin-4-yl)- lH-pyrazol-l-yl]propanenitrile trifluoroacetate Step 1: 3-(2-cyano-l-[4-(7-[2-(trimethylsilyI)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]ethyl)benzoic acid To a solution of methyl 3-2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylbenzoate (50 mg, 0.0001 mol) (prepared as in Example 61) in methanol (2 mL, 0.05 mol), lithium hydroxide (1 mg, 0.0001 mol) in water (1 mL, 0.06 mol) was added slowly. Water was added and also some IN HC1 was added until the solution was slightly acidic. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated to give 3-(2-cyano-l-[4-(7-[2-(trimethylsiIyl)ethoxy]- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)benzoic acid as a crude residue (35 mg, 72.0%). MS (ES): 489 (M+l). Step 2: 3-[3-(Morpholine-l-ylcarbonyl)phenyl]-3-[4-(7~{[2-(trimethylsilyl)ethoxy]methyl}- 7H- pyrrolo[2,3-d]pyrimidine-4-yl)-lH-pyrazole-l-yl]propanenitrile To a solution of 3-(2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)benzoic acid (40 mg, 0.00008 mol) in DMF (1 mL, 0.01 mol), N)N-N,N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluqrophosphate (36 mg, 0.000095 mol) and DIPEA (30 L, 0.0002 mol) were added. The reaction was stirred for 10 minutes and then morpholine (10 mg, 0.00012 mol) was added and the resulting mixture was stirred for 3 hours. Water was added and the product was extracted with ethyl acetate. The combined organic extracts were washed with IN HC1, brine, dried over magnesium sulfate, filtered and concentrated to give 3-[3- (morpholine-l-ylcarbonyl)phenyl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3- d]pyrimidine-4-yl)-lH-pyrazole-l-yl]propanenitrile as a crude (40 mg, 88%) product. MS (ES): 558 (M+l). Step 3: 3-[3-(Morpholin-4-ylcarbonyI)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l - yl]propanenitrile trijluoroacetate Using A procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was isolated as an amorphous white solid (18 mg, 50 %). 1H NMR (400 MHz, DMSO): 5. 9.05 (s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 7.85 (b, 1H), 7.665 (s, 1H), 7.55- 7.35 (m, 3H), 7.15 (s, 1H), 6.15 (m, 1H), 3.85 (m, 1H), 3.65-3.4 (m, 6H), 3.25 (m, 2H), 3.05 (m, 1H); MS(ES): 428 (M+l). Step 1: 3-(5-Phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsllyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yljpropanenitrile To a solution of 3-(5-biomopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrunidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (from Example 429) (60 mg, 0.0001 mol) in 1,4-dioxane (2 mL, 0.02 mol), phenylboronic acid (15 mg, 0.00012 mol) and sodium bicarbonate (30 mg, 0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resulting mixture was degassed using nitrogen. Tetrakis(triphenylphosphine)palladiuni(0) (10 nig, 0.00001 mol) was added and nitrogen was bubbled through the reaction again. The reaction was heated at 80 °C in oil bath for lhour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+l). Step 2: 3-(5-Phenylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile trifluoroacetate Using a procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was isolated as an amorphous white solid (20 rng, 40 %). 1H NMR (400 MHz, DMSO): 5. 9.15 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.22 (s.lH), 7.85 (b, 1H), 7.67 (m, 2H), 7.45(m 2 H), 7.43 (m, 1H), 7.15 (s, 1H), 6.25 (m 1H), 3.95 (dd, 1H), 3.80 (dd, 1H), 3.0 (m, 1H); MS (ES): 392.1 (M+l) Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pytrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- 3-5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitrile To a solution of 3-(5-1bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (from Example 429) (0.080 g, 0.00015 mol) in TEA (0.300 mL, 0.00215 mol) was degassed with nitrogen, and then copper(I) iodide (0.005 g, 0.00003 mol), (trimethylsilyl)acetylene, and bis(triphenylphosphine)palladium(II)chloride were added. The reaction mixture was sealed in a tube and stirred at room temperature overnight. The resulting black solution was partitioned between water (10 mL) and ethyl ether. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pvrimidin-4-yl)-l H-pyrazol-1 -yl]-3- 5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitriie as a yellow oil (60 mg,72.6), LCMS (M+1H:542). Step 2: 3-(5-EthynyIpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4~yl)-lH-pyrazol-l-yl]propane- nitrile trifluoroacetate 3-[4-(7-t2-(Trimethylsilyi)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-r- yl]-3-5-[(trimethyIsilyl)ethynyl]pyridin-3-ylpropanenitrile (0.050 g, 0.000092 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol). The reaction mixture was stirred at room temperature, for 90 minutes and was concentrated in vacuo. The dry residue dissolved in methanol cooled in an ice bath and a solution of potassium hydroxide (0.482 g, 0.00859 mol) in methanol (10 mL, 0.2 mol) was added. The reaction solution was stirred for 30 mm was concentrated and the crude product was purified by preparative HPLC eluting with a water: ACN gradient with 0.2% TFA, to give the title compound as a white amorphous solid (15 mg, 35.85%). LCMS (M+l)+:340, 'H NMR (400 MHz, DMSO-dg): 5. 12.1(bs, 1H), 9.02(s, 1H), 8.80(s, 1H), 8.70(m, 2H), 8.48(s, 1H), 8.00(s, IH), 7.80(d, 1H), 7.15(d, 1H), 6.20(m, 1H), 4.82(s, 1H), 3.90(m, 1H), 3.70(m, 1H). Stepl: 3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile To the 3-(5-bromopyridm-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), bis(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3h. The-reaction mixture was diluted with ethyl acetate, washed with water (2X), brine (IX), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated-with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z = 554.2. Step 2: 3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile trifluoroacetate The 3-[5-(phenylthio)pyridin-3-yl]0-[4-(742-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (0.110 g, 0.000199 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol), and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo, and the resulting residue was dissolved in raethanol (5.0 mL, 0.12 mol), and ethylenediamine (0.1 mL, 0.002 mol) was added. This reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the crude product was purified by LCMS ( pH=2) to yield the title compound as an amorphous solid (62 mg, 58.07%). 'H NMR (400 MHz, DMSO): 5. 12.80 (s), 9.10 (s) 8.87(d), 8.60 (s), 8.50 (s), 8.43 (s), 7.82 (s), 7.78 (m), 7.39 (m), 7.25 (m), 7.18 (d), 6.20 (m), 3.84 (m), 3.70 (m). LC/MS (M+H)+: m/z = 424.15 Step 1: 4-(5-Bromopyridin-3-yl)morpholine To a solution of [3,5-dibromopyridine (1000 mg, 0.004 mol) in 1,4-dioxane (8 mL, 0.1 mol), morpholine (400 mg, 0.004 mol) and sodium terf-butoxide (400 mg, 0.004 mol) were added. The reaction was bubbled with nitrogen. Tetrakis(triphenylphosphine)palladiuin(0) (200 mg, 0.0002 mol) was added and nitrogen was bubbled through for couple of minutes. The mixture was heated at 80 °C overnight. The reaction was allowed to cool to rt and was then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a crude residue. The crude product was purified by FCC on silica gel eluting with 1:1, EtOAC:Hexane gave to give 4-(5-bromopyridin-3-yl)morpholine as a viscous oil (400 mg, 40 %). 'H NMR (400 MHz, CDC13): 6. 8.2 (s, 1H), 8.1 (s, 1H), 7.2 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H). A solution of 4-(5-bromopyridin-3-yl)morpholine (100 mg, 0.0004 mol) in ether (2 mL, 0.02 mol) cooled at -78 "C was treated with 2.5 M n-butyllithium in hexane (0.2 mL) and was stiired for lh. To this mixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 5-morpholin-4- ylnicotinaldehyde (70 mg, 90%) as a crude product. 'H NMR (400 MHz, CDC13): £ 10.1 (s, 1H), 8.0 (s, 2H), 7.6 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H). Step 3: (2E)-3-(5-Morpholin-4-ylpyridin-3-yl)acrylonitrile To a solution of diethyl cyanomethylphosphonate (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) cooled at 0 °C was added 1.0 M potassium tert-butoxide in THF (0.50 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature over 30 minutes. The reaction was cooled to 0 °C and a solution of 5-morpholin-4-ylnicotinaldehyde (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was stirred at room temperature for 4 h, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (2E)-3-(5- morpholin-4-ylpyridin-3-yl)acrylonitrile (75 mg, 100%) as a mixture of isomers; LC/MS: 216 (M+l). Step 4: 3-(5-Morpholin-4-ylpyHdin-3-yl)-3-[4-(7-[2-(trimethyMlyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-JH-pyrazol-l-yl]propanenitrile To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3-(5-morpholin-4-yIpyridin-3- yl)acrylonitrile (70 mg, 0.0003 mol) ( mixture of isomers), DBU (50 L, 0.0003 mol) was added and the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitriIe (200 mg, 100%) as a crude product; L/MS = 531 (M+l). Step 5: 3-(5-Morpholin-4-ylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-ylJ- propanen itrile Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (18 mg, 50 %). 1H NMR (400 MHz, DMSO): & 8.8 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.4 (m, 1H), 6.9 (d, 1H), 6 (m, 1H), 3.8 (dd, 1H), 3.7(m, 4H), 3.6 (dd, 1H), 3.1 (m, 4 H); LC/MS: 401(M+l). Example 496: 3-[5-(PhenyIsuIfinyI)pyridin-3-yll-3-[4-(7H-pyrroIo[2^-d]pyriniidiii-4-yl)-lH- pyrazol-1-yllpropanenitrile, and Example 497: 3-[5-(Phenylsulfonyl)pyridin-3-yI]-3-[4-(7H-pyrroIo [2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]propanenitrile To the solution of 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyriraidin-4-yl)-lH- pyrazo1-1-yl]propanenitrile trifluoroacetate (0.050 g, 0.000093 mol) from Example 488, Step 2, in THF (1.0 mL, 0.012 mol) was added MCPBA (0.022 g, 0.00013 mol) (0.031g of 77% in water), in a water ice bath. The reaction mixture was stirred for 1 h at room temperature. The crude products were purified by LCMS (pH=10). Two peaks were collected : # 1 - to yield 3-t5-(phenylsulfinyl)pyridin-3-yl]-344-(7H-pyrrolo[2)3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]propanenitrile (8 mg, 19.57%). 1H NMR (400 MHz, DMSO): 8. 12.1 (s), 8.89 (d), 8.80 (d), 8.70 (s), 8.62 (s), 8.40 (s), 8.19 (s), 7.70 (m), 7.58 (s), 7.42 (m), 6.90 (s), 6.20 (m), 3.82 (m), 3.65 (m). LC/MS(M+H)+:m/z = 440.0 # 2 - to yield 3-[5^henylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3Hl]pyrimidm-4-yl)-lH- pyrazol-l-yl]propanenitrile (21 mg, 50%). 1H NMR (400 MHz, DMSO): 5. 12.1 (s), 9.10 (s), 8.86 (m), 8.6 l(s), 8.40 (m), 7.98 (m), 7.62 (m), 7.58 (m), 6.90 (s), 6.20 (m), 3.82 (m), 3.65 (m). LC/MS (M+H)+: m/z = 456.0 Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]pentanal To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (100 mg, 0.0003 mol) in ACN (2 mL, 0.04 mol) and DBU (50 L, 0.0003 mol), the (2E)- pent-2-enal (4.0E1 mg, 0.00048 mol) in lml ACN was added drop wise. The reaction was stirred for 1 h, and then water was added and the resulting mixture extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the crude as the hydrated product form. LC/MS (M+H)+: m/z = 400. Step 2: 3-[4- (7-[2-(Trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l - yl]pentan-l-ol A mixture of [3-[4-(7-[2-(trunethylsilyl)ethoxy]memyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]pentanal (50 mg, 0.0001 mol) in methanol (2 mL, 0.05 mol) was treated with sodium tetrahydroborate (8 mg, 0.0002 mol). The mixture was stirred at room temperature for 1 h, and then water was added and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the desired product as an oil. LC/MS (M+H)+: m/z = 402. Step 3: Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compound was isolated as an amorphous white solid (6 mg, 20 %). 1H NMR (400 MHz, DMSO): $ 8.65 (d, 1H), 8.60 (d, 1H), 7.55 (s, 1H), 6.95 (s, 1H), 4.50 (b, 1H), 4.4 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.1 (m, 1H), 1.8-2.0 (m, 3H), 0.7(t, 3H); LC/MS (M+H)+: m/z = 272. Example 499: Methyl 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl]pentyl carbonate Step 1: Methyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]pentyl carbonate To a solution of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl]pentan-l-ol (50 mg, 0.0001 mol) from Example 498 Step 2 in pyridine (1 mL, 0.01 mol), methyl chloroformate (30 L, 0.0003 mol) was added. The reaction was stirred for 3h, water was added and the product was extracted with ethyl acetate. The combined organic layers were washed IN HC1, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 3-[4- (7-[2-(trimethylsilyl)ethoxy]methyl-7H-pvn-olo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yljpentyl carbonate as a semisolid residue (30 mg, 50%). LC/MS (M+H)+: m/z = 460. Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (8 mg, 20 %). 'H NMR (400 MHz, DMSO): 5 . 12.0 (b, 1H), 8.65 (d, 1H), 8.35 (s, 1H), 7.65 (b, 1H), 7.600 (s, 1H), 7.0 (s, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (s, 3H), 2.1 (m, 1H), 2.2 (m, 1H), 1.95 (m7 2H), 0.75 (t, 3H); LC/MS (M+H)+:m/z = 330. Step 1: (lE)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]meti^l-7H-pyrrolo[2,3Hl]pyrimidin-4-yl)-IH-pyrazol- 1-yljpentanal oxime To a solution of 3-[4-(7-[2-(trimethylsilyl)emoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl]pentanal (60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05 mol) was added hydroxylamine hydrochloride (16 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (lE)-3-[4-(7-[2-(trimethyl- silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanal oxime as a semisolid residue (50 mg, 80%). LC/MS (M+H)+: m/z = 415. Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid. 1H NMR (400 MHz, DMSO): £ 12.0 (b, 1H), 8.6 (m, 2H), 8.2 (m, 1H), 7.5 (d, 1H), 7.1 and 6.5 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.6-2.8 (m, 2H), 1.8 (m, 2H), 0.65 (t, 3H); LC/MS (M+H)+: m/z = 285. Example 501(a): (lE)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanaI O- metbyloxime, and Example 502(a): (lZ)-3-[4-(7H-Pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]pentanal O- methyloxime Step 1: (lE)-3-[4-(7-[2-(Tnmethylsilyl)ethoxy]methyl-7H-pynolo[2,3]pyrimidin-4-yl)-lH-pyrazol- l-yllpentanal O-methyloxime and (1Z)-3-f4-(7-f2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolof2J-dJpyrimidin-4-yl)-1H-pyrazol-l- yljpentanal O-methyloxime To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyirolo[2,3-d]pyrimidin-4-yI)- lH-pyrazol-l-yl]pentanal (70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added methoxylamine hydrochloride (19 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, was filtered and was concentrated to give 3-[4-(7-[2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljpentanal O-methyloxime as a mixture of isomers (70 mg, 90%) crude product. LC/MS (M+H)+: m/z = 429. Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (4 mg, 25 %). Isomer 1, !H NMR (400 MHz, DMSO): 8. 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s, 1H), 7.3 (t, 1H), 7.0 (s, 1H), 4.6(m, 1H), 3.3 (s, 3H), 2.8 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/S (M+H)+: m/z = 299.1somer 2 (3 mg, 22%), H NMR (400 MHz, DMSO): 5 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s, 1H), 7.0 (s, 1H), 6.7 (t, 1H), 4.5(m, 1H), 3.3 (s, 3H), 2.8-3.0 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/MS (M+H)+: m/z = 299. Example 503: 4-[l-(4,4-Dibromo-l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d)- pyrimidine trifluoroacetate Step 1: 4-[l-(4,4-Dibromo-l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-dJpyrimidine To a solution of 3-[4-(7-[2-(trimethylsilyl)elhoxy]methyl-7H-pynx)lo[2,3-d]pyriniidin-4-yl)- lH-pyrazol-l-yl]pentanal (300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0 °C, triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg, 0.002 mol) were added. The reaction was stirred at 0 °C for 10 min, water was added and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by prep LC-MS (ACN, water, NHUOH) to give 4-tl-(4,4-dibromo-l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as an amorphous solid (50 mg, 10%).1H NMR (400 MHz, CDC13): 5 . 8.9 (s, 2H), 8.4 (s, 1H), 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H), 6.4 (m, 1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m, 1H), 2.0 (m, 1H), 1.0 (m, 5H), LC/MS (M+H)+: m/z = 556 Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (8 mg, 40 %). 'H NMR (400 MHz, DMSO): 8. 8.8 (s, 2H), 8.4 (s, 1H), 7.7 (b, 1H), 7.2 (b, 1H), 6.5 (t, 1H), 4.4 (m, 1H), 2.6 (m, 2H), 1.8 (m, 2H), . 0.8 (t, 3H); LC/MS (M+H)+: m/z =: 426. Example 506: 4-[l-(l-EthyIbut-3-yn-l-yl)-lH-pyrazol-4-ylI-7H-pyrrolo[2,3-d]pyrimidinc trifluoroacetate. Step 1:4-[l-(l-Ethylbut-3-yn-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidine A solution of 4-[l-(4,4-dibromo-l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)- ethoxy]methyl-7H-pyirolo[233-d]pyrimidine (20 mg, 0.00004 mol) (from Example 503 Step 1) in THF (1 mL, 0.01 mol) at -78 °C was treated with 2.5 M n-butyllithium in hexane (0.032 mL). The mixture was stirred at -78 °C for lh and then at room temperature for lh. The reaction was quenched with water (1 mL, 0.06 mol) and IN HC1. The reaction was partitioned between water and ethyl acetate. The organic extract was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-[l-(l-ethylbut-3-yn-l-yl)-lH-pyrazol-4-yl]-7-[2-(tri- methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a semisolid (12 mg, 80%). LC/MS (M+H)+:m/z = 396. Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (4 mg, 30 %). 1H NMR (400 MHz, DMSO): £ 12.2 (b, 1H), 8.8 (s, 2H), 8.4 (s, 1H), 7.6 (s, 1H), 7.1 (s, 1H), 4.4 (m, 1H), 2.8 (m, 3H), 1.9 (m, 2H), 0.8(t,3H);LC/MS(M+H)+:m/z= 266. Example 516: (R)-3-[3-(Ethylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]propanenitrile, and (S)-3-[3-(EthylsuIfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- Step 1: l-Bromo-3-(ethylthio)benzene Iodoethane (0.46 mL, 0.0058 mol) was added to a suspension of 3-bromothiophenol (0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) and potassium carbonate (2.0 g, 0.014 mol). The reaction was stirred for 2 h at rt, was diluted with ethyl acetate and filtered to remove the solids. The reaction was concentrated in vacuo to give 1 -bromo-3-(ethylthio)benzene as a colorless oil 1.0 gm, 100% Step 2: l-Bromo-3-(ethylsulfonyl)benzene The MCPBA (2.37 g, 10.6 mmol) was added to a solution of l-bromo-3-(ethylthio)benzene (1.00 g, 4.80 mmol) in DCM (10 ml, 156 mmol) cooled to 0 °C. The reaction was stirred for 1 h and then was dilated with water and extracted with ethyl acetate three times. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude residue was purified by flash column chromatography with a hexane: ethyl acetate gradient to give 1 -bromo- 3-(ethylsulfonyl)benzene as a colorless oil 1.1 gm 92%, 'H NMR (300 MHz, CDC13): £8.09(m, 1H), 7.85(d,lH), 7.78(d, 1H) 7.45(t,lH), 3.14(q, 2H), 1.25(t, 3H). Step 3: (2E&Z)-3-[3-(Ethylsulfonyl)phenyl]acrylonitrile l-Bromo-3-(ethylsulfonyl)benzene (1.3 g, 0.0052 mol) was dissolved in the DMF (15.0 mL, 0.194 mol) and 2-propenenitrile (0.68 mL, 0.010 mol), TEA (1.4 mL, 0.010 mol) and triphenylphosphine (0.23 g, 0.00089 mol) were added. The resulting solution was degassed with nitrogen, and palladium acetate (0.07 g, 0.0003 mol) was added. Again the reaction was degassed with nitrogen and then heated to 110 °C in a sealed tube for 8 hrs. The reaction was complete by HPLC, and was then allowed to cool to rt and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The product was purified by FCC on silica gel eluting with a hexane; ethyl acetate gradient to give (2E&Z)-3-[3- (ethylsulfonyl)phenyl]acrylonitrile as an amber oil (1.1 gm, 92%) LC/MS (M+H)+: m/z = 222. Step 4: 3-[3-(Ethylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrinudin-4-yl)-lH-pyrazol-l-yl]propanenitrile The (2E&Z)-3-[3-(ethylsulfonyl)ph6nyl]acrylonitrile (1.0 g, 0.0045 mol) was combined with 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsiIyI)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 0.0041 mol) and DBU (0.61 mL, 0.0041 mol) in ACN (10.0 mL, 0.191 mol) under nitrogen at rt. The reaction was stirred at rt for 24 h. This was partitioned between ethyl acetate and water, and 0.1N HC1 was added to adjust the pH to 7. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give a crude oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to give 3-[3-(ethylsulfonyl)phenyl]-3-[4-(7-[2- (trimethylsilyl)emoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yljpropanenitrile as an oil (1.5 gm, 68%). LC/MS (M+H)+: m/z = 537. The oil was a racimate, which was separated by chiral column chromatography (Chiracel OD-H, eluting with ethanol: methanol: hexane 30:30:40, Rt 13,2 and 17.1 minutes) to give the two enantiomers, each as a glass (0.51 gm) LC/MS (M+H)+: m/z = 537, 'H NMR (300 MHz, CDC13): 5 8.89(s, 1H), 8.45(s, 1H), 8.35(s,lH), 8.09(s, lh), 8.05(d, 1H), 7.75(d, 1H), 7.71(t, 1H), 7.45(d, 1H), 6.83(d, 1H), 5.85(t, 1H), 5.75(s, 2H), 3.78-3.42(m, 4H), 3.18(m, 2H), 1.35(t, 3H), O.97(t, 2H), 0.05(s, 9H). Step 5: Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compounds were prepared to give isomer #1 as an amorphous white solid (300 mg, 80 %). H NMR (400 MHz, DMSO): S 9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1 (s, 1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)+: m/z = 407. Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compounds were prepared to give isomer #2 as an amorphous white solid (300 mg, 80 %). JH NMP (400 MHz, DMSO): 8. 9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1 (s, 1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)+: m/z = 407. Step 1: 4-[l-(l-Ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(triTnethylsilyl)ethoxy]methyl-7H-pyrrolo- [2,3-dJpyrimidine To an ice cooled solution of methyl triphenylphosphonium bromide (100 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added 0.5 M potassium bis(trimethylsilyl)amide in toluene (0.8 mL). The mixture was stirred for lh at 0 °C ice bath, and was then cooled to -78 °C and treated with 3-[4-(7-[2- (trimethylsilyI)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]pentanal (80 mg, 0.0002 mol) (from Example 498). The reaction was stirred at -78 °C and gradually was warmed to room temperature overnight. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-[l-(l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidine 150 mg as a crude product. LC/MS = 398 (M+l). Step 2: 4-[l-(l-Ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compound was isolated as an amorphous white solid (25 mg, 1%). 'H NMR (400 MHz, DMSO): 5. 8.6 (s, 2H), 8.2 (s, 1H), 7.4 (s, 1H), 6.9 (s, 1H), 5.8 (m, 1H), 5.0 (dd, 2H), 4.2 (m, 1H), 2.4-2.6 (m, 2H), 1.7-1.9 (m, 2H), 0.6 (t, 3H); LC/MS: 268 (M+l). Step 1. 4-Chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloropyrrolo[233-d]pyrimidine (2.00 g, 0.0130 mol) and ethyl orthoformate (25 mL, 0.15 mol) was heated to reflux for 2 hours. The solvent was evaporated, and the residue was purified by flash column chromatography (eluting with ethyl acetate/hexanes) to yield the desired product (1.13 g, 34%). 1H NMR (400 MHz, CDC13): 5 8.63 (s, 1H), 7.58 (d, 1H), 6.71 (s, 1H), 6.65 (d, 1H), 3.77-3.67 (m, 2H), 3.58-3.49 (m, 2H), 123 (t, 3H), 1.23 (t, 3H). Step 2. 7-(Diethoxymethyl)-4-(lH-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine To a degassed solution of 4-chloro-7-(diethoxvmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.13 g, 0.00442 mol) and l-(triisopropylsilyl)-3-boronic acid (1.00 g, 0.00374 mol) and sodium carbonate (0.396 g, 0.00374 mol) in 1,2-dimethoxyethane (15 mL) and water (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.00019 mol). This mixture was stirred at ambient temperature for 2 hours, and then was heated to reflux for 4 hours. The mixture was then cooled, concentrated, and purified by flash column chromatography (eluting with ethyl acetate/hexanes) to afford a residue as an oil. ACN was added to the residue, and the product which precipitated was filtered off and washed with a small quantity of ACN (165 mg, 13%). 'H NMR (400 MHz, Dg-dmso): § 11.44 (or s, 1H), 8.66 (s, 1H), 7.80-7.78 (m, 1H), 7.58 (d, 1H), 7.03 (d, 1H), 6.94 (dd, 1H), 6.90 (dd, 1H), 6.75 (s, 1H), 3.74-3.65 (m, 2H), 3.59-3.50 (m, 2H), 1.15 (t, 6H); MS(ES): M+H = 287. Step 3. To a solution of 7-(diethoxvmethyl)-4-(lH-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.125 g, 0.436 mmol) and 4,4,4-trifluorobut-2-enenitrile (0.0476 mL, 0.480 mmol) in ACN (1 mL) was added DBU (0.0653 mL, 0.436 mmol). TFA (0.5 mL) was added and the mixture was stirred for 1 hour. The TFA and solvent was removed in vacuo. The residue was purified by preparative- HPLC/MS (C-18 eluting with a gradient of H2O/ACN containing 0.15% NH4OH) to afford the product (102 mg, 76%). Where desired, the enantiomers were separated in substantially pure form by chiral HPLC (AD-H, 20% EtOH/Hexane). 1H NMR (300 MHz, D6-dmso): 8 12.05 (br s, 1H), 8.65 (s, 1H), 8.04 (s, 1H), 7.56 (dd, 1H), 7.21 (t, 1H), 7.02 (dd, 1H), 6.93 (dd, 1H), 5.89-5.74 (m, 1H), 3.95 (dd, 1H), 3.66 (dd, 1H); MS(ES): M+H = 306. The analog in Table 12 was prepared in racemic form according to the same procedure, using a different conjugate acceptor and with the exception that in the conjugate addition in Step 3, the reaction was carried out at 40 °C for 3 days. Step 1: 4-[(3-Bromophenyl)sulfonyl]morpholine Morpholine (0.19 mL, 0.0022 mol) in 1.0 ml of THF was added dropwise to a solution of 3- bromobenzenesulfonyl chloride (0.3 mL, 0.002 mol) and TEA (0.30 mL, 0.0022 mol) in dry 4.0 mL of THF cooled in an ice bath. The reaction mixture was stirred overnight at room temperature and was then partitioned between 0.05N HC1 and ethyl acetate. The organic layer was washed with water (2X), and brine (IX), and was then dried over anhydrous magnesium sulfate, filtered and then was concentrated in vacuo to give 4-[(3-bromophenyl)sulfonyl]morpholine as a white crystalline product (470mg,78%). LCMS (M+H)+: m/z= 306,308. Step 2: (2E&Z)-3-[3-(Morpholin-4-ylsulfonyl)phenyl]acrylonitrile The 4-[(3-bromophenyl)sulfonyl]morpholine (0.250 g, 0.000816 mol) was dissolved in dry DMF (2.5 mL, 0.032 mol) and the mixture was degassed using a stream of nitrogen. To this mixture ' was added TEA (0.23 mL, 0.0016 mol), 2-propenenitrile (0.11 mL, 0.0016 mol), palladium acetate (0.011 g, 0.000049 mol), and triphenylphosphine (0.0364 g, 0.000139 mol) and again the mixture was degassed with nitrogen. The reaction mixture in a sealed tube was heated at 110 °C for 16 hours. The reaction mixture, after cooling to room temperature, was partitioned between 0.05N HC1 and ethyl acetate. The organic layer was washed with water (2X), and brine (IX), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacua, to give (2E&Z)-3-[3-(morpholin-4-yl- sulfonyl)phenyl]acrylonitrile as an oil (0.240gm, 85%) which was a mixture of cis and trans isomers. LCMS (M+H)+: m/z - 279. Step 3: 3-[3-(Morpholin-4-ylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyI-7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljpropanenitrile To a mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (0.100 g, 0.000317 mol) and (2E&Z)-3-[3-(morpholin-4-ylsulfonyl)phenyl]acrylonitrile (0.097 g, 0.00035 mol) in dry ACN (2.0 mL, 0.038 mol) was added DBU (0.095 mL, 0.00063 mol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phase was washed with water (2X), and brine (IX), dried over magnesium sulfate, filtered and then concentrated in vacuo to give the crude product. The crude product was purified by silica gel flash column chromatography using ethyl acetate-hexanes (6:4) as an eluent to give 3-[3-(morpholin-4-ylsulfonyl)phenyl]-3-[4-(7- [2-(trimethylsilyl)ethoxy]memyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile as a viscous oil (62 mg, 32.94%). LCMS (M+H)+: m/z = 594 Step 4: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (30 mg, 63.84%. LCMS (M+H)+: m/z = 464. 1H NMR (400 MHz, DMSO-d6): 8 8.88 (s), 8.62 (s), 8.1(s), 7.78(m), 7.70(m), 7.58(m), 6.95(m), 6.20(m), 3.84(m), 3.70(m),3.45(m), 2.78(m). Example 679: cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexyl- acetonitrile Step 1: 4-(Hydroxymethyl)cyclohexanol. Ethyl 4-oxocyclohexanecarboxylate (2.0 g, 0.012 mol) was dissolved in ether (20.0 mL) and was then cooled at 0 °C Into the mixture was added 1 M lithium tetrahydroaluminate in ether (20 mL) and the resulting mixture was stirred at 0 °C for 2 hours. The reaction was quenched with water (2 mL) and 1 N NaOH (2 mL) and ether was added (100 mL). The precipitated solids were filtered off and the residue was used in the next reaction. 1H NMR(CDC13):6 4.02 and 3.75 (m, 1H), 3.45-3.61 (m, 2H), 2.02 (m, 2H), 1.84 (m, 1H), 1.52-1.80 (m, 2H), 1.44 (m, 1H), 1,32 (m, 2H), 1.03 (m, 1H). Step 2: 4-[(Trityloxy)methylJcyclohexanol. 4-(Hdroxymethyl)cyclohexanol (2.0 g, 0.015 mol) was dissolved in pyridine (15.0 mL) and the mixture was cooled to 0 °C. To the reaction was added triphenylmethyl chloride (4.7 g, 0.017 mol) and the resulting mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. The reaction was then concentrated using a rotory evaporator, and the concentrate was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The reaction was chromatographed on silica gel using 30% EtOAc/hexanes to give the cis isomer (0.74 g) 1H NMR(CDC13):5 7.52 (m, 6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (m, 2H), 1.21-1.68 (m, 9H); and the trans isomer (2.72 g) 'H NMR(CDC13):8 7.44 (m, 6H), 7.20-7.31 (m, 9H), 3.54 (m, 1H), 2.88 (m, 2H), 1. 98 (m, 2H), 1.88 (m, 2H), 1.60 (m, 1H), 0.99-1.37 (m, 4H). Step 3: trans-4-[(Trityloxy)methyl]cyclohexyl methanesulfonate. trans-4-[(Trityloxy)methyl]cyclohexanol (2.72 g, 0.00730 mol) was dissolved in chloroform (30.0 mL) and the mixture was cooled at 0 °C To this mixture was added TEA (1.4 mL, 0.010 mol) and methanesulfonyl chloride (0.68 mL, 0.0088 mol) and the resulting mixture was stirred at 0 °C for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and the concentrated in vacuo. 'H NMR (CDC13):5 7.43 (m, 6H), 7.20-7.31 (m, 9H), 4.57 (m, 1H), 3.00 (m, 3H), 2.90 (m, 2H), 2.16 (m, 2H), 1.93 (m, 2H), 1.09-1.60 (m,5H). Step 4: 7-[2-(Trimethylsilyl)ethoxy)methyl-4-(l-cis-4-[(trityloxy)methyl]cyclohexyl-lH^ 7H-pyrrolo[2,3-d]pyrimidine. 4 0.0048 mol) was mixed with sodium hydride (0.34 g, 0.0086 mol) and trans-4- [(trityloxy)methyl]cyclohexyl metbanesulfonate (3.00 g, 0.00666 mol) and the mixture was cooled to -78 °C To this mixture was added DMF (8.3 mL) and the mixture was allowed to warm to 25 °C and was stirred for 20 minutes. The wanned mixture was stirred at 55 °C for 48 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The concentrate was chromatographed on silica gel using 40% EtOAc/hexanes to give the product. LC/MS (M+H)+: 670, 1H NMR(CDC13):5 8.89 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 6.84-7.51 (m, 10H), 6.87 (d, 1H), 5.73 (s, 2H), 4.39 (m, 1H), 3.60 (m, 2H), 3.12 (m, 2H), 1.76-2.11 (m, 9H), 0.96 (m, 2H), 0.00 (s, 9H). Step 5: cis-4-[4~(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2J-dJpynmidin-4-yl)-lH-pyrazol-l- yljcyclohexylmethanol. 7-[2-(Trimethylsilyl)ethoxy]methyl-4-(l-cis-4-[(trityloxy)methyl]cyclohexyl-lH-pyrazoI-4- yl)-7H-pyrrolo[2,3-d]pyrimidine (0.3 g, 0.0004 mol) was dissolved in methanol (7.0 mL) and THF (2.0 mL, 0.025 mol) and 4.0 M HC1 in 1,4-dioxane (0.5 mL) was added. The reaction was then stirred at 25 °C for 2 hours TLC analysis showed no starting material present and LCMS analysis showed the presence of the product. The reaction was added to a saturated NaHCO3 solution and was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSCXt) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 428 1H NMR (CDC13):5 8.89 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H), 5.73 (d, 2H), 4.41 (m, 1H), 3.51-3.71 (m, 4H), 2.31 (m, 2H), 2.08 (m, 3H), 1.70-1.93 (m, 4H), 0.98 (m, 2H), 0.00 (s, 9H). Step 6: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3^]pyrimidin-4-yl)-lH-pyrazol-l- yl]cyclohexylmethyl methanesulfonate. cis-4-[4-(7-[2-(Trimemylsilyl)emoxy]methyl-7H-pyrTolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol- l-yl]cyclohexylmethanol was dissolved in chloroform (3.00 mL) and was cooled to 0 °C To the reaction was added TEA (0.10 mL, 0.00072 mol) and methanesulfonyl chloride (0.05 mL, 0.0006 mol) and this mixture was stirred at 0 °C for 2 hours at which time LCMS analysis showed mainly the product present in the mixture. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. LC/MS (M+H)+: 506 Step 7: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]metkyl-7H-pyrrolo[2,3^Jpyrimidin-4-yl)-lH-pyrazol-l- yl] cyclohexylacetonitrile. cis-4-[4-(7-[-2-(TriethylsilyOethoxylmethyl-TH-pyrrolo[2,3,4]pyrimidin-4y1)-lH-pyrazol- l-y]]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) and sodium cyanide (0.050 g, 0.0010 mol) and DMSO (1.0 mL) were mixed. The mixture was stirred at 60 °C for 24 hours, at which time LCMS analysis showed most of the starting material had been consumed. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LCMS (M+H)+: 437, 1H NMR(CDC13):5 8.90 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.43 (m, 1H), 3.60 (m, 2H), 2.45(d, 2H, J = 7.6 Hz), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H). Step 8: cis-4-[4-(7H-Pyrrolo[2,3-d]pyritnidin-4-yl)-lH-pyrazol-l-ylJcyclohexylacetonitrile. cis-4-[4-(7-[2-(Trimethykilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrirnidin-4-yl)-lH-pyrazol- l-yl]cyclohexylacetonitrile (0.080 g, 0.00018 mol) and TFA (0.50 mL, 0.0065 mol) were added to DCM (3.00 mL, 0.0468 mol) and the mixture was stirred at 25 °C for 16 hours. The reaction was concentrated by roto-evaporation and the concentrate was dissolved in raethanol (3.0 mL, 0.074 mol) and ammonium hydroxide (0.5 mL, 0.01 mol) was added This reaction was stirred at 25 °C for 6 hours at which time LCMS analysis showed no starting material present. The reaction was chromatographed on silica gel using 5% MeOH/EtOAc to give the product. LCMS (M+H)+:307, 'H NMR(CD3OD):5 8.64 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.42 (m, 1H), 2.61(d, 2H, J = 8.0 Hz), 2.27 (m, 2H), 1.70-2.15 (m, 7H). Step J: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxyJ]methyl-7H-pyrrolo[2,3-d]pyrimidin4--yl)-lH-pyreaol-l- yl]cyclohexylmethyl thiocyanate cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- l-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) was dissolved in DMSO (1.00 mL) with potassium thiocyanate (0.082 g, 0.00084 mol). The reactioa was heated at 68 °C for 4 days at which time LCMS analysis showed ~4:1 product/starting material ratio. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (M+H)+: 469, 1H NMR(CDC13):5 8.89 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (m, 1H), 3.60 (m, 2H), 3.05 (m, 2H), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H). Step 2: cis-4-[4-(7H-PyrTolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl thiocyanate). cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrinnidin-4-yl)-lH-pyrazol- l-yl]cyclohexylmethyl thiocyanate was dissolved in methanol (2.0 mL, 0.049 mol) and DCM (2.0 mL, 0.031 mol), and TFA (0.5 mL, 0.006 mol) was added. The resulting mixture was stirred at 25 °C for 16 hours. TLC analysis showed no starting material present and LCMS analysis showed product. The reaction was concentrated using a rotary evaporator and the concentrate was chromatographed on silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+H)+:339, 1H NMR(CD3OD) 6 8.65 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.43 (m, 1H), 3.20 (d, 2H, J = 7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H). Step 1: 5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrmiditdin -4-0-1H pyrazol-l-yl]cyclohexylmeikyl)thio]-4H-l,2,4-triazol-3-amin cis-4-[4-(7-t2-(Trimethylsilyl)ethoxy]methyl-7H-pynrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- l-yl]cyclohexylmethyl methanesulfonate (124.56 mg, 0.00024 mol), and 5-amino-4H-l,2,4-triazole- 3-thiol (43.00 mg, 0.0003702 mol) were dissolved in DMF (1.20 mL) and potassium carbonate (0.122 g, 0.000887 mol) was added. The reaction was stirred at 50 °C for 18h, at which time LCMS showed nearly complete reaction, and product present. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4,) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 526, 1H NMR(CDC13):8 8.90 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41 (m, 1H), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H), 1.70-2.10 (m,7H), 0.98 (m,2H), 0.00 (s,9H). Step 2.- 5-[(cis-4-[4-(7H-Pyrrolo[2,3^Jpyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohe^lmethyl)thioJ-4H^ 1,2,4-triazol-3-amine 5-[(cis-[4-(742-(TrimethyIsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazoI-l-yl]cyclohexylmethyl)thio]-4H-l,2,4-triazoll-3-amine (9a) was dissolved in TFA (1 mL) and was stirred for 2h. The solution was concentrated using a rotary evaporator to remove TFA. The residue was dissolved in methanol (1 mL) and ammonium hydroxide (I mL) added. The solution was stirred overnight. LCMS showed complete de-protection. The solution was concentrated using a rotary evaporator. The product was isolated by prep LCMS using a 30mm x 100mm C18 column; 11%CH3CN-H2O (0.1%TFA), 1.5 min, to 33% at 6 min; 60 mL/min; detector set at m/z 396; retention time, 5.5min (2 runs). The eluate was freeze dried. Yield 21 mg (di-TFA salt). LC/MS (M+H)+:396, 1HNMR (4,-DMSO) 8 12.9 (brs, 1H, NH); 8.9 (2 singlets, 2H); 8.5 (s, 1H); 7.9 (m, 1H); 7.3 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (d, 2H); 2.2 (m, 2H); 1.9 (m, 3H); 1.7 (m, 2H); 1.6 (m, 2H). MS(ES) 396 (M+l). Step J: N-5-((cis^-[4-(7-[2-(TrimethylsUyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidm-4-yl)-lH- pyrazol-l-yl]cyclohexylmethyl)thio]-4H'l,2,4-triazol-3-ylpyrimidin-2-amxne In a vial [A] 5-[(cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-lH-pyrazol-l-yl]cyclohexyhnethyl)thio]-4H-l,2,4-triazol-3-amine (0.047 g, 0.000089 mol) was heated with 2-chloropyrimidine (0.011 g, 0.000096 mol) in 1,4-dioxane (1.00 mL, 0.0128 mol) at ISO °C for 40 minutes in a microwave reactor. LCMS analysis showed that no reaction had taken place. To the reaction was added 2-chloropyrimidine (0.020 g, 0.00017 mol) with cesium carbonate (0.033 g, 0.00010 mol) and copper(I) iodide (4.00 mg, 0.0000210 mol) and this mixture was heated at 115 °C for 3 hours, at which time LCMS analysis showed no starting material present and mainly product was present. The reaction was chromatographed on silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+l)+:604, 'NMR(CDCl3): 8.89 (s, 1H), 8.82 m, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 7.44 (d, 1H), 7.23 (m, 1H), 7.03 (br s, 2H), 6.88 (d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 3.60 (m, 2H), 3.35 (d, 2H), 2.34 (m, 2H), 1.80-2.15 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H). Step 2: N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)thio]- 4H-1,2,4-triazol~3-ylpyrimidin-2-amine. N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy3methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH- pyrazol-l-yl]cyclohexylmethyl)thio]-4H-l,2,4-triazol-3-ylpyrimidin-2-amine (0.024 g, 0.000040 mol) was dissolved in DCM (4.00 mL), and TFA (0.50 mL, 0.0065 mol) was added. The reaction was stirred at 25 °C for 16 hours and was concentrated in vacuo. The residue was dissolved in methanol (3.00 mL) and concentrated ammonium hydroxide (0.50 mL) was added. This reaction was stirred at 25 °C for 2 hours at which time LCMS analysis showed mostly product. The reaction was concentrated using a rotary evaporator and the concentrate was purified by prep LC to give the product as the trifluoroacetate salt. LC/MS (M+H)+:474, 1H NMR(CD3OD) 8 8.87 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.79 (s, 1H), 8.45 (s, 1H), 7.85 (d, 1H), 7.34 (m, 2H), 4.43 (m, 1H), 3.20 (d, 2H, J = 7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H). Step 1: 2-(l,4-Dioxaspiro[4.5]dec-8-yl)ethanol. Ethyl l,4-dioxaspiro[4.5]dec-8-ylacetate (3.40 g, 0.0149 mol) prepared according to the procedure of Itagaki, Noriaki; Kimura, Man; Sugahara, Tsutomu; Iwabuchi, Yoshiharu. (Organic Letters 2005; 7(19); 4181-4183.) was dissolved in ether (30.00 mL) and the mixture was cooled to 0 °C. To the reaction was added 1.00 M lithium tetrahydroaluminate in ether (15.0 mL) and the resulting mixture was stirred at 0 °C for 60 minutes and at 25 °C for 2 hours. The reaction was cooled and water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL). To the reaction was then added ether (100.00 mL) and the solid that precipitated was filtered off. The filtrate was concentrated using a rotary evaporator to give the product. 1H NMR(CDCI3): 3.94 (s, 4H), 3.67 (t, 2H), 1.20-1.80 (m, 11H). Step 2: 4-(2-Hydroxyethyl)cyclohexanone. 2-(l,4-Dioxaspiro[4.5]dec-8-yl)ethanol (2.70 g, 0.0145 mol) was dissolved in acetone (10.00 mL) and THF (10.00 mL) and 6.00 M HC1 (6.00 mL) was added. The reaction was stirred at 25 °C for 16 hours, neutralized with NaHCO3 solution and was then extracted with ethyl acetate. The organic extracts were washed with water, and with saturated NaCl, then dried (MgSO4) and concentrated in vacua. The crude product was used in the next reaction without further purification. 1H NMR(CDC13): 3.75 { m, 2H), 2.36 (m, 4H), 1.20-2.13 (m, 7H). Step 3: 4-(2-Hydroxyethyl)cyclohexanol. 4-(2-Hydroxyethyl)cyclohexanone (2.00 g, 0.0141 mol) was dissolved in ether (30.00 mL) and was cooled at 0 °C. To the reaction was added 1.0 M lithium tetrahydroaluminate in ether (14.1 mL) and the resulting mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. To the reaction was added THF (20.00 mL) and this mixture was cooled at 0 °C and then water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL). To the reaction was then added ether (100.00 mL) and the resulting mixture was stirred for 10 minutes, then was filtered and the filtrate was concentrated using a rotary evaporator to provide the crude product. The crude product was used in the next reaction without further purification. 'H NMR(CDC13): 3.96 and 3.57 (m, 1H) minor and major CHOH (-1:5 ratio) 3.70(m, 2H), 0.94-2.02 (m, 11H). Step 4: 4-[2-(Trityloxy)ethyl]cyclohexanol. 4-(2-Hydroxyethyl)cyclohexanol (crude from the previous reaction) (1.88 g, 0.0130 mol) was dissolved in pyridine (20.00 mL) and was cooled at 0 °C. To the reaction was added triphenylmethyl chloride (4.0 g, 0.014 mol) and this mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. The reaction was concentrated using a rotary evaporator and the concentrate was extracted with ethyl acetate. The organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chrornatographed on silica gel (30%EtOAc/hexanes) to give the trans isomer (1.98 g) 1H NMR(CDC13): 7.42-7.45 (m, 6H), 7.20-7.30 (m, 9H), 3.50 (m, 1H), 3.07 (m, 2H), 1.93 (m, 2H), 1.66 (m, 2H), 1.17-1.60 (m, 5H)5 0.89 (m, 2H). Step 5: trans-4-[2-(Trityloxy)ethyl]cyclohexyl methanesulfonate. trans-4-[2-(Trityloxy)ethyl]cyclohexanol (1.95 g, 0.00504 mol) was dissolved in chloroform (40.00 mL) and the mixture was cooled to 0 °C. To the reaction was added TEA (0.98 mL, 0.0071 mol) and methanesulfonyl chloride (0.47 mL, 0.0060 mol) and this mixture was stirred at 0 °C for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, and saturated Nad, then dried (MgSO4) and concentrated in vacua. 'H NMR(CDC13): 7.41-7.45 (m, 6H), 7.20-7.32 (m, 9H), 4.55 (m, 1H), 3.07 (m, 2H), 2.10 (m, 2H), 1.70 (m, 2H), 1.20-1.60 (m, 5H), 0.95 (m, 2H). Step 6; 7-[2-CTrimethylsilyt)ethoxyJmethyl-4-(l-cis-4-[2-(trityloxy)ethylJcyclohexyl-lH-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine. 4-(lH-Pyrazol-4-yl)-7-[2-(triraethylsuyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrirnidine (1.0 g, 0.0032 mol) was mixed with sodium hydride (0.23 g, 0.0058 mol) and trans-4-[2- (trityloxy)ethyl]cyclohexyl methanesulfonate (2.10 g, 0.00452 mol) and this mixture was cooled to -78 °C. To the reaction was added DMF (6.00 mL) and this mixture was allowed to warm to 25 °C and was then stirred for 20 minutes. The reaction was stirred at 55 °C for 48 hours at which time LCMS analysis showed mostly product. The reaction was extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 40% EtOAc/hexanes to give the product. LC/MS (M+H)+:684, 'H NMR(CDC13): 8.89 (s, 1H), 8.35 (br s, 1H), 8.30 (s, 1H), 7.50 (m, 6H), 7.44 (d, IH), 7.27-7.32 (m, 9H), 6.87 (d, 1H), 5.73 (s, 2H), 4.33 (m, 1H), 3.60 (m, 2H), 3.17 (t, 2H), 1.50- 2.25 (m, 11H). 0.98 (m, 2H), 0.00(s, 9H). Step 7: 2-cis-4-[4-p-[2-(Trimethylsilyl)ethoxy]methyl-7H-pytrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- l-yljcyclokexylethanol (7b). 7-[2-(Trimethylsilyl)ethoxy]methyl-4-(l-cis-4-[2-(trityloxy)ethyl]cyclohexyl-lH-pyrazol-4- yl)-7H-pyrrolo[2,3-d]pyrimidine (1.45 g, 0.00212 mol) was dissolved in methanol (30.00 mL) and THF (10.00 mL) and 4.0 M HC1 in 1,4-dioxane (2.00 mL) was added. The mixture was stirred at 25 °C for 2 hours, at which time, TLC analysis showed no starting material present and LCMS analysis showed the presence of the product. The reaction was added into a saturated NaHCO3 solution, and was then extracted with ethyl acetate. The organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 442 Step 8: 2-cis-4-l4-(7-[2-(Trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- l-yl]cyclohexylethyl methanesulfonate (8b). 2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]cyclohexylethanol (0.89 g, 0.0020 mol) was dissolved in DCM (12.00 mL, 0.1872 mol) and was cooled at 0 °C To the reaction was added TEA (0.43 mL, 0.0031 mol) and methanesulfonyl chloride (0.19 mL, 0.0024 mol) and this mixture was stirred at 0 °C for 2 hours at which time LCMS analysis showed mainly product present. The reaction was extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. LCMS (M+H)+:520, 1H NMR(CDCl3): 8.90 (s, 1H), 8.38 (br s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 4.27 (t, 2H), 3.60 (m, 2H), 3.07 (s, 3H), 1.60-2.40 (m, 11H). 0.98 (m, 2H), 0.00(s, 9H) Step 9: 3^is-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylpropanenitrile trifluoroacetate (9b). 2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-yrrolo[2,3-]pyrimidin-4-yl)-lH- pyrazol-l-yl]cyclohexylethyl methanesulfonate (0.075 g, 0.00014 mol) was dissolved in DMSO (1.50 mL) and sodium cyanide (0.035 g, 0.00072 mol) was added. The reaction was stirred at 40 °C for 16 hours at which time LCMS analysis showed no starting material present. The reaction was then extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (3.00 mL) and TFA (0.50 mL, 0.0065 mol) was added. This mixture was stirred at 25 °C for 16 hours at which time LCMS analysis showed mostly the hydroxymethyl intermediate. The mixture was concentrated using a rotary evaporator and the concentrate was dissolved in methanol (3.00 mL) and concentrated ammonium hydroxide (0.50 mL) was added. The reaction was stirred at 25 °C for 3 hours at which time LCMS analysis showed no starting material present. The reaction was then concentrated using a rotary evaporator and the concentrate was purified by prep LC to give the product as the TFA salt (47.8 mg). LC/MS (M+H)+:321, 1H NMR(CD3OD): 8.86 (s, 1H), 8.81(s, 1H), 8.44 (s, 1H), 7.84 (d, 1H), 7.31 (d, 1H), 4.48 (m, 1H), 2.51 (m, 2H), 2.28 (m, 2H), 2.00 (m, 2H), 1.80 (m, 5H), 1.67 (m, 2H). 2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriniiclin-4-yl)-lH- pyrazol-l-yl]cyclohexylethyl methanesulfonate (0.060 g, 0.00012 mol) was dissolved in DMF (1.31 mL) with 5-amino-4H-l,2,3-triazole-3-thiol (0.020 g, 0.00017 mol) and potassium carbonate (0.024 g, 0.00017 mol). This mixture was heated at 40 °C for 18 hours at which time LCMS analysis showed no starting material present. The reaction was diluted with EtOAc, filtered and was then concentrated using a rotary evaporator. The residue was dissolved in DCM (3.60 mL) and TFA (0.60 mL, 0.0078 mol) was added. This mixture was stirred at 25 °C for 5 hours and was then concentrated using a rotary evaporator. The residue was dissolved in methanol (3.60 mL) and concentrated ammonium hydroxide (0.60 mL) was added and this mixture was stirred at 25 °C for 2 hours. The reaction was concentrated using a rotary evaporator and the concentrate was purified by prep. LC to give the product. LC/MS (M+H)+:410, 1H NMR(CD3OD): 8.85 (s, 1H), 8.80(s, 1H), 8.44 (s, 1H), 7.83 (d, 1H), 7.30 (d, 1H), 4.46 (m, 1H), 3.17 (m, 2H), 2.27 (m, 2H), 2.00 (m, 2H), 1.62-1.90 (m, 7H). Step 1: 1,4-Dioxaspiro[4.5]decan-8-ol l,4-Dioxa-spiro[4.5]decan-8-one (2.00 g, 0.0128 mol) was dissolved in ether (50 mL) and the mixture was cooled to 0 °C. To the reaction was added 1 M lithium tetrahydroaluminate in ether (7.0 mL) and this mixture was stirred at 0 °C for 2 hours at which time TLC analysis showed no starting material present. The reaction was then quenched with water and 1 N NaOH (0.5 mL of each) and then filtered. The filtered solid was washed with ether and the combined ether filtrate was concentrated using a rotary evaporator to give the product. NMR (CDC13): 3.94 (m, 4H), 3.81 (m, 1H), 1.79-1.92 (m, 4H), 1.54-1.70 (m, 4H). Step 2: l,4-Dioxaspiro[4.5]dec-8-yl methanesulfonate. l,4-Dioxaspiro[4.5]decan-8-ol (0.40 g, 0.0025 mol) was dissolved in chloroform (10.0 mL) and the resulting mixture was cooled at 0 °C. To the mixture was added TEA (0.49 mL, 0.0035 mol) and methanesulfonyl chloride (0.23 mL, 0.0030 mol) and this mixture was stirred at 0 °C for 2 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR(CDC13): 4.85 (m, 1H), 3.95 (m, 4H), 3.02 (s, 3H), 1.98-2.05 (m, 4H), 1.82-1.89 (m, 2H), 1.61-1.70 (m,2H). Step3:4-[l-(lA-Dioxaspiro[4.S]dec^-yl)-lH-pyrazol-4-yl]-7-[2-(trirmihylsilyl)ethoxyl] methyl -7H pyrrolo[2,3-d]pyrimidine. A mixture of l,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (0.50 g, 0.0015 mol) with 4-(lH- pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyirolo[2,3-d]pyrimidme (0.36 g, 0.0011 mol) and sodium hydride (0.082 g, 0.0020 mol) was cooled at -78 °C and DMF (2.0 mL) was added. The reaction was allowed to warm to 25 °C and was then stirred for 20 minutes and was then heated to 55 °C for 24 hours. The reaction was then extracted with ethyl acetate. The organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (M+H)+:456, 1H NMR(CDC13): 8.89 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H), 5.73 (s, 2H), 4.38 (m, 1H), 4.06 (s, 4H), 3.60 (m, 2H), 2.22-2.31 (m, 4H), 2.00 (m, 2H), 1.86 (m, 2H), 0.98 (m, 2H), 0.00(s, 9H) Step 4: 4-[4-(7-[2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]cyclohexanone To 4-[l-(l,4-dioxaspiro[4.5]dec-8-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidine (2.13 g, 0.00467 mol), was added acetone (85 mL) followed by 12 M HC1 in water (4.0 mL). The reaction was stirred at RT. After 1 h, LCMS analysis showed 66% reaction. After 4 h, HPLC showed 80% reaction. After 20 h, HPLC showed no change (and no loss of SEM). The reaction mixture was quenched into excess sat'd NaHCO3. The acetone was removed by roto-evaporation. The resulting mixture of aqueous bicarbonate and a white solid was then extracted with EtOAc. The combined organic extract was shaken with sat'd NaCl, dried over Na2SO4, then concentrated to dryness to leave 2.0 g of a crude product. TLC (5% iPrOH-40% EtOAc-hexane): product Rf 0.12 (ketal 0.22). The crude product was purified by automatic flash chromatography on silica gel. Used a 40g column; flow 40 mL/min; [A= 2% iPrOH-hexane] [B= 6% iPrOH-50% EtOAc/hexane]; A, 2 min; Gradient to B in 25 min, then B for 10 min. The eluent was concentrated . using a rotary evaporator to give 1.3 g of a white solid. HPLC Method: Zorbax SB C18, 5 m, 15 cm, 35 °C, flow 1.2 ml/min, 10% CH3CN-H2O (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 268 nm; retention time starting material, 7.4 min; product, 6.9 min (UV max 220, 268, 300, 322 nm). 1H NMR (CDC13) 8 8.8 (s, 1H); 8.3 (m, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.8 (d, 1H); 5.7 (s, 2H); 4.7 (m, 1H, NCH); 3.6 (t, 2H); 2.3-2.5 (m, 8H); 0.9 (t, 2H); -0.1 (s, 9H). MS(ES) 412 (M+l). Step 5: 4-[4-(7-[2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l~ yl]cyclohexylideneacetonitrile To a solution of 1.0 M potassium terf-butoxide in THF (1.90 mL) at 0 oC was added a solution of diethyl cyanomethylphosphonate (321 L, 0.00198 mol) in THF (4 mL) dropwise. The reaction was held for 10 min, then it was added to a solution of 4-[4-(7-[2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo[2,3-d]pyrmidin-4-yl)-lH-pyrazol-l-yl]cycIohexanone (743 mg, 0.00180 mol) in THF (5 mL) stirring at 0 °C under a nitrogen atmosphere. The reaction was stirred 1.5 h at rt. LCMS analysis showed clean conversion to the desired product. To the reaction mixture was then added water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extract was washed with water, then sat'd NaCl, then dried over Na2SO4, and concentrated to dryness to yield 0.76 g of a white crystalline solid (TLC (EtOAc) Rf 0.33). The product was purified by automatic flash chromatography on silica gel. Used 40g column; flow 40 mL/min; [A= hexane] [B= EtOAc]; A, 2 min; Gradient to B in 20 min. Rotary evaporation yielded 0.70 g of a white crystalline solid (89% yield). 'H NMR (CDCfe) 8 8.9 (s, 1H); 8.3 (s, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.9 (d, 1H); 5.7 (s, 2H); 5.3 (s, 1H, olefin); 4.5 (m, 1H, NCH); 3.6 (m, 2H); 3.2 (m, 1H); 2.7 (m, 1H); 2.5 (m, 4H); 2.1 (m, 2H); 1.0 (m, 2H); -0.1 (s, 9H). MS(ES) 435 (M+l). Step 6: 4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylideneacetonitrile A solution of TFA (0.5 mL, 0.006 mol) and 4-[4-(7-[2-(trimethylsilyI)ethoxy]methyI-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yljcyclohexylideneacetonitrile (22.7 mg, 0.0000522 mol), was stirred for 1.5h. The solution was then concentrated using a rotary evaporator to remove TFA. LCMS analysis showed conversion to the hydroxymethyl intermediate, M+H 335. Methanol was added; and the methanol mixture was concentrated again using a rotary evaporator. The resulting residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL, 0.0064 mol) was added. The resulting solution was stirred for 16 h. LCMS analysis showed complete de-protection. The solution was then concentrated using a rotary evaporator. The product was isolated by prep HPLC using a 30 mm x 100 mm C18 column; 18% CH3CN-H2O (0.1%TFA), lmin, to 35% at 6min; 60 mL/min; detector set at 254nm; retention time, 4.4min. The eluate was freeze dried, yield 7.6 mg of a white solid (TFA salt; racemic; 34.6%). 'H NMR G/eJDMSO) 6 12.9 (br s, 1H, NH); 8.9 (s, 2H); 8.5 (s, 1H); 7.8 (m, 1H); 7.3 (m, 1H); 5.6 (s, 1H, olefin); 4.6 (m, 1H,NCH); 2.8 (m, 1H); 2.6 (m, 1H); 2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS(ES) 305 (M+l). Example 686: cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI] cyclohexanecarbo- nitrile trifluoroacetate Step 1: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyt- 7H~pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl] cyclohexanecarbaldehyde oxime A solution of sulfur trioxide-pyridine complex (53.4 mg, 0.000336 mol) in DMSO (0.3 mL, 0.004 mol) was added to a solution of cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethanol (57.4 mg, 0.000134 mol) and TEA (56.1 uL, 0.000403 mol) in DCM (0.3 mL, 0.004 mol) at -10 °C. The mixture was stirred vigorously at 10-20 °C for one hour. LCMS analysis showed conversion to the aldehyde. The mixture was then poured into ice-water, and extracted with DCM. The extracts were washed with 10 % citric acid, water, saturated aqueous sodium bicarbonate, water, and brine, and then dried over sodium sulfate. Concentration gave 57 mg of a residue. To the resulting residue was added hydroxylamine-HCl (50mg), 1 mL 20% K2CO3, and 3 mL MeOH and this mixture was stirred at rt until LCMS showed conversion to the corresponding oxime, M+H 441. The product was isolated by prep HPLCMS using a 30 mm x 10, 0 mm, Cl 8 column; 30% CH3CN-H2O (0.1%TFA), 1 min, to 60% at 6 min; 60 mL/min; detector set at m/z 441; retention time, 6.0min. freeze-dried. yield 17.4 mg of a white solid. Step 2: cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazot-J-yl]cyclohexanecarbonitrile [A] cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyra2ol-l-yl]cyclohexanecarbaldehyde oxime (11.0 mg, 0.0000250 mol) was dissolved in pyridine (0.25 mL, 0.0031 mol), and benzenesulfonyl chloride (10.0 L, 0.0000784 mol) was added and the resulting mixture was stirred at rt. After stirring 15 h, LCMS analysis showed formation of the product, M+H 423. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 45% CH3CN-H2O (0.1% NH4OH), lmin, to 75% at 6 min; 30 mL/min; detector set at m/z 423; retention time, 4.8 min. The eluent was concentrated using a rotary evaporator to give 8 mg of the desired product The product was dissolved in TFA (0.25 mL). stirred for 2h. The solution was concentrated using a rotary evaporator to remove TFA. Methanol was added and the mixture was concentrated again. LCMS showed clean conversion to the hydroxymethyl intermediate (M+H 323). The residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL) was added. The solution was stirred 0.5 h, at which time, LCMS showed complete de-protection to the desired product M+H 293. The mixture was then concentrated by roto-evaporation, and the product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH3CN-H2O (0.1% TFA), 1.5 min, to 30% at 6 min; 30 mL/min; detector set at m/z 293; retention time, 5.2 min. The eluate was freeze dried to yield 5.5 mg of the product as a TFA salt. 1H NMR (d6DMSO) 5 12.82 (br s, 1H, NH); 8.87 (s, 1H); 8.85 (s, 1H); 8.48 (s, 1H); 7.82 (m, 1H); 7.24 (m, 1H); 4.40 (m, 1H, NCH); 3.22 (m, 1H); 2.05 (m, 6H); 1.79 (m, 2H). MS(ES) 293 (M+l). Step /: 4-[l-(cis-4-[(2-Bromaphenyl)thio]methylcyclohexyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)- ethoxy] methyl- 7H-pyrrolo[2,3-d]pyrimidine This compound was prepared from (cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl methanesulfonate as in Example 686[A]. Yield 73%. The product was purified using the following HPLC method: Zorbax SB C18, 5 m, 15cm, 35 C, flow 1.2 mL/min, 10% CH3CN-H2O (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 254 nm; retention time starting mesylate, 7.5 min; product, 9.9 min (UV max 215, 258, 300, & 326 nm). TLC: Rf 0.3 using 35% EtOAc/5% iPrOH/hexane. The product was purified by automated silica gel flash chromatography using 30% EtOAc/5% iPrOH/hexane. 'H NMR (CDC13) 8 8.84 (s, 1H); 8.31 (s, 1H); 8.26 (s, 1H); 7.55 (m, 1H); 7.39 (d, 1H); 7.27 (m, 2H); 7.03 (m, 1H); 6.82 (d, 1H); 5.67 (s, 2H); 4.34 (m, 1H, NCH); 3.55 (m, 2H); 2.98 (d, 2H); 2.28 (m, 2H); 2.02 (m, 3H); 1.83 (m, 4H); 0.92 (m, 2H); -0.06 (s, 9H). MS(ES) 598/600 1:1 (M+l). Step 2: 2-[(cis-4-[4-(7-[2'(Tnmethylsilyl)ethoxyl]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]cyclohexylmeihyl)thio]benzonitrile 4-[l-(cis-4-[(2-Bromophenyl)thio]methylcyclohexyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)- ethoxy3methyl-7H-pyrTolo[2,3-d]pyrimidine (62.7 mg, 0.000105 mol), zinc cyanide (123 mg, 0.00105 mol), and tetrakis(triphenylphosphine)palladium(0) (30.2 mg, 0.0000262 mol) were stirred in DMF (3 mL) and the solution was flushed with nitrogen. The solution was then heated to 100 °C for 25 min in a microwave reactor. LCMS and HPLC analyses showed > 90% reaction. The product was isolated by prep HPLCMS using a 30 mm x 100 mm C18 column; 52%CH3CN-H2O (0.1%TFA), 1.5 min, to 75% at 6 min; 60 mL/min; detector set at 545 nm. The eluent was concentrated using a rotary evaporator to give 37 mg of the 2-cyanophenylsulfide TFA salt. HPLC Method: Zorbax SB C18, 5 m, 15 cm, 35 C, flow 1.2 ml/min, 10% CH3CN-H2O (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 265 nm; retention time starting material, 9.9 min; product, 8.9 min. MS(ES) 545 (M+l). Step 3: 2-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-I-yl]cyclohexylmethyl)sulflnyl]- benzonitrile A solution of 2-[(cis-4--[4-(7-[2-(trimeihylsilyl)etlioxy]methyI-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-lH-pyrazol-l-yl]cyclohexylmethyl)thio]benzonitrile (30.6 mg, 0.0000562 mol), in TFA (1 mL) was stirred for 2 h. The solution was concentrated using a rotary evaporator to remove TFA. Methanol was added, and the mixture was concentrated again. The resulting residue was dissolved in methanol (1 mL) and ammonium hydroxide (1 mL) was added. The resulting solution was stirred overnight, at which time HPLC showed complete deprotection. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 30% CH3CN-H2O (0.1% TFA), 1.5 min, to 59% at 6 min; 30 mlVmin; detector set at m/z 415 nm; retention time, 4.7 min. The eluate was concentrated using a rotary evaporator to give 36 mg of the sulfide TFA salt, a colorless glassy material. NMR (d6-DMSO) 8 12.82 (or s, 1H, NH); 8.84 (2 singlets, 2H); 8.45 (s, 1H); 7.8 (m, 2H); 7.64 (m, 2H); 7.34 (td, 1H); 7.24 (s, 1H); 4.39 (m, 1H, NCH); 3.23 (d, 2H); 2.19 (m, 2H); 1.89 (m, 3H); 1.72 (m, 4H). MS(ES) 415 (M+l). This material was then dissolved in CH2C12 and cooled to 0 °C. To the cooled mixture was added MCPBA(12.9 mg, 0.0000562 mol), and the resulting mixture was stirred for 1 h. LCMS showed conversion to the product, and no remaining sulfide. The reaction mixture was concentrated by rotovap, and the product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 18% CH3CN-H2O (0.1% TFA), 1. 0 min, to 35% at 6 min; 30 mL/min; detector set at m/z 431 nm; retention time, 5.6 min. The product was isolated from the eluent by freeze-drying. The yield was 27.6 mg of the TFA salt. The HPLC method was: Zorbax SB C18, 5 m, 15 cm, 35 °C, flow 1.2 mL/min, 10% CH3CN-H20 (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 268 nm; retention time starting material, 5.6 min; sulfbxide, 4.8 min; sulfone, 5.2 min; MCPBA, 6.0 min. 1H NMR (CDC13) 8 12.1 (br s, 1H, NH); 9.0 (s, 1H); 8.9 (s, 1H); 8.3 (s, 1H); 8.1 (m, 1H); 7.9 (m, 1H); 7.8 (m, 1H); 7.6 (m, 2H); 7.0 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (dd, 1H); 2.9 (dd, 1H); 2.5 (m, 1H); 2.3 (m, 1H); 2.3-1.7 (m, 7H). MS(ES) 431 (M+l). 2-[(cis-4-t4-(7H-Pyrrolo[2,3-d3pyaimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)sulfinyl]- benzonitrile (17.2 mg, 0.0000400 mol) (21 mg TFA salt), was dissolved in DCM (10 mL) and cooled to 0 °C. To this mixture was added MCPBA (18 mg, 0.0000800 mol). The resulting mixture was stirred for lh at 0 DC, and then for 16 h at rt. HPLC and LCMS showed 80 area% product, and 3 area% sulfoxide. The MCPBA was removed using a sat'd NaHCO3 wash, and the resulting washed mixture was concentrated by roto-evaporation. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 23%CH3CN-H2O (0.1%TFA), 1.0 min, to 43% at 6 min; 30 mL/min; detector set at m/z 447 nm; retention time, 5.1 min. The product was isolated from the eluent by freeze-drying. The yield was 5 mg of the TFA salt. 'H NMR (dg-DMSO) 5 12.70 (br s, 1H, NH); 8.83 (s, 1H); 8.82 (s, 1H); 8.41 (s, 1H); 8.21 (dd, 1H); 8.16 (dd, 1H); 8.01 (td, 1H); 7.95 (td, 1H); 7.78 (s, 1H); 7.19 (s, 1H); 4.34 (m, 1H, NCH); 3.62 (d, 2H); 2.28 (m, 1H); 2.10 (m, 2H); 1.90 (m, 2H); 1.72 (m, 4H). MS(ES) 447 (M+l). Step 1: 3-[4-(7-[2-(Tnmethyhilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-I-yl]- cyclohexanone To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (309 mg, 0.980 mmol) in ACN (6 mL) was added 2-cyclohexen-l-one (190 L, 01.96 mmol), followed by DBU (40 L, 0.3 mmol). The resulting mixture was stirred for one hour at which point LCMS indicated complete addition. The mixture was reduced in vacuo and the crude product was purified by column chromatography to obtain the product (397 mg, 98%). 1H NMR (400 MHz, CDC13): 5 8.84 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.45 (d, 1H), 6.79 (d, 1H), 5.67 (s, 2H), 4.61 (m, 1H), 3.55 (m, 2H), 3.05-2.90 (m, 2H), 2.45-2.30 (m, 4H), 2.05 (m, 1H), 1.90 (m, 1H), 0.92 (m, 2H), -0.06 (s, 9H). MS (El) m/z = 412.2 (M+H). Step 2: (2E,Z)-3-[4-(7-[2-(Trimethyhilyl)ethoxy]methyl-7H~pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]cyclohexylideneacetonitrile To a solution of t-BuOK in THF (1.0 M, 0.255 mL, 0.255 nunol) at 0 °C was added a solution of diethyl cyanomethylphosphonate (43 L, 0.27 mmol) in THF (0.6 mL) dropwise. The reaction was held for 10 minutes, then a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexanone (100.0 mg, 0.2430 mmol) in THF (0.34 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction was held at ambient temperature for 16 hours, at which point LCMS indicated complete addition to yield the desired product as a mixture of E and Z isomers (87.9 mg, 83%). 'H NMR (400 MHz, CDC13): 5 8.84 (s, 0.5H), 8.83 (s, 0.5 H), 8.27 (d, 1H), 8.25 (s, 1H), 7.40 (s, 0.5H), 7.39 (s, 0.5H), 6.81 (d, 0.5H), 6.79 (d, 0.5H), 5.67 (s, 2H), 5.28 (s, 0.5H), 5.24 (s, 0.5H), 4.4 (m, 1H), 3.55 (m, 2H), 3.1-2.8 (m, 2H), 2.5- 2.1 (m, 6H), 0.92 (m, 2H), -0.06 (s, 9H). MS (EX) m/z = 435.2 (M+H). Step 3: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- cyclohexylaceton itrile To (2E, Z)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH- pyrazol-l-yl]cyclohexylideneacetonitrile (42.0 mg, 0.0966 mmol) was added THF (0.5 mL). The resulting solution was cooled to -78 °C, and then 1.0 M L-Selectride® in THF (120 uL, 0.12 mmol) was added dropwise. The reaction was held at -78 °C for lh at which point LCMS indicated complete reduction. The reaction was quenched at -78 °C by addition of saturated aqueous NH4CI and EtOAc, and was then allowed to warm to ambient temperature. The phases were separated and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then saturated NaCl, and then was dried over MgSO4. The crude product was purified by column chromatography to obtain the product (26.5 mg, 63%). 1H NMR (400 MHz, CDC13): S 8.84 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.53 (m, 1H), 3.52 (m, 2H), 2.6-1.4 (m, 11H), 0.92 (m, 2H), -0.06 (s, 9H). MS (El) m/z = 437.2 (M+H). Step 4: 3-[4-(7H-Pyrrolo[2,3-dJpyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylacetonitrile trifluoroacetate To 3-[4-(7-[2-(triniethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 - yl]cyclohexylacetonitrile (30.1 mg, 0.0689 mmol) was added DCM (1.0 mL) and TFA (1.0 mL). The resulting mixture was stirred for 1 hour at ambient temperature, at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (37 L, 0.55 mmol), after which the reaction was stirred for 5 hours, at which point LCMS indicated complete reaction. The solvent was removed and the residue was purified by preparative LCMS to provide the product as a TFA salt (24 mg, 83%). 1H NMR (400 MHz, CD3OD): 8 8.91 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.31 (s, 1H), 4.69 (s, 1H), 2.58 (d, 2H), 2.5-1.5 (m, 9H). MS (El) m/z = 307.10 (M+H). Step 1: trans-4-[4-(7-[2-(Trimethylsilyl)ethoxy]meikyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-J-ylJcyclohexanol A solution of 4-[4-(7-[2^trimethylssilyl)e1thoxy]methyl-7H-pyrrolo[2,3^]pyriniidin-4-yl)-lH- pyrazol-l-yl]cyclohexanone (662 mg, 1.61 mmol) in THF (5 mL) was cooled to 0 °C and lithium tetrahydroaluminate (2M in THF, 0.804 mL, 1.61 mmol) was added slowly. The mixture was allowed to warm slowly to ambient temperature until LCMS indicated complete reduction. The reaction was cooled to 0 °C and quenched with dropwise addition of water (0.5 mL). DCM was added, and the mixture was stirred for 1 hour at ambient temperature, after which the precipitated solids were removed by filtration. The filtrate was reduced in vacuo to leave a white solid (0.63g, 99%). HPLC of the solid showed an approximately 4:1 ratio of trans to cis product. Tic (6:3:1 EtOAc:hexanes:isopropanol) gave an Rf of 0.25 for the cis product , and 0.18 for the trans product. The product was purified by flash chromatography on silica gel to recover 230 mg of the pure trans alcohol and 25 mg pure of the cis alcohol, and 350 mg of mixed isomers. 1H NMR (400 MHz, CDC13): 5 8.83 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H)5 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.24 (m, 1H), 3.79 (m, 1H), 3.54 (m, 2H), 2.28 (m, 2H), 2.17 (m, 2H), 1.94 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), -0.06 (s, 9H). MS (El) m/z = 414 (M+H). Step 2: trans-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol- j-yljcyclohexyl methanesulfonate To trans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]cyclohexanol (154 mg, 0.372 mmol) was added DCM (1.0 mL) and TEA (73 L, 0.52 mmol). The resulting solution was then cooled to 0 °C and methanesulfonyl chloride (34 L, 0.45 mmol) was added. The reaction was held for 2 hours, at which point tic and LCMS indicated complete reaction. The reaction was partitioned between water and DCM, the phases were separated and the aqueous phase was extracted with additional solvent. The combined organic phase was washed with water, then saturated NaCl, then was dried over MgSO4 and reduced in vacuo to give the crude product which was used without further purification (173 mg, 95%). 1H NMR (400 MHz, CDC13): 8 8.83 (s, 1H), 8.24 (s, 2H), 8.24 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, 1H), 4.27 (m, 1H), 3.54 (m, 2H), 3.06 (s, 3H), 2.36 (m, 4H), 2.03 (m, 2H), 1.82 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), -0.06 (s, 9H). MS (El) m/z = 492.1 (M+H). Step 3: 5-({cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cycloh^ triazol-3-amine bis(trifluoroacetate) To a solution of trans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriniidin- 4-y])-lH-pyrazol-l-yl]cyclohexyl methanesulfonate (42 mg, 0.085 mmol) in DMF (800 uL) was added 3-amino-lH-l,2,4-triazole-5-thiol (30 mg, 0.26 mmol) and K2CO3 (36 mg, 0.26 mmol). The reaction was sealed and held at 100 °C for 2 hours at which point LCMS indicated conversion to desired product. The reaction was diluted with water and extracted successively with ether, ethyl acetate, and 3:1 chloroform:isopropyl alcohol. The combined organic phase was washed with water, then saturated NaCl, dried over MgSO4 and reduced in vacua, and the crude product was purified by column chromatography to give 5-({cis-4-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexyl}thio)-lH-l,2,4-triazol-3-amine (27.3 mg, 63%). To the product was added DCM (0.5 mL) and TFA (0.5 mL), and the reaction was stirred for 1 hour at ambient temperature at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by NH4OH (0.3 mL), the reaction was stirred for 16 hours at which point LCMS indicated complete deprotection. The solvent was removed and the residue was purified by preparative LCMS to provide the product as a bis-TFA salt (15.1 mg, 29%). 1HNMR (400 MHz, CD3OD): 8 8.77 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.74 (d, 1H), 7.21 (d, 1H), 4.40 (m, 1H), 3.97 (m, 1H), 2.25(m, 2H), 2.04 (m, 6H). MS (ET)tm/z= 382.2 (M+H). Stepl.N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxyJmethyl-7H-pynolo[2,3^Jpyrimidin-4-yl)-lH- pyrazol-l-yl]cyclohexylmethyl)thio]-4H-l,2,4-triazol-3-ylmethanesulfonamide 5-[(cis-4-[4-(7-[2-(Trim6thylsilyl)ethoxy]mcthy]-7H-pyrrolo[2,3-dl]pyrimidm-4-yl)-lH- pyrazol-l-yl]cyclohexylmethyl)thio]-4H-l,2,4-triazol-3-amine (30.00 mg, 5.706E-5 mol) was dissolved in DCM (2.00 mL, 0.0312 mol) with TEA (0.024 mL, 0.00017 mol) and was cooled at 0 °C. To the reaction was added methanesuifonyl chloride (0.0066 mL, 0.000086 mol) and the resulting mixture was stirred at 0 °C for 60 minutes, at which time LCMS analysis showed mostly product. The reaction was chromatographed on silica gel using EtOAc as ehient to give the product. LC/MS (M+l)+:604 Step2.N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)thio] 4H-l,2,4-triazol-3-ylmethanesulfonamide Into a 1-neck round-bottom flask [A] N-5-[(cis-4-[4-(7-[2-(trimethylsilyI)ethoxy]methyl-7H- pyrroloP.S-dlpyrimidin^-y^-lH-pyrazol-l-ylJcyclohexylmethyOthiol^H-l^^triazol-S-ylmethane- ulfonamide (0.025 g, 0.000041 mol) was dissolved in DCM (3.00 mL, 0.0468 mol) and TFA (mL, 0.006 mol) was added. The reaction was stirred at 25 °C for 16 hours at which time LCMS analysis showed no starting material present. The reaction was concentrated using a rotary evaporator and was dissolved in methanol (2.00 mL, 0.0494 mol) and 16 M ammonia in water (0.2 mL) was added. The reaction was stirred at 25 °C for 3 hours at which time LCMS analysis showed no starting material present. The reaction was concentrated using a rotary evaporator and was purified by prep LC to give the product as the trifluoroacetate salt. LC/MS (M+l)+:474, 1HNMR(CD3OD): 8.87 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.85 (d, 1H), 7.33 (d, 1H), 4.48 (m, 1H), 3.36 (s, 3H), 3.23 (d, 2H), 2.30 (m, 2H), 2.04 (m, 3H), 1.85 (m, 4H). 1H-1,2,4-Triazole (91.0 mg, 0.00132 mol), DBU (174 L, 0.00070 mol), [A] 4-[4-(7-[2- (1ximethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylidene- acetonitrile (86.4 mg, 0.000199 mol), and ACN (2.0 mL) were stirred at rt. After 4d, LCMS showed about 58 area% product (two peaks, M+H 504, ratio 1:1). The DBU in the reaction was neutralized with TFA. The product was isolated by prep HPLC using a 30 mm x 100 mm C18 column; 32% CH3CN-H2O (0.1%TFA), 1 min, to 47% at 6 min; 60 mL/min; detector set at 254 nm; retention time, 5.1 (A) & 5.4 (B) min. The eluent was concentrated using a rotary evaporator to give 22 mg of (A) & 36 mg of (B). Deprotection: The products were dissolved separately in TFA (0.5 mL) and stirred for lh. LCMS showed conversion to the hydroxymethyl derivative (M+H 404). The solutions were concentrated using a rotary evaporator to remove TFA. Methanol was added, and the resulting mixtures were concentrated again. The resulting residue was dissolved in methanol (1 mL), and ammonium hydroxide (0.25 mL) added. The solution was stirred 0.5h. LCMS showed complete de- protection (M+H 374) and the mixture was then concentrated by roto-evaporation. Each isomer was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH3CN-H2O (0.1% TFA), 1.5 min, to 32% at 6 min; 30 mL/min; detector set at m/z 374; retention time, 4.5 min (A) & 4.7 min (B) . The eluates were freeze dried. Yield 13 mg isomer A and 24 mg isomer B (TFA salts, white solids). NMR analysis (including NOE & COSY) was consistent with expectation for the structures, with A=cis, and B=trans. NMR (d6DMSO) 5 cis: 12.94 (br s, 1H, NH); 8.95 (s, 1H); 8.87 (s, 1H); 8.81 (s, 1H); 8.42 (s, 1H); 8.14 (s, 1H); 7.85 (m, 1H); 7.22 (m, 1H); 4.48 (m, 1H, NCH); 3.12 (s, 2H); 2.84 (m, 2H); 2.07 (m, 4H); 1.69 (m, 2H). MS(ES) 374 (M+l). trans: 12.85 (br s, 1H, NH); 8.94 (s, 1H); 8.89 (s, 1H); 8.84 (s, 1H); 8.47 (s, 1H); 8.11 (s, 1H); 7.84 (m, 1H); 7.26 (m, 1H); 4.50 (m, 1H, NCH); 3.48 (s, 2H); 2.42-2.10 (m, 8H). MS(ES) 374 (M+l). 1 M Diisoburylalumimim hydride in hexane (0.31 mL) was added dropwise to a solution of methyl 3-3-cyanophenyl-2-[4--(7-[2-(trimethylsily)ethoxylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-lH-pyrazol-l-yl]propanoate (100 mg, 0.0002 mol) (prepared by using a procedure analogous to Example 712, Step 1) in DCM (3 mL, 0.05 mol) and the mixture was cooled to -78 °C. The reaction mixture was stirred at -78 CC for 4 h and was afterward quenched with cold methanol (3 mL, 0.07 mol). The reaction was allowed to warm to 0 °C and potassium carbonate (60 mg, 0.0004 mol) and Bestmann-Ohira reagent (1.5 eq, 57 mg) (E. Quesada et at, Tetrahedron, 62 (2006) 6673-6680) were added. The reaction was stirred at room temperature overnight, and then partitioned between ethyl acetate and water. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give the crude product. The crude product was purified using silica gel (EtOAC/Hexane 1:3 to 1:1) to give the desired product, 3-{l-[4-(7-{[2-(trimethylsilyl)ethoxy]- memyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]but-3-yn-l-yl}beiizonitrile (40 mg of mixture), m/z = 469 (M+l). Step 2: 3-l-[4-(7H-Pyrrolo[2,3d]pyrirrudin-4-yl)-lH-pyrazol-l-ylJbut-3-yn-l-ylbenzonitrile trifluoroacetate Using a procedure analogous to Example 712, Step 4, the title compound was prepared (4.5 mg, 46%) as an amorphous white solid. 1HNMR (500 MHz, DMSO): 8. 12.5 (b, 1H), 9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8 (s, 1H), 7.8 (m 2H), 7.7 (s, 1H), 7.6 (m, 1H), 7 (m, 1H), 5.9 (m, 1H), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z = 339 (M+l). Using the procedure of Example 705, the title compound was prepared as a secondary product (4.5 mg, 46%) as an amorphous white solid. H NMR (400 MHz, CDC13): £ 10 (s, 1H), 9 (s, IH), 8.8 (s, 1H), 8.4 (s, 1H), 8 (s, 1H), 7.9 (m 1H), 7.8 (m, 1H), 7.7 s, 1H), 7.6 (m, 1H), 7.1 (s, 1H), 5.9 (m, 1H), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z = 342. A solution of methyl (2E)-3-phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol) was slowly added to a solution of 4-(lH-pyrazol-4-yl)-7-t2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrirnidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 L, 0.003 mol). The reaction was stirred at room temperature over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel using EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanoate (500 mg, 70%) as a semisolid residue. 1H NMR (400 MHz, CDC13): 8. 8.9 (s, 1H), 8.4 (s, 2H), 7.4 (m, 5H), 6.8 (d, 1H), 6 (m, 1H), 5.7 (s, 2H), 3.7-3.8 (m, 3H), 3.6 (m, 2H), 2.2 (m, 1H), 1.4 (m, 2H), 1.1 (m, 2H), 0.02 (s, 9H), m/z = 478 (M+l). Diisobutylaluminum hydride in hexane (1 M, 0.69 mL) was added to a solution of methyl 3- phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI]- propanoate (150 mg, 0.00031 mol) in DCM (3 mL, 0.05 mol) and the mixture was cooled to -78 oC under a nitrogen atmosphere. The reaction was stirred for 1 h at -78 oC and was allowed to warm to room temperature for 4 hrs. The reaction was quenched with methanol (100 L), and saturated ammonium chloride (100 L), and then taken up in ethyl acetate dried over MgSO4 and filtered. The filtrate was concentrated to give 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propan-l-ol (130 mg, 92%) as an oil. m/z = 450 (M+l). Step 3: 4-[l-(3-Methoxy-l-phenylpropyl)-lH-pyrazol-4-yl]- 7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-djpyrimidine Sodium hydride (9.6 mg, 0.00040 mol) was added to a solution of 3-phenyl-3-[4-(7-{2-(tri- methylsilyl)ethoxy]memyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propan-l-ol (120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0 °C. The reaction was stirred for 20 min and methyl iodide (22 L, 0.00035 mol) was added. The reaction was allowed to warm to room temperatures and stirred overnight. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give 4- [l-(3-methoxy-l-phenylpropyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyi-7H-pyrrolo[2,3- d]pyrimidine (100 mg, 88%) as a semisolid. m/z = 464 (M+l). Step 4: 4-[l-(3-Methoxy-l-pkenylpropyl)-lH-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate Trifluoroacetic Acid (2 mL, 0.02 mol) was added to a mixture of 4-[l-(3-methoxy-l- phenylpropyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.0002 mol) in DCM (3 mL, 0.05 mol) at room temperature. The starting material was consumed after stirring for 2hrs and the reaction solution was concentrated to remove the TFA. The crude reaction was diluted with methanol (3 mL, 0.07 mol) and was treated with ethylenediamine (0.3 mL, 0.004 mol) at room temperature. The reaction mixture was stirred for 18 hs and was concentrated and purified using HPLC on a C-1 8 column eluting with an ACN: water gradient containing 0.2% TFA, to give the title compound (43 mg, 60%) as a white amorphous solid. 1H NMR (400 MHz, CDC13): §8.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.8 (s, 1H), 7.4 (m, 1H), 7.3 (m, 5H), 7.2 (h, 1H), 5.7 (m, 1H), 3.3 (m, 1H), 3.2 (s, 3H), 2.7 (m, 1H), 2.4 (m, IH). m/z = 334 (M+l). A mixture of [4-l-[l-(3-bromophenyl)but-3-en-l-yl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-d]- pyrimidine (20 nag, 0.00005 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (60 mg, 0.0005 mol) was degassed with a nitrogen stream. The mixture was then treated with tetrakis(triphenyl- phosphine)palladium(O) (40 mg, 0.00003 mol), again degassed with nitrogen, and was then heated in a microwave reactor to 170 °C for 15 min. The reaction was allowed to cool, was filtered and purified by HPLC on a C-l 8 column eluting with an ACN/water/TFA gradient to give the title compound (10 mg, 40%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): 8 8.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.9 (s, 1H), 7.8 (m, 3H), 7.6 (m, 1H), 7.1 (b, 1H), 5.6-5.8 (m, 2H), 5.1 (d, 1H), 5 (d, 1H), 3.3 (m, 1H), 3 (m, 1H). m/z = 341 (M+l). Example 716: 4-l-[l-(3-Bromophenyl)but-3-en-l-ylJ-lH-pyrazoI-4-yI-7H-pyrrolo [2,3-dl- pyrimidine Diisobutylaluminum hydride in hexane (1 M, 4 mL) was added to a -78 °C solution of ethyl 3-(3-bromophenyl)0-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pynx)lo[2)3-d]pyrmidin-4-yl)-lH- pyrazol-l-yl]propanoate (600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirring, for 4 h, the reaction was quenched with cold methanol (300 L), and then saturated ammonium chloride (500 L) was added and the resulting solution was stirred for 1 h. The reaction was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel eluting with hexane: EtOAc, (2:1 to 1:2), to give 3-(3-bromophenyl)-3-[4-(7-[2-(triniethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (400 mg, 70%) as an oil.. 1H NMR (400 MHz, CDCI3): 5 9.9 (s, 1H), 8.9 (s, 1H), 8.4 (s, 2H), 7.6 (d, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.4 (m, 2H), 6.8 (d, 1H), 6.1 (m, 1H), 5.7 (s, 2H), 4 (m, 1H), 3.6 (m, 2H), 3.3 (dd, 1H), 1.0 (m, 2H), 0.01(s, 9H). m/z - 526, 528 (M+l), Step 2: 4-l-[l-(3-Bronwphenyl)but-3-en-l-ylj-lH~pyrazol^-yl-7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidine Potassium tert-butoxide in THF (!M, 200 L) was added to a solution of methyltriphenyl- phosphonium iodide (80 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) at 0 °C. The reaction was stirred at room temperature for 1h and then cooled to -78 °C. The 3-(3-bromophenyl)-3-[4-(7-[2-(triniethyl- silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (90 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was allowed to warm to room temperature gradually. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAc:Hexane, (1:1) to give 4-l-[l-(3- bromophenyl)but-3-en-l-yl]-lH-pyrazo-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine (35 mg, 40%) as an oil. m/z = 524, 526 (M+l). Step 3: 4-l-[l-(3-Bromophenyl)but-3-en-l-yl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-dJpyrimidine Using a procedure analogous to Example 712, Step 4, but using 4-l-[l-(3-bromophenyl)but- 3-en-l -yl]-l H-pyrazo1-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine the title compound was prepared (10 mg, 30%) as a white amorphous solid, 1H NMR (400 MHz, DMSO):& 8.9(s,lH), 8.8(s,lH), 8.4(s,lH), 7.8(s,lH), 7.7(s,lH), 7.5 (m,2H), 7.3(m,lH), 7.1(s,lH), 5.7(m,2H), 5.2(d,lH), 5.0(d,lH), 3.2(m,lH), 3.0(m,lH). m/z = 394, 396 (M+l). To a solution of 3-(3-bromophenyl)-3-t4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (0.05 g, 0.00009 mol) in N,N-dimethylacetamide (2 mL, 0.02 mol) was added triphenylphosphine (0.1 g, 0.0006 mol), dibromodifluoromethane (50 L, 0.0006 mol) and 0.76 M zinc in THF (0.7 mL). The reaction was stirred at room temperature for 18 hs. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAc, Hexane (1:2) to give 4-{l-[l-(3-bromophenyl)-4,4-difluorobut-3-en- l-yl]-lH-pyrazoM-yl}-7-{[2^trimethylsUyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (20 mg, 40%) as a clear oil. m/z = 560, 562 (M+l). Using a procedure analogous to Example 712, Step 4, but using 4-{l -[l-(3-bromophenyl)-4,4- difluorobut-3-en-l -yl]-l H-pyrazol-4-yl} -7- {[2-(trimethylsilyl)ethoxy]methyl} -7H-pyrroIo[2,3- d]pyrimidme, the compound 4-l-[l-(3-bromophenyl)-4,4-difluorobut-3-en-l-yl]-lH-pyrazol-4-yl-7H- pyrrolo[2,3-d]pyrimidine was prepared (30 mg, 99%) as an oil. m/z = 430,432 (M+l). Step 3: 3-4A-Difluoro-l-[4-(7H-pyrrolo[2,3-d]pyrimidm-4-yl)-lH-pyrazol-l-yl]but-3-en-l-yl- benzonitrile A mixture of 4-l-[l-(3-bromophenyl)-4,4-difluorobut-3-en-l-yl]-lH-pyrazol-4-yl-7H- pyrrolo[2,3-djpyrirnidine (30 mg, 0.00007 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (80 mg, 0.0007 mol) was degassed with nitrogen. The mixture was then treated with tetrakis(triphenyl- phosphine)palladium(O) (50 mg, 0.00004 mol) and was degassed with nitrogen, and then was heated in microwave at 170 °C for 15 min. The reaction was then allowed to cool, filtered and purified by HPLC on a C-18 column eluting with an ACN/water/TFA gradient to give the title compound (10 mg, 30%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): £8.9 (s, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 7.9 (s, 1H), 7.7 -7.8 (m, 3H), 7.5 (m, 1H), 7.1 (m, 1H), 5.7 (m, 1H), 4.3-4.4 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H). m/z = 377 (M+l). The following compounds in Table 14 were prepared as indicated in the column labeled "Prep. Ex. No." and the details of certain exemplary synthetic procedures are provided following * Step 1 of example 731 was modified as follows: The Ph3P and CF2Br2 were combined in DMAC at 0 °C and then allowed to warm to room temperature until the ylid formation was complete as determined by LCMS. The solution of the ylid was then re-cooled to 0 °C and the aldehyde and zinc were added to the ylid solution and the reaction was slowly warmed to room temperature. Example 727: 4-[l-(l-Cyclopentylbat-3-eii-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2r3-dJpyriniidine trifluoroacetate salt Step 1: (2h)-3~L,yclopentylacrylic acid t To a solution of malonic acid (1.06 g, 10.2 mol) in pyridine (1.25 mL) was added pipendine (0.15 mL) and cyclopentanecarbaldehyde (1.00 g, 10.2 mmol). The mixture was heated to 40 °C for 2 hours, followed by stirring at room temperature for 16 hours. The mixture was then cooled in an ice bath and 2N HC1 was added to acidify. The product was extracted with ether. The ether extract was washed with aq. HC1 and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo to afford the product (1.30 g, 77%), which was used without further purification. 'H NMR (300 MHz, CDC13): 57.06 (dd, 1H), 5.80 (dd, 1H), 2.70-2.54 (m, 1H), 1.93-1.32 (m, 8H); MS(ES):141(M+H). Step 2. Methyl (2E)-3-cyclopentylacrylate To a solution of (2E)-3-cyclopentylacrylic acid (1.3 g, 9.3 mmol) in DCM (65 mL) at 0 °C was added oxalyl chloride (3.1 mL, 37 mmol), dropwise. The resulting solution was stirred at 0 °C for 40 minutes, then at room temperature for 2 hours. The volatiles were evaporated to afford (2E)-3- cyclopentylacryloyl chloride as a colorless liquid. A portion of this (2E)-3-cyclopentylacryloyl chloride (0.75 g, 4.7 mol) was dissolved in methanol (10 mL) and the resulting solution was stirred for 2 hours. The solvent was evaporated to afford the product (700 mg, 96%). 1H NMR (300 MHz, CDC13): 86.94 (dd, 1H), 5.79 (dd, 1H), 3.71 (s, 3H), 2.66-2.50 (m, 1H), 1.92- 1.27 (m,8H). Step 3. Methyl 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-IH-pyrazol-l-yl]propanoate To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine (2.9 g, 9.2 mmol) and methyl (2E)-3-cyclopentylacrylate (1.70 g, 11.0 mmol) in ACN (100 mL), was added DBU (2.7 mL, 18 mmol). The resulting mixture was stirred for 96 hours. The ACN was removed in vacuo, and the resulting residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HC1, followed by brine, and then dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-70% ethyl acetate in hexanes) afforded the product (2.73 g, 63%). 'H NMR (300 MHz, CDC13): & 8.84 (s, 1H), 8.28 (s, 2H), 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.46 (dt, 1H), 3.60 (s, 3H), 3.54 (t, 2H), 3.18 (dd, 1H), 2.89 (dd, 1H), 2.59-2.42 (m, 1H), 1.95-1.80 (m, 1H), 1.75-1.10 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):470(M+H). Step 4. 3-Cyclopentyl-3-[4-(7-f2-(trimethylsilyl)etho^Jmethyl-7H-pyrrolo[2,3-dJpyrimidin-4-yl)-JH- pyrazol-l-yljpropanal To a solution of methyl 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanoate (0.501 g, 1.07 mmol) in THF (5.0 mL) at -78 °C was added 1.00 M diisobutylaluminum hydride in DCM (2.35 mL) dropwise. The reaction was stirred with gradual warming to -10 °C over the course of 2 hours. At this temperature, a further portion of 1.0 M diisobutylaluminum hydride in DCM (1.50 mL) was added. When the reaction was determined to be complete by LCMS, a saturated solution of K/Na tartrate was added, followed by ether. The resulting mixture was stirred for two hours at room temperature. The organic layer was separated and washed with water, and brine, then dried over sodium sulfate and the solvent was removed in vacuo to give a viscous oil, which was used without further purification. MS(ES):442(M+H). To a solution of oxalyl chloride (0.108 mL, 1.28 mmol) in DCM (10.0 mL) at -78 °C was added DMSO (151 L. 2.13 mmol). After stirring for 5 minutes, 3-cyclopentyl-3-[4-(7-[2- (trimethylsilyl)ethoxy]methyl-7H-pyirolo[2J3-d]pyriimdin-4-yl)-lH-pyrazol-l-yl]propan-l-ol (471 mg, 1.07 mmol) in DCM (3.00 mL) was added. The mixture was stirred for 30 minutes at -78 °C. TEA (594 L, 4.26 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over the course of 30 minutes. Water was added, and the layers were separated. The organic layer was washed successively with 0.1 N HC1, water, saturated sodium bicarbonate solution, and brine, and was then dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient of 0-60% ethyl acetate in hexanes) afforded the product (384 mg, 82%). 1H NMR (300 MHz, CDC13): 5 9.73 (s, 1H), 8.87 (s, 1H), 8.71 (br s, 1H), 8.30 (s, 1H), 7.47 (br s, 1H), 6.88 (br s, IH), 5.69 (s, 2H), 4.66-4.49 (m, 1H), 3.54 (t, 2H), 3.40 (ddd, 1H), 2.95 (ddd, 1H), 2.55-2.44 (m, 1H), 2.01-1.21 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):440(M+H). Step j. 4-[1-(l-Cyclopentylbut-3-en-l-yl)-lH-pyrazol^~ylJ~7-[2-(lrirnethyhilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidine To a solution of 1.0 M potassium ter/-butoxide in THF (0.207 mL) in THF (2.0 mL) at 0 °C was added triphenylmethylphosphonium bromide (77.8 mg, 0.218 mmol). The resulting mixture was warmed to room temperature and allowed to stir for 30 minutes. A solution of 3-cyclopentyl-3-[4-(7- [2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]propanal (0.100 g, 0.228 mmol) in THF (2.0 mL) was added. After 30 minutes, the mixture was quenched by the addition of saturated ammonium chloride solution and the product was then extracted with ether. The ether extract was dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient of 0-40% ethyl acetate in hexanes) afforded the product (40 mg, 44%). 'H NMR (400 MHz, CDCl3): 8 8.84 (s, IH), 8.26 (s, IH), 8.19 (br s, IH), 7.40 (s, IH), 6.83 (br s, IH), 5.67 (s, 2H), 5.60 (ddt, IH), 5.01 (dq, 1H), 4.97-4,93 (m, IH), 3.99 (dt, IH), 3.54 (t, 2H), 2.79-2.60 (m, 2H), 2.60-2.40 (m, IH), 1.99-1.89 (m, IH), 1.75-1.41 (m, 5H), 1.37-1.12 (m, 2H), 0.92 (t, 2H), - 0.06 (s, 9H); MS(ES):438(M+H). Step 6. 4-[l-(l-Cyelopentylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-dJpyrimidine trifluoroacetate salt 4-[l-(l-Cyclopentylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidine (13 mg, 0.030 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The resulting solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in THF (2 mL), and 6 N NaOH (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and then was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (10 nag, 80%). 1H NMR (400 MHz, ds-DMSO): £12.73 (s, 1H), 8.88 (s, 2H), 8.43 (s, 1H), 7.79 (t, 1H), 7.19 (dd, 1H), 5.60 (ddt, 1H), 5.00-4.93 (m, 1H), 4.91-4.87 (m, 1H), 4.23 (dt, 1H), 2.76-2.59 (m, 2H), 2.47-2.34 (m, 1H), 1.92-1.82 (m, 1H), 1.68-1.22 (m, 6H), 1.21-1.09 (m, 1H); MS(ES):308(M+H). Step I. 4-[l-(l-Cyclopentyl-2-cyclopropylethyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidine trijluoroacetate salt A solution of 4-[l-(l-cyclopentylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared in Example 727, Step 5) (54.0 mg, 0.123 mmol) in DCM (1 mL) was added to a freshly prepared ethereal solution of excess CH2N2 held at 0 °C. Palladium acetate (10.0 mg, 0.044 mol) was added. After standing for 2 hours, the excess CH2N2 was quenched by the addition of acetic acid. The solution was then diluted with further DCM, washed successively with saturated sodium bicarbonate solution, water, and brine, and dried over sodium sulfate, and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (13 mg, 18%). 'H NMR (300 MHz, CDC13): £ 9.05 (s, 1H), 8.81 (d, 1H), 8.35 (s, 1H), 7.59 (t, 1H), 7.03 (t, 1H), 5.76 (s, 2H), 4.10 (t, 1H), 3.59 (t, 2H), 2.57-2.36 (m, 1H), 2.15-2.00 (m, 1H), 2.00-1.83 (m, 1H), 1.79-1.40 (m, 6H), 1.37-1.09 (m, 2H), 0.97 (t, 2H), 0.55-0.26 (m, 3H), 0.07- "0.15 (m, 11H); MS(ES):452(M+H). Step 2. 4-[l-(lCyclopentyl-2-cyclopropylethyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrirnidinfi trijluoroacetate salt 4-[l-(l-Cyclopentyl-2-cyclopropylethyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3-d3pyrimidine.trifluoroacetatc salt (13 mg, 0.023 mol) was stilted at room temperature in a solution of DCM (2 mL) containing TFA (1.5 mL) for two hours. The solvent was removed in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stirring for one hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification, via preparative-HPLC/MS (Cl 8 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (9 mg, 90%). 1H NMR (400 MHz, dg-DMSO): § 12.75 (s, 1H), 8.90 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.81 (s, 1H), 7.22 (s, 1H), 4.19 (dt, 1H), 2.43-2.29 (m, 1H), 2.03-1.92 (m, 1H), 1.88-1.76 (m, 1H), 1.68-1.37 (m, 5H), 1.35-1.08 (m, 3H), 0.43-0.26 (m, 2H), 0.24-0.13 (m, 1H), 0.07- 0.03 (m, 1H), 0.14- "0.24 (m, 1H); MS(ES):322(M+H). Step 1. 4-[l-(l-Cyclopentylbut-3-yn-l-yl)-lH-pyrazol1-4yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrlmidine To a mixture of potassium carbonate (38.4 mg, 0.278 mmol) in methanol (2.0 mL) at 0 °C was added a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (prepared as in Example 727, step 4) (61.0 mg, 0.139 mmol) in methanol (1.0 mL), followed by a solution of dimethyl (l-diazo-2-oxopropyl)phosphonate (40.0 mg, 0.208 mmol) in methanol (1.0 mL). The mixture was slowly warmed to ambient temperature and stirred for 16 hours. The mixture was then diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, saturated ammonium chloride, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the product, which was used without further purification (52 mg, 86%). H NMR (300 MHz, CDC13): 5 8.85 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.41 (d, 1H), 6.84 (d, 1H), 5.67 (s, 2H), 4.14 (ddd, 1H), 3.53 (t, 2H), 2.90 (ddd, 1H), 2.79 (ddd, 1H), 2.66-2.49 (m, 1H), 1.98 (t, 1H), 2.00-1.88 (m, 1H), 1.78-1.44 (m, 5H), 1.39-1.11 (m, 2H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):436(M+H). Step 2. 4-[l-(l-Cyclopenfylbut-3-yn-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrirnidine trifluoroacetate salt A solution of 4-[l-(l-cyclopentylbut-3-yn-l-yl)-lH-pyrazol-4-yl3-7-[2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo{2,3-d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred for 2 hours. The solvents were removed in vacuo. The resulting residue was dissolved in THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded product (30 mg, 60%). 1H NMR (300 MHz, d6-DMSO): § 12.72 (s, 1H), 8.91 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.80 (s, 1H), 7.19 (s, 1H), 4.34 (dt, 1H), 2.97-2.69 (m, 3H), 2.50-2.32 (m, 1H), 1.93-1.77 (m, 1H), 1.70-1.09 (m, 7H); MS(ES):306(M+H). 4-[l-(1 -Cyclopentylbut-3-yn-l -yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd-C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg 69%). 1H NMR (400 MHz, d6-DMSO): § 12.73 (s, 1H), 8.86 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.79 (t, 1H), 7.20 (d, 1H), 4.11 (dt, 1H), 2.43-2.26 (m, 1H), 2.02-1.70 (m, 3H), 1.68-1.35 (m, 4H), 1.33-0.89 (m, 5H), 0.83 (t, 3H); MS(ES):310(M+H). Example 732: 4-[l-(l-Cyclopentyl-4,4-difluorobut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3- d]pyrimidine trifluoroacetate salt Step 1. 4-[l-(l-Cyclopentyl-4,4-difluorobut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trirnethylsilyl)ethoxy]- methyl- 7H-pyrrolo[2,3-dJpyrimidine To a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (prepared as in Example 727, Step 4) (181 mg, 0.41 mmol) in N.N-dimethylacetamide (3.6 mL) was added triphenylphosphine (294 mg, 1.12 mmol) followed by dibromodifluoromethane (235 mg, 1.12 mmol). Rieke® Zinc (1.8 mL of a suspension of 2.5 g in 50 ml THF) was then added in one portion. The resulting mixture was stirred at room temperature for 4.5 hours. The mixture was filtered through diatomaceous earth. The filtrate was partitioned between ether and water. The ether layer was washed with water, and brine, then dried over sodium sulfate, and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0- 30% ethyl acetate in hexanes) afforded product (104 mg, 53%). 1H NMR (400 MHz, CDC13): £ 8.91 (s, 1H), 8.51 (br s, 1H), 8.34 (s, 1H), 7.51 (d, 1H), 6.93 (d, 1H), 5.74 (s, 2H), 4.05 (ddd, 1H), 4.04-3.96 (m, 1H), 3.60 (t, 2H), 2.78-2.62 (m, 2H), 2.58-2.45 (m, 1H), 2.07-0.87 (m, 10H), 0.00 (s, 9H); MS(ES):474(M+H). Step 2. 4-[l-(l-Cyclopentyl-4,4-difluorobut-3-en-l-yl)~lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin.e trifluoroacetate salt A solution of 4-[l-(l-cyclopentyl-4,4-difluorobut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(tri- methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (41 mg, 0.086 mmol) in DCM (3 mL) and TFA (1.5 mL) was stirred for two hours at room temperature. The solution was then concentrated in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via' preparative- HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the desired product (39 mg, 98%). 'H NMR (400 MHz, ds-DMSO): 8 12.72 (s, 1H), 8.84 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.80 (t, 1H), 7.18 (d, 1H), 4.32 (ddt 1H), 4.20 (dt, 1H), 2.72-2.37 (m, 3H), 1.95-1.81 (m, 1H), 1.69-1.06 (m, 7H); MS(ES):344(M+H). Where conjugate acceptors, such as were used in Example 737, Step 3 were not commercially available, such compounds were generated according to the procedure provided below for ethyl (2E)- 3-(tetrahydrofuran-3-yl)acrylate (toward the preparation of Example 733). Preparation of ethyl (2E)-3-(tetrahydrofuran-3-yl)acrylate: To a solution of Dess-Martin periodinane (3.37 g, 7.95 mmol) in DCM (20 mL) was added tetrahydrofuran-3-ylmethanol (0.701 mL, 7.23 mmol). The reaction was stirred at ambient temperature for 2 hours, and the solvent was then removed in vacuo. Flash column chromatography (using DCM as eluent) afforded the product as a clear oil, which was used without further purification. 1H NMR (400 MHz, CDC13): & 9.65 (d, 1H), 4.12-4.07 (m, 1H), 3.92-3.85 (m, 2H), 3.80-3.73 (m, 1H), 3.10-3.02 (m, 1H), 2.26-2.10 (m, 2H). Step B: Ethyl (2E)-3-(tetrahydrofuran-3-yl)acrylate To a 0 °C mixture of sodium hydride (60% in mineral oil) (382 mg, 9.40 mmol) in DMF (15.0 mL) (THF may also be used) was added triethyl phosphonoacetate (1.72 mL, 8.68 mmol) dropwise. The resulting mixture was warmed to room temperature and stirred for 30 minutes, then was re-cooled to 0 °C, at which time a solution of tetrahydrofuran-3-carbaldehyde (724 mg, 7.23 mmol) in DMF (4.0 mL) was added dropwise. The resulting mixture was stirred at this temperature for 1.5 hours, at which time the mixture was diluted with water and the product was extracted with ether. The combined extracts were washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-40% ethyl acetate in hexanes) afforded the product (640 mg, 52%). 'H NMR (400 MHz, CDC13): 5. 6.87 (dd, 1H), 5.86 (dd, 1H), 3.96-3.88 (m, 2H), 3.81 (dd, 1H), 3.53 (dd, 1H), 3.04-2.93 (m, 1H), 2.20-2.10 (m, 1H), 2.03 (s, 3H), 1.79 (dq, 1H). Example 736: 4-Il-(l-Cyclopentyl-4,4-difluorobutyl)-lH-pyrazol-4-yl]-7H-pyrroloI2,3-d]- pyrimidine trifluoroacetare salt 4-[ 1 -(1 -Cyclopentyl-4,4-difluorobut-3 -en-l-yl)-l H-pvrazol-4-yl]-7H-pyrrolo[2,3 -d]- pyrimidine trifluoroacetate salt (prepared as in Example 731) (20.0 mg, 0.041 mmol) was dissolved in methanol (3 mL), and a catalytic amount of 5% Pd on C was added. The mixture was stirred at room 5 temperature for 2 hours, under an atmosphere of hydrogen provided by an affixed balloon. The mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford product (4 mg, 21%). 1H NMR (400 MHz, de-DMSO): 8 12.74 (s, 1H), 8.88 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.80 (t, 1H), 7.20 (dd, 1H), 6.05 (tt, 1H), 4.17 (dt, 1H), 2.47-2.34 (m, 1H), 2.14-1.08 (m, 12H); MS(ES):346(M+H). Example 737: 3-(l-Methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]propanenitrile trifluoroacetate salt To a solution of cyclopentanecarbaldehyde (1.00 mL, 9.36 mmol) in DCM (47 mL) at 0 °C was added solid potassium terf-butoxide (1.44 g, 12.2 mmol) in one portion followed by methyl iodide (1.7 mL, 28 mmol) in one portion. After 30 minutes at 0 °C, the reaction mixture was allowed to warm to room temperature and stirred at that temperature for 16 hours. The mixture was poured into brine, and the layers were separated. The organic layer was dried over sodium sulfate, decanted and concentrated, and used without further purification in Step 2. Step 2: (2Z)- and (2E)-3-(l-Methylcyclopentyl)acrylonitrile To a solution of 1.0 M potassium terf-butoxide in THF (9.36 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (1.59 mL, 9.81 mmol) in THF (10 mL) dropwise. The cooling bath was removed and the reaction was wanned to room temperature followed by re-cooling to 0 °C, at which time a solution of 1-methylcyclopentanecarbaldehyde (1.0 g, generated in Step 1) in THF (2 mL) was added dropwise. The bath was removed and the reaction was stirred at ambient temperature for 3 hours. To the mixture was added water and ethyl ether. The aqueous layer was further extracted with ethyl ether. The combined extracts were washed with brine, dried over sodium sulfate, filtered and adsorbed onto silica gel in vacuo. Flash column chromatography (eluting with a gradient from 0-10% ethyl acetate in hexanes) afforded product as a mixture with hexanes, which product was used without further purification in Step 3. Step 3: 3-(l-Methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile trifluoroacetate salt To a mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine (0.134 g, 0.426 mmol) in ACN (3 mL) was added a mixture of (2Z)- and (2E)-3-(l- methylcyclopentyl)acrylonitrile (0.12 g, 0.9 mmol) followed by DBU (0.13 mL, 0.90 mmol). The reaction was heated to 60 °C for 6 h. The ACN was removed in vacuo. Ethyl acetate was added, followed by 0.1 N HC1. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated. The crude material was deprotected by stirring with TFA (2 mL) in DCM (8 mL) for 2 hours. The solvent and TFA were removed in vacuo. THF (8 mL) was used to dissolve the residue, and 6.0 M sodium hydroxide in water (8 mL) was added. The reaction was stirred in this basic mixture for 2 hours. Ethyl acetate was used to extract the product. The combined extracts were dried (Na2SO4) and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded product (44 mg, 24%). 1HNMR (400 MHz, d6-DMSO): 6 12.71 (s, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.51 (s, 1H), 7.81 (s, 1H), 7.18 (s, 1H), 4.72 (dd, 1H), 3.47 (dd, 1H), 3.21 (dd, 1H), 1.74-1.51 (m, 6H), 1.44-1.32 (m, 1H), 1.09- 1.00 (m, 1H), 0.97 (s, 3H); MS(ES):321(M+H). Example 739: l-2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]ethylcycIo- propanecarbonitrile trifluoroacetate salt Stepl: l-(Hydroxymethyl)cyclopropanecarbomtrue Ethyl 1-cyanocyclopropanecarboxylate (801 mg, 5.76 mmol) in THF (12.0 mL) was treated with lithium tetrahydroborate (251 mg, 11.5 mmol). The solution was heated to reflux for 1.5 hours. Upon cooling to room temperature, the reaction was quenched with water, and extracted with ethyl acetate. The combined extracts were dried over MgSO4, filtered and concentrated to afford a clear oil, which was used without further purification in the following step (482 mg, 86%). 1H MMR (400 MHz, CDCl3): 5 3.61 (s, 2H), 1.27 (dd, 2H), 0.98 (dd, 2H). Step2: 1-Formylcyclopropanecarbonitrile Dess-Martin periodinane (1.11 g, 2.62 mmol) was dissolved in DCM (12 mL) and 1- (hydroxymethyl)cyclopropanecarbonitrile (231 mg, 2.38 mmol) was added. The reaction was stirred at ambient temperature for one hour. The mixture was then purified by flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes) to afford the product (106 mg, 46%). 1H NMR (400 MHz, CDC13): & 9.35 (s, 1H), 1.79-1.74 (m, 4H). Step 3: l-[(E)-2-Cyanovinyl]cyclopropanecarbonitrile To a solution of 1.0 M potassium tert-butoxide in THF (1.12 mL) at 0 °C was added slowly dropwise a solution of diethyl cyanomethylphosphonate (210 mg, 1.2 mmol) in THF (2 mL). The cold bath was removed and the reaction was warmed to ambient temperature. The solution was then re- cooled to 0 °C and a solution of 1-formylcyclopropanecarbonitrile (101 mg, 1.06 mmol) in THF (1.0 mL) was added dropwise. The cold bath was removed and the reaction was stirred for 3 hours at ambient temperature. The mixture was then diluted with ether and water, the ether solution was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacua. Flash column chromatography (eluting with a gradient from 0-60% ethyl ether in hexanes) afforded the product (24 mg, 19%). 'H NMR (400 MHz, CDC13): £ 5.94 (d, 1H), 5.82 (d, 1H), 1.80 (dd, 2H), 1.39 (dd, 2H). Step 4: l-2-Cyano-l-[4-(7-[2-(trimethyIsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin~4-yl)-lH- pyrazol-l-yl]ethylcyclopropanecarbonitrile To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (61.4 mg, 0.0195 mmol) and l-[(E)-2-cyanovinyl]cyclopropanecarbonitrile (23 mg, 0.19 mmol) in ACN (2 mL) was added DBU (58 uL, 0.39 mmol) and the resulting mixture was stirred for 16 hours. The ACN was evaporated, and the residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HC1, water, and brine, and dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes) afforded the product (49 mg, 58%). 1H NMR (400 MHz, CDC13): § 8.85 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 3.54 (dd, 1H), 3.51 (dd, 1H), 3.36 (dd, 1H), 1.62 (ddd, 1H), 1.45 (ddd, 1H), 1.34 (ddd, 1H), 1.25 (ddd, 1H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):434(M+H). Step 5: l-2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylcyclopropane- carbonitrUe trifluoroacetate salt l-2-yano-l-[4-(7-[2-(1rimethylsilyl)emoxy]methyl-7H-pyrrzolo[23-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]ethylcyclopropanecarbonitrile (48 mg, 0.11 mmol) was stirred in a mixture of DCM (3 mL) and TFA (2 mL) for 3 hours. The solvents were removed in vacuo and the residue was re- dissolved in THF (3 mL). 6N NaOH (2 mL) was added and the resulting mixture was stirred at ambient temperature for 3 hours. The crude reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1 % TFA) afforded product (20 mg, 43%). 1H NMR (400 MHz, d6-DMSO): £12.74 (s, 1H)S 8.99 (s, 1H), 8.88 (s, 1H), 8.60 (s, 1H), 7.83 (t, 1H), 7.17 (dd, 1H), 4.55 (dd, 1H), 3.66 (dd, 1H), 3.54 (dd, 1H), 1.55-1.30 (m, 4H); MS(ES):304(M+H). Step 1: Methyl 1 -cyanocyclopentanecarboxylate To a solution of acetic acid, cyano-, methyl ester (2.66 mL, 30.3 mmol) and 1,4- dibromobutane, (3.62 mL, 30.3 mmol) in acetone (50 mL) was added potassium carbonate (8.37 g, 60.6 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction was filtered through diatomaceous earth and concentrated.. The resulting residue was partitioned between ether and saturated NH4C1 solution, and the aqueous layer was extracted with two further portions of ether. The combined ethereal extracts were washed with brine, and dried over sodium sulfate, then filtered and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded the product (2.92 g, 63%). 'H NMR (300 MHz, CDC13): £3.82 (s, 3H), 2.30-2.21 (m, 4H), 1.93-1.82 (m, 4H). Step 2: Methyl l-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate To a solution of methyl 1-cyanocyclopentanecarboxylate (1.26 g, 8.22 mmol) in methanol (100 mL) was added cobalt dichloride (2.1 g, 16.0 mmol). The purple mixture was cooled in an ice- water bath. Sodium tetrahydroborate (3.11 g, 82.2 mmol) was added portionwise with caution (exothermic) to provide a black mixture. Upon complete addition, cooling was discontinued and the reaction was .stirred for 40 minutes under nitrogen and the reaction was quenched by the careful addition of IN HCI (700 ml). The methanol was removed in vacuo, and the solution was then made alkaline (pH ~ 9) by the addition of concentrated NH4OH(aq). The mixture was extracted with DCM (6 times), and the combined DCM extracts were dried over sodium sulfate and concentrated to afford the crude product as a light yellow oil. To this crude amine in DCM (50 ml) was added di-tert- butyldicarbonate (1.31 g, 6.01 mmol) and the reaction was stirred at 25 °C for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.5 g, 71%). 'H NMR (300 MHz, CDC13): £ 5.03 (s, 1H), 3.69 (s, 3H), 3.26 (d, 2H), 2.02-1.33 (m, 17H). Step 3: tert-Butyl [l-(hydroxymethyl)cyclopentyl]methylcarbamate To a solution of methyl l-[(fer/-butoxycarbonyl)ammo]methylcyclopentanecarboxylate (1.50 g, 5.83 mmol) in THF (25.0 mL) at -78 °C was added dropwise 1.0 M diisobutylaluminum hydride in DCM (17.5 mL). The reaction was stirred for 2 hours with slow wanning to -10 °C. A saturated solution of K/Na tartrate was added, followed by ether. This mixture was stirred for 30 minutes at ambient temperature and the organic layer was separated and washed with water, and brine. The organic layer was then dried over sodium sulfate, and the solvent was removed in vacuo to afford the product (1.03 g, 77%). 'H NMR (300 MHz, CDC13): § 4.90 (br s, 1H), 3.27 (s, 2H), 3.06 (d, 2H), 1.5- 1.17 (m, 8H), 1.44 (s, 9H). Step 4: tert-Butyl [(l-formylcyclopentyl)methyl]carbamate To a solution of oxalyl chloride (456 L, 5.38 mmol) in DCM (30.0 mL) at -78 °C was added DMSO (637 L, 8.97 mmol) and the resulting mixture was stirred for 5 minutes. tert-Butyl [1- (hydroxymethyl)cyclopentyl]methylcarbamate (1.03 g, 4.48 mmol) in DCM (10.0 mL) was added and the resulting mixture was stirred for 30 minutes at -78 °C. TEA (2.50 mL, 17.9 mmol) was added and the resulting mixture was allowed to warm to ambient temperature over 30 minutes. Water was added. The organic phase was washed sequentially with 0.1 N HC1, water, saturated sodium bicarbonate solution, and brine, and then dried over sodium sulfate and the solvent was removed in vacua to afford the product (957 mg, 94%). ]H NMR (300 MHz, CDC13): 5 9.39 (s, 1H), 4.94 (br s, 1H), 3.25 (d, 2H), 1.89-1.46 (m, 8H), 1.41 (s, 9H). Step 5: tert-Butyl (l-[(E)-2-eyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (l-[(Z)-2-cyano- vinyl]cyclopentylmethyl)carbamate To a solution of 1.0 M potassium tert-butoxide in THF (4.4 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (820 mg, 4.6 mmol) in THF (6.0 mL) dropwise. The cold bath was removed and the reaction was warmed to ambient temperature. The mixture was then re-cooled to 0 °C and a solution of tert-butyl [(l-formylcyclopentyl)methyl]carbamate (952 mg, 4.19 mmol) in THF (4.0 mL) was added dropwise. The reaction was allowed to warm to ambient temperature and the wanned mixture was stir for 16 hours. The reaction mixture was then diluted with ether and water. The organic layer was separated and washed sequentially with water and brine, then dried over sodium sulfate, then filtered, and the solvent was removed in vacuo to afford the product (1.05 g, 99%) as a mixture of (E) and (Z) isomers. 1H NMR (300 MHz, CDC13): 8 6.71 (d, 1H, E), 6A6 (d, 1H, Z), 5.36 (d, 1H, Z), 5.36 (d, 1H, £), 4.70 (br s, 1H, 2), 4.51 (br s, 1H, E), 3.25 (d, 2H, Z), 3.18 (d, 2H, £), 1.88-1.48 (m, 8H (E) and 8H (Z», 1.43 (s, 9H (E) and 9H (£)); MS(ES):151(M+H-Boc). Step 6: tert-Butyl [(l-2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]rnethyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-JH-pyrazol-l-yl]ethylcyclopentyl)methyl]carbamate To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (355 mg, 1.12 mmol) and tert-butyl (l-[(E)-2-cyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (l-[(Z)-2-cyanovinyl]cyclopentylmethyl)carbamate as a mixture of isomers (329 mg, 1.31 mmol) in ACN (10 mL) was added DBU (0.168 mL, 1.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours followed by heating to 60 GC for 2.5 hours. The ACN was removed in vacuo and the resulting residue was purified by flash column chromatography (eluting with 0-55% ethyl acetate in hexanes) to afford the product (350 mg, 55%). 1H NMR (300 MHz, CDClj): £ 8.85 (s, 1H), 8.37 (br s, 1H), 8.34 (s, 1H), 7.41 (d, 1H), 6.82 (d, 1H), 5.68 (s, 2H), 5.37 (br s, 1H), 4.52 (dd, 1H), 3.54 (t, 2H), 3.40 (dd, 1H), 3.23 (dd, IH), 3.08 (d, 1H), 2.90 (dd, 1H), 1.84-1.47 (m, 8H), 1.45 (s, 9H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):566(M+H). Siep 7: N-[(l-2-Cyano-l-[4-(7H-pyrralo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylcyclopentyl)- methyljbenzamide A solution of tert-bxxtyl [(l-2-cyano-l-[4-(7-t2-(trimethylsilyl)ethoxy]methyl-7H-pyrroIo[2,3- d]pyrimidin-4-yl)-lH-pyrazo]-l-yl]ethylcyclopentyl)memyl]carbamate (175 mg, 0.309 mmol) in DCM (5 mL) and TFA (5 mL) was stirred for 3 hours and the solvents were then removed in vacuo. The resulting residue was stirred in a mixture of THF (3 mL) and 6N NaOH (3 mL) for 3 hours. The THF was removed in vacuo, and water (10 mL) was added. The mixture was extracted with several portions of DCM containing 15% isopropanol. The combined extracts were dried over sodium sulfate and the solvents were removed in vacuo to afford the product, which was used without further purification. MS(ES):336(M+H). To a solution of 3-[l-(aminomethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]propanenitrile (31 mg, 0.060 mmol) and benzoyl chloride (7.0 L, 0.060 mol) in DCM (1.0 mL), was added TEA (17 L, 0.12 mmol). After 15 minutes, the solvent was removed in vacuo and the mixture was purified via preparative-HPLC/MS (C18 eluting first with a gradient of H2O and ACN containing 0.1% TFA, followed by chromatographic purification, eluting with a gradient of H2O and ACN containing 0.15% NH4OH) to afford the product (7 mg, 27%). 'H NMR (400 MHz, d6-DMSO): £12.12 (s, 1H), 8.95 (s, IH), 8.68 (s, IH), 8.55 (s, 1H), 8.41 (s, IH), 7.92-7.87 (m, 2H), 7.60 (d, IH), 7.59-7.48 (m, 3H), 7.02 (d, IH), 4.83 (dd, 1H), 3.52-3.45 (m, 2H), 3.42 (dd, IH), 3.27 (dd, 1H), 2.06-1.95 (m, IH), 1.68-1.12 (m, 7H); MS(ES):440(M+H). Step 1: l-(Hydroxymethyl)cyclopentanecarbonitrile A mixture of methyl 1-eyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours. The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, then filtered and the solvent was removed in vacua to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDC13): 53.62 (s, 2H), 2.39-1.60 (m, 8H). Step 2: l-[(Benzyloxy)methyl]cyclopentanecarbonitrile To a solution of l-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol). The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%). 1H NMR (300 MHz, CDC13): £7.40-7.27 (m, 5H), 4.62 (s, 2H), 3.44 (s, 2H), 2.18-2.03 (m, 2H), 1.90- 1.62 (m,6H). Step 3: l-[(Benzyloxy)methyl]cyclopentanecarbaldehyde To a mixture containing l-[(benzyloxy)methyl]cyclopentanecarbonitrile (0.16 g, 0.75 mmol) in toluene (5 mL) at 0 °C was added 1.0 M diisobutylaluminum hydride in hexanes (0.8 mL). The reaction was stirred at 0 °C for 1.5 hours, during which time the starting nitrile was consumed. The reaction was cooled to -78 °C and quenched by the addition of methanol. The mixture was warmed to ambient temperature and 3 N HC1 was added. Following stirring for 45 minutes, solid NaCl was added, and the mixture was extracted with three portions of ethyl acetate. The combined extracts were dried (Na2SO4), and filtered, and the solvent was removed in vacuo. Flash column chromatography of the resulting residue (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded the product (20 mg, 12%). 1H NMR (300 MHz, CDC13): 6 9.60 (s, 1H), 7.38-7.26 (m, 5H), 4.52 (s, 2H), 3.54 (s, 2H), 2.00-1.89 (m, 2H), 1.66-1.46 (m, 6H). Step 4: (2E)- and (2Z)-3-I-[(Benzyloxy)methyl]cyclopentylacrylonitriIe To a stirred solution of diethyl cyanomethylphosphonate (18 L, 0.11 mmol) in THF (1 mL) was added 1.0 M potassium tert-butoxide in THF (0.10 mL). The resulting mixture was stirred 30 minutes, after which a solution of l-[(benzyloxy)methyl]cyolopentanecarbaldehyde (0.020 g, 0.092 mmol) in THF (1 mL) was added. The resulting mixture was stirred for 16 hours. Water was then added to the reaction and the resulting mixture was extracted with three portions of ethyl ether. The combined extracts were washed with brine, then dried over sodium sulfate, decanted from the sodium sulfate, and the solvent was removed in vacuo to afford the product, which was used without further purification in the subsequent conjugate addition step. 1H NMR (400 MHz, CDCl3): § 7.37-7.27 (m, 5H), 6.80 (d, 1H (E)), 6.59 (d, 1H (Z)), 5.34 (d, 1H (E)), 5.33 (d, 1H (Z)), 4.53 (s, 2H (Z)), 4.50 (s, 2H (E)), 3-45 (s, 2H (Z)), 3.31 (s, 2H (E)), 1.80-1.55 (m, 8H); MS(ES>=242(M+H). Step 5: 3-l-[(Benzyloxy)methylJcyclopentyl-3-[4-(7H-pyrrolo[2,3-dJpyrimidin-4-yl)-lH-pyrazal-l- yljpropanenitrile trifluoroacetate salt To a mixture of (2E)- and (2Z)-3-l-[(benzy]oxy)methyl]cyclopentylacrylonitrile (generated in Step 4) and 4-(lH-pyrazo1-4-yl)-7-[2-(trimemylsilyl)emoxy]meth.yl-7H-pynx3lo[2,3-d]pyrirnidine (0.037 g, 0.12 mmol) in ACN (1.5 mL) was added DBU (18 fiL, 0.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours, and then was heated to 60 °C for 28 hours. The reaction mixture was diluted with diethyl ether and 0.1 N HC1. The layers were separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, decanted, and the solvent was removed in vacuo. The resulting residue was dissolved in DCM (3 mL) and TFA (0.75 mL), and this solution was stirred for 3 hours. The solvents were removed in vacuo, and the resulting residue was dissolved in THF (5 mL) and 6.0 M sodium hydroxide in water (3 mL) and stirred for 2 hours. The reaction mixture was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted, and the solvent was removed in vacuo. The crude mixture was purified by preparative- HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) and lyophilized to afford the desired product (10 mg, 20% over the two steps). 'H NMR (400 MHz, de-DMSO): $12.71 (br s, 1H), 8.99 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 7.80 (s, 1H), 7.38-7.23 (m, 5H), 7.19-7.16 (m, 1H), 4.92 (dd, 1H), 4.50 (d, 1H), 4.44 (d, 1H), 3.49 (dd, 1H), 3.35 (d, 1H), 3.23 (dd, 1H), 3.05 (d, 1H), 1.92-1.82 (m, 1H), 1.66-1.27 (m, 7H); MS(ES):427(M+H). Example 742: 3-[l-(MethyIsuIfonyl)pyrroIidin-3-yl]-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-lH- pyrazol-l-yl]propanenitrile trifluoroacetate salt Step 1: Benzyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate To a solution of l-[(benzyloxy)carbonyl]pyrrolidine-3-carboxylic acid (1.0 g, 4.0 mmol) in THF (37 mL) at 0 °C was added dropwise a solution of 1.0 M borane in THF (16.4 mL). The reaction was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to 0 °C and 10% HC1 (50 mL) was added. After the addition, the mixture was extracted with DCM, and the extract was washed sequentially with saturated NaHCQ3 solution and brine, then dried over sodium sulfate, filtered and the solvent was removed in vacuo. The product was used without further purification in the subsequent oxidation step. 'H NMR (300 MHz, CDC13): £ 7.39-7.26 (m, 5H), 5.11 (s, 2H), 3.61-3.31 (m, 5H), 3.18 (dt, 1H), 2.75 (br s, 0.45H), 2.59 (br s, 0.45H), 2.49-2.31 (m, 1H), 2.19 (br s, 0.1H), 2.05-1.89 (m, 1H), 1.77- 1.58 (m, 1H); MS(ES):236(M+H). Step 2: Benzyl 3-formylpyrrolidine-l-carboxylate DMSO (597 L,, 8.42 mmol) was added to a solution of oxalyl chloride (427 L, 5.05 mmol) in DCM (25 mL) at -78 °C. After 5 minutes, benzyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate (generated in Step 1) was added. The reaction was continued for 30 minutes at -78 °C. TEA (2.3 mL, 17 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over the course of 30 minutes. Water was then added. The layers were separated and the organic phase was washed sequentially with 0.1 N HC1, water, saturated NaHCO3, and brine. The organic phase was then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (0.82 g, 88% over two steps). !H NMR (300 MHz, CDC13): 0 9.68 (d, 1H), 7.38-7.28 (m, 5H), 5.13 (s, 2H), 3.79 (dd, 1H), 3.65-3.35 (m, 3H), 3.11-2.99 (m, 1H), 2.32-2.04 (m, 2H). Step 3: Benzyl 3-[(E)-2-cyanovinyl]pyrrolidine-l-carboxylate and benzyl 3-[(Z)-2-cyanovinyl]- pyrrolidine-1 -carboxylate To a solution of 1.0 M potassium tert-butoxide in THF (4.40 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (820 mg, 4.6 mmol) in THF (6.0 mL) dropwise. The cold bath was removed and the reaction was wanned to room temperature and stirred for 15 minutes. The mixture was cooled to 0 °C and a solution of benzyl 3-formylpyrrolidine-l-carboxylate (0.82 g, 2.3 mmol) in THF (4.00 mL) was added dropwise. Cooling was discontinued and the reaction stirred for 16 hours at ambient temperature. The mixture was diluted with ether and water, the layers were separated and the organic layer was washed with water, followed by brine, and then dried aver sodium sulfate, filtered and the solvent was removed in vacuo. The resulting residue was purified by flash column chromatography (eluting with a gradient from 0-35% ethyl acetate in hexanes) to afford the product as a mixture of E and Z isomers (246 mg, 42%). 'H NMR (300 MHz, CDC13): 8 7.41-7.27 (m, 5H), 6.70-6.58 (m, 0.3H (E)), 6.38 (dt, 0.7H (2)), 5.50- 5.30 (m, 1H), 5.14 (s, 2H), 3.79-3.11 (m, 5H), 2.27-2.06 (m, 1H), 1.90-1.70 (m, 1H); MS(ES):279(M+Na). Step 4: Benzyl 3-2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-ylJethylpyrrolidine-l-carboxylate To a mixture of benzyl 3-[(E)-2-cyanovinyl]pyrroh'dine-l-carboxylate and benzyl 3-[(Z)-2- cyanovinyllpyrrolidine-1-carboxylate (241 mg, 0.940 mmol) and DBU (234 L, 1.57 mmol) in ACN (13 mL) was added 4-(lH-pyrazol-4-yl)-7-[2-(trimethy]silyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine (250 mg, 0.78 mmol). The mixture was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed sequentially with IN HC1, water, saturated NaHCO3, and brine. The washed solution was dried over sodium sulfate and the solvent was removed in vacuo. Purification via flash column chromatography (eluting with a gradient of 0-100% [5% MeOH/DCM] in hexanes) afforded the produce as a mixture of diastereomers (400 mg, 89%). 1H NMR (400 MHz, CDC13 a mixture of diastereomers):§ 8.85 (s, 1H), 8.35-8.28 (m, 2H), 7.42-7.25 (m, 6H), 6.80-6.76 (m, 1H), 5.69-5.66 (m, 2H), 5,15-5.04 (m, 2H), 4.46-4.32 (m, 1H), 3.84-3.84 (m, 6H), 3.54 (t, 2H), 2.26-2.13 (m, 1H), 1.84-1.54 (m, 2H), 0.95-0.89 (m, 2H), -0.06 (s, 9H); MS(ES):572(M+H). Step 5. 3-Pyrrolidin-3yl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl]propanenitrile Benzyl 3-2-cyano-l-[4-(7-[2-(trimethyIsiIyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidm-4- yl)-lH-pyrazol-l-yl]ethylpyrrolidine-l-carboxylate (161 mg, 0.282 mmol) was dissolved in methanol (5 mL), and a catalytic amount of 5% Pd-C was added. The suspension was stirred at ambient temperature for 1 hour under an atmosphere of hydrogen provided by a balloon. A catalytic amount of 10% Pd-C was then added, and the reaction stirred for 2 hours under an atmosphere of hydrogen provided by a balloon. The mixture was then filtered, and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing G. 15% NH4OH) to afford the product as a mixture of diastereomers (57 mg, 46%). 1H NMR (400 MHz, CDC13, a mixture of diastereomers): 5 8.84 (s, 1H), 8.34-8.32 (m, 2H), 7-40 (d, 1H), 6.81-6.78 (m, 1H), 5.67 (s, 2H), 4.38 (dt, 1H), 3.54 (t, 2H), 3.30-1.38 (m, 9H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):438(M+H). Step 6: 3-[l-(Methylsulfonyl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2J-d]pyrimidin-4-yl)-1H- pyrazol-1 yl]propanenitrile trifluoroacetate salt To a solution of 3-pyrrolidin-3-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3- d]pyrimidinyl)lH-pyrazol-l-yl]propanenitrile (25 mg, 0.057 mmol) and TEA (10 L, 0.074 mmol) in DCM (1.0 mL) at 0 °C was added methanesulfonyl chloride (6 L, 0.074 mmol). The reaction was allowed to reach ambient temperature and stir for 16 hours. Half of the solvent was removed in vacuo and TFA (1 mL) was added to the vial. After stirring for 1 hour at room temperature, the solvents were removed in vacuo and the resulting residue reconstituted in THF (0.5 mL). To this was added 6 N NaOH (1 mL) and this solution was stirred for 2 hours. The reaction mixture was extracted with five portions of ethyl acetate. The combined extracts were dried (Na2SO4), decanted and concentrated. Preparative-HPLC/MS (Cl 8 eluting with a gradient of H2O and ACN containing 0.1% TFA) was used to afford the product (16 mg, 57%). 'H NMR (400 MHz, ds-DMSO, a mixture of diastereomers): 8 12.69 (s, 1H), 8.98 (s, 0.5H), 8.95 (s, 0.5H), 8.84 (s, 1H), 8.53-8.51 (m, 1H), ,7.80-7.77 (m, 1H), 7.16-7.13 (m, 1H), 4.86-4.75 (m, 1H), 3.55-3.48 (m, 1H), 3.42-3.08 (m, 4H), 2.99-2.91 (m, 1H), 2.90 (s, 1.5H), 2.85 (s, 1.5H), 2.16-2.07 (m, 1H), 1.82-1.70 (m, 1H), 1.64-1.48 (m, 1H); MS(ES):386(M+H). Step I: tert-Butyl 4-(cyanomethylene)piperidine-l-carboxylate To a solution of 1.0 M potassium ter/-butoxide in THF (10.1 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (1.66 mL, 0.0102 mol) in THF (20 mL) dropwise. The reaction was held for 10 min, then added to a solution of ferf-butyl 4-oxo-l-piperidinecarboxylate (2.00 g, 0.0100 mol) in THF (30 mL) stirring at 0 °C under an atmosphere of nitrogen. After complete addition, the cold bath was removed and the reaction was allowed to stir 1.0 h at 20 °C. LGMS analysis showed the desired product and no remaining starting material. HPLC showed the product UVmax at 200 & 230 nm. Water and EtOAc were added to the reaction mixture. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, then saturated NaCl, then dried over Na2SO4, and concentrated to drysoess to provide 2.5 g of the product as a yellow oil. TLC (25% EtOAc/hexane) Rf 0.22. The product was purified by automatic flash chromatography on silica gel. Used a 40g column; flow 40 mL/min; [A= hexane] [B= EtOAc]. A, 4 min; Gradient to 20% B in 30 min. Collected 44 mL fractions. The product eluted in 21-27 min. The fractions were contrated to yield 0.67 g of a white solid. lH NMR (CDC13) 8 5.19 (s, 1H); 3.51 (m, 4H); 2.56 (t, 2H); 2.33 (t, 2H); 1.50 (s, 9H). MS(ES) 245 (M+Na, weak; base peak M+H-56 = 167). Step 2: tert-Butyl 4-(cyanomethyl)-4-[4-(7-[2-(tHmethylsilyl)ethoxy]methyl'7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]piperidine-l-carboxylate 4 g, 2.66 mmol) was slurried in a mixture of ACN (20 mL) and DBU (398 \iL, 2.66 mmol), and tert- butyl 4-(cyanomethylene)piperidine-l-carboxylate (0.651 g, 2.93 mmol) was added. The pyrazole did not dissolve at 20° C, but a solution was formed when the mixture was heated to 40 °C for l h. LCMS and HPLC analyses showed about 20% conversion to product. The mixture was stirred at 40-45 °C overnight. HPLC showed 60 area% product. The ACN was removed by retory evaporator at 20 °C. To the resulting residue was added saturated NaHCO3 and EtOAc. The organic layer was shaken with more aqueous saturated NaHCO3, then dried (Na2SO4) and rotovaped to give 1.6g of a brown oil residue. TLC (60% EtOAc/hexane): product Rf = 0.25. The product was purified by automatic flash chromatography on silica gel, using a 40g column, at a flow of 40 mL/min; [A= hexane] [B= EtOAc]. A, 3min; Gradient to 100% B in 50 min. Collected 44 mL fractions. The product eluted in 24-29 min; the pyrazole in 39-46 min; and the olefin in 13-15 min. Solvent was removed in vacuo for the appropriate fractions to give 0.27 g olefin; 0.30 g pyrazole; and a yield of 0.67 g of the product, all of which were isolated as white solids. 1H NMR (CDC13) 8 8.84 (s, 1H); 8.42 (s, 1H); 8.33 (s, 1H); 7,40 (d, 1H); 6.79 (d, 1H); 5.67 (s, 2H); 3.94 (m, 2H); 3.54 (m, 2H); 3.07 (m, 2H); 2.90 (s, 2H); 2.72 (m, 2H); 2.08 (m, 2H); 1.45 (s, 9H); 0.91 (m, 2H); -0.06 (s, 9H). MS(ES) 538 (M+H). Step 3: 4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]piperidin-4-ylacetonitrile tert-Butyl 4-(cyanomethyl)-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]piperidine-l-carboxylate (0.670 g, 1.24 mmol) was dissolved in TFA (5.0 mL, 65 mmol) and was stirred for 1.3 h. LCMS showed conversion to the hydroxymethyl intermediate, M+H 338. The solution was concentrated to remove the TFA. Methanol was added to the resulting residue, and the resulting mixture was concentrated. The resulting residue was dissolved in methanol (10 mL) and 15.0 M ammonium hydroxide in water (1.66 mL) was added. The resulting solution was stirred for 2 h. LCMS and HPLC analyses showed complete deprotection. The mixture was concentrated. Toluene was added to the resulting residue and the resulting mixture was concentrated to provide a white semisolid. Most of this intermediate product was used for the next step. The rest was purified by prep HPLC using a 30 mm x 100 mm C18 column; 8% ACN-H2O (0.1% NH4OH), l.Omin, to 27% at 6min; 60 mL/min; detector set at m/z 308; retention time, 5.4 min. Tubes containing pure product were combined and freeze dried to give 13.6 mg of the product. 1H NMR (ds-DMSO) 8 12.07 (s, 1H); 8.68 (s, 1H); 8.62 (s, 1H); 8.36 (s, 1H); 7.54 (d, 1H); 7.00 (d, 1H); 3.16 (s, 2H); 2.87 (m, 2H); 2.55 (m, 4H); 1.94 (m, 2H). MS(ES) 308 (M+H). Step 4: Methyl N-cyano-4-(cyanomethyl)~4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- piperidine-1-carbimidothioate 4-[4-(7H-Pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]piperidln-4-ylacetomtrile (361 mg, 1.17 mmol) and iV-cyano-S',S-dimethyldithioimido carbonate (344 mg, 2.35 mmol) were dissolved in isopropyl alcohol (2.5 mL) and DMSO (2.5 mL) at 20 °C. After 16 h reaction time, LCMS analysis showed the presence of some product, M+H 406; of the reagent, M+H 147; and of the piperidine, M+H 308. HPLC analysis showed about 2% reaction. The HPLC method was: Zorbax SB C18, 5m, 15 cm, 35 °C, flow 1.2 mL/min, 5% ACN-H2O (0.05% TFA), 1.5 min, to 100% ACN in 15.0 min; detector set at 324, 225, and 265 nm. The retention time of the starting material was 4.9 min (UV max 224, 262,292, & 325 nm); of the product, 6.5 min (UV max 226,262,290, & 324nm); and of the reagent, 7.7min (UV max 265nm). To the product was added TEA (327 L, 2.35 mmol), and the resulting mixture was stirred at RT. After stirring for 3 h, HPLC and LCMS analyses showed 60% reaction. The product and the unreacted piperidine were isolated by prep HPLC using a 30 mm x 100 mm C18 column; 5%ACN-H2O (0.1%TFA), l.Omin, to 35% at 6min; 60 mL/min; detector set at 326 nm. The retention time for the product was 5.9 min; and for the starting piperidine was 3.5-4.3 min. The product was freeze dried to yield 301 mg of a white solid TFA salt. 1H NMR (d6-DMSO) 6 12.85 (s, 1H); 9.01 (s, 1H); 8.90 (s, 1H); 8.59 (s, 1H); 7.85 (m, 1H); 7.30 (m, 1H); 4.23 (m, 2H); 3.35 (m, 2H); 3.30 (s, 2H); 2.78 (m, 2H); 2.68 (s, 3H); 2.16 (m, 2H). MS(ES) 406 (M+H). Step 5: N'-Cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]piperi- dine-1-carboximidamide Methyl N-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pvrazol-l-yl]- piperidine-1-carbimidothioate (41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M ammonia in isopropyl alcohol (4.00 mL). The resulting mixture was heated to 100 °C for 1 h in a microwave reactor. Analysis by HPLC and LCMS showed 60% reaction to give the expected M+H 375 (50 area%). To this mixture was added 2 mL of 7 N NH3/MeOH. The resulting mixture was heated at 120 °C for one hour. HPLC and LCMS analyses showed no remaining starting material. The reaction mixture was concentrated on a rotory evaporator. The product was isolated by prep HPLCMS using a 30 mm x 100 mm C18 column, eluting with a solvent gradient; 10% ACN-H2O (0.1%TFA), 1.5min, to 30% at 6min; 60mL/min; detector set at m/z 375; retention time, 4.7 rain. The eluate was freeze-dried to yield 11.7 mg of the product TFA salt as a white solid. 1H NMR (dr DMSO) δ 12.69 (s, 1H, NH); 8.92 (s, 1H); 8.81 (s, 1H); 8.51 (s, 1H); 7.75 (m, 1H); 7.22 (m, 1H); 7.18 (s, 2H, NH2); 3.84 (m, 2H); 3.23 (s, 2H); 2.99 (m, 2H); 2.60 (m, 2H); 1.97 (m, 2H). MS(ES) 375 (M+H). To a -70 °C solution of (3R)-4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyr- rolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Stepl) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). The resulting mixture was stirred for 3h and allowed to warm during this time interval from -70 to -25 °C, after which the reaction was cooled back at -70 °C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HC1 in water (15 mL). Insoluble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HC1 in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0-80% ethyl acetate/hexanes to give the purified product (0.9 g) as a pale orange oil (47% yield). 'H NMR (400 MHz, CDC13): 6 9.85 (IH, s); 8.95 (1H, s); 8.5 (1H, s); 8.4 (1H, s); 7.5 (1H, d); 6.85 (1H, d); 5.75 (2H, s); 5.5 (1H, m); 4.0 (1H, dd); 3.6 (2H, t); 3.3 (IH, dd); 1.99 (2H, t); 0.0 (9H, s). MS (M+H): 440. Step2: 4-J-f2,2,2-Trifltwro-I-(lH-imidazol-2-ylmethylJethylJ-IH-pyrcaol-4-yl-7-f2-Ctrimethylsily0- ethoxy] methyl- 7H-pyrrolo[2,3-dJpyrimidine A solution of 4,4,4-trifluoro-3-[4-(7-t2-(trimethyIsilyl)ethoxy3raethyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]butanal (0.138 g, 0.000314 mol), 7.0 M ammonia in methanol (1 mL), ethanedial (0.5 mL, 0.004 mol) and acetic acid (20 L, 0.0004 mol) in methanol (2 mL, 0.05 mol) was microwaved on 100 watts, at 80 °C for 60 minutes. Following the microwave reaction, elhyl acetate/water was added. The organic phase was separated and washed with saturated NaHCO3 and saturated NaCl. The washed organic phase was dried and concentrated (rotory evaporator) to give 196 mg of the crude product as an orange glass. The crude product was purified by chromatography with 0-100% ethyl acetate/hexanes to give 57 mg of purified product as an off-white solid (38% yield). 1H NMR (400 MHz, CDC13): δ 8.91 (1H, s); 8.4 (IH, s); 8.2 (IH, s); 7.5 (1H, d); 7.0 (2H, s); 6.83 (IH, d); 5.75 (2H, s); 5.62 (IH, m); 4.15 (IH, dd); 3.8 (IH, dd); 3.6 (2H, t); 1.99 (2H, t); 0.0 (9H, s). MS (M+H): 478. Step3: 4-l-[2,2,2-Triftuoro-l-(lH-imidazol-2-ylmethyl)ethyl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-dJ- pyrimidine A solution of 4-l-[2,2,2-trifluoro-l-(lH-imidazol-2-ylmethyl)ethyl]-lH-pyrazol-4-yl-7-[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.055 g, 0.12 mmol) in 1,2-dichloro- ethane (1 mL, 10 mmol) and TFA (0.5 mL, 6 mmol) was stirred overnight. The reaction was concentrated to provide an orange oil. The oil was stirred in methanol (1 mL, 20 mmol) and 8.0 M ammonium hydroxide in water (1 mL) for 4h. This mixture was then concentrated to provide a crude product as an orange glass/solid. The crude product was purified by Prep HPLC (pHIO) to give 28 mg of purified product as a colorless glass, which was triturated with 2-methoxy-2-methylpropane (1 mL, 8 mmol), and then filtered and washed to provide 15 mg of the product as a white solid (38% yield) which then was dried rt-50 °C for 3h. 'H NMR (400 MHz, DMSO): 6 12.13 (1H, s); 11.89 (1H, s); 8.65 (1H, s); 8.37 (1H, s); 7.6 (1H, d); 6.95 (1H, d); 6.92 (1H, d); 5.91 (1H, m); 3.78 (1H, dd); 3.47 (H, dd). MS (M+H): 348. Example 745: 4-(l-(lR)-2,2,2-Trilluoro-l-[(4-methyl-l,3-thiazol-2-yl)methyl]ethyl-lH-pyrazol- 4-yl)-7H-pyrrolo[2,3-d]pyriinidine A suspension of phosphorus pentasulfide (0.46 g, 1.0 mmol) in ethanol (0.5 mL, 8 mmol) was stirred for Ih. (3RH,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3^]pyrimidin-4-yl)-lH-pyra2ol-l-yl]butane- nitrile (0.15 g, 0.50 mmol) (see, Example 93) was added and the resulting mixture was heated at 80 °C in a sealed vial for 0.5h, during which reaction the mixture became a yellow solution. The reaction was heated overnight. The reaction was then cooled to rt. Water (1 g, 60 mmol) and ethyl acetate were added to the mixture. The organic phase was separated and washed with saturated NaHCO3 and saturated aqueous NaCl. The washed organic phase was then dried and concentrated to give 387 mg of a crude product as a white glass/oil. The crude product was chromatographed with 0- 10% MeOH/DCM, 0-1 %NH4OH to give 0.13 g of the purified product as a white solid (76% yield). 1H NMR (400 MHz, CDCI3): δ 8.7 (1H, s); 8.5 (1H, s); 8.3 (1H, s); 7.4 (1H, d); 7.0 6.75 (1H, d); 5.82 (1H, m); 3.75 (1H, dd); 3.2 (1H, dd). MS (M+H): 341. A suspension of (3R)-4,4,4-trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l- yl]butanethioamide (0.038 g, 0.00011 mol), chloroacetone (15 L, 0.00019 mol) in ethanol (1 mL, 0.02 mol) and 1,2-dichloroethane (1 mL, 0.01 mol) was heated to reflux overnight. Following this, the reaction mixture was filtered to remove insoluble material. The filtrate was dissolved in MeOH (1 mL) and DMF (1 mL) and purified by prep HPLC at pH10 to provide 6 mg of the purified product as a colorless glass/oil, which was then triturated with MTBE/hexanes and was dried at 40 °C overnight to give 5.2 mg of the purified product as an off-white solid (13% yield). 1H NMR (400 MHz, CDC13): δ 10.11 (1H, s); 8.88 (1H, s); 8.42 (1H, s); 8.38 (1H, s); 7.45 (1H, d); 6.79 (1H, s); 6.65 (1H, d); 5.41 (1H, m); 4.15 (1H, dd); 3.75 (H, dd); 2.18 (3H, s). MS (M+H): 379. Example A: In vitro JAK Kinase Assay Compounds herein were tested for inhibitory activity of JAK targets according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC30s of compounds were measured for each kinase in the reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 g/mL (0.01%) BSA. The ATP concentration in the reactions was 90 M for Jakl, 30 M for Jak2 and 3 M for Jak3. Reactions were carried out at room temperature for 1 hr and then stopped with 20 (L 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA). Compounds having an ICS0 of 10 uM or less for any of the above-mentioned JAK targets were considered active. Example B: Cellular Assays One or more compounds herein were tested for inhibitory activity of JAK targets according to at least one of the following cellular assays. Cancer cell lines dependent on cytokines and hence JAK/STAT signal transduction, for growth, were plated at 6000 cells per well (96 well plate format) in RPMI 1640, 10% FBS, and 1 nG/mL of appropriate cytokine. Compounds were added to the cells in DMSO/media (final concentration 0.2% DMSO) and incubated for 72 hours at 37 °C, 5% CO2- The effect of compound on cell viability was assessed using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) followed by TopCount (Perkin Elmer, Boston, MA) quantitation. Potential off-target effects of compounds were measured in parallel using a non-JAK driven cell line with the same assay readout. Compounds having an IC50 of 10 uM or less with selectivity for JAK driven proliferation were considered active. All experiments were performed in duplicate. The above cell lines can also be used to examine the effects of compounds on phosphorylation of JAK kinases or potential downstream substrates such as STAT proteins, Akt, Shp2, or Erk. These experiments can be performed following an overnight cytokine starvation, followed by a brief preincubation with compound (2 hours or less) and cytokine stimulation of approximately 1 hour or less. Proteins are then extracted from cells and analyzed by techniques familiar to those schooled in the art including Western blotting or ELISAs using antibodies that can differentiate between phosphorylated and total protein. These experiments can utilize normal or cancer cells to investigate the activity of compounds on tumor cell survival biology or on mediators of inflammatory disease. For example, with regards to the latter, cytokines such as IL-6, IL-12, JL-23, or IFN can be used to stimulate JAK activation resulting in phosphorylation of STAT protein(s) and potentially in transcriptional profiles (assessed by array or qPCR technology) or production and/or secretion of proteins, such as IL-17. The ability of compounds to inhibit these cytokine mediated effects can be measured using techniques common to those schooled in the art. Compounds herein can also be tested in cellular models designed to evaluate their potency and activity against mutant JAKs, for example, the JAK2V617F mutation found in myeloid proliferative disorders. These experiments often utilize cytokine dependent cells of hematological lineage (e.g. BaF/3) into which the wild-type or mutant JAK kinases are ectopically expressed (James, C, et al. Nature 434:1144-1148; Staerk, J., et al. JBC 280:41893-41899). Endpoints include the effects of compounds on cell survival, proliferation, and phosphorylated JAK, STAT, Akt, or Erk proteins. Certain compounds herein have been or can be evaluated for their activity inhibiting T-cell proliferation. Such as assay can be considered a second cytokine (i.e. JAK) driven proliferation assay and also a simplistic assay of immune suppression or inhibition of immune activation. The following is a brief outline of how such experiments can be performed. Peripheral blood mononuclear cells (PBMCs) are prepared from human whole blood samples using Ficoll Hypaque separation method and T-cells (traction 2000) can be obtained from PBMCs by elutriation. Freshly isolated human T- cells can be maintained in culture medium (RPMI 1640 supplemented withl0% fetal bovine serum, 100 U/ml penicillin, 100 fig/ml streptomycin) at a density of 2 x 10s cells/ml at 37 "C for up to 2 days. For IL-2 stimulated cell proliferation analysis, T-cells are first treated with Phytohemagglutinin (PHA) at a final concentration of 10 ug/mL for 72h. After washing once with PBS, 6000 cells/well are plated in 96-well plates and treated with compounds at different concentrations in the culture medium in the presence of 100 U/mL human EL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel). The plates are incubated at 37 °C for 72h and the proliferation index is assessed using CellTiter-Glo Luminescent reagents following the manufactory suggested protocol (Promega; Madison, WT). Example C: In vivo anti-tumor efficacy Compounds herein can be evaluated in human tumor xenograft models in immune compromised mice. For example, a tumorigenic variant of the INA-6 plasmacytoma cell line can be used to inoculate SCBD mice subcutaneously (Burger, R., et al. Hematol J. 2:42-53, 2001). Tumor bearing animals can then be randomized into drug or vehicle treatment groups and different doses of compounds can be administered by any number of the usual routes including oral, i.p., or continuous infusion using implantable pumps. Tumor growth is followed over time using calipers. Further, tumor samples can be harvested at any time after the initiation of treatment for analysis as described above (Example B) to evaluate compound effects on JAK activity and downstream signaling pathways. In addition, selectivity of the compound(s) can be assessed using xenograft tumor models that are driven by other know kinases (e.g. Bcr-Abl) such as the K562 tumor model. Example D: Murine Skin Contact Delayed Hypersensitivity Response Test Compounds herein can also be tested for their efficacies (of inhibiting JAK targets) in the T- cell driven murine delayed hypersensitivity test model. The murine skin contact delayed-type hypersensitivity (DTH) response is considered to be a valid model of clinical contact dermatitis, and other T-lymphocyte mediated immune disorders of the skin, such as psoriasis (Immunol Today. 1998 Jan;19(l):37-44). Murine DTH shares multiple characteristics with psoriasis, including the immune infiltrate, the accompanying increase in inflammatory cytokines, and keratinocyte hyperproliferation. Furthermore, many classes of agents that are efficacious in treating psoriasis in the clinic are also effective inhibitors of the DTH response in mice (Agents Actions. 1993 Jan;38(l-2):116-21). On Day 0 and 1, Balb/c mice are sensitized with a topical application, to their shaved abdomen with the antigen 2,4,dinitro-fluorobenzene (DNFB). On day 5, ears are measured for thickness using an engineer's micrometer. This measurement is recorded and used as a baseline. Both of the animals' ears are then challenged by a topical application of DNFB in a total of 20 L (10 L on the internal pinna and 10 L on the external pinna) at a concentration of 0.2%. Twenty-four to seventy-two hours after the challenge, ears are measured again. Treatment with the test compounds was given throughout the sensitization and challenge phases (day -1 to day 7) or prior to and throughout the challenge phase (usually afternoon of day 4 to day 7). Treatment of the test compounds (in different concentration) was administered either systemically or topically (topical application of the treatment to the ears). Efficacies of the test compounds are indicated by a reduction in ear swelling comparing to the situation without the treatment. Compounds causing a reduction of 20% or more were considered efficacious. In some experiments, the mice are challenged but not sensitized (negative control). The inhibitive effect (inhibiting activation of the JAK-STAT pathways) of the test compounds can be confirmed by immunohistochemical analysis. Activation of the JAK-STAT pathway(s) results in the formation and translocation of functional transcription factors. Further, the influx of immune cells and the increased proliferation of keratinocytes should also provide unique expression profile changes in the ear that can be investigated and quantified. Formalin fixed and paraffin embedded ear sections (harvested after the challenge phase in the DTH model) are subjected to immunohistochemical analysis using an antibody that specifically interacts with phosphorylated STAT3 (clone 58E12, Cell Signaling Technologies). The mouse ears are treated with test compounds, vehicle, or dexamethasone (a clinically efficacious treatment for psoriasis), or without any treatment, in the DTH model for comparisons. Test compounds and the dexamethasone can produce similar transcriptional changes both qualitatively and quantitatively, and both the test compounds and dexamethasone can reduce the number of infiltrating cells. Both systemically and topical administration of the test compounds can produce inhibitive effects, i.e., reduction in the number of infiltrating cells and inhibition of the transcriptional changes. Example £: In vivo anti-inflammatory activity Compounds herein can be or have been evaluated in rodent or non-rodent models designed to replicate a single or complex inflammation response. For instance, rodent models of arthritis can be used to evaluate the therapeutic potential of compounds dosed preventatively or therapeutically. These models include but are not limited to mouse or rat collagen-induced arthritis, rat adjuvant- induced arthritis, and collagen antibody-induced arthritis. Autoimmune diseases including, but not limited to, multiple sclerosis, type I-diabetes mellitus, uveoretinitis, thyroditis, myasthenia gravis, immunoglobulin nephropathies, myocarditis, airway sensitization (asthma), lupus, or colitis may also be used to evaluate the therapeutic potential of compounds herein. These models are well established in the research community and are familiar to those schooled in the art (Current Protocols in Immunology, Vol 3., Coligan, J.E. et al, Wiley Press.; Methods in Molecular Biology: Vol. 225, Inflammation Protocols., Winyard, P.G. and Willoughby, D.A., Humana Press, 2003.). Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is incorporated herein by reference in its entirety. including pharmaceutically acceptable salt forms or prodrugs thereof, wherein: A1 and A2 are independently selected from C and N; T, U, and V are independently selected from O, S, N, CRS, and NR6; wherein the 5-membered ring formed by A1, A2, U, T, and V is aromatic; X is N or CR4; Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11Ri2)p-(C3.locycloalkylene)- (CR11R12)p , (CR11R12)p-(arylene)-(CR11R12)q, (CR11R12)p-(C1-10 oheterocycloalkylene)-(CR11R12)q, (CR11R12)p-(Cheteroarylene)-((CR11R12)p, (CR11R12)pO(CR11R12)p\|, (CR11R12)p-s(CR11R12)p (CR11'R12)p (CR11R12)p, (CR11R12)pC(CR11R12)p, (CR11R12)pC(O)O(CR11R12)p, (CR11R12)p(CR11R12)q, (CR11R12)pOC(O)NRc(CR11R12)p> (CR11R12)qNRc(CR11R12)q, (CR11R12)pNRcC(O)NRd(CR11R12)q, (CR11R12)qS(OXCR11R12),, (CR11R12)pS(O)NRc(CR11R12)q (CR11R12)pS(CR11R12)q or (CR11R12)pS(O)2NRc(CR11R12)q) wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1,2, or 3 substituents independently selected from -D1-D2-D3-D4; Z is H, halo, C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, =C-R', =N-R!, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NReRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NR°Rd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl)Rb, and S(O)2NRcRl1, wherein said C2-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1,2, 3,4,5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, Cy1, CN, NO2, OR', SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NR'C(O)NRcHd, NRCC(O)OR°, C(=NR1)NRcRd, NR°C(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOKDRb, C(=NO(C1-6 alkyl))Rb, and S(O)2NRcRd; wherein when Z is H, n is 1 or the -(Y)n-Z moiety is taken together with i) A2 to which the moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which the Rs or R6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3,4, or 5 substituents independently selected from-(W)ra-Q; W is C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, O, S, C(O), C(O)NRC', C(O)O, OC(O) OC(O)NRC", NRC, NRc'C(O)NRd', S(O), S(O)NRC, S(O)2, or S(O)2NRC; Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halosulfanyl, aryl cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1,2,3 or 4 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy2, CN, NO2) ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRc'Rd,NRcC(O)Rb, NRcC(O)NRcRd, NRC'C(O)ORa, S(O)Rb S(O)NRe'Rd, S(O)2Rb, NRe S(O)2Rb', and SC(O)2NRaRd; Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each, optionally substituted by 1,2, 3,4 or 5 substituents independently selected from halo,C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, CN, NO2) OR9, SRa, C(O)Rb, C(O)NRcRd, C(O)ORB, OC(O)Rb", OC(O)NRcRd, NRcRd, NRcC(O)Rb,NRcC(O)ORa,NR°S(O)Rb,NRcS(O)2Rb, S(O)Rb, S(O)NRCRd, S(O)2Rb, and S(O)2NRcRd; R1, R2, R3, and R4 are independently selected from H, halo,C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NReC(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and SC(O)2NR9R10; Rs is H, halo, G1-4 alkyl,C1-4alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)2NR9R10; R6 is H, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, OR7, C(O)R8, C(O)NR9R10, C(O)OR7, S(O)R8, S(O)NR9R10, SC(O)2R8, or SCO)2NR9R10; R7 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R8 is H, C1-4 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R9 and R10 are independently selected from H, C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R9 and R10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; R11 and R12 are independently selected from H and -E1-E2-E3-E4; D1 and E1 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1-6alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1,2 or 3 substitoents independently selected from halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and C2-8 dialkylamino; D2 and E2 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, (C1-6 alkylene)r-O-( C1-6 alkylene)s, (C1-6 alkylene)r-S-(C1-4 alkylene)s, (C1-6 alkylene)r-NRe-(C1-6 alkylene)s, (C1-6 alkylene),-CO(C1-6 alkylene)B, (C1-6alkylene)r-COO-(C1-6 alkylene)s (C1-6 alkylene)r-CONRe-(C1-6 alkylene),, (C1-6 alkylene)-SO-C1-6 alkylene),, (C1-6 alkylene)r-SO2-(C1-6 alkylene)s, (C1-6 alkylene)r-SONRe-(C1-4 alkylene)s, and (d1-6 alkylene)r- NReCONRf-(C1-6 alkylenes, wherein each of the C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN, OH, C1-4alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6alkoxy, C1-6 haloalkoxy, amino, C1-6alkylamino, and C2-8 dialkylamino; D3 and E3 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN,NO2, N3, SCN, OH, C1-4alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and C2-8 dialkylamino; D4 and E4 are independently selected from H, halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRC(O)NRcRd, NRcC(O)ORa, C(=NR1)NReRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(CM alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C1-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR", SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NR.cRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NR°C(=NR1)NRcRd, S(O)Rb, S(O)NReRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-4alkyl))Rb, and S(O)NRcRd; Ra is H, Cy1, -(C1-6 alkyO-Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy1 -(C1-6 alkyO-Cy1, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1,2, or 3 substituents independently selected from OH, GN, amino, halo, C1-4alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Ra and Ra are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb' and Rb are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc and Rd are independently selected from H, Cy1, -(C1-6 alkyl)-Cy1, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, -(C1-6 alkyl)-Cy1, OH, CN, amino, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 haloalkyl,and halosulfanyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently selected from Cy1, -(C1-6 alkyl)-Cy1, OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6haloalkyl, and halosulfanyl; Rc" and Rd are independently selected from H, C1-10 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C1-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc' and Rd' together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc" and Rd" are independently selected from H, C1-10 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aiylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclpalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C\|.(alkyl, C1-6 haloalkyl, halosulfanyl, C1-6 haloalkyl, aryl, arylalkyi, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc" and Rd" together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R1 is H, CN, NO2, or C1-6 alkyl; R1 and Rf are independently selected from H and C1-4 alkyl; R1 is H,CN,or NO2; m is 0 or 1 ; n is O or 1; p is O, 1,2,3,4, 5, or 6; q is 0,1, 2, 3,4, 5 or 6; risOor 1; and s is O or 1; wherein when X is N, n is 1, and the moiety formed by A1, A2, U, T, V, and -(y)n-Z has the formula: then Y is other than (CR11R12)qC(O)NRc(CR' 'R12)q. 2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is N. 3. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is CR4. 4. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A1 is C. 5. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A1 is N. 6. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A2 is C. 7. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A2 is N. 8. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein at least one of A1, A2, U, T, and V is N. 9. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the 5- membered ring formed by A1, A2, U, T, and V is selected from: wherein: a designates the site of attachment of moiety-(Y)n-Z; b designates the site of attachment to the core moiety: c and c' designate the two sites of attachment of the fused 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring. 10. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein n is 0. 11. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1. 12. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1 and Y is C1-8 alkylene, C2-8 alkenylene, (CR11R12)p C(O)(CR11R12)q, (CR11'R12)p C(O)NRcCR11R12)q,, (CR11R12)pC(O)O(CR11R12)q, (CR11R12)qOC(O)(CR11R12)p > wherein saidC1-4alkylene or C2-8 alkenylene, is optionally substituted with 1,2, or 3 halo, OH, CN, amino, C1-4 alkylamino, or C2-8 dialkylamino. 13. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1 and Y is C1-8 alkylene, (CR11R12)pC(O)(CR11R12)q, (CR11R12)pC(O)NRc(CR11R12)p , (CR11R12)qC(O)O(CR11R12)q> wherein said C1-10, alkylene is optionally substituted with 1,2, or 3 halo, OH, CN, amino, C1-4 alkylamino, or C2-8 dialkylamino. 14. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1 and Y is C1-8 alkylene optionally substituted with 1, 2, or 3 halo, OH, CN, amino,C1-4alkylamino, or C2-8 dialkylamino. 15. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1 and Y is (CR11R12)qC(O)(CR11R12)q (CR11R12)qC(O)NRc(CR11R12)q, or (CRllRI2)pC(O)O(CR11R12)q. 16. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 0. 17. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 1. 18. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 2. 19. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein q is 0. 20. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein q is 1. 21. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein q is 2. 22. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein one of p and q is 0 and the other of p and q is 1,2, or 3. 23. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR', SRa, C(O)Rb, C(O)NRCR OC(O)NRcRa, NR0Rd NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. 24. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is aryl or heteroaryl, each optionally substituted with 1, 2,3, 4, 5, or 6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR", SRa, C(O)Rb, C(O)NReRd, C(O)ORa, OC(O)Rb, OC(O)NRGRdl NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR!)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. 25. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3,4, 5, or 6 substituents selected from halo,C1-4alkyl, C1-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy', CN, NO2, OR', SRa, C(O)Rb, C(O)NRcRd, C(O)OR8, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NReC(O)NReRd, NRcC(O)ORa, C(=MRl)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcSCO)2Rb1, and S(O)2NRcRd. 26. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is phenyl optionally substituted with 1,2, 3, 4, 5, or 6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl, d1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR", SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, 0C(O)Rb, OC(O)NRcRd, NR'R", NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR8, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. 27. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1,2, 3, 4, 5, or 6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl,C1-4alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4 cyanoalkyl. Cy1, CN, NO2 OR", SRa, C(O)Rb, C(O)NRcRd, C(O)OR\ OC(O)Rb, OC(O)NRcRd, NRcRd, NReC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. 28. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z is Cx.s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted with 1,2, 3, 4, 5, or 6 substituents selected from halo, C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SR", C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)R6, OC(O)NB.cRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NReRa, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. 29. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z isC1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2,3,4,5, or 6 substituents selected from halo, C1-4 alkyl,C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, C(O)NRcR6, C(O)ORa, NRcRd, NRcC(O)Rb, and S(O)2Rb. 30. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1,2, or 3 substituents selected from halo,C1-4alkyl,C1-4haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, Cy1, CN, NO2, ORa, C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, and S(O)2Rb. 31. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z is substituted with at least one substituent comprising at least one CN group. 32. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with at least one CN or C1-4 cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NReRd, C(O)OR", OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd. 33. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein the -(Y)n-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R3 or R6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2,. U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from -(W)ra-Q. 34. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the -(Y)n-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and Hi) the C or N atom to which said Rs or R6 of either T or V is attached to form a 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3,4, or 5 substituents independently selected from -(W)m-Q- 35. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the -(YV-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said Rs or R6 of either T or V is attached to form a 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1,2, or 3 substituents independently selected from halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl wherein said C1-8 alkyl, C2-6 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted by 1, 2 or 3 CN. 36. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1, R2, RJ, and R4 are independently selected from H, halo, and C1-4 alkyl. 37. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are each H. 38. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1 is H, halo, orC1-4alkyl. 39. The compound of claim 1, or phaxmaceutically acceptable salt thereof, wherein R5 is H, halo, C1-4 alkyl,C1-4 haloalkyl, halosulfanyl, CN, or NR9R10. 40. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R5 is H. 41. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R6 is H or C1-4alkyl. 42. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R6 is H. 43. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula II: The compound of claim 1 selected from: 3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]benzonitrile; 3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]aciylonitrile; 3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yI)-lH-pyrazol-4-yl]propanenitrile; 4-(4-phenyl-lH-imidazol-l-yl)-lH-pyrrolo[2,3-b]pyridine; [3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-piperidin-l-yl-methanone; [3-methyl-l-(lH-pyrrolo[2,3-b]pyridin'4-yl)-lH-pyrazol-4-ylmethyl]-phenyl-ainine; 3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yI]-cyclohexanol; 4-[l-(3-methoxy-l-methyl-propyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[l-(l-methyl-3-pyrazol-l-yl-propy])-lH-pyrazol-4-yl]-lH-pyrrolo[2J3-b]pyridine; 1 -(lH-pyrroIo[2,3-b]pyridin-4-yl)-lH-pyrazole-4-carboxylic acid ethyl ester; 4-(3-methyl-4-phenyl-pyrazol-l-yl)-lH-pyrroIo[2,3-b]pyridine; 4-(3-phenyl-pyrazol-l-yl)-lH-pyrrolo[2,3-b]pyridine; 4-(4-bromo-imidazol-l -yl)-1 H-pyrrolo[2,3-b]pyridine; 4-(4-bromo-3-methyl-pyra2ol-l-yl)-lH-pyrrolo[2,3-b]pyridine; 3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-ben2onitri]e; 4-[3-methyl-l -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-4-yl]-benzonitriIe; 4-[4-(3-f]uoro-phenyl)-3-methyl-pyrazol-l-yl]-lH-pyrrolo[233-b]pyridine; 4-[4-(3,5-bis-trifluoromethyl-phenyl)-3-methyl-pyrazol-l -yl]-l H-pyrrolo[2,3-b]pyridine; 4-[4-(3,5-difluoro-phenyl)-3-methyl-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine; {3-[3-methyl-l -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-phenyl} -methanol; 4-(3-methyl-4-pyrimidin-5-yl-pyrazol-l -yl)-l H-pyrrolo[2J3-b]pyridine; 4-[3-methy1-4-(l-methyl-lH-indol-5-yl)-pyra2ol-l-yl]-lH-pyrrolo[253-b]pyridine; 4-(3-methy1-4-tiuophen-3-yl-pyrazol-l-yl)-lH-pyrrolo[2,3-b]pyridine; N,N-imethy1-4-[3-methyl-l-(lH-pynx)lo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-benzene- sulfonamide; N-{4-[3-raethyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-phenyl}-acetainide; 3-tert-buty]-l-(lH-pyrro]o[2)3-b]pyridin-4-yl)-lH-pyrazole-4-carbonitrile; 4-bromo-1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazole-3-carbonitrile; 4-(3-cyano-phenyl)-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazole-3-carbonitrile; 3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-3-trifluoromethyl-lH-pyrazol-4-yl]-propan-l-ol; 3-[3-methy]-l -(1 H-pyrrolo[2,3-b]pyridm-4-yl)-l H-pyrazol-4-yl]-prop-2-en-l -ol; 2-[4-bromo-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yl]-isoindole-l,3-dione; 4-[4-(2,6-dimethyl-phenyl)-3-methyl-pyrazol-l -yl]-l H-pyrrolo[2,3-b]pyridine; 3-[3-anuno-l-(lH-pyrro]o[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-ben2onitrile; 3-[3-benzylamino-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-benzonitrile; N-[4-(3-cyano-phenyl)-l-(lH-pyn'olo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yI]-acetamide; 3-[4-(lH-pyrro]o[2J3-b]pyridin-4-yl)-pyrazoH-yl]-propan-l-ol; 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-l-yl]-butan-l-01: 4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-pyrazoH-yl]-pentanenitrile; 4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-l-yl]-pentanoic acid amide; 4-[l-(3-imidazol-l-yl-l-methyl-propyl)-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine; 4-cyclopentyl-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-l-yl]-butyronitrile; 4-cyclopentyl-4-[4-(lH-pyiTolo[2,3-b]pyridin-4-yl)-pyrazol-l-yl]-butyramide; 3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-l-yl]-propionitrile; 4-(2-tert-butyl-l-methyl-lH-imidazol-4-yl)-lH-pyrrolo[2,3-b]pyridine; 4-(2-phenyl-lH-imidazol-5-yl)-lH-pyrrolo[2,3-b]pyridine; 4-(2-benzyl-lH-imida2ol-5-yl)-lH-pyrrolo[2,3-b]pyridme; 4-[2-(l-phenylethyl)-lH-imidazol-5-yl]-lH-pyrrolo[2,3-b]pyridine; 4-(2-phenyM,3-thiazol-4-yl)-lH-pyrrolo[2,3-b]pyridine,- N-methyl-N-propyl-4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l,3-tbia2ol-2-aniine; N-phenyl-4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l,3-thiazol-2-amine; N-methyl-N-phenyl-4-(lH-pyrroloP.S-b]pyridin-4-yl0-l,3-thiazo1-2-amine; 4-(2-phenyl-l,3-thiazol-5-yl)-lH-pyrrolo[2,3-b]pyridine; ethyl 2-methyl-2-[4-(lH-pyirolot2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanoate; 2-methyl-2-[4-(lH-pyrrolo[2,3-b]pyridiii-4-yl)-lH-pyrazol-l-yl]propanoicacid; 2-methyl-2-[4-(l H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]propanamide; ethyl 3-methyl-3-[4-(lH-pyiTolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanoate; 3-methyl-3-[4-(lH-pyiTolo[2,3-b]pyridin-4-yl)-lH-pytazol-l-yl]butan-l-ol; 4-methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-y]]pentanenitrile; 4-methyl-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]pentanamide; 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile; 3-[4-(lH-pyrrolo[2,3-b]pyiidin-4-yi)-l H-pyrazol-1 -yl]propanenitrile; 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]hexanenitrile; 3-cyclopentyl-3-[4-(lH-pyirolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3-cyclohexyl-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanenitrile; 3-cyclopentyl-3-[4-(7H-pyirolo2,3-d]pyrimidin-4-y1)-1H-pyrazol-l-y1)propanenitrile; 2-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidm-4-yl)-lH-pyrazol-l-yl]propanenitxile; 3-[4(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile; 5-methyl-3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]hexanenitriIe; 3-cyclohexyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 4-cyclopropyl-3-[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl3butanenitrile; 4-{ 1 -[1 -methylbutyl]-lH-pyrazoI-4-yl}-7H-pyrrolo[2,3-d]pyriinidine; 4-tnethyl-4-[4-(7H-pyrrolot2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl3pentanenitrile; 3-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclopropylpropanenitrile; 4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile; 3-raethyl-3-[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanenitrile; 3-ethyl-3-[4-^7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile; l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclopropylacetonitrile; 4-l-[(pyrrolidin-2-ylmethyl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrirnidine; 4-(l-[l-(methylsulfonyl)pyrrolidin-2-yl]methyl-lH-pyrazol-4-72yl)-7H-pyrrolo[2,3-d]- pyrimidine; ethyl 2-methyl-2-[4-(7H-pyrrolo[2,3-ki]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanoate; 3-cycIopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]acrylonitrile; 3-cyclopentylidene-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3-methyl[5^7H-pyrrolo[2,3-d]pyrimidin-4-yl)~l,3-thiazol--2-yl]aminopropanenitrile; 3-[5-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]hexaneaitrile; 3-cyclopentyI-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]propanenitrile; 5-methyl-3-[5-(7H-pyiTolo[2,3-d]pyriinidin-4-yl)-l,3-thiazol-2-yI]hexanenitriIe; 3-pyridin-3-yl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l13-thia2ol-2-yl]propanenitrile; 3(5-bromopyridinO-yl)-3-[5-(7H-pyn-olo[2,3-d]pyrimidin-4-y])-l,3-thiazol-2-yl)propane- nitrile; 5-2-cyano-l-[5-(7H-pyrrolo[23d]pyrimidin-4-yl)-l,3-thiazol-2-yl]ethyl)nicotinonitrile; 3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]butanenitrile; 2-[5-(7H-pyTrolo[2)3-d]pyrimidin-4-yl)-l,3-thia2ol-2-yl]pentanenitrile; 4-[5-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-l,3-thiazol-2-yl]heptanenitrile; 3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thia2ol-2-yl]pentanedinitrile; 3-cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-oxa2o]-2-yl]propanenitrile; 3-[5-(7H-pyrrolo[2,3-d]pyrimiditi-4-yl)-l>3-oxazol-2-yl]hexanenitrile; 5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyratiudin-4-yl)-lH-pyrazol-l-yl]pentanenitrile; 5-(methylsulfinyl)-3-[4-(7H-pyrrolo[2,3di]pyriraidin-4-yl)-lH-pyrazol-l-yl]-pentanenitrile; 5-(methylsulfonyl)-3-[4-(7H-pyn-olo[23d]pyriiniditi-4-yl)-lH-pyrazol-l-yl]-pentanenitrile; 4,4J4-trifluoro-3-[4^7H-pyn-olo[2,3d]pyrimidin-4-yl)-pyra2ol-2-yl]-butyronitrile; 5,5-dimethyl-3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-pyrazol-l-yl]-hexanenitrile; 4-[l-(2-methanesulfonyl-ethyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 5,5,5-trifluoro-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-l-yl]-pentanenitrile; 3-(2-cyano-1 -[4-(7H-pyrrolo[2J3-d]pyrimidin-4-y!)-lH-pyrazol-1 -yl]ethyl)-cyclopentane- carbonitrile; 343-(hydroxymethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4--yl)-lH-pyrazol-l-yl]- propanenitrile; l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-indazole; 2-(l H-pyrrolo[2,3-b]pyridin-4-yl)-2H-indazole; 3-[3-(l H-pyrrolo[2,3-b]pyridin-4-y])-1,2,4-oxadiazol-5-yl]benzonitrile; 4-(I-benzothien-2-yl)-lH-pyrrolo[2,3-b]pyridine; 4-fluoro-2-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yl]phenoI; 4-3-[3-(trifluoromethyl)phenyl]-lH-pyrazol-l-yl-lH-pyrrolo[2,3-b]pyridine; 3-[l-(lH-pyrrolo[2,3-b3pyridin-4-yl)-lH-pyrazol-3-yl]benzonitrile; 3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl3benzonitrile; 2-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-l,3-benzoxazole; cyclohexyl[ 1 -(1 H-pyrrolo[2,3 -b]pyridin-4-yl)-l H-pyrazol-4-yl]methanol; 4-[4-(l-phenylvinyl)-lH-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine; 4-(l -benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridme; 4-fl-(2-naphthylmethyl)-lH-pyrazol-4-yl]-lH-pyiTolo[2,3-b]pyridine; 4-(l -phenyl-1 H-pyrazol-4-yl)-l H-pyrrolo[2,3-bjpyridine; 3-[4-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]benzonitrile; 4-{l-[l-methylbutyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridiiie; 4-methyl-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazoI-I-yl]benzonitrile; 2-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazole; 5-nitro-2-(l H-pyrrolo[2,3-b]pyridin-4-y])-2H-indazole; 6-nitro-2-(lH-pyrrolo[2,3-b]pyridin-4-yl)-2H-indazole; 3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-imidazol-4-yl]benzonitrile; 4-[4-(3-methoxyphenyl)-lH-imidazol-l-yl]-lH-pyrrolo[2,3-b]pyridine; 4-(5-phenyl-2-thienyl)-lH-pyrrolo[2,3-b]pyridine; 4-[3-(4-fluorophenyl)-l H-pyrazol-1 -yl]-lH-pyrrolo[2,3-b]pyridine; 4-[3-(3-nitrophenyl)-lH-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[3-(4-cIilorophenyl)-lH-pyrazol-l-yl3-lH-pyrrolo[2,3-b]pyridine; 4-[3-(4-methoxyphanyl)-lH-pyrazol-l-yl]-lH-pyrrolo[253-b]pyridine; 4-[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-3-yl]benzonitrile; 3-[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-3-yl]aniline; 4-[3-(3-methoxyphenyl)-lH-pyrazol-l -yl]-l H-pyrrolo[2s3-b]pyridine; {3-[l-(lH-pyrrolo[273-b]pyridin-4-yl)-lH-pyrazol-3-yl]phenoxy}acetonitrile; 2-cyano-N-{3-[l-{lH-pyiTOlo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yl]phenyl}acetamide; 3-cyano-N-{3-[l-(lH-pyrrolo[2s3-b]pyridin-4-yl)-lH-pyrazol-3-yl]phenyl}ben2amide; 4-[4-(4-nitrophenyl)-lH-pyrazol-l -yl]-l H-pyrrolo[2,3-b]pyridine; 4-[l -(1 H-pyirolo[2,3-b]pyridin-4-yl)-lH-pyTazol-4-yl]anilinie; 4-(4-phenyl-lH-pyrazol-l -yl)-lH-pyrrolo[2,3-b]pyridine; 4-(4-pyridin-3-yl-lH-pyrazoI-l-yl)-lH-pyniolo[2,3-b]pyridine; 2-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazo]-4-yl]benzonitrile; {2-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]phenyl}acetonitrile; 4-[4-(3-nitrophenyl)-lH-pyrazol-l-yl]-IH-pyrrolo[2,3-b]pyridine; 3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]aniline; {3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]phenyl}acetonitrile; 4-[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]benzonitrile; 3-[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazoI-4-yl]phenoI; methyl 3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]benzoate; {4-[l-(lH-pyrrolo[2J3-b]pyridin-4-yl)-lH-pyrazol-4-yl]phenyl}acetonitri]e; 2-cyano-N- {3-[l -(1 H-pyrroIo[2,3-b]pyridin-4-yl)-1 H-pyrazol-4-yl]phenyl} acetamide; 4-[l-(lH-pyrrolo[2I3-b]pyridin-4-yl)-lH-pyrazoM-yl]phenol; 5-[l-(lH-pyrro]ot2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]nicotinonitrile; {4-[l-(lH-pyiroIo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]phenoxy}acetonitrile; 4-(4-cyclohex-1 -en-1 -yl-1 H-pyrazol-1 -yl)-l H-pyrrolo[2,3-b]pyridine; 4-[4-(4-methoxyphenyl)-lH-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine; 4-(4-pyrimidin-4-yl-1 H-pyrazol-1 -yl)-l H-pyrrolo[2,3-b]pyridine; 3-{hydroxy[l--(lH-pyrrolo[2)3-b]pyridin-4-yl)-IH-pyrazol-4-yl]methyl}ben2onitrile; 4-[4-(cyclohex-l-en-l-ylmethyl)-lH-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[ 1 -(3,5-dimethoxybenzyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine; 4- [ 1 -(1 -phenylethyl)-1 H-pyrazoI-4-yl]-l H-pyrrolo[2,3-b]pyridine; 4-[l-(cyclohexylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2J3-b]pyridine; 3-{[4-(lH-pyrro]o[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]methyl}benzonitrile; 2-{[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]methyl}benzonitrilei 4- {[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l -yl]methyl} benzonitrile; l-phenyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]ethanone; 3,3-dimethyl-l-(-4lH-pyrrolo[2,3-blpyridin-4-yl)-1H-pyrazol-l-yl]butan-2-one,- 4-{l-[(5-methylisoxazol-3-yl)methyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine; 4-[ 1 -(tetrahydro-2H-pyran-2-ylmethyl)-l H-pyrazol-4-yl]-1 H-pyrrolo[2,3 -b]pyridine; 4-(l-cyclohex-2-en-l-yl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine; 4-[l-(l-ethylpropyI)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-(l-cyclohexyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine; 2-[4-(lH-pyrro]o[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]acetaniide; 4'- {[4-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]methyl} biphaiyl-2-carbonitrile; 4-[ 1 -(2-nitrobenzyl)-1 H-pyrazol-4-yl]-1 H-pyrrolo[2,3-b]pyridine; 4-{l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine; 4-[ 1 -(3-nitrobenzyl)-1 H-pyrazol-4-yl]-1 H-pyrrolo[2,3-b]pyridine; 4-[ 1 -(2-bromobenzyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine; N-phenyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanamide; 4-{ 1 -[3-(trifluoromethoxy)benzyl]-lH-pyrazol-4-yl} -lH-pyrrolo[2,3-b]pyridine; 4-{l-[2-fluoro-5-(trifluoromethyl)benzyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine; 4-{l-[3-(trifluoromethyl)benzyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine; 4-[l-(pyridin-3-ylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-{l-[l-phenylbutyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine; l-phenyl-2-[4-(lH-pyrrolot2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propan-l-one; 4-[l-(2,6-dichlorobenzyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[l-(2,6-dimcthylphenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine- 2-[4-(1H-ppyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-5-(trifluoroinetliyl)-bcnzonitrile; 4-[l-(4-bromo-3J5)6-trifluoropyridin-2-yl)-lH-pyra2ol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[ 1-(cyclopropylmethyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine; 4-[l-(2,5-dimethylphenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridJne; 4-[l-(2-methylphenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridiiie; 4-[ 1-(2-methoxyphenyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine; 3-{l-[4-(lH-pyrroIo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]ethyl}benzonitrile; 3-chloro-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile; 4-[l -(1 -cyclohexylethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-fluoro-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-y0-lH-pyrazol-l-yl]benzonitrile; 2-fluoro-4-[4-(l H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]benzonitrile; 3-fluoro-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]ben2onitrile; 4-(l-{l-[3-(trifluoromethyl)phenyl]ethyl}-lH-pyrazo]-4-y])-lH-pyrrolo[2,3-b]pyridine; 4-[ I -(3,5-dimethylphenyl)-l H-pyrazol-4-yl] -1 H-pyrrolo[2,3-b]pyridine; 4-[4-(l H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazol-1 -yl]benzonitrile; {4-[4-{lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]phenyl}acetonitrile; 4-[l-(l-methylhexyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-(l-sec-butyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine; 4-[ 1 -(1 -phenylpropyl)-l H-pyrazol-4-yl] -lH-pyrrolo[2,3-b]pyridine; 4-(l-{l-[4-(methylsulfonyl)phenyl]ethyl}-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine; 4-{l-[l-(3-fluoro-4-methoxyphenyl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine; 4-(l-{l-[2-(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-yl)-lH-pyrrolo[2>3-b]pyridine; 4-(l-{l-[3,5-bis(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine; 4-{l-[4-(lH-pyrrolo[2,3-b]pyridin-4-yI)-lH-pyrazol-l-yl]ethyl}benzonitrile; 4- {1 -[4-nitro-2-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl} -1 H-pyrrolo[2,3-b]pyridine; 3-methyl-4-[4-(lH-pyiTolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile; 4-[l-(2-chlorophenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2s3-b]pyridine; 3-bromo-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yI]benzonitrile; ethyl 4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzoate; 4-{l-[2-chloro-6-nitro-4-(trifluoromethyl)phenyl]-]H-pyrazol-4-yl}-lH-pyrrolo[2,3-b]- pyridine; 4-( 1 - {1 -[4-(trifluoromethyl)phenyl]ethyl} -1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridine; 4-[l-(2,3-dihydro-lH-indea-l-yl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[l-(l,2,3,4-tetrahydronaphthalen-l-yl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b}pyridine; 4-(l-{l-[2-cWoro-5-(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-yl)-lH-pyrroIo[2,3-b]- pyridine; 4-{l-[l-C214-dicbJoro-5-fluorophenyl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine; 4-[l-(l-cyclopentylethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2J3-b]pyridine; 4-[l-(l-methyl-3-phenylpropyl)-lH-pyra2ol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[l -(1 -cyclobutylethyl)-lH-pyrazol-4-yl]-lH-pyirolo[2,3-b]pyridine; [2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-5-(trifluoromethy])phenyl]- acetonitrile; [5-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-2-(trifluoroinethyl)phenyl]- acetonitrile; 4-{l-[pent-3-en-l-yl]-lH-pyrazol-4-yl}-lH-pyrroIo[2,3-b]pyridine; 2-[4-( lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l -yl]propanenitrile; 4- {1 -[4-phenylbut-3-en-l -yl]-lH-pyrazol-4-yl} -1 H-pyrrolo[2,3-b]pyridine; 6-[4-(lH-pyrroIo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]hexanenitrile; ethyl 3-amino-2-{[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]methyl}-propanoate; ethyl 2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanoate; 4-[ 1 -(1-propylbutyl)-1 H-pyrazol-4-yl]-1 H-pyrrolot2,3-b]pyridine; 4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile; [3-chloro-2-[4-(lH-pyxrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-5-(trifluoromethyl)phenyl]- acetonitrile; 5-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-2-(trifluoromethyl)-benzonitrile; 4-{l-[2-chloro-4-(trifluoromethyl)phenyl]-lH-pyra2ol-4-yl}-lH-pyrrolo[2,3-b]pyridine; 4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-2-(trifluoromethyl)-benzonitrile; 2-[4-(lH-pyrroIo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-ylJbenzonitrile; 3-chloro-2-[4-(lH-pynx)lo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile; 4-amino-5,6-difluoro-2-[4-(lH-pyrrolo[2,3-b3pyridin-4-yl)-lH-pyrazol-l-yl]isophthalonitrile; 1 - {[4-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazol-1 -yl]methyl} -cyclopropanecarbonitrile; 5-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]hexanenitrile; 2J2-dimethyl-6-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]hexanenitrile; 4-[ 1 -(1 -ethyl-2-methylpropyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine; 5-bromo-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yI)-lH-pyrazol-l-yl]benzonitrile; 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-4-(trifluoromethyl)-benzonitrile; 2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-3-(trifluoromethyl)-benzonitrile; 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-4-(trifluoromethyl)beiizamide; 3-[4-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]eyclohexanone; 2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]cyclohexanol; 4-(l-{[l-(methylsulfonyl)piperidin-4-yl]methyl}-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]- pyridine; 2-[4-(lH-pyrrolo[2J3-b]pyridin-4-yl)-lH-pyrazol-l-yl]cyclohexanecarbonitrile; 4-{l-[2-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine; 4-[l-(2,6-dichlorophenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b3pyridine; (4-{[4-(lH-pyirolo[2,3-b]pyridin-4-yl>lH-pyrazol-l-yl]raethyl}cyclohexyl)methanol; 4-[l-(tetrahydrofuran-2-ylmethy])-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[ 1-(1-cyclopentylpropyl)-1 H-pyrazol-4-yl]-lH-pyiTolo[2,3-b]pyridine; 4-[l-(tetrahydrofuran-3-ylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 2-chloro-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile; 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-3-(lJ3-thiazo]-5-y])propanenitrile; l-ben2yl-4-{[4-1H-pyrrolo[2J3-b]pyridin-4-yl)-lH-pyrazol-l-yl]methyl}pyrrolidin-2-one; 3-(l-methyl-lH-imidazol-5-yl)-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-3-(3-thienyl)propanenitrile; {l-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]cyclopentyl}acetonitrile; 4-chloro-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile; 4-[4-(lH-pyiTolo[2>3-b]pyridin-4-yl)-lH-pyrazol-l-yl]phthalonitrile; S-methyW-[-4lH-pyrrolo[2,3-b]pyridin-4--y1)-1H-pyrazol-l-yl]benzaldehyde; 4-[l-(2-methyl-4-nitrophenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]cyclopentanone; 4-[l-(3-furylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 4-[l-(2-furylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine; 3-{2-cyano-l-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]ethyl}benzonitrile; {3-methy-4--[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]phcnyl}niethanol; 4-methyl-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]pentan-2-onej 3-(l-benzofuran-2-yl)-3-[4-(lH-pyrro]o[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3-(3-furyI)-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]piopanenitrile; {3-methyM-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]phenyl}acetonitrile; 4-methy]-3-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l-yl]benzonitrile; 4-[ 1 -(1 -cyclopentylpropyl)-1 H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; {1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]cyclopentyl}acetonitrile; 3 - {(2-cyano-1 -[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yljethyl} benzonitrile; 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-3-(3-thienyl)propanenitrile; 4-chloro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]benzonitrile; 3-(3-furyl)-3-[4-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]propanenitrile; 3-[4-(7H-pyrro]o[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanedinitrile; 3-{l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclopentyl}-propanenitrile; {1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]cyclohexyl} acetonitrile; {3-methyl-4-[4-(7H-pyrrolo[2,3-d]pyritnidin-4-yl)-lH-pyra2ol-l-yl]phenyl}methanol; 3-pyridin-4-ylO-[4^7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazo]-l-yl]propanenitrile; 3-pyridin-3-ylO-[4-(7H-pyrrolot2,3-d]pyriniidin-4-yl)-lH-pyrazol-I-yl]propanenitrile; S-^-(methylthio)phenyy-S--4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl]propane- nitrile; 3-(3-methoxyphenyl)-3-[4-(7H-pyrrolo[2,3d]pyrmidin-4-yl] 21 H pyrazol -1- propanenitrile- 3-(4-methoxyphenyl)0-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH--pyrazoI-1-yI]propanenitrile; {3-methyl-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]phenyl}acetonitriIe; 3-[4-(methylsulfiyl)phenyl]-3-[4^7H-pyirolo[2,3^]pyrii!iaidin-4-yl)-lH-pyrazol-l-y]]- propanenitrile; 3-[4-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3 -[3 -(cyanomethoxy)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazo1-1 -yl] - propanenitrile; 3-(6-chloropyridin-3-y])-3-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH~pyrazol-l-yl]- propanenitrile; 5-{2^yano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}pyridine-2- carbonitrile; 3-(3,5^imethylisoxazol^-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrinaidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[4-(7H-pyiTolo[2^-d]pyrimidin^-yl)-lH-pyrazol-l-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]- propanenitrile; 3-(6-methoxypyridin-3-yl)-3-[4 nitrile; 3-pyridin-2-yl-3-[4-(7H-pyrro]o[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3^6-bromopyridin-2-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 6- {2-cyano-l -[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} pyridine-2- carbonitrile; 4-[4-(7H-pyrrolo[2,3-d]pyriraidin-4-yl)-lH-pyrazol-l-yl]heptanedinitrile; 3^5-bromopyridin-3-yl)^-[4-(7H-pyrrolo[2,3Kl]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 4-[4-(7H-pyrroIo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l-yl]heptanedinitrile; 5-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} nicotinonitrile; 3-(2-methoxypyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 3-[4-(cyanomethoxy)phenyl]-3-[4-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[2-(cyanomethoxy)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l-yl]- propanenitrile; 3-(3,5-dibromophenyl)-3-[4-(7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 5-{2-cyano-l -[4-(7H-pyinolo[2,3-d]pyrimidin-4-yl)--lH-pyrazol-1-yl]ethyl}isophthalonitrile; 3-[6-(dimethylamino)pyridin-2-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-(4-bromo-2-thienyl)-3-[4-(7H-pyrrolo[2,3-d]pyrmidin-4-yl)-lH-pyra2ol-l-yl]propane- nitrile; 5- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} thiophene-3- carbonitrile; 3-(5-bromo-2-fluorophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-(3-nitrophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3-(5-bromo-2-methoxyphenyl)0-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-]-yl]- propanenitrile; 3-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-l H-pyrazol-1-yl]ethyl}-4-methoxybenzo- nitrile; 3-(3-bromophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyroraidin-4-yl)-lH-pyra2ol-l-yl]propanenitrile,: 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]ethyl}-4-fluorobenzo- nitrile; 3-[5-bromo-2-(cyanomethoxy)phenyl]-3-[4(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]propanenitrile; 3-(4-bromo-2-furyl)-3-[4-(7H-p3mrolo[2,3d]3yrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 4-(cyanomethoxy)-3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl3- ethyl}benzonitrile; 3-(4-brdmopyridin-2-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 2-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}isonicotinonitrile; 5- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -3-furonitrile; 3-[2-bromo-5-(cyanomethoxy)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidiri-4-yl)-lH-pyrazo1-1- yl]propanenitrile; 4-(cyanomethoxy)-2- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]- ethyl} benzonitrile; 3-pyrimidin-5-ylO-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3-(2-bromopyridin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimLidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 4-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-y]]ethyl}p3aidine-2-carbo- nitrile; 3-(5-methoxypyridin-3-yl)-3-t4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 3-(3-chlorophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyritnidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l-yl]-3-[3-(trifluoromethyl)phenyl]- propanenitrile; 3-(3-phcnoxyphenyl)-3-[4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-3-[3-(trifluoromethoxy)-phenyl]- propanenitrile; methyl 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrmidin-4-yl)-lH-pyrazol-l-yl]ethyl}benzoate; 3-{2-oyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4--yI)-lH-pyrazol-l-yl]ethyl}benzoic acid; 3-[3-(lH-pyrazoll-yl)phenyl]-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-(3-aminophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile; N-(3- {2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)4H-pyrazol-l -yl]ethyl}phenyl)- acetamide; N-(3-{2-cyano-l-[4-(7H-pyn-olot2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)- methanesulfonamide; 4-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}thiophene-2- carbonitrile; 5-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrinudin-4-yl)-lH-pyrazol-l-yl]ethyl}thiophene-2- carbonitrile; 3-[3-(morpholin-4-ylcarbonyl)phenyl]-3-[4-(7H-pyirolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l - yl]propanenitrile; N-(2-aminoethyl)-3-{2cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- ethyl} benzamide; 3-(5-formyl-3-thienyl)-3-[4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-methylbenz- amide; 2-yano-N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl3ethyl}- phenyl)acetamide; N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)- nicotinamide; N-(3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]ethyl}phenyl)-N'- isopropylurea; isopropyl (3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]ethyl}- phenyl)carbamate; 3-(5-phenylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l-yl3propane- nitrite; 3-(3,3'-bipyridin-5-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrmidin-4-yl)--lH-pyrazol-l-yHpropane- nitrile; 3^5-pyrimidin-5-ylpyridin-3-yl)-3-[4-(7H-pyn:olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[5-91-methyl-lH-pyrazol-4-yl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-1 -yl]propanenitrile; 3-(5ehynylpyridin-3-yl)-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane- nitrile; 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl]- propanenitrile; 3-(2-bromo-1,3-thiazol-5-yl)-3 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-y 1)-1 H-pyrazol-1 -yl] - propanenitrile; ethyl 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanoate; 3-(5-morpholin-4--ylpyridin-3-yl)-3-[4-47H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-(l-methyl-lH-pyrazo-4--yl0-3-[4-(7H-pyreolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 4-{l-[l-phenyl-2-(lH-lJ2,4-triazol-l-yl)ethyl]-lH-pyrazol-4-yl}-7H-pyrrolo[2,3-d]- pyrimidine; 4- {1 -[ 1 -phenyJ-2-(4H-l ,2,4-triazol-4-yl)ethyl]-l H-pyrazol-4-yl} -7H-pyrrolo[2,3-d]- pyrimidine; 3-(3-pyridin-3-ylphenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[5-(pheny]sulfinyl)pyridinO-yl]0-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[5-(phenylsulfonyl)pyridinO-yl]-3-[4 propanenitrile; 3-[4-(7H-pyrrolo[2,3-d]pyrimidin'4-yl)-lH-pyrazol-l-yl]pentan-l-ol; methyl 3--4H-pyrrolo]2,3-dlpyrimidin-4-yl-lH-pyrazol-l-yllpentyl carbonate; (lE)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanaloxime; (lE)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanalO-methyloxime; (lZ)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanalO-methyloxime; 4-[l -(4,4-dibromo-l -ethylbut-3-en-l -yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]0-[5-(l,3-thiazol-2-ylthio)pyridin- 3-yl]propanenitrile; 3-[5-(ethylthio)pyridin-3-yl]-3-[4^7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 4-[l-(l-ethylbut-3-yn-l -yl)-l H-pyrazol-4-yl]-7H-pyrrolot2,3-d]pyrimidine trifluoroacetate; 4-{l-[l-methyl-2-(lH-l>2,4-triazol-l-yl)ethyl]-lH-pyrazol-4-yl}-7H-pyrrolo[2,3-d]- pyrimidine; 4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentan-2-one trifluoroacetate; l-phenyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propan-l-one; S-[5-(ethylsulfinyl)pyridin-3-yll]-3-(7H-pyrrolo[2,3-dlpyrimidin-4-y1)-lH-pyrazol-l-yl]- propanenitrile; 3-[5-(ethylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[5-(cycloh6xylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; l-phenyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propan-l-ol; l-phenyl-2-t4-(7H-pyrrolo[2,3-d]pyrimidin-4-y])-lH-pyrazol-l-yl]propan-l-ol; 3-[3-(ethylthio)phenyI]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[3-(ethylsulfiny])phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[3-(ethylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[5-(cyclohexylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3d]-pyrimidin-4-yl)-lH-pyrazol- 1 -yl]propanenitrile; 3-[5-(cyclohexylsulfinyl)pyridinO-yl]-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]propanenitrile; 4-[ 1 -(1 -methyl-2-phenylethyl)-1 H-pyrazol-4-yl]-7H-pyrrolot2,3-d]pyriniidine; 4- {1 -[ 1 -methyl-2-(3-thienyl)ethyl]-l H-pyrazol-4-yl} -7H-pyrrolo[2,3-d]pyrimidine; 3-{l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}benzonitrile; 4-{ 1 -[2-(l H-imidazol-1 -yl)-l -methylethyl]-lH-pyrazol-4-yl}-7H-pyrrolot2,3-d]pyrimidine; 4-{l-[l-methyl-2-(3-methyl-l,2,4-oxadiazol-5-yl)ethyI]-lH-pyrazol-4-yl}-7H-pyrrolot2J3-d]- pyrimidine; 3-[3-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-(3-pyridin-4-ylphenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl3propane- nitrile; 4-[l-(I-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyriinidine; 4-[l--(l,3-dimethylbut-3-en-l-yl)-lH-pyra2ol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 3-[5-(isopropylthio)pyridin-3-yl]-3-l\|4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[5-(isopropylsulfinyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l- - yl]propanenitrile; 3-[5-(isopropylsulfonyl)pyridin-3-yl3^-3-[4 yljpropanenitrile; 3-[4-(7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-3-[5-(trifluoromethyl)pyridin-3-yl]- propanenitrile; 3-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyra2ol-l-yl]-3-[5-(trifluoromethyl)pyridin-3-yl]- propanenitrile; 2-[4-(7H-pyrrolo[2)3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-N-[3-(trifluoromethyl)phenyl]- propanamide; N-2-naphthyl-2-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanamide; N-l-naphthyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-y]]propaiiamide; N-(3-(yanophenyl)-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanamide; N-benzyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanamide; N-phenyl-2-[4-(7H-pyrrolo[2,3-d]-]-yrirnidin-4-yl)-lH-pyrazol-l-yl]-]butanamide; N-(4-phenoxyphenyl)-2-[4-(7H-pyrrolo[2,3-d]pyriraidin-4-yl)-lH-pyrazol-l-yl]butanamide; N-2-naphthyl-2- [4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl) -1 H-pyrazol-1 -yl]butanamide; N-(3-cyanophenyl)-2-[4(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanamide; N-bipheny-4-yl-2-[4-(7H-pynx)lo[2,3-d3pyrimidin-4-yl)-lH-pyrazol-I-yl]butanamide; N-(biphenyl-4-ylrnethyl)-2-[4-(7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- butanamide; N-(biphenyl-3-ylmethyl)-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI]- butanamide; N-(4-cyanophenyl)-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]butanamide; N-l-naphthyl-(4H-pyrrolo]2,3]pyrimidin-4--yl]-lH-pyrazol-l-yl]butanamide; 5-{2-cyano-l-[4-(7H-pyrrolo[213-d]pyrimidin-4-y0-lH-pyrazol-l-yl]ethyl}-N-phenylnicotin- amide; N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-3- (trifluoromethyl)benzamide; N-(3-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyI}phenyl)-3-(trifluoro- methyl)benzamide; 3-[3-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]- propanenitrile; 3-[3-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; N(-3-{[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}phenyl)benzene- sulfonamide; 3- {[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]methyl} -N-[3-(trifluoromethyl)- phenyl]benzamide; 3-{2-cyano-l -[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-l H-pyrazol-1-yl]ethyl} -N,N-dimethyl- benzenesulfonamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N,N-dimethyl- benzenesulfonamide; N-benzyl-3- {2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yl]ethyl} - benzenesulfonamide; N-benzyl-3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethy]}- benzamide; 3-{2-cyano-l-[4-(7H-pyrTolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-phenyl- benzamide; 3-{2-cyano-l-[4-(7H-pyixolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-[3-(trifluoro- methyl)phenyl]benzamide; N-(3-cyanophenyl)-3-{[4-(7H-pyrrolo[2,3^]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}- benzamide; N-benzyl-3-{[4-(7H-pyrrolo-i[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl} benzamide; N-l-naphthyl-3-{[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazo]-l-yl]methyl}benzamide; N-2-naphthyl-3-{[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}benzamide; N-(3-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}phenyl)-2-naphthaniide; N-(3-{[4-(7H-pyiTolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]methyl}phenyl)-l-naphthamide; 2-phenyl-N-(3-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}phenyl)- acetamide; 3-chloro-N-(3-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyTazol-l-yl]inethyl}phenyl)- benzamide; N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-2- naphthamide; N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-l- naphthamide; N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-ethyl}phenyl)-2- phenylacetamide; 3-cyano-N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}- phenyl)benzamide; N-(3- {2-cyano-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} phenyl)- benzamide; N-(3-{2-yano-l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyO-4- (trifluoromethyl)benzamide; N-(3-{2-cyano-l-[4-(7H-pyn:olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-Nl- phenylurea; 3-{2^yano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-[4-(trifluoro- methyl)phenyl]benzamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(4-inethyl- phenyl)benzamide; N-(4-cyanophenyl)-3-{2-cyano-l-[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- ethyl} benzamide; 3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl}-N-2-naphthyl- benzamide; 3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]ethyl}-N-l -naphthyl- benzamide; 3- {2-cyano-l -[4-(7H-pyirolo[2,3-d]pyrimidin-4-yl) -1 H-pyrazol-1 -yl]ethyl} -N,N-dimethyl- benzamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-pyridin-3-yl- benzamide; 3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]ethyl}-N-methyl-N- phenylbenzamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-cyclohexyl- benzamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(4-phenoxy- phenyl)benzamide; N-(3-cyanophenyl)-3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- ethyl}benzamide; N-biphenyl-4-yl-3-{2-cyano-l-t4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]- ethyl} benzamide; N-(4-chlorophenyl)-3-{2-cyano-l -[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl]- ethyljbenzamide; 3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yl]ethyl}-N-(3,4-dimethyl- phenyl)benzamide; 3- {2-cyano-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yl]ethyl}-N-(3-methoxy- phenyl)benzamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(4-methoxy- phenyl)benzamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-isoxazol-3-yl- benzamide; 3-{2-oyano-l-[4-(7H-pyirolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-methyl-N- phenylbenzenesulfonamide; 3- {2-cyano-l -[4-{7H-pyiTolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-propyl- benzenesulfonamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyriinidm-4-yl)-lH-pyrazol-l-yl]ethyl}-N-phenyl- benzenesulfonamide; 3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yljethyl} -N-2-naphthyl- benzenesulfonamide; 3-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-cyclopropyl- benzenesulfonamide; 3-[3-(piperidin-l-ylsulfonyl)phenyl]-3-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]propanenitrile; 3-[3-(morpholin-4-ylsulfonyl)phenyl]-3-[4-(7H-pynx)lo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l yl]propanenitrile; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(4-methyl- phenyl)benzenesulfonamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(3,4-dimethy] phenyl)benzenesulfonamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(3-methoxy- phenyl)benzenesulfonamide; 3-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-(4-methoxy- phenyl)benzenesulfonamide; 3-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-(3,5- dimethoxyphenyl)benzamide; 3-{2-cyano-l-[4-(7H-pynolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-[4-(dimethyl- amino)phenyl]benzamide; 3-[3-(benzylsulfonyl)phenyI]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[3-(ben2ylthio)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 4-{[(3-{2-cyano-l-[4-C7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)- sulfonyl]methyl}benzonitrile; 3-{2-cyano-l -[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-methyl- benzenesulfonamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-l-naphthyl- benzenesulfonamide; N-biphenyM-y]-3-{2-cyano-l-[4-(7H-pyrrolo[2J3^]pyrifflidin-4-yl)-lH-pyrazol-l-yl]ethyl}- benzenesulfonamide; 3-{2^yano-l-[4-(7H-pyrrolot2,3^]pyrimidir,-4-yl)-lH-pyrazol-l-yl]ethyl}-N-[4-(trifluoro- methoxy)phenyl]benzamide; 3 - {2-cyano-l -t4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl]ethyl} -N-(2-methoxy- phenyl)benzamide; 3-[3-(benzyloxy)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pynizoI-l-yl]- propanenitrile; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-cyclohexyI- benzenesulfonamide; 3-[3-(3,4-dmydroisoquinolin-2(lH)-ylsulfonyl)phenyl]-3-[4-(7H-pyiTolo[2,3-d]pyrimidin-4- yl)-lH-p yrazol-l-yl]propanenitrile; 3-{2-cyano-l-[4-(7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(2-methoxy- ethyl)benzenesulfonamide; 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N,N-diethyl- benzenesulfonamide; 3-{3-[(4-ethylpiperazm-l-yl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl>lH- pyrazol-1 -yl]propanenitrile; N-l,3-benzodioxol-5-yl-3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]ethy 1} benzenesulfonamide; 3-{3-[(3-methoxybenzyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-1 -yl]propanenitrile; 3-{3-[(4-methoxybenzyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-1-yl]propanenitrile; 3-{3-[(2,6-dimethylmorpholm-4-yl)sulfonyl]phenyl}-344-(7H-pyrrolo[2,3d]pyrunidin-4-yl)- 1 H-pyrazol-1 -yljpropanenitrile; 3- {3-[(4-oxopiperidin-l -yl)sulfonyl]phenyl} -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H- pyrazol-1 -yl]propanenitrile; 3-[3-(isopropylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-lH-pyrazol-1-ylj- propanenitrile; 3-{3-[(cyclohexylmethyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-1 -yljpropanenitrile; 3-[3-(octahydroisoqumolin-2(lH)-ylsulfonyl)phenyl]-3-[4-(7H-pyn-olo[2J3-d]pyriniidin-4- yl)-1H-pyrazol-1 -yl]propanenitrile; 3-{2-cyano-l-[4-(7H-pyrrdlo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(2-phenyl- ethyl)benzenesulfonaroide; cia-4-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]cyclohexylacetonitrile; cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethylthiocyanate; N-5-[(cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)thio]- 4H-I,2,4-triazol-3 -ylpyrimidin-2-amine; N-5-[(cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI]cycIohexyImethyl)thio]- 4H-1,2,4-triazol-3 -ylpyrimidin-2-amine; 3-cis-4-[4-(7H-pyiTolo[23-d]pyriniidin-4-yl)-lH-pyrazol-l-yl]cyclohexylpropanenitrile; 5-[2-cis-4-[4H-pyrrolop2,3-d]pyrimidin-4-yl)-IH-pyrazoI-l-yl]cyclohexylethyOthio]-4H- 1 ,2,4-triazol-3-amine; 4-[4-(7H-pyrrolot2,3-d]pyrirnidin-4-yl)-lH-pyrazol-l-yl]cyclohexylideneacetonitrile; cis-4-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexanecarbonitrile; 2-[(cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)sulfinyl]- benzonitrile; 2-[(cis-4-[4-(7H-pyrrolo[23-d]pyritnidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)sulfonyl]- benzonitrile; 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylacetonitrile; 5-({cis-4-[4-(7H-pyrrolo[2,3-d3pyrimidin-4-yl)-lH-pyra2ol-l-yl]cyclohexyl}thio)-lH-l,2,4- triazol-3-amine; N- {5-[( {cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]cyclohexyl}methyl)- thio]-4H-l,2,4-triazol-3-yI}methanesulfonamide; [cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-l-(lH-l,2,4-triazol-l-yl)cyclo- hexyljacetonitrile; 3-[3-(piperazin-l -ylsulfonyl)phenyl]-3-[4-(7H-pyr rolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l - yl]propanenitrile; 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-3-[3-(thiomorpholin-4-ylsulfonyl)- phenyl]propanenitri le; 3-{3-[(4-hydroxypiperidin-l-yl)sulfonyl]phenyl}-3 -[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)- lH-pyrazol -l-yl]propanenitrile; 3-[3-(isobutylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanenitrile; 3-[4-(7H-pyrrolo[2)3-d]pyrimidin-4-yl)-lH-pyrazol -1 -yl]-3-{3-[(tetrahydro-2H-pyran-4- ylmethyl)sul fonyl]phenyl}propanenitrile; 3-{3-[(2-methoxyethyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH- pyrazol-1 -yl]propanenitrile; 3-{3-[(3-furylmethyl)sulfonyl]phenyl}-3-[4--(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- 1 -yl]propanenitrile; 3- {3-[(l, 1 -dioxidothiomorpholin-4-yl)sulfonyI]phe nyl} -3-[4-(7H-pyrroIo[2,3-d]pyrimidin-4- yl)-lH-p yrazol-l-yl]propanenitrile; 3-{3-f(4-acetylpiperazin-l-yl)sulfonyl]phenyl}-3-r4-(7H-pyrTolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-1 -yl]propanenitrile; 3-{3-[(pyridin-4-ylmethyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-1 -yl]propanenitrile; 4-[l-(l-phenylbut-3-yn-l-yl)-lH-pyrazol-4-yl]-7H- pyrrolot2,3-d]pyrimidine; 4-(l-{l-[3-(morpholin-4-ylsulfonyl)phenyl]but-3-yn-l-yl}-lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidine; 3-{l-[4-(7H-pynrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]but-3-yn-l-yl}benzonitrile; 3-{l-[4-(7H-pyn-olo[2,3-d]-pyrimidin-4-yl)-lH-pyrazol-l-yl]but-3-yn-l-yl}benzaldehyde; methyl 3-(3-cyanophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]- propanoate; N,N-dimethyl-3-{l-[4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l-yl]but-3-yn-l-yl}- benzenesulfonamide; 3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 -yl]ethyl) -N-[4-{dimethyl- amino)phenyl]benzenesulfonamide; 3-{3-methoxy-l-[4-(7H-pyirolo[2,3Kl]pyrimidin-4-yl)-lH-pyrazol-l-yl]propyl}-JV;iV- dimethylbenzenesulfonamide; N-phenyl-3-{l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazo]-l-yl]but-3-yn-l-y]}- benzamide; 4-[l -(3-methoxy-l -phenylpropyl)-lH-pyrazol-4-yl]- 7H-pyrrolo[2,3-d]pyrimidine; Ar-[4-(dimethylamino)phenyl]-3-{l-[4-(7H-pyn-o]o[2,3-d]-pyrimidin-4-yl)-lH-pyrazol-l- yl]but-3-yn-l-yl}benzamide; 3-{3-hydroxy-l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-y l)-lH-pyrazol-l-yl]propyl}-iV;7V- dimethylbenzenesulfonamide; 3-{l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]but-3-en-l -yl}benzonitrile; 4-{l-[l-(3-bromophenyl)but-3-en-l-yl]-lH-pyrazol-4-yl}-7H-pyrroIo[2,3-d]pyrimidine; 3-{4,4-difluoro-l-t4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-l H-pyrazol-1 -yl]but-3-en-l -yl}- benzonitrile; 4-(i-{4,4-difluoro-l-t3-(morpholin-4-ylsulfonyl)phenyl]but-3-en-l-yl}-lH-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidine; 4-(l - {1 -[3-(ethylsulfonyl)phenyl]-4,4-difluorobut-3-en-l -yl} -1 H-pyrazol-4-yl)-7H-pyrrolo- [2,3-d]pyrimidine; 4-(l-{l-[3-(benzyloxy)phenyl]-4)4-difluorobut-3-en-l-yl}-lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidine; 441-(2-methoxy-lphenylethyl)-lH-pyrazoM-yl]-7H-pyrrolo[2,3HJ]pyrimidine; 4-(l-{4,4-difluoro-l-[3-(methylsulfonyl)phenyl]but-3-en-l-yl}-lH-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidine; 3-{[4-(7H-pynrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}beiizonitrile; 3-{l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]-ibutyl}ben2onitrile; 4-(l-{l-[3-(ethylsulfonyl)phenyl]-4,4-difluorobutyl}-lH-pyrazoI-4-yl)-7H-pyrrolo[2,3-d]- pyrimidine; 4-[l-(4,4-difluoro-l-{3-t(2-methoxyethyl)sulfonyl]phenyl}-but-3-en-l-yl)-lH-pyrazol-4-yl]- 7H-pyrrolo[2,3-d]pyrimidine; 4-[l-(l-cyclopentylbut-3-en-l-yl)-lH-pyrazol-4-y]]-7H-pyiTolo[2,3-d]pyrimidine; 4-[l-(l-methylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 4-[l-(l-cyclopentyl-2-cyclopropylethyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 4-[ 1 -(1 -cyclopentylbut-3-yn-l -yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 4-[l-(l-cyclopentylbutyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin.e; 4-[l-{l-cyclopentyl-4,4-difluorobut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]- pyrimidin.e; 4-1 -[4,4-difluoro-l -(tetrahydrofuran-3-yl)but-3-en-l -yl]-lH-pyrazo]-4-yl-7H-pyrrolo[2,3- d]pyrimidine; 4-[l-(l-methylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 4-[ 1 -(1 -cyclopropyl-4,4-difluorobut-3-en-l -yl)-l H-pyrazol-4-yl] -7H-pyrrolo[2,3-d]- pyrimidine; 4-[l-(l-cyclopentyl-4,4-difluorobutyl)-lH-pyTazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 3-( 1 -methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]propane- nitrile; (3R)-and(3S)-4,4-dimethyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]niethyl-7H-pyrroIo[2,3-d3- pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile; l-2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylcyclopropane- CEtrbonitrile; N-[{ 1 -2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidm-4-yl)-lH-pyrazol-l -yl]ethylcyclopentyl)- methyl]benzamide; 3-l-[(benzyloxy)metoyI]cyclopentyl-3-[4-(7H-pyrTolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]propanenitrile; 3-[l^rnethy]sulfonyl)pyn-olidin-3-yl]-3-[4-(7H-pyrTolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]propanenitrile; N-cyano-4-cyanomethyl)-4-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl]-lH-pyrazol-l-yl]- piperidine-1-carboximidamide; 4-l-[2,2,2-trifluoro-l-(lH-imidazol-2-ylmethyl)ethyl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3- d]pyrimidine; 4-(l-(lR)-2,2,2-trifluoro-l-[(4-methyl-l,3-thiazol-2-yl)methyl]ethyl-lH-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidine; 4-l-[-1trifluoromethy)but-3-yn-l-yy-lH-pyrazo1-4-yl-7H-pynrolo[2,3-d]pyrimidine; 4-l-[l-(trifluoromethyl)but-3-en-l-yl]-lH-pyrazol1-4-yl-7H-pyrrolo[23-d]pyrimidine; 4-1 -[1 -(trifluoromethyl)butyl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine; 4-1 -[4,4-difluoro-l -(trifluoromethyl)but-3-en-l -yl]-l H-pyrazol-4-yl-7H-pyrrolo[2,3-d]- pyrimidine; 4-l-[4,4-difluoro-l-(trifluororaethyl)butyl]-lH-pyrazol-4-yl-7H-pyrrolot2,3-d]pyrimidine; 3-pyridin-4-yl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]propanenitrilc; 4-2-cyano-l-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]ethylpyridine-2- carbonitrile; and 3-pyridin-2-yl-3-[5-(7H-py]ToIo[2,3-d]pyriiiudin-4-yl)-l,3-thiazol--2-yl]propanenitrile; and pharmaceutically acceptable salts thereof. 47. A composition comprising a compound of any one of claims 1 to 46, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 48. The composition of claim 47 which is suitable for topical administration. 49. A method of modulating an activity of JAK comprising contacting JAK with a compound c Formula I: including pharmaceutically acceptable salt forms or prodrugs thereof, wherein: A1 and A2 are independently selected from C and N; T, U, and V are independently selected from O, S, N, CRS, and NR6; wherein the 5-membered ring formed by A1, A2, U, T, and V is aromatic; X is N or CR4; Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R12)p -(C3-10 cycloalkylene)- (CR11R12)q (CR11R12)q-(arylene)-(CR11R12)q) (CR11Rl2)p-(G1-10heterocycloaIkylene)(CR11R12)q (CR11R12)q-(heteroarylene)-(CR11R21)q, CR11R21)POCR11R21)q CR11R21)pSCR11R21)q, CR11R21)qC(O)CR11R21)q, CR11R21)pC(O)NReCR11R21)q,, CR11R21)pC(O)O(CR11R21)qq> CR11R21)POC(O)CR11R21)q, (CR11R12)qOC(O)NRc(CR11R21)q, (CR11R12)qNRCCR11R21)q CR11R21)qC(O)NRd(CR11R12)p , CR11R21)qS(O)CR11R21)q, (CR11R12)p S(O)NRc(CR11R12)q, CR11R21)qS(O)2CR11R21)q, or (CR11R12)qS(O)2NRc(CR11R12),, wherein saidC1-4alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1,2, or 3 substituents independently selected from -D'-D2-D3-D4; Z is H, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4 hydroxyalkyl,C1-4cyanoalkyl, -C-R1, =N-R!, Cyl, CN, NO2, OR", SRa, C(O)Rb, CCONRHd. C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcWd, NRcC(O)Rb, NR1C(O0NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR')NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, Cy1 CN, NO2 ORa, SRa, C(O)Rb, C(O)NScBd. C(O)ORa, OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)IMRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRa, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-4alkyl))Rb, and S(O)2NRcRd; wherein when Z is H, n is 1; or the -(Y)n-Z moiety is taken together with i) A2 to which the moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which the R5 or R6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or S substituents independently selected from-(W)m-Q; W is C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, O, S, C(O), C(O)NR°\ C(O)O, OC(O), OC(O)NRC, NRC, NRc'C(O)NRd', S(O), S(O)NRC, S(O)2, or S(O)2NRC'; Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-6 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalky] is optionally substituted with 1,2, 3 or 4 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C1-4alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy2, CN, NO2, OR"', SRa\ C(O)Rb', C(O)NRcRd', C(O)ORa', OC(O)Rb, OC(O)NRcRd, NRcRd. NR°'C(O)Rb',NRCC(O)NRcRd,NRcC(O)OR0, S(O)Rb>, S(O)NRc'Rd', S(O)2Rb>, NRc>S(O)2Rb', and S(O)2NRcRd; Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1,2, 3, 4 or 5 substituents independently selected from halo,C1-4alkyl,C1-4alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C\^ cyanoalkyl, CN,NO2, OR"", SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", OC(O)Rb", OC(O)NRc"Rd", NRc"Rd", NRc"C(O)Rb", NRc"C(O)ORa", NRcS(O)R1", NRc"S(O)2Rb", S(O)Rb.", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRcRd; R1, R2, R3, and R4 are independently selected from H, halo,C1-4alkyl, C2-4 alkenyl,C1-4alkynyl, C1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)RS, OC(O)NR9R10, NR9R10, NR9C(O)R8, NRCC(O)OR7, S(O)R8, S(O)NER9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10; Rs is H, halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4, haloalkyl, halosulfanyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)2NR9R10; R6 is H, C1-6 alkyl,C1-4alkenyl, C2-4 alkynyl,C1-4 haloalkyl, OR7, C(O)R8, C(O)NR9R10, C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, or S(O)2NR9R10; R7 is H, C1-4alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R8 isH, C1-8 alkyl, C1-4haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R9 and R10 are independently selected from H, C1-10 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkylcarbonyl, arylcarbonyl, C1-4 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R9 and R10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; Ru and R12 are independently selected from H and -E1-B2-E3-E4; D1 and E1 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1,2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN, OH, C1-6alkyl, C1-6haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and C2-8 dialkylamino; D2 and E2 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene,C1-4alkynylene, (C1-4alkylene)r-O-( C1-6alkylene)s, (C1-6 alkylene)r-S-(C1-6 alkylene)s, (C1-6 alkylene)r-NRe-(C1-4 alkylene)s, (C1-6 alkylene)r-CO-(C1-6 alkylene)s, (C1-6alkylene)r-COO-(C1-6 alkylene)5, (C1-6alkylene)r-CONRc-(C1-6 alkylene)s, (C1-4alkylene)r-SO-(C1-6 alkylene)s, (C1-6 alkylene)r-S02-(C1-4alkylene)S, (C1-4alkylene)rSONRe-(C1-6 alkylene)s, and (C1-4alkylene)r- NReCONRf-(C1-6 alkylene)s, wherein each of the C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene is optionally substituted by 1,2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-4alkoxy, C1-4 haloalkoxy, amino, C1-6 alkylamino, and C2-8 dialkylamino; D3 and E3 are independently absent or independently selected from C1-6alkylene, C2-6 alkenylene, C2-6 alkynylene, aiylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C^alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO2,N3, SCN, OH, C1-6 alkyl, C1-6haloalkyl, C2-8 alkoxyalkyl, C1-4alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and C2-8 dialkylamino; D4 and E4 are independently selected from H, halo,C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR", SR", C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(0)ORa, C(=NR1)NRcRd, NRCO(-NR1)NRI!R-, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3,4,5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NReR NRcC(O)NReRd, NRCC(O)OR85 C(=NR1)NRcRd, NRcC(=NR')NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C2-6 alkyl))Rb, and S(O)2NRcRd; Ra is H, Cy', -(C1-6 alkyl)-Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, hcteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy1, -(C1-4alkyl)-Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Ra' and Ra" are independently selected from H, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1,2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-4 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb and Rb" are independently selected from H, C1-6 alkyl, C1-6haloalkyl,C1-4alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Chalky!, C1-6haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Re and Rd are independently selected from H, Cy\ -(C1-4alkyl)-Cy1, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-8 alkrenyl, or C2-6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy\ -(C1-6 alkyl)-Cy1 OH, CN, amino, halo, C1-6 alkyl, C1-6haloalkyl, C1-6 haloalkyl,and halosulfanyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently selected from Cy1, -(C1-6 alkyO-Cy1, OH, CN, amino, halo, C1-6alkyl, C1-4haloalkyl, C1-6haloalkyl, and halosulfanyl; Rc and Rd are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc' and Rd> together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc" and Rd" are independently selected from H, C1-10 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl,C1-4alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 haloalkyl, halosulfanyl, C1-4 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc" and Rd" together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-4 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R! is H, CN, NO2 or C1-6alkyl; Rc and Rf are independently selected from H and C1-6 alkyl; R' is H, CN,or NO2; m is 0 or 1; n is 0 or 1; p is 0, 1, 2, 3,4, 5, or 6; q is O, 1,2, 3,4, 5 or 6; r is 0 or 1; and s is 0 or 1. 50. The method of claim 49 wherein said JAK is JAK1, JAK2, JAK3 or TYK2. 51. The method of claim 49 wherein said JAK is JAK1 or JAK2. 52. The method of claim 49 wherein said JAK is JAK2. 53. The method of claim 49 wherein said modulating is inhibiting. 54. The method of claim 49 wherein said compound is a selective inhibitor of JAK2 over JAK1, JAK3 and TYK2. 55. A method of treating a disease in a patient, wherein said disease is associated with JAK activity, comprising administering to said patient a therapeutically effective amount of a compound of Formula I: including pharmaceutically acceptable salt forms or prbdrugs thereof, wherein: A1 and A2 are independently selected from C and N; T, U, and V are independently selected from O, S, N, CR5, and NR6; wherein the 5-membered ring formed by A1, A2, U, T, and V is aromatic; X is N or CR4; Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R21)p-(C3-10 cycloalkylene)- (CRllR12)q,(CR1IRl2)p-(arylene)-(CR11R12)q,(CR11R12)p -(C1-10 heterocycloalkylene)-(CR11R12)p ) (CR11R12)q (heteroarylene(CR11R12)q (CR11R12)qO(CR11R12)Q, (CR11R12)qS(CR11R12)q, (CR11R12)qC(O)(CR11R12)q (CR11R12)p C(O)NRc(CR11R12)q, (CR11R12)pC(O)O(CR11R12)p , (CR11'R12)p OCCO)(CR11R12)q, (CR11R12)q)OC(O)NR.c(CR11R12)q, (CR11R12)pNRC(CR11R12)q, (CR11R12)qNRcC(O)NRd(CR11R12)q, (CR11Rl2)pS(O)(CR11R12)q (CR11R12)qS(O)NRc(CR11R12)q (CR11R12)qs(CR11R12)q,, or (CR11'R12)p S(O)NRc(CR11R12)q, wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D'-D2-D3-D4; Z is H, halo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, =C-R\ =N-R\ Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NR°Rd, C(O)OR\ OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NR°Rd, NRcC(O)ORa, C(=NR1)NRcRd NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-6 alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-6 alkynyl, C1-6 1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)OR", OC(O)Rb, OC(O)NRcRd, NR^, NRcC(O)Rb, NR"C(O)NRCR-, NRcC(O)ORa, C(=MRi)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl))Rb, and S(O)2NRcRd; wherein when Z is H, n is 1; or the -(Y)n-Z moiety is taken together with i) A2 to which the moiety is attached, ii) R3 or R6 of either T or V, and iii) the C or N atom to which the Rs or R6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from -(W)m-Q; W is C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, O, S, C(O), C(O)NRC, C(O)O, OC(O), OC(O)NRe>, NRC', NRc'C(O)NRd>, S(O), S(O)NRC S(O)2, or S(O)2NRC"; Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1,2,3 or 4 substituents independently selected from halo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-6 cyanoalkyl, Cy2, CN, NO2, ORa>, SRa%, C(O)Rb', C(O)NRc>Rd', C(O)ORa>, OC(O)Rb', OC(O)NRcRd,NRcRd',NRc'C(O)Rb>, NRc'C(O)NRc'Rd', NRcC(O)ORa', S(O)Rb', S(O)NRc'Rd', S(O)2Rb\ NRc'S(O)2Rb', and S(O)2NRc>Rd>; Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4hydroxyalkyl, C1-4 cyanoalkyl, CN, NO2, ORa", SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", OC(O)Rb", OC(O)NRc"Rd", NRc"Rd", NRc"C(O)Rb' NRc"C(O)ORa", NRc"S(O)Rb", NRcSCO)2Rb", S(O)Rb' S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd>; R1, R2, R and R4 are independently selected from H, halo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR'R10, NR9C(O)R8, NRCC(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10; R5 is H, halo,C1-4alkyl, C2-4 alkenyl,C1-4alkynyl, C1-4 haloalkyl, halosulfanyl, CN, NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NR'C(O)OR7, S{O)R8, S(O)NR9R10, S(O)2R8, NR'SCOaR8, or S(O)2NR9R10; R6 is H,C1-4alkyl,C1-4alkenyl, C2-6 C1-4 alkynyl, C1-6 haloalkyl, OR7, C(O)R8, C(O)NR9R10, C(O)OR7, S(O)R8, S(O)NR9R10, SCO)2R8, or S(O)NR9R10; R7 is H, C1-4alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R8 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R9 and R10 are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4alkylcarbonyl, arylcarbonyl, C1-6alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R9 and R10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group; Rn and R12 are independently selected from H and -E1-E2-E3-E4; D1 and E1 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1,2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6alkylamino, and C2-8dialkylamino; D2 and E2 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, (C1-6 alkylene),-O-(C1-6 alkylene)s, (C1-6 alkylene)r-S-(C1-6 alkylene)s, (C1-6 alkylene)r-NRe-(C1-6alkylene)s, (C1-6 alkylene)r-CO-(C1-6 alkylene)s, (C1-6 alkylene)r-COO-(C1-6 alkylene),, (C1-6alkylene)r-CONRe-(C1-6 alkylene)s> (C1-6alkylene)t-SO-(C1-6alkylene)s, (C1-6 alkylene)r-SO2-(C1-6 alkylene)s, (C1-6alkylene)r-SONRe-(C1-6alkylene)s, and (C1-6 alkylene)r- NRcCONRf-(C1-6 alkylene),, wherein each of the C1-4 alkylene, C2-6 alkenylene, and C2-6 alkynylene is optionally substituted by 1,2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6alkoxy, C1-4haloalkoxy, amino, C1-4 alkylamino, and C2-6 dialkylamino; D3 and E3 are independently absent or independently selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1-4alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN, OH, C1-6alkyl, C1-4haloalkyl. C2-8 alkoxyalkyl, C1-4alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and C2-8 dialkylamino; D4 and E4 are independently selected from H, halo,C1-4 alkyl, C2-4 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NReC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NR°Rd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl,C1-4alkynyl, C1-4haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRTcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRTR.d, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl))Rb, and S(O)2NRcRd; Ra is H, Cy1, -(C1-6 alkyl)-Cy1, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C1-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy1, -(C1-6 alkyO-Cy1, C168 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1,2, or 3 substituents independently selected from OH, CN, amino, halo, C1-8 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Ra and Ra" are independently selected from H, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with I, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb> and Rb" are independently selected from H, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc and Rd are independently selected from H,Cy1,-(C1-6 alkyl)-Cy1, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, is optionally substituted with. 1,2, or 3 substituents independently selected from Cy1, -C1-6 alkyl)-Cy1, OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6 haloalkyl,and halosulfanyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently selected from Cy1, -(C1-8alkyl)-Cy', OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6haloalkyl, and halosulfanyl; Rc> and Rd' are independently selected from H, C1-10alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10alkyl, C1-4haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1,2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc' and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-6haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rc" and Rd" are independently selected from H, C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc" and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-4haloalkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rl is H, CN, NOz, or C1-6 alkyl; Re and Rf are independently selected from H and C1-6 alkyl; Ri is H,CN,or NO2; m is 0 or 1; n is 0 or 1; p is 0,1, 2, 3,4, 5, or 6; q is O, 1,2, 3,4, 5 or 6; r is O or 1; and s is O or 1. 56. The method of claim 55 wherein said disease is allograft rejection or graft versus host disease. 57. The method of claim 55 wherein said disease is an autoimmune disease. 58. The method of claim 57 wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder. 59. The method of claim 57 wherein said autoimmune disease is bullous skin disorder. 60. The method of claim 59 wherein said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP). 61. The method of claim 55 wherein said disease is a skin disorder. 62. The method of claim 61 wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization. 63. The method of claim 55 wherein said disease is a viral disease. 64. The method of claim 63 wherein said viral disease is Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicell-Zoster Virus (VZV) or Human Papilloma Virus (HPV). 65. The method of claim 55 wherein said disease is cancer. 66. The method of claim 65 wherein said cancer is a solid tumor 67. The method of claim 66 wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease or pancreatic cancer. 68. The method of claim 66 wherein said cancer is prostate cancer. 69. The method of claim 65 wherein said cancer is hematological. 70. The method of claim 69 wherein said cancer is lymphoma, leukemia, or multiple myeloma. 71. The method of claim 69 wherein said cancer is a skin cancer. 72. The method of claim 71 wherein said skin cancer is cutaneous T-cell lymphoma or cutaneous B-cell lymphoma. 73. The method of claim 69 wherein said cancer is multiple myeloma. 74. The method of claim 55 said disease is characterized by a mutant JAK2. 75. The method of claim 74 wherein at least one mutation of said mutant JAK2 resides in the pseudo-kinase domain of said JAK2. 76. The method of claim 55 wherein said disease is a myeloproliferative disorder. 77. The method of claim 76 wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), mycloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), or systemic mast cell disease (SMCD). 78. The method of claim 55 wherein said disease is an inflammatory disease. 79. The method of claim 78 wherein said disease is an inflammatory disease of the eye. 80. The method of claim 79 wherein said disease is iritis, uveitis, scleritis, or conjunctivitis.. 81. The method of claim 78 wherein said disease is an inflammatory disease of the respiratory tract. 82. The method of claim 81 wherein said inflammatory disease concerns the upper respiratory tract. 83. The method of claim 81 wherein said inflammatory disease concerns the lower respiratory tract. 84. The method of claim 55 wherein said inflammatory disease is an inflammatory myopathy. 85. The method of claim 84 wherein said inflammatory disease is myocarditis. 86. The method of claim 55 wherein said disease is ischemia reperfusion or related to an ischemic event. 87. The method of claim 55 wherein said disease is anorexia or cachexia resulting from or associated with cancer. 88. The method of claim 55 wherein said disease is fatigue resulting from or associated with cancer. The present invention provides heteroaryl substituted pyrrolo[2,3-b]pyridines (I) and heteroaryl substituted pyrrolo[2,3-b]pyrim- idines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

Full Text

HETEROARYL. SUBSTITUTED PYRROLO[2,3-b]PYKIDINES AND
PYRROLO[2,3-b]PYRDMIDINES AS JANUS KINASE INHIBITORS
FIELD OF THE INVENTION
The present invention provides heteroaryl substituted pyrrolo[2,3-b]pyridines and heteroaryl
substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases and are useful in the
treatment of diseases related to activity of Janus kinases including, for example, immune-related
diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.
BACKGROUND OF THE INVENTION
Protein kinases (PKs) are a group of enzymes that regulate diverse, important biological
processes including cell growth, survival and differentiation, organ formation and morphogenesis,
neovascularization, tissue repair and regeneration, among others. Protein kinases exert their
physiological functions through catalyzing the phosphorylation of proteins (or substrates) and thereby
modulating the cellular activities of the substrates in various biological contexts. In addition to the
functions in normal tissues/organs, many protein kinases also play more specialized roles in a host of
human diseases including cancer. A subset of protein kinases (also referred to as oncogenic protein
kinases), when dysregulated, can cause tumor formation and growth, and further contribute to tumor
maintenance and progression (Blume-Jensen P et al, Nature 2001, 411(6835):355-365). Thus far,
oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for
cancer intervention and drug development.
Protein kinases can be categorized as receptor type and non-receptor type. Receptor tyrosine
kinases (RTKs) have an extracellular portion, a transmembrane domain, and an intracellular portion,
while non-receptor tyrosine kinases are entirely intracellular. RTK mediated signal transduction is
typically initiated by extracellular interaction with a specific growth factor (ligand), typically followed
by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity, and receptor
transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules
and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that
facilitate the appropriate cellular response such as cell division, differentiation, metabolic effects, and
changes in the extracellular microenvironment
At present, at least nineteen (19) distinct RTK subfamilies have been identified. One RTK
subfamily, designated the HER subfamily, includes EGFR, HER2, HER3 and HER4, and bind such
ligands as epithelial growth factor (EGF), TGF-, amphiregulin, HB-EGF, betacellulin and heregulin.

A second family of RTKs, designated theiuisulin subfamily, includes the INS-R, the IGF-1R and the
IR-R. A third family, the "PDGF" subfamily, includes the RDGF alpha and beta receptors, CSFIR, c-
kit and FJJfC-H. Another subfamily of RTKs, referred to as the FLK subfamily, encompasses the
Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4)
and the fins-like tyrosine kinase 1 (flt-1). Two other subfamilies of RTKs have been designated as the
FGF receptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-Met, Ron and
Sea). For a detailed discussion of protein kinases, see for example, Blume-Jensen, P. et ah, Nature.
2001, 411(6835):355-365, and Manning, G. et al., Science. 2002, 298(5600): 1912-1934.
The non-receptor type of tyrosine kinases is also composed of numerous subfamilies,
including Src, Btk, Abl, Fak, and Jak. Each of these subfamilies can be further subdivided into
multiple members that have been frequently linked to oncogenesis. The Src family, for example, is
the largest and includes Src, Fyn, Lck and Fgr among others. For a detailed discussion of these
kinases, see Bolen JB. Nonreceptor tyrosine protein kinases. Oncogene. 1993, 8(8):2025-31.
A significant number of tyrosine kinases (both receptor and nonreceptor) are associated with
cancer (see Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem.
2004, 37(7):618-35.)- Clinical studies suggest that overexpression or dysregulation of tyrosine
kinases may also be of prognostic value. For example, members of the HER family of RTKs have
been associated with poor prognosis in breast, colorectal, head and neck and lung cancer. Mutation of
c-Kit tyrosine kinase is associated with decreased survival in gastrointestinal stromal tumors. In acute
myelogenous leukemia, Flt-3 mutation predicts shorter disease free survival. VEGFR expression,
which is important for tumor angiogenesis, is associated with a lower survival rate in lung cancer.
Tie-1 kinase expression inversely correlates with survival in gastric cancer. BCR-Abl expression is
an important predictor of response in chronic myelogenous leukemia and Src tyrosine kinase is an
indicator of poor prognosis in all stages of colorectal cancer.
The immune system responds to injury and threats from pathogens. Cytokines are low-
molecular weight polypeptides or glycoproteins that stimulate biological responses in virtually all cell
types. For example, cytokines regulate many of the pathways involved in the host inflammatory
response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and they can
modulate both proinflammatory and anti-inflammatory responses to allow the host to react
appropriately to pathogens.
Binding of a cytokine to its cell surface receptor initiates intracellular signaling cascades that
transduce the extracellular signal to the nucleus, ultimately leading to changes in gene expression. The
pathway involving the Janus kinase family of protein tyrosine kinases (JAKs) and Signal Transducers
and Activators of Transcription (STATs) is engaged in the signaling of a wide range of cytokines.
Generally, cytokine receptors do not have intrinsic tyrosine kinase activity, and thus require receptor-
associated kinases to propagate a phosphorylation cascade. JAKs fulfill this function. Cytokines bind
to their receptors, causing receptor dimerization, and this enables JAKs to phosphorylate each other as

well as specific tyrosine motifs within the cytokine receptors. STATs that recognize these
phosphotyrosine motifs are recruited to the receptor, and are then themselves activated by a JAK-
dependent tyrosine phosphorylation event. Upon activation, STATs dissociate from the receptors,
dimerize, and translocate to the nucleus to bind to specific DNA sites and alter transcription (Scott, M.
J., C. J. Godshall, et al. (2002). "Jaks, STATs, Cytokines, and Sepsis." Clin Diagn Lab Immunol 9(6):
1153-9).
The JAK family plays a role in the cytokine-dependent regulation of proliferation and
function of cells involved in immune response. Currently, there are four known mammalian JAK
family members: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3
(also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3) and TYK2 (also known as
protein-tyrosine kinase 2). The JAK proteins range in size from 120 to 140 kDa and comprise seven
conserved JAK homology (JH) domains; one of these is a functional catalytic kinase domain, and
another is a pseudokinase domain potentially serving a regulatory function and/or serving as a
docking site for STATs (Scott, Godshall et al. 2002, supra).
While JAK1, JAK2 and TYK2 are ubiquitously expressed, JAK3 is reported to be
preferentially expressed in natural killer (NK) cells and not resting T cells, suggesting a role in
lymphoid activation (Kawamura, M., D. W. McVicar, et al. (1994). "Molecular cloning of L-JAK, a
Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes." Proc
Natl Acad Sci USA 91(14): 6374-8).
Not only do the cytokine-stimulated immune and inflammatory responses contribute to
normal host defense, they also play roles in the pathogenesis of diseases: pathologies such as severe
combined immunodeficiency (SCID) arise from hypoactivity and suppression of the immune system,
and a hyperactive or inappropriate immune / inflammatory response contributes to the pathology of
autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus
erythematosus, inflammatory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia
gravis, thyroiditis, immunoglobulin nephropathies, myocarditis as well as illnesses such as
scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). "Janus kinases and signal
transducers and activators of transcription: their roles in cytokine signaling, development and
immunoregulation." Arthritis Res 2(1): 16-32). Furthermore, syndromes with a mixed presentation of
autoimmune and immunodeficiency disease are quite common (Candotti, F., L. Notarangelo, et at.
(2002). "Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling
pathways." J Clin Invest 109(10): 1261-9). Thus, therapeutic agents are typically aimed at
augmentation or suppression of the immune and inflammatory pathways, accordingly.
Deficiencies in expression of JAK family members are associated with disease states. Jakl-/-
mice are runted at birth, fail to nurse, and die perinatally (Rodig, S. J., M. A. Meraz, et al. (1998).
"Disruption of the Jakl gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-
induced biologic responses." Cell 93(3): 373-83). Jak2-/- mouse embryos are anemic and die around

day 12.5 postcoitum due to the absence of definitive erythropoiesis. JAK2-deficient fibroblasts do not
respond to IFN gamma, although responses to IFNalpha/beta and IL-6 are unaffected. JAK2 functions
in signal transduction of a specific group of cytokine receptors required in definitive erythropoiesis
(Neubauer, H., A. Cumano, et al. (1998). Cell 93(3): 397-409; Parganas, E., D. Wang, et al. (1998).
Cell 93(3): 385-95.)- JAK3 appears to play a role in normal development and function of B and T
lymphocytes. Mutations of JAK3 are reported to be responsible for autosomal recessive severe
combined immunodeficiency (SCID) in humans (Candotti, F., S. A. Oakes, et al. (1997). "Structural
and functional basis for JAK3-deficient severe combined immunodeficiency." Blood 90(10): 3996-
4003).
The JAK/STAT pathway, and in particular all four members of the JAK family, are believed
to play a role in the pathogenesis of the asthmatic response, chronic obstructive pulmonary disease,
bronchitis, and other related inflammatory diseases of the lower respiratory tract. For instance, the
inappropriate immune responses that characterize asthma are orchestrated by a subset of CD4+ T
helper cells termed T helper 2 (Th2) cells. Signaling through the cytokine receptor JX-4 stimulates
JAK1 and JAK3 to activate STAT6, and signaling through IL-12 stimulates activation of JAK2 and
TYK2, and subsequent phosphorylation of STAT4. STAT4 and STAT6 control multiple aspects of
CD4+ T helper cell differentiation (Pernis, A. B. and P. B. Rothman (2002). "JAK-STAT signaling in
asthma." J Clin Invest 109(10): 1279-83). Furthermore, TYK2-deficient mice were found to have
enhanced Th2 cell-mediated allergic airway inflammation (Seto, Y., H. Nakajima, et al. (2003).
"Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice." J Immunol 170(2):
1077-83). Moreover, multiple cytokines that signal through JAK kinases have been linked to
inflammatory diseases or conditions of the upper respiratory tract such as those affecting the nose and
sinuses {e.g. rhinitis, sinusitis) whether classically allergic reactions or not.
The JAK/STAT pathway has also been implicated to play a role in inflammatory
diseases/conditions of the eye including, but not limited to, iritis, uveitis, scleritis, conjunctivitis, as
well as chronic allergic responses. Therefore, inhibition of JAK kinases may have a beneficial role in
the therapeutic treatment of these diseases.
The JAK/STAT pathway, and in particular, JAK3, also plays a role in cancers of the immune
system. In adult T cell leukemia/lymphoma (ATLL), human CD4+ T cells acquire a transformed
phenotype, an event that correlates with acquisition of constitutive phosphorylation of JAKs and
STATs. Furthermore, an association between JAK3 and STAT-1, STAT-3, and STAT-5 activation
and cell-cycle progression was demonstrated by both propidium iodide staining and
bromodeoxyuridine incorporation in cells of four ATLL patients tested. These results imply that
JAK/STAT activation is associated with replication of leukemic cells and that therapeutic approaches
aimed at JAK/STAT inhibition may be considered to halt neoplastic growth (Takemoto, S., J. C.
Mulloy, et al. (1997). "Proliferation of adult T cell leukemia/lymphoma cells is associated with the
constitutive activation of JAK/STAT proteins." Proc Natl Acad Sci USA 94(25): 13897-902).

Blocking signal transduction at the level of the JAK kinases holds promise for developing
treatments for hitman cancers. Cytokines of the interleukin 6 (IL-6) family, which activate the signal
transducer gp130, are major survival and growth factors for human multiple myeloma (MM) cells.
The signal transduction of gp130 is believed to involve JAK1, JAK2 and Tyk2 and the downstream
effectors STAT3 and the mitogen-activated protein kinase (MAPK) pathways. In IL-6-dependent MM
cell lines treated with the JAK2 inhibitor tyrphostin AG490, JAK2 kinase activity and ERK2 and
STAT3 phosphorylation were inhibited. Furthermore, cell proliferation was suppressed and apoptosis
was induced (De Vos, J., M. Jourdan, et al. (2000). "JAK2 tyrosine kinase inhibitor tyrphostin AG490
downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of
transcription (STAT) pathways and induces apoptosis in myeloma cells." Br J Haematol 109(4): 823-
8). However, in some cases, AG490 can induce dormancy of tumor cells and actually then protect
them from death.
Activation of JAK/STAT in cancers may occur by multiple mechanisms including cytokine
stimulation (e.g. IL-6 or GM-CSF) or by a reduction in the endogenous suppressors of JAK signaling
such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT)
(Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002). Importantly, activation of STAT
signaling, as well as other pathways downstream of JAKs (e.g. Akt), has been correlated with poor
prognosis in many cancer types (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Moreover,
elevated levels of circulating cytokines that signal through JAK/STAT may adversely impact patient
health as they are thought to play a causal role in cachexia and/or chronic fatigue. As such, JAK
inhibition may be therapeutic for the treatment of cancer patients for reasons that extend beyond
potential anti-tumor activity. The cachexia indication may gain further mechanistic support with
realization that the satiety factor leptin signals through JAKs.
Pharmacological targeting of Janus kinase 3 (JAK3) has been employed successfully to
control allograft rejection and graft versus host disease (GVHD). In addition to its involvement in
signaling of cytokine receptors, JAK3 is also engaged in the CD40 signaling pathway of peripheral
blood monocytes. During CD40-induced maturation of myeloid dendritic cells (DCs), JAK3 activity
is induced, and increases in costimulatory molecule expression, IL-12 production, and potent
allogeneic stimulatory capacity are observed. A rationally designed JAK3 inhibitor WHI-P-154
prevented these effects arresting the DCs at an immature level, suggesting that immunosuppressive
therapies targeting the tyrosine kinase JAK3 may also affect the function of myeloid cells (Saemann,
M. D., C. Diakos, et al. (2003). "Prevention of CD40-triggered dendritic cell maturation and induction
of T-cell hyporeactivity by targeting of Janus kinase 3." Am J Transplant 3(11): 1341-9). In the
mouse model system, JAK3 was also shown to be an important molecular target for treatment of
autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor
JANEX-1 exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD
mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M., A. L. Dragt, et al. (2003).

"Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice." Clin
Immunol 106(3): 213-25).
It has been suggested that inhibition of JAK2 tyrosine kinase can be beneficial for patients
with myeloproliferative disorder. (Levin, et al, Cancer Cell, vol. 7, 2005: 387-397)
Myeloproliferative disorder (MPD) includes polycythemia vera (PV), essential thrombocythemia
(ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML),
chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES) and systemic mast
cell disease (SMCD). Although the myeloproliferative disorder (such as PV, ET and MMM) are
thought to be caused by acquired somatic mutation in hematopoietic progenitors, the genetic basis for
these diseases has not been known. However, it has been reported that hematopoietic cells from a
majority of patients with PV and a significant number of patients with ET and MMM possess a
recurrent somatic activating mutation in the JAK2 tyrosine kinase. It has also been reported that
inhibition of the JAK2V617F kinase with a small molecule inhibitor leads to inhibition of
proliferation of hematopoietic cells, suggesting that the JAK2 tyrosine kinase is a potential target for
pharmacologic inhibition in patients with PV, ET and MMM.
Inhibition of the JAK kinases is also envisioned to have therapeutic benefits in patients
suffering from skin immune disorders such as psoriasis, and skin sensitization. In psoriasis vulgaris,
the most common form of psoriasis, it has been generally accepted that activated T lymphocytes are
important for the maintenance of the disease and its associated psoriatic plaques (Gottlieb, A.B., et al,
Nat Rev Drug Disc, 4:19-34). Psoriatic plaques contain a significant immune infiltrate, including
leukocytes and monocytes, as well as multiple epidermal layers with increased keratinocyte
proliferation. While the initial activation of immune cells in psoriasis occurs by an ill defined
mechanism, the maintenance is believed to be dependent on a number of inflammatory cytokines, in
addition to various chemokines and growth factors (JCI, 113:1664-1675). Many of these, including
interleukins -2, -4, -6, -7, -12, -15, -18, and -23 as well as GM-CSF and EFNg, signal through the
Janus (JAK) kinases (Adv Pharmacol. 2000;47:113-74). As such, blocking signal transduction at the
level of JAK kinases may result in therapeutic benefits in patients suffering from psoriasis or other
immune disorders of the skin.
It has been known that certain therapeutics can cause immune reactions such as skin rash or
diarrhea in some patients. For instance, administration of some of the new targeted anti-cancer agents
such as Iressa, Erbitux, and Tarceva has induced acneiform rash with some patients. Another example
is that some therapeutics used topically induce skin irritation, skin rash, contact dermatitis or allergic
contact sensitization. For some patients, these immune reactions may be bothersome, but for others,
the immune reactions such as rash or diarrhea may result in inability to continue the treatment.
Although the driving force behind these immune reactions has not been elucidated completely at the
present time, these immune reactions are likely linked to immune infiltrate.

Inhibitors of Janus kinases or related kinases are widely sought and several publications
report effective classes of compounds. For example, certain inhibitors are reported in WO 99/65909,
US 2004/0198737; WO 2004/099204; WO 2004/099205; and WO 01/42246. Heteroaryl substituted
pyrroles and other compounds are reported in WO 2004/72063 and WO 99/62908.
Thus, new or improved agents which inhibit kinases such as Janus kinases are continually
needed that act as immunosuppressive agents for organ transpiants, as well as agents for the
prevention and treatment of autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis,
asthma, type I diabetes, inflammatory bowel disease, Crohn's disease, autoimmune thyroid disorders,
Alzheimer's disease), diseases involving a hyperactive inflammatory response (e.g., eczema),
allergies, cancer (e.g., prostate, leukemia, multiple myeloma), and some immune reactions (e.g., skin
rash or contact dermatitis or diarrhea) caused by other therapeutics, to name a few. The compounds,
compositions and methods described herein are directed toward these needs and other ends.
SUMMARY OF THE INVENTION
The present invention provides compounds of Formula I:

or pharmaceutically acceptable salt forms or prodrugs thereof, wherein constituent members are
defined herein.
The present invention further provides compositions comprising a compound of Formula I, or
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention further provides methods of modulating an activity of JAK comprising
contacting JAK with a compound of Formula I, or pharmaceutically acceptable salt thereof.
The present invention further provides methods of treating a disease in a patient, wherein the
disease is associated with JAK activity, comprising administering to the patient a therapeutically
effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
The present invention further provides compounds of Formula I for use in therapy.
The present invention further provides compounds of Formula I for the preparation of a
medicament for use in therapy.

DETAILED DESCRIPTION
The present invention provides, inter alia, compounds that modulate the activity of one or
more JAKs and are useful, for example, in the treatment of diseases associated with JAK expression
or activity. The compounds of the invention have Formula I:

including phannaceutically acceptable salt forms or prodrugs thereof, wherein:
A1 and A2 are independently selected from C and N;
T, U, and V are independently selected from O, S, N, CR5, and NR6;
wherein the 5-membered ring formed by A1, A2, U, T, and V is aromatic;
X is Nor CR4;
Y is C1-8 alkylene, C2_8 alkenylene, C2-8 alkynylene, (CR11R12)p-(C3-10cycloalkylene)-
(CR1 'R12)q, (CRlIR12)p-(arylene)-(CR11R12)q, (CR11R12)p-(C1-10 heterocycloalkylene)-(CR"RI2)qj
(CR11R12)p (heteroarylene)-(CR11R12)q, (CR11R12)p O(CR11R12)q, (CR11R12)p SCR11R12)q)
(CR11RI2)PC(O)(CR11R12)p , (CR11R12)pC(O)NRC(CR11R12)q (CR11RI2)PC(O)O(CR11Rl2)q,
(CR11R12)p 0C(O)(CR11R12)p , (CR11R12)pOC(O)NRc(CR11R12)q, (CR11R12)P NRC(CR11R12)Q ,
(CR11R12)p NRcC(O)NRd(CR11R12)q, (CR11R12)pS(O)(CR1 'R12),, (CR11R12)q S(O)NRC(CR11R21),,,
(CR11R12)Q(O)2(CR11R12)Q, or (CR11R12)p S(O)2NRc(CR11R12)p , wherein said C1-8 alkylene, C2-8
alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is
optionally substituted with 1, 2, or 3 substituents independently selected from -D1D2D3-D4;
Z is H, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4
hydroxyalkyl, C1-4 cyanoalkyl, =C-Rf, =N-R!, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd,
C(O)ORa, OC(O)Rb, OC(O)NRcRd5 NRcRd, NRcC(O)Rb, NR'C(O)NRCRD, NRcC(O)ORa,
C(=NR1)NRcRd,NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NReS(O)2Rb, C(=NOH)Rb,
C(=NO(C1-6 alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl,
C2-4 alkenyl,C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN,
NO2, OR", SR", C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NR°Rd, NRcRd, NRcC(O)Rb,
NRcC(O)NRcRd, NRcC(0)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl))Rb, and S(O)2NRcRd;
wherein when Z is H, n is 1;

or the -(Y)n-Z moiety is taken together with i) A2 to which the moiety is attached, ii) R5 or R6
of either T or V, and iii) the C or N atom to which the R5 or R6 of either T or V is attached to form a
4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring
formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring is optionally substituted by 1, 2,3,4, or 5 substituents independently selected
from -(W)m-Q;
W is C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, O, S, C(O), C(O)NRC', C(O)O, OC(O),
OC(O)NRC', NRC', NRcC(O)NRd", S(O), S(O)NRC', S(O)2, or S(O)2NRC';
Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halosulfanyl, aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8
haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4
substituents independently selected from halo, C1-4 alkyl, C2.4 alkenyl, C2.4 alkynyl,C1-4 haloalkyl,
halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl. Cy2, CN, NO2, OR"', SRa', C(O)Rb, C(O)NRc'Rd',
C(O)ORa', OC(O)Rb>, OC(O)NRcRd',NRcRd",NRcC(O)Rb',NRcC(O)NRc'Rd",NRC>C(O)OR"',
S(O)Rb>, S(O)NRc'Rd', S(O)2Rb>, NRc'S(O)2Rb\ and S(O)2NRcRd';
Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected
from halo, C1-4alkyl,C2-4 alkenyl, C2.4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4
cyanoalkyl. CN, NO2, ORa", SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", 0C(O)Rb", OC(O)NRC "Rd",
NRc'Rd",NRc"C(O)Rb",NRc"C(O)ORa",NRc"S(O)Rb",NRc"S(O)2Rb", S(O)Rb", S(O)NRc"Rd",
S(O)2Rb", and S(O)2NRc"Rd";
R1, R2, R3, and R4 are independently selected from H, halo, C1-4 alkyl, C2.4 alkenyl,C2-4
alkynyl, C1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2> OR7,
SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR9R10,NR9C(O)R8, NRCC(O)OR7,
S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10;
R5 is H, halo,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, CN, NO2,
OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8,
NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)N9R10;
R6 is H, C1-4 alkyl,C1-4alkenyl, C2-4 alkynyl,C1-4 haloalkyl, OR7, C(O)R8, C(O)NR9R10,
C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, or S(O)2NR9R10;
R7 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R8 is H, C1-6 alkyl, C1-4 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R9 and R10 are independently selected from H, C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;

or R9 and R10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group;
R" and R12 are independently selected from H and -E1-E2-E3-E4;
D1 and E1 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein
each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from
halo, CN, NO2 N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy,
amino, C1-6 alkylamino, and C2-8 dialkylamino;
D2 and E2 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, (C1-6 alkylene)r-O-( C1-6 alkylene)s, (C1-6 alkylene)r-S-(C1-6alkylene)S) (C1-6
alkylene)r-NRe-(C1-6 alkylene)s,(C1-6 alkylene)r-CO-(C1-6 alkylene)s, (C1-6 alkylene)r-COO-(C1-6 alkylene)s, (C1-6 alkylene)r-CONRe-(C1-6 alkylene)s, (C1-6alkylene)r-SO-(C1-6 alkylene)s, (C1-6
alkylene)r-SO2-(C1-6 alkylene)s, (C1-6 alkylene)r-SONRe-(C1-6 alkylene)s, and (C1-6alkylene)r-
NReCONRf-(C1-6 alkylene)s, wherein each of the C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene is
optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN,
OH, C1-6 alkyl, C1-6 haloalkyl, C2_8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino,
and C2-8 dialkylamino;
D3 and E3 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein
each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from
halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy,
amino, C1-4 alkylamino, and C2-8 dialkylamino;
D4 and E4 are independently selected from H, halo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy', CN, NO2, ORa, SRa, C(O)Rb,
C(O)NR0Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NR°Rd, NRCC(O)OR°,
C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O02Rb, NRcS(O)2Rb, C(=NOH)Rb,
C(=NO(C1-6alkyl)Rb, and S(O)2NR°Rd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1,2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl,
C2-4 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN,
NO2, OR", SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb,
NRcC(O)NRcRd, NRcC(O)ORa, C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C,.fi alkyl))Rb, and S(O)2NRcRd;
Rq is H, Cy1, -(C1-6 alkyl)-Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein
said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3

substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl,
aryl, arylalkyl, heteroaiyl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rb is H, Cy1, -(C1-6 alkyl)-Cy', C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein
said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6
haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R8> and Ra' are independently selected from H, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected
from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rb' and Rb" are independently selected from H, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl,
C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl, wherein said C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc and Ra are independently selected from H, Cy1, -(C1-6 alkyl)-Cy', C1-10 alkyl, C1-6
haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6
alkynyl, is optionally substituted with 1,2, or 3 substituents independently selected from Cy1, -(C1-6
alkyl)-Cy1, OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6 haloalkyl,and halosulfanyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently
selected from Cy1, -(C1-6 alkyl)-Cy', OH, CN, amino, halo, d.6alkyl, d.6haloalkyl, C1-6 haloalkyl,
and halosulfanyl;
Rc and Rd are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-6 alkyl, CC1-6 haloalkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc" and Rd' together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently

selected from OH, CN, ammo, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroaiylalkyl, cycloalkyl and heterocycloalkyl;
Rc and Rd are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R! is H, CN, NO2, or C1-6alkyl;
Re and Rf are independently selected from H and C1-6 alkyl;
R' is H.CN.or NO2;
m is 0 or 1;
n is 0 or 1;
pis 0,1, 2, 3,4, 5, or6;
q is O, 1,2, 3,4, 5 or 6;
r is 0 or 1; and
s is O or 1.
In some embodiments, when X is N, n is 1, and the moiety formed by A1, A2, U, T, V, and
-(Y)n-Z has the formula:

then Y is other than (CR11R12)qC(O)NR(CR11R12)q.
In some embodiments, when X is N, the 5-membered ring formed by A1, A2, U, T, and V is
other than pyrrolyl.
In some embodiments, when X is CH, n is 1, and the moiety formed by A1, A2, U, T, V, and
-(Y)n-Z has the formula:

then -(Y)n-Z is other than COOH.
In some embodiments, when X is CH or C-halo, R1, R2, and R3 are each H, n is 1, and the
moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula:

then Y is other than (CR11R12)pC(O)NRc(CR11R12)q or (CR11R12)p C(O)(CR11Rl2)q.
In some embodiments, when X is CH or C-halo, R1, R2, and R3 are each H, n is 0, and the
moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula:

then Z is other than CN, halo, or C1-4 alkyl.
In some embodiments, when X is CH or C-halo, R1, R2, and R3 are each H, n is 1, and the
moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula:

then Y is other than (CR11R12)pC(O)NRc(CR11R12)p or (CR11R12)pC(O)(CR11R12)q.
In some embodiments, when X is CH or C-halo, R1, R2, and R3 are each H, n is 1, and the
moiety formed by A1, A2, U, T, V, and -(Y)n-Z has the formula:

then Y is other than (CR11'R12)qNR(CR11R12)q.
In some embodiments, when X is CH or C-halo and R1, R2, and R3 are each H, then the
moiety formed by A1, A2, U, T, V, and —(Y)n-Z has a formula other than:

In some embodiments:
Z is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl,
heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3,4, 5, or 6 substituents
independently selected from halo,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, C1-4
hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NReRd, C(O)OR°, OC(O)Rb,
OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR8, C(=NRi)NRcRd,
NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd;
Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl,
heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents
independently selected from halo,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4 haloalkyl,C1-4 hydroxyalkyl,
C1-4 cyanoalkyl, Cy2, CN, NO2, ORa', SR" C(O)Rb', C(O)NRcRd\ C(O)ORa', OC(O)Rb',
OC(O)NRcRd', NRc'Rd>, NRcC(O)Rb', NRcC(O)NRcRd', NRc'C(O)ORa', S(O)Rb", S(O)NRcRd",
S(O)2Rb', NRc'S(O)2Rb', and S(O)2NRcRd';
Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocyclo-
alkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo,C1-4
alkyl, C2-4 alkenyl,C1-4 alkynyl,C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, CN, NO2, ORa",
SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", OC(O)Rb>, OC(O)NRc"Rd'\NRc"Rd",NRc"C(O)Rb",
NRc"C(O)ORa", NRc"S(O)Rb", NRc"S(O)2Rb", S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd";
R1, R2, R3, and R4 are independently selected from H, halo, C1-4 alkyl, C2-6 alkenyl, C2-4
alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7, SR7, C(O)R8,
C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NRCC(O)OR7, S(O)R8,
S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10;
R5 is H, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN, NO2, OR7, SR7,
C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R83 NR9C(O)OR7,
S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)2NR9R10;
R6 is H,C1-4 alkyl,C1-4 alkenyl,C1-4 alkynyl, C1-4 haloalkyl, OR7, C(O)R8, C(O)NR9R10,
C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, or S(O)2NR9R10;
R7 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R8 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R9 and R10 are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;

or R9 and R10 together with the N atom to which, they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group;
R" and R12 are independently selected from H, halo, OH, CN, C1-6 alkyl,C1-4haloalkyl, C1-4
alkenyl, C2-4 alkynyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl;
R°, Ra', and Ra' are independently selected from H, C1-4 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl
is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo,
C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rb, Rb' and Rb" are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1.6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl
is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo,
C1-6 alkyl, C1-6 haloalkyl, C1-8 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and
heterocycloalkyl;
Rc and Rd are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl
is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo,
C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or
heterocycloalkyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc' and Rd' are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, hetero-
aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl
is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo,
C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and
heterocycloalkyl;

or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc and Rd are independently selected from H, C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl
is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo,
C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and
heterocycloalkyl; and
or R° and R together with the N atom to which they are attached form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-4haloalkyl, C1-6 haloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl.
In some embodiments, X is N.
In some embodiments, X is CR4.
In some embodiments, A1 is C.
In some embodiments, A1 is N.
In some embodiments, A2 is C.
In some embodiments, A2 is N.
In some embodiments, at least one of A1, A2, U, T, and V is N.
In some embodiments, the 5-membered ring formed by A1, A2, U, T, and V is pyrrolyl,
pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or oxadiazolyl.
In some embodiments, the 5-membered ring formed by A1, A2, U, T, and V is selected from:

wherein:
a designates the site of attachment of moiety -(Y)n-Z;
b designates the site of attachment to the core moiety:

c and c' designate the two sites of attachment of the fused 4- to 20-membered aryl, cycloalkyl,
heteroaiyl, or heterocycloalkyl ring.
In some embodiments, the 5-membered ring formed by A1, A2, U, T, and V is selected from:

wherein:
a designates the site of attachment of moiety -(Y)n-Z;
b designates the site of attachment to the core moiety:

wnerein:
a designates the site of attachment of moiety -(Y)n-Z;
b designates the site of attachment to the core moiety:

In some embodiments, n is 0.
In some embodiments, n is 1.
In some embodiments, n is 1 and Y is C1-8 alkylene, C2-8 alkenylene,
(CR11RI2)PC(O)(CR"RI:2)()> (CR11R12)pC(O)NRc(CR11R12)q, (CR11R12)pC(O)O(CR11R12)q)
(CRllRl2)pOC(O)(CR11R12)q, wherein said C1-8 alkylene or C2-8 alkenylene, is optionally substituted
with 1, 2, or 3 halo, OH, CN, amino, C1-6alkylamino, or C2-8 dialkylamino.

In some embodiments, n is 1 and Y is C1-8 alkylene, (CR11R12)pC(O)(CR11R12)p ,
(CR11R12)qC(O)NRc(CRnRI2)q, (CR11R12)qC(O)O(CR11R12)p , wherein said C1-8 alkylene is optionally
substituted with 1, 2, or 3 halo, OH, CN, amino, C1-4 alkylamino, or C2-6 dialkylamino.
In some embodiments, n is 1 and Y is C1-8 alkylene optionally substituted with 1, 2, or 3 halo,
OH, CN, amino, C1-4 alkylamino, or C2-8 dialkylamino.
In some embodiments, n is 1 and Y is ethylene optionally substituted with 1,2, or 3 halo, OH,
CN, amino,C1-4alkylamino, or C2-8 dialkylamino.
In some embodiments, n is 1 and Y is (CRllRl2)pC(O)(CRI1RI2)q (CR11R12)pC(O)NR°-
(CR11R12)q, or (CR11R12)qC(O)O(CR11R12)q.
In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R12)q-(C3-10
cycloalkyleneX(CR11R12)q, (CR11R12)p-(arylene)-(CR11R12)q, (CR11R12q(C)(C1-10 heterocycloalkylene)-
(CR11R12)q, (CR11R12)q-(heteroarylene)-(CR11R12)q, (CR11R12)qO(CR11R12)p , or (CR11R12)qS(CR11R12)qi
wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene,
heterocycloalkylene, or heteroarylene, is optionally substituted with 1,2, or 3 substituents
independently selected from -D'-D2-D3-D4.
In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R12)q-(C3-10
cycloalkylene)-(CR11R12)q, (CR11R12)p -(arylene)-(CR11R12)q, (CR11R12)q-(C1-10 heterocycloalkylene)-
(CR11R12)q> (CR11R12)q-(heteroarylene)-(CR11R12)q, (CR11R12)q O(CR11R12)Q, or (CR11R12)pS(CR11R12)p )
wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, cycloalkylene, arylene,
heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents
independently selected from D4.
In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, or (CR11R12)p-(C3.
10 cycloalkylene)-(CR11R12)q, wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, or
cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D1-
D2-D3-D4.
In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, or (CR11R12)q-(C3.
10 cycloalkylene)-(CR11R12)p , wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, or
cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from D4.
In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, or C2-6 alkynylene, each optionally
substituted with 1, 2, or 3 substituents independently selected from -D1-D2-D3D4.
In some embodiments, Y is C1-8 alkylene optionally substituted with 1, 2, or 3 substituents
independently selected from -D1-D2-D3-D4.
In some embodiments, Y is C1-8 alkylene optionally substituted with 1,2, or 3 substituents
independently selected from D4.
In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-6 alkynylene, (CR11R12)qO-
(CR11R12)p , (CR11R12)pS(CR11R12)p , (CR11Rl2)pC(O)(CR11R12)q, (CR11R12)pC(O)NR0(CR11R12)q,
(CR11R12)qC(O)O(CR11R12)p , (CR11R12)qOC(O)(CR11R12)q, (CR11R12)pOC(O)NRC(CR11R12)q,

(CR11R12)qNRC (CR11R12)Qi (CR11R12)pNRcC(O)NRd(CR11R12)q, (CR11R12)qSCO)(CR11R12)Q,
(CR11R12)p S(O)NRc(CR11R12)p , (CR11R12)pS(O)2(CR11R12)q, or (CR11R12)qS(O)2NRc(CR11R12)p ,
wherein said C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene is optionally substituted with 1, 2, or 3
substituents independently selected from halo, OH, CN, amino,C1-4alkylaraino, and C2-8
dialkylamino.
In some embodiments, Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R12)q-(C3-10
cycloalkylene)-(CR11R12)q,(CR11RI2)p-(arylene)-(CRllR12)q,(CRllR12)p-(C1-10 heterocycloalkylene)-
(CR11R12)q, (CR11R12)q-(heteroarylene)-(CR11R12)q, (CR11R12)qO(CR11R12)q, (CR11R12)qS(CR11R12)q,
(CR11R12)qC(O)(CRllR12)q,(CR11R12)qC(O)NRc(CR11R12)q, (CR11R12)qC(O)O(CR11R12)q,
(CR11R12)qOC(O)(CR11R12)q, (CR11R12)qOC(O)NRC(CR11R12)q, (CR11R12)qNRC(CR11R12)Q,
(CR11R12)p NRcC(O)NRd(CR11R12)q, (CR11R12)qSCO)(CR11R12)q, (CR11R12)q,S(O)NRc(CR11R12)q,
(CR11R12)qS(O)2(CR11R12)q, or (CR11R12)pS(O)2NRc(CR11R12)q, wherein said C1-8 alkylene, C2-8
alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is
optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, amino,
C1-4 alkylamino, and C2-8 dialkylamino.
In some embodiments, p is 0.
In some embodiments, p is 1.
In some embodiments, p is 2.
In some embodiments, q is 0.
In some embodiments, q is 1.
In some embodiments, q is 2.
In some embodiments, one of p and q is 0 and the other of p and q is 1, 2, or 3.
In some embodiments, Z is H, halo,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl,
halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN,NO2, ORa, SRa, C(O)Rb, C(O)NRcRd,
C(O)OR°, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NReRdl, NRcC(O)ORa,
C(=NRi)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb,
C(=NO(C1-6alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo, C1-4 alkyl,
C2-4 alkenyl, C2-4 alkynyl, C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN,
NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb,
NR'CCONRcRd, NRcC(O)ORa, C(=NR1)NRcRd,NRcC(=NRi)NReRd) S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl))Rb, and S(O)2NRcRd.
In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally
substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR0, SR\ C(O)Rb,
C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR°,
C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NReS(O)2Rb, and S(O)2NRcRd.

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally
substituted with 1,2, 3, 4, 5, or 6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,
C1-4 haloalkyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy\ CN, NO2> ORa, SRa, C(O)Rb, C(O)NRcRd,
C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa,
C(=NRi)NRcRd, MReC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or
6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,
C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR", SRa, C(O)Rb, C(O)NcRd, C(O)ORa,
OC(0)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd,
NR°C(=NRl)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NR°Rd.
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3,4,5, or
6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-6 alkynyl, C1-4 haloalkyl,
C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2 ORa SRa, C(O)Rb, C(O)NRcRd, C(O)OR°,
OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)NR°Rd, NRcC(O)ORa, C(=NR1)NRcRd,
NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, SC(O)2R1", NRcS(O)2Rb, and SC(O)2NRcRd.
In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally
substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-6 alkenyl, C2-6 alkynyl,
C1-4 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb,
C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NR°C(O)NReRd, NRcC(O)ORa,
C(=NRi)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NReRd.
In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally
substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl,C1-4alkenyl, C2-6 alkynyl,
C1-4 haloalkyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd,
C(O)OR°, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa,
C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NR°Rd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is phenyl optionally substituted with 1, 2, 3,4, 5, or 6 substituents
selected from halo,C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl,
C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, CCO)NR°Rd, C(O)ORa, OC(O)Rb,
OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd,
NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-6 hydroxyalkyl, C1-4
cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd,
NRcRd,NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NRi)NRcRd, S(O)Rb,
S(O)NReRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1,
2, 3, 4, 5, or 6 substituents selected from halo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl,C1-4 haloalkyl,

halosulfanyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)RD, C(O)NRcRd,
C(O)ORa, OC(O)Rb, OC(O)NR°Rd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa,
C(=NR1)NRcRd, NRcC(=NR1)NR°Rd, S(O)Rb, S(O)NR'R4, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1,
2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl,C1-4
hydroxyalkyl,C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb,
OC(O)NRcRd, NReRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd,
NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycioheptyl,
each optionally substituted with 1, 2, 3,4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-6
alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2,
ORa, SRa, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NReRd, NRcRd, NRcC(O)Rb,
NReC(O)NRBRd,NRcC(O)ORa, C(=NR1)NRcR NRcS(O)aRb and S(O)2NRCd.
In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted
with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4
haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb,
C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRCRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa,
C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted
with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4
haloalkyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa SRa C(O)Rb, C(O)NRcRd,
C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa,
C(=NR1)NRcRd, NR°C(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally
substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4
alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy', CN, NO2,
OR", SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb,
NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally
substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4
alkenyl,C1-4alkynyl,C1-4haloalkyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa,
C(O)Rb, C(O)NReRd, C(O)OR\ OC(O)Rb, OC(O)NR°Rd, NR°Rd, NRcC(O)Rb, NRcC(O)NRcRd,
NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or
6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,
halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR", SR", C(O)Rb, C(O)NRcRd,

C(O)ORa, OC(O)Rb, OC(O)NR°Rd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR", S(O)Rb,
S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or
6 substituents independently selected from halo, C1-4 alkyl, C2-4alkenyl, C2-6 , alkynyl, C1-4 haloalkyl,
C1-6 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa,
OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd,
S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally
substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4
alkenyl, C2-4 alkynyl, C:.4 haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2,
ORa SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb,
NRcC(O)NRcRd, NRCC(O)ORB, S(O)R°, S(O)NRcRd, S(O)2Rb, NRCS(O)2R\ and S(O)2NRcRd.
In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally
substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl, C1-4 haloalkyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa,
C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd,
NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,
C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SR", C(O)Rb, C(O)NRcRd, C(O)ORa,
0C(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd,
S(O)2Rb, NRcS(O)2Rb, and SCO)2NRcRd.
In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
independently selected from halo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4
hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb,
OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NR°Rd, S(O)2Rb,
NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1,
2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb,
C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NR°Rd, NR'R", NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)Ra,
S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NR°Rd.
In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1,
2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4
haloalkyl,C1-4 hydroxyalkyl, C1-6 cyanoalkyl, Cy1, CN, NO2, OR", SRa, C(O)Rb, C(O)NRcRd,
C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb,
S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.

In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted
with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4
alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyi, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa,
C(O)Rb, C(O)NRcRd, C(O)ORa, OC(0)Rb, OC(O)NRcRd, NRTRcRd, NRcC(O)Rb, NRcC(O)NRcRd,
NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted
with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4
alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyi, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb,
C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa,
S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and'S(O)2NRcRd.
In some embodiments, Z is C1-8 alkyl, C2_8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl,
or heterocycloalkyl, each optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently
selected from halo,C1-4alkyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyi,C1-4cyanoalkyl, Cy1,
CN, NO2, OR", C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, and S(O)2Rb.
In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl,
or heterocycloalkyl, each optionally substituted with 1, 2, 3,4,5, or 6 substituents independently
selected from halo, C1-4 alkyl, C1-4 haloalkyl,C1-4hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2, OR",
C(O)NReRd, C(O)ORa, NRcRd, NReC(O)Rb, and S(O)2Rb.
In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl,
or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected
from halo,C1-4alkyl,C1-4haloalkyl, halosulfanyl, C1-4 hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2,
ORa, C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, and S(O)2Rb.
In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected
from halo, C1-4 alkyl,C1-4haloalkyl,C1-4hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2, ORa,
C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, and S(O)2Rb.
In some embodiments, Z is substituted with at least one substituent comprising at least one
CN group.
In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl,
or heterocycloalkyl, each substituted with at least one CN orC1-4cyanoalkyl and optionally
substituted with 1,2, 3, 4, or 5 further substituents selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4
alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4hydroxyalkyi,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SRa,
C(O)Rb, C(O)NRcRd, C(O)OR°, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd,
NRCC(O)OR3, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
In some embodiments, Z is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl,
or heterocycloalkyl, each substituted with at least one CN orC1-4cyanoalkyl and optionally
substituted with 1, 2, 3, 4, or 5 further substituents selected from halo,C1-4alkyl,C2-4alkenyl, C2-4 ,

alkynyl,C1-4haloalkyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NOz, OR\ SRa, C(O)Rb,
C(O)NRTR.d, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR%
S(O)Rb, S(O)NRcRd, S(O)2Rb,NRcS(O)2Rb, and S(O)2NRCRd.
In some embodiments, wherein the -(Y)o-Z moiety is taken together with i) A2 to which said
moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of
either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl
ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 20-membered
aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1,2, 3, 4, or 5
substituents independently selected from —(W)m-Q.
In some embodiments, wherein the -(Y)n-Z moiety is taken together with i) A2 to which said
moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of
either T or V is attached to form a 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl
ring fused to the 5-membered ring formed by A1, A2, U, T, and V, wherein said 4- to 8-membered
aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1,2, 3, 4, or 5
substituents independently selected from -(W)m-Q.
In some embodiments, the -(Y)n-Z moiety is taken together with i) A2 to which said moiety is
attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said Rs or R6 of either T or V
is attached to form a 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-
membered ring formed by A1, A2, U, T, and V, wherein said 6-membered aryl, cycloalkyl, heteroaryl,
or heterocycloalkyl ring is optionally substituted by 1, 2, or 3 substituents independently selected
from halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl,
or heterocycloalkyl wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl,
heteroaryl, or heterocycloalkyl is optionally substituted by 1, 2 or 3 CN.
In some embodiments, Cy1 and Cy2 are independently selected from aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents
independently selected from halo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4
hydroxyalkyl, C1-4 cyanoalkyl, CN, NO2, ORa", SRa", C(O)Rb", C(O)NRc"Rd"\ C(O)ORa", OC(O)Rb",
OC(O)NRc"Rd", NRc"Rd", NRc"C(O)Rb",NRc"C(O)ORa", S(O)Rb", S(O)NRcRd'", S(O)2Rb", and
S(O)2NRc"Rd".
In some embodiments, Cy1 and Cy2 are independently selected from aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl, each optionally substituted by 1,2, 3,4 or 5 substituents
independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN, NO2, OR"",
SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", OC(O)Rb", OC(O)NRc"Rd", NRc"Rd", NR°"C(O)Rb",
NRc"C(O)ORa", S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd".
In some embodiments, Cy1 and Cy2 are independently selected from cycloalkyl and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected
from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN, NO2, OR"", SRa", C(O)Rb",

C(O)NRt"Rd", C(O)ORa",OC(O)Rb", OC(O)NRc"Rd",NRc"Rd",NRc"C(O)Rb",NRc"C(O)ORa",
S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and S(O)2NRc"Rd".
In some embodiments, Cy1 and Cy2 are independently selected from cycloalkyl optionally
substituted by 1, 2, 3,4 or 5 substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C2.
4 alkynyl, C1-4 haloalkyl, CN, NO2) OR8", SRa", C(O)Rb", C(O)NRc"Rd", C(O)OR°", OC(O)Rb",
OC(O)NRc"Rd", NRc"Rd", NRc"C(O)Rb", NRc"C(O)ORa", S(O)Rb", S(O)NRc"Rd", S(O)2Rb", and
S(O)2NRc"Rd".
In some embodiments, R1, R2, R3, and R4 are independently selected from H, halo,C1-4alkyl,
C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7,
SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NRCC(O)OR7,
S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10.
In some embodiments, R1, R2, R3, and R4 are independently selected from H, halo, andC1-4alkyl.
In some embodiments, R1, R2, R3, and R4 are each H.
In some embodiments, R1 is H, halo, orC1-4alkyl.
In some embodiments, R5 is H, halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, CN,
NO2, OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR'R'0, NR9C(O)R8,
NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)2NR9R10.
In some embodiments, R5 is H, halo, C1-4 alkyl,C1-4haloalkyl, halosulfanyl, CN, or NR9R10.
In some embodiments, Rs is H, halo, C1-6 alkyl,C1-4haloalkyl, CN, orNR9RID.
In some embodiments, R5 is H.
In some embodiments, R6 is H or C1-4 alkyl.
In some embodiments, R6 is H.
In some embodiments, R11 and R12 are independently selected from H, halo, C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-6 cyanoalkyl, Cy1, CN, NO2,
ORa, SRa, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRCRD, NRCRD, NRcC(O)Rb,
NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NR°Rd, NR°C(=-NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8
alkenyl, or C2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently
selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4
hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2 ORa, SRa, C(O)Rb, C(O)NRcRd, C(0)ORa, OC(O)Rb,
OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRCC(O)OR°, C(=NR1)NRcRd,
NRcC(=NR1)NRcRd, S(O)Rb, S(O)NR°Rd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6 alkyl))Rb,
and S(O)2NRcRd.
In some embodiments, R11 and R12 are independently selected from H, halo, OH, CN,C1-4
alkyl, C1-4 haloalkyl, halosulfanyl, SCN,C2-4 alkenyl, C2-4alkynyl,C1-4hydroxyalkyl,C1-4 cyanoalkyl,
aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In some embodiments, R11 and R12 are independently selected from H, halo, OH, CN, C1-4
alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl.
In some embodiments, the compound has Formula la or Ib:

At various places in the present specification, substituents of compounds of the invention are
disclosed in groups or in ranges. It is specifically intended that the invention include each and every
individual subcombination of the members of such groups and ranges. For example, the term "C1-6
alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and
C6 alkyl.
It is further appreciated that certain features of the invention, which are, for clarity, described
in the context of separate embodiments, can also be provided in combination in a single embodiment.
Conversely, various features of the invention which are, for brevity, described in the context of a
single embodiment, can also be provided separately or in any suitable subcombination.
At various places in the present specification, linking substituents are described. It is
specifically intended that each linking substituent include both the forward and backward forms of the
linking substituent. For example, -NR(CRR")n- includes both NR(CR'R")n and -(CR'R")nNR
Where the structure clearly requires a linking group, the Markush variables listed for that group are
understood to be linking groups. For example, if the structure requires a linking group and the
Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl"
or "aryl" represents a linking alkylene group or arylene group, respectively.
The term "n-membered" where n is an integer typically describes the number of ring-forming
atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an
example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene is an example of
a 10-membered cycloalkyl group.
As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group which is
straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-
propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl,
neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to
about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
A linking alkyl group is referred to herein as "alkylene."

As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon
bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. A linking
alkenyl group is referred to herein as "alkenylene."
As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon
bonds. Example alkynyl groups include ethynyl, propynyl, and the like. A linking alkynyl group is
referred to herein as "alkynylene."
As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents.
Example haloalkyl groups include CF3, C2F5, CHF2, CC13, CHC12, C2C15, and the like.
As used herein, "halosulfanyl" refers to a sulfur group having one or more halogen
substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SF5.
As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings)
aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl,
indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. A
linking aryl group is referred to herein as "arylene."
As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized
alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2,
3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be
optionally substituted by oxo or sulfido. Cycloalkyl groups also include cycloalkylidenes. Example
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,
adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or
more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example,
benzo or thienyl derivatives of pentane, pentene, hexane, and the like. A cycloalkyl group containing
a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom
of the fused aromatic ring. A linking cycloalkyl group is referred to herein as "cycloalkylene."
As used herein, "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom
ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and
polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without
limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fury], quinolyl, isoquinolyl, thienyl,
imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,
pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl,
carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has
from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms.
In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to
6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1
to 2 heteroatoms. A linking heteroaryl group is referred to herein as "heteroarylene."

As used herein, "heterocycloalkyl" refers to non-aromatic heterocycles including cyclized
alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by
a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups include monocyclic and polycyclic
(e.g., having 2, 3 or 4 fused rings) systems as well as spirocycles. Example "heterocycloalkyl" groups
include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-
dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl,
isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-forming
carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or
sulfido. Also included in the definition of heterocycloalkyl are moieties that have one or more
aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for
example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles. The heterocycloalkyl
group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. The
heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming
atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the
heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about
3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14,
4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl
group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the
heterocycloalkyl group contains 0 to 3 double or triple bonds. In some embodiments, the
heterocycloalkyl group contains 0 to 2 double or triple bonds. A linking heterocycloalkyl group is
referred to herein as "heterocycloalkylene."
As used herein, "halo*' or "halogen" includes fluoro, chloro, bromo, and iodo.
As used herein, "arylalkyl" refers to alkyl substituted by aryl and "cycloalkylalkyl" refers to
alkyl substituted by cycloalkyl. An example arylalkyl group is benzyl.
As used herein, "heteroarylalkyl" refers to alkyl substituted by heteroaryl and
"heterocycloalkylalkyl" refers to alkyl substituted by heterocycloalkyl.
As used herein, "amino" refers to NH2.
As used herein, "alkylamino" refers to an amino group substituted by an alkyl group.
As used herein, "dialkylamino" refers to an amino group substituted by two alkyl groups.
As used herein, "hydroxylalkyl" refers to an alkyl group substituted by hydroxyl.
As used herein, "cyanoalkyl" refers to an alkyl group substituted by cyano. The carbon of the
cyano group is typically not counted if a carbon count precedes the term. For example, cyanomethyl
is considered herein to be a Ci cyanoalkyl group.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters).
All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
Compounds of the present invention that contain asymmetrically substituted carbon atoms can be
isolated in optically active or racemic forms. Methods on how to prepare optically active forms from

optically active starting materials are known in the art, such as by resolution of racemic mixtures or
by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can
also be present in the compounds described herein, and all such stable isomers are contemplated in the
present invention. Cis and trans geometric isomers of the compounds of the present invention are
described and may be isolated as a mixture of isomers or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods
known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional
recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric
acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various
optically active camphorsulfonic acids such as (3-camphorsulfonic acid. Other resolving agents
suitable for fractional crystallization methods include stereoisomerically pure forms of a-methyl-
benzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine,
ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an
optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent
composition can be determined by one skilled in the art.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the
swapping of a single bond with an adjacent double bond together with the concomitant migration of a
proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having
the same empirical formula and total charge. Example prototropic tautomers include ketone — enol
pairs, amide - imidic acid pairs, lactam — lactim pairs, amide - imidic acid pairs, enamine - imine
pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system,
for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H-
and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by
appropriate substitution.
Compounds of the invention further include hydrates and solvates, as well as anhydrous and
non-solvated forms.
Compounds of the invention can also include all isotopes of atoms occurring in the
intermediates or final compounds. Isotopes include those atoms having the same atomic number but
different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
In some embodiments, the compounds of the invention, and salts thereof, are substantially
isolated. By "substantially isolated" is meant that the compound is at least partially or substantially
separated from the environment in which is was formed or detected. Partial separation can include,
for example, a composition enriched in the compound of the invention. Substantial separation can
include compositions containing at least about 50%, at least about 60%, at least about 70%, at least

about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by
weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their
salts are routine in the art.
The expressions, "ambient temperature" and "room temperature," as used herein, are
understood in the art, and refer generally to a temperature, e.g a reaction temperature, that is about the
temperature of the room in which the reaction is carried out, for example, a temperature from about
20 °C to about 30 °C.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds,
materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
The present invention also includes pharmaceutically acceptable salts of the compounds
described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the
disclosed compounds wherein the parent compound is modified by converting an existing acid or base
moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues
such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention
include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic
inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be
synthesized from the parent compound which contains a basic or acidic moiety by conventional
chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of
these compounds with a stoichiometric amount of the appropriate base or acid in water or in an
organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in
Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.
1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by
reference in its entirety.
The present invention also includes prodrugs of the compounds described herein. As used
herein, "prodrugs" refer to any covalently bonded carriers which release the active parent drug when
administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups
present in the compounds in such a way that the modifications are cleaved, either in routine
manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl,
amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a
mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group
respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate
derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation

and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,"
Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward
B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby
incorporated by reference in their entirety.
Synthesis
Compounds of the invention, including salts thereof, can be prepared using known organic
synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
The reactions for preparing compounds of the invention can be carried out in suitable solvents
which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be
substantially nonreactive with the starting materials (reactants), the intermediates, or products at the
temperatures at which the reactions are carried out, e.g., temperatures which can range from the
solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out
in one solvent or a mixture of more than one solvent. Depending on the particular reaction step,
suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of compounds of the invention can involve the protection and deprotection of
various chemical groups. The need for protection and deprotection, and the selection of appropriate
protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting
groups can be found, for example, in T.W. Green and P.G.M. Wuts, Protective Groups in Organic
Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference
in its entirety.
Reactions can be monitored according to any suitable method known in the art. For example,
product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., *H or 13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass
spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin
layer chromatography.
Compounds of the invention can be prepared according to numerous preparatory routes
known in the literature. Example synthetic methods for preparing compounds of the invention are
provided in the Schemes below.
As shown in Scheme 1, pyrazole-containing cores 1-9 and 1-6 can be synthesized starting
with pyrrolo[2,3-b]pyridine or pyrrolo[2,3-b]pyrimidine 1-1. The compound 1-1 can be converted to
an active species such as an N-oxide analog (1-2) by using an oxidant such as m-CPBA. The N-oxide
1-2 can be halogenated with a halogenating agent such as a combination of tetramethylammonium
bromide and methanesulfonic anhydride to form a 4-halo compound 1-3 such as a 4-bromo compound
while the N-oxide is reduced at the same time. The amine group of the compound 1-3 can be
protected by a suitable amine protecting group to afford the protected compound 1-7, which
subsequently undergoes a Suzuki coupling with a boric acid 1-8 to afford the pyrazole-containing

cores l-9a which can be further reacted with reagent L-(Y)n-Z (where L is a leaving group) to give
compounds of the invention l-9b. Alternatively, the N-oxide 1-2 can be halogenated with a
halogenating agent such as MeSO2Cl to form a 4-halo compound 1-4 such as a 4-chloro compound
while the N-oxide is reduced at the same time. The 4-halo compound 1-4 can be coupled to a bromo-
substituted pyrazole compound 1-5 under suitable conditions such as heating to afford the pyrazole-
containing core 1-6, which may contain some functional groups such as bromo or cyano suitable for
further chemical modification.
Similarly, an imidazole core 1-11 can be synthesized by coupling of the 4-halo compound 1-4
to an imidazole derivative 1-10 under suitable conditions such as heating to afford the imidazole-
containing core 1-11, which may contain some functional groups such as bromo or cyano suitable for
further chemical modification.

As shown in Scheme 2, pyrazole-containmg cores 2-3, 2-5 and 2-6 can be synthesized starting
with a bromo-substituted pyrazole derivative 2-1 (a compound 1-6 in Scheme 1 wherein one of R5 is

Br). The bromo-substituted pyrazole derivative 2-1 can be coupled to boron-containing aromatic
species such as an aromatic boric acid 2-2 using Suzuki coupling wherein Ar is aryl or heteroaryl,
each of which can be optionally substituted by one or more substituents such as alky, aryl, CN, nitro,
alkoxy, etc. Alternatively, an alkene- or alkyne-containing compound such as an alkene-containing 2-
5 can be obtained by coupling the bromo-substituted pyrazole derivative 2-1 to an unsaturated
compound such as an alkene 2-4 in the presence of a metal catalyst such as bis(triphenylphcs-
phine)palladium (IT) chloride wherein t can be 0, 1, 2, and the like; and R can be a substituent such as
alkyl, aryl, CN, nitro, alkoxy, etc. The alkene group of compound 2-5 can be reduced by
hydrogenation to afford the corresponding compound 2-6.

As shown in Scheme 3, imidazole-containing cores 3-7 can be synthesized starting with an N-
protected 4-bromo-pyrrolo[2,3-b]pyridine or an N-protected 4-bromo-pvrrolo[2,3-b]pyrimidine 3-1
wherein P is a suitable amine protecting group such as {[2-(trimethylsilyl)ethoxy]methyl} (SEM).
Compound 3-1 can be reacted with a Grignard reagent such as isopropyl magnesium chloride to
generate an aromatic anion through ion exchange. The subsequent addition of a chloroacetyl-
containing compound such as 2-chloro-N-methoxy-N-methylacetarnide 3-2 to the anion will typically
afford the chloroacetyl derivative 3-3. The derivative 3-3 can be reacted with an organic acid salt
such as a cesium salt R5CO2Cs to afford a compound 3-4. In the presence of a suitable ammonia
source such as ammonium acetate, the compound 3-4 can react with ammonia under suitable
conditions such as at a high temperature to form the imidazole ring of the compound 3-5. The free

amine nitrogen of the imidazole derivative 3-5 can undergo further modification such as reacting with
a compound X-(Y)n-Z where X is a leaving group such as chloro, bromo or iodo so as to afford
compound 3-6. The protecting group of compound 3-6 can be removed by an appropriate method
according to the nature of the protecting group to yield compound 3-7. It should be noted that if there
are functional groups present within the R, R5, and —(Y)n-Z group, further modification can be made.
For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be
converted to a ester, which in turn can be further reduced to an alcohol, which in turn can be further
modified. One skilled in the art will recognize appropriate further modifications.

As shown in scheme 4, thiazole-contammg cores 4-3 can be synthesized starting with an N-
protected chloroacetyl derivative 4-1 wherein P is a suitable amine protecting group such as SEM.
Compound 4-1 can be reacted with a thioamide 4-2 to form the thiazole ring, followed by
deprotection of the amine nitrogen of the pyrrole ring by removal of the P group to afford the
compound 4-3. Various thioureas 4-5 (equivalent to compound 4-2 wherein — (Y)n-Z is NR'R"; and
R* and R" are H, alkyl, aryl or the like; or R' and R" together with the N atom to which they are
attached form a heterocycloalkyl) useful in preparing the thiazole compounds 4-3 can be made from
secondary amines 4-4. A secondary amine 4-4 can be reacted with 1,1 '-thiocarbonyldiimidazole; and
the resulting intermediate can further be reacted with ammonia to afford a thiourea 4-S.

As shown in Scheme 5, thiazole-containing cores 5-5 can be synthesized starting with a
thiazole compound 5-1. The compound 5-1 can be reacted with a metal alkyl such as n-butyl lithium
via ion exchange to generate an aromatic anion in situ. The subsequent addition of boric acid
trimethyl ester followed by hydrolysis will typically afford the boric acid 5-2. The boric acid 5-2 can
undergo Suzuki coupling with an N-protected 4-bromo-pyrrolo[2,3-b]pyridine or an N-protected 4-
bromo-pyrrolo[2,3-b]pyrimidine 5-3 wherein P is a suitable amine protecting group such as SEM.
The protecting group P of the coupling product 5-4 can be removed by an appropriate method
according to the nature of the protecting group to yield the compound of the invention 5-5.

As shown in Scheme 6, pyrazole-containing compounds 6-1 can further be modified by
substitution on the pyrazole NH group with appropriate reagents. For example, a compound 6-1

wherein P is a suitable amine protecting group such as SEM can be reacted with L-(Y)n-Z where L
represents a leaving group such as halo, triflate or the like to afford compound 6-2 under basic
condition. If there are some functional groups present within the Y and/or Z group, further
modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a
carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol. One
skilled in the art will recognize the further modifications if appropriate.
Additionally, compound 6-1 can be reacted with alkene 6-3 (wherein R' and R" can be H,
alkyl, cycloalkyl and the like; and Z' can be an electron withdrawing group such as an ester or CN) to
afford the compound 6-4. Further, substitution can be made on alkene 6-3 at the alpha position (alpha
to Z') to generate a substituted derivatives of product, 6-4 (see, e.g., Example 68).
Compounds 6-2 and 6-4 can be deprotected by appropriate methods according to the nature of
the protecting group used to afford their corresponding de-protected counterpart.

As shown in Scheme 7, bromo pyrazole containing compounds 7-1 can be further modified
by metallation with reagents like butyl lithium and reaction with electrophiles like aldehydes to give
the alcohol containing compounds 7-2 which can be deprotected to yield compounds of the invention
having formula 7-3. One skilled in the art will recognize the further modifications where appropriate.

As shown in Scheme 8, pyrazole-containing compounds 8-4 and 8-5 can be prepared by
reaction of the N-protected bromo compound 8-1 with hydrazine in an appropriate solvent such as
iV;Af-dimethylformamide (DMF) to give the hydrazine intermediate 8-2. The hydrazino intermediate
8-2 is reacted with an appropriately substituted 1,3 bis-aldehyde like 8-3 to give the pyrazole
containing compound 8-4. If there are some functional groups present within the Y and/or Z group,
further modification can be made. For example, a CN group can be hydrolyzed to afford an amide
group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol.
One skilled in the art will recognize further potential modifications.

As shown in Scheme 9, the 1,2,4-oxadiazole compound 9-6 can prepared from the N-
protected bromo compound 9-1 by treatment with zinc cyanide in DMF in the presence of a catalyst
like bis(tributyl) palladium to give the N-protected cyano compound 9-2. The N-hydroxy carbox-
imidamide compound 9-3 can be prepared by heating the N-protected cyano compound 9-2 with
hydroxylamine hydrochloride in an appropriate solvent like ethanol and a base like potassium
carbonate at a temperature below the boiling point of the solvent. The N-protected 1,2,4-oxadiazole
compound can be prepared by treating the N-hydroxy carboximidamide compound 9-3 with an
appropriately substituted acid chloride compound 9-4 in a solvent like pyridine at a sufficient
temperature to complete the ring closure. If there are some functional groups present within the Y
and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to

afford an amide group; a carboxylic acid can be converted to an ester, which in turn can be further
reduced to alcohol. One skilled in the art will recognize further modifications where appropriate.

As shown in Scheme 10, the 3- and 4-arylpyrazolo compounds 10-9 can be prepared by
reaction of the respective 3-arylpyrazolo compound 10-4 or 4-aryl pyrazolo compound 10-7 with an
appropriately substituted bromo compound 10-8 as previously described. The 3-aryl pyrazolo
compound 10-4 can be prepared by reacting an appropriately substituted aryl group containing a
halogen like bromo or a triflate with the N-protected boronic acid or boronic acid ester pyrazole
compound 10-2 under Suzuki-like conditions known in the literature. The N-protecting group of 10-3
can be removed by conditions previously described and known in the literature for removing groups
like SEM.
The 4-arylpyrazolo compounds 10-7 can be prepared by reacting the appropriately
substituted acetophenone compound 10-5 with DMF acetal in DMF at elevated temperatures to give
the dimethylamino compound 10-6. The 4-arylpyrazolo compounds 10-7 can be prepared by treating
the dimethylamino compound 10-6 with hydrazine in a solvent such as ethanol.

As shown in Scheme 11 the substituted pyrazole compound 11-5 can be prepared by a variety
of methods, such as by removing the protecting group e.g., SEM from compound 11-4 under
conditions previously described. For example the substituted pyrazole N-protected compound 11-4
can be prepared by reaction of the intermediate pyrazole N-protected compound 11-3 with an
appropriately substituted alkyl halide, benzyl halide, alkyl sulfonates, e.g., mesylate or tosylate, or
other suitable leaving group L, in an appropriate solvent such as MeCN, DMF or tetrahydrofuran
(THF), in the presence of a base such a sodium hydride or cesium carbonate. The N-aryl pyrazole 11-
4 (wherein Y is aromatic) may be prepared by reacting the intermediate pyrazole 11-3 with an
appropriately substituted aryl boronic acid in a solvent such as dichloromethane (DCM) with copper
acetate and pyridine. Alternatively the N-aryl pyrazole 11-4 (wherein Y is aromatic) can be prepared
by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl-fluoride in a solvent
such as DMF at elevated temperature. Or, the substituted pyrazole compounds 11-4 (wherein Z is a
group such as nitrile or ester and Y is at least two carbons) can be prepared by the reaction of
intermediate pyrazole 11-3 with an appropriately substituted acrylate, acrylonitrile or other Michael-
like acceptors in a solvent such as DMF in the presence of a base such as 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylamine (TEA) and at a temperature below the boiling
point of the solvent. If there are some functional groups present within the Y and/or Z group, further
modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a
carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol. One
skilled in the art will recognize the further modifications if appropriate.

As shown in Scheme 12, pyrazole 12-1 wherein P is a suitable amine protecting group such as
SEM can be reacted with an alkyne-containing conjugate acceptor such as 12-2, wherein Z is an
electron-withdrawing group (for example, -CN) optionally in the presence of a base (DBU or K2CO3
and the like) in a solvent such as DMF or MeCN for variable lengths of time to provide olefin-
containing adducts 12-3. Compounds represented by the formula 12-3 can be deprotected by
appropriate methods according to the nature of the protecting group used to afford compounds of the
invention 12-4.

As shown in Scheme 13, oxazole- or thiazole-containing compounds 13-6 can be prepared
starting with N-protected 4-chloro-pyrrolo[2,3-b]pyrimidine 13-1 wherein P is a suitable amine
protecting group such as SEM. Oxazole- or thiazole-containing products of formula 13-2 can be

prepared by palladium-catalyzed coupling of 13-1 with oxazole or thiazole. The compound 13-2 can
be reacted with a metal alkyl such as n-butyllithium to generate the aromatic anion in situ to which
can be added at low temperatures (preferably between -78°C and 0°C) derivatives of carboxylic acids
13-3 (wherein W = N(Me)(OMe) when X1=S; and W = Cl when X'=O), in the presence of other
additives such as zinc chloride and copper(I) iodide when X1=O, in a suitable solvent such as THF to
generate a variety of ketones 13-4. Ketones 13-4 can be caused to react with a variety of reagents
such as diethyl (cyanomethyl)phosphonate or triethylphosphonoacetate in the presence of a base like
potassium tert-butoxide followed by reduction (including hydrogenation or a copper-hydride
catalyzed conjugate reduction), or with reagents such as tosylmethyl isocyanide to provide products of
formula 13-5 wherein Z is an electron-withdrawing group such as ester or -CN. If there are functional
groups present within the R group or encompassed by the Z group, further modification can be made,
and such appropriate further modifications will be recognized by one skilled in the art. Compounds
13-5 can be deprotected by appropriate methods according to the nature of the protecting group used
to afford their corresponding deprotected counterparts 13-6.

As shown in Scheme 14, aminothiazole-containing cores 14-5 can be synthesized starting
with thiazole-containing core 14-1 wherein P is a suitable amine protecting group such as SEM. The
compound 14-1 can be treated with a metal alkyl such as n-butyllithium to generate the aromatic
anion in situ to which can be added a suitable source of electrophilic halogen such as carbon
tetrabromide to afford the halogenated derivative 14-2. The protecting group P of 14-2 can be
removed by an appropriate method according to the nature of the protecting group to yield product

14-3. The compound 14-3 can be reacted with amines 14-4 at elevated temperatures in a suitable
solvent such as DMF to afford the compound of the invention, 14-5.

As shown in Scheme 15, pyrrole-containing cores 15-4 can be synthesized starting with N-
protected 4-chloro-pyrrolo[2,3-b]pyrimidine 15-1 wherein P is a suitable amine protecting group such
as DEM (diethoxymethyl). The compound 15-1 can be reacted with l-(triisopropylsilyl)pyrrole-3-
boronic acid under Suzuki coupling conditions to afford the simultaneously pyrrole-deprotected core
15-2. Pyrrole-containing compounds 15-2 can be reacted with alkenes 15-3 containing an electron-
withdrawing group Z (such as —CN) in the presence of an appropriate base (such as DBU) at various
temperatures (e.g., between room temperature and 40° C) followed by an in situ or separate
deprotection step that is suitable for the selected protecting group to afford compounds of the
invention 15-4.

As shown in Scheme 16, a substituted pyrazole compound containing a sultone or
sulfoxide functionality as in 16-6 can be prepared by a variety of methods, such as starting

with an appropriately substituted bromo thiophenyl ether 16-2. Thioether 16-2 may be
readily prepared by alkylation of the thiophenol 16-1 with an alkyl halide, mesylate or the
like using a base like DBU, potassium carbonate or sodium hydride. The cinnamyl nitrile
16-3 may be prepared by Heck chemistry and the like, using palladium acetate and
triphenylphosphine in DMF at an appropriate temperature with acrylonitrile. The SEM
protected intermediate 16-4 may be prepared by methods previously described for performing
the Michael like addition of the pyrazole core to an appropriately substituted — unsaturated
nitrile like 16-3. The sulfoxide 16-5, where n=l, and sulfone 16-5, where n=2, may be
prepared by methods well known in the literature for the oxidation of the thio ether 16-4 like
m-chloroperbenzoic acid (MCPBA) in DCM. The final compounds 16-6, where n= 0, 1 or 2,
may be prepared by methods previously described for the removal of the SEM protecting
group. Alternatively, the sulfur oxidation may be performed on compounds 16-2 or 16-3
depending on the compatibility of the substitution in the synthetic scheme.

Also, as shown in Scheme 17, substituted pyrazole compounds containing a sulfonamide
functionality, such as 17-6 can be prepared by a variety of methods. For example, one may start with
an appropriately substituted bromo phenyl sulfonamide 17-2, where Rc and Rd are suitable
substituents. A compound 17-2 may be readily prepared by reaction of the bromo phenyl sulfonyl
chloride 17-1 and an appropriately substituted amine such as an aniline, or a primary or secondary
amine in a suitable solvent such as DCM, THF or pyridine. The cinnamyl nitrile 17-3 may be
prepared by Heck chemistry or the like, using palladium acetate and triphenylphosphine in DMF at an

appropriate temperature with acrylonitrile. The final compounds 17-6 where Rc and Rd are part of the
sulfonamide functional group may be prepared by methods analogous to those described in Scheme
16 starting with the cinnamyl nitrile 17-3.

Also, as shown in Scheme 18, substituted pyrazole compounds containing an alpha-
allyl cyclopentylmethylene functionality, such as 18-8, can be prepared by, for example,
reacting a pyrazole 18-3, wherein P is a suitable amine protecting group such as SEM and X
is N or C, with a cyclopentylacrylate ester 18-4 to form the ester 18-5. The ester 18-5 may
then be reduced to the corresponding aldehyde, 18-6, for example, by the two-step procedure
of reducing to the alcohol and selectively oxidizing the intermediate alcohol to the aldehyde,
e.g., via a Swern oxidation.. The aldehyde, 18-6, may then be converted to the corresponding
olefin, 18-7, for example by reaction with a Wittig reagent. The olefin 18-7, may then be
deprotected, as described earlier, to produce the formula 18-7 compound. The intermediate,
18-4, may be prepared, for example as shown in Scheme 18, stearting with
cyclopentylaldehyde.

Also, as shown in Scheme 19, the cyanoguanidine derivative 19-6 can be prepared starting
from substituted pyrazole compounds such as pyrazole 18-3, wherein P is a suitable protecting group
such as SEM and X is N or C. A compound 18-3 may, for example, be reacted with olefin 19-1,
prepared by Horner-Wadsworth Emmons reaction of the corresponding Boc-protected piperidone, in
the presence of a suitable basic catalyst, in a suitable solvent, to form 19-2. The intermediate 19-2 is
deprotected using a suitable deprotection reaction, to provide the amine compound 19-3, which then
reacts selectively with a cyanoimidocarbonate reagent such as 19-4, in a polar solvent at a suitable
temperature, for example, about 20 °C to give a cyanoimidocarbamate such as 19-5, which can then
be reacted with any of a variety of amines at elevated temperature to give product 19-6.

The intermediate compounds 20-5 and 20-6 may be prepared by a variety of methods in the
literature, for example, methods such as are outlined in Scheme 20. The intermediate compound 20-3
may be prepared by reaction of the aldehyde compound 20-1 with an appropriately substituted Wittig
reagent or Horner Emmons reagents to give the a-p unsubstituted ester 20-3. Alternatively, 20-3 may
be prepared by a Heck-like reaction with an appropriately substituted aryl bromide 20-2 and an acrylic
ester in the presence of a palladium reagent at elevated temperatures. The compound 20-4 may be
prepared by methods previously described for the Michael-like addition of an appropriately
substituted pyrrole 18-3 on the a-p unsaturated ester compound 20-3. The aldehyde compound 20-5
may be prepared by reduction of the ester compound 20-4 with reagents such as diisobutyl aluminium
hydride at low temperatures such as about -78 °C in an appropriate solvent. The aldehyde compound
20-5 can be further reduced to the corresponding alcohol compound 20-6 with reagents such as
sodium borohydride in methanol. Alternatively the alcohol compound 20-6 may be prepared directly
by reduction of the ester 20-4 with reagents such as lithium aluminium hydride in appropriate solvent
and at appropriate temperatures.

The compounds 21-2 and 21-3 may be prepared by using a variety of methods in the
literature, such as, for example, methods outlined in Scheme 21. The olefin compound 21-1 may be
prepared by the reaction of aldehyde compound 20-5 with an appropriately substituted Wittig reagent
or Homer Emmons reagents using a base such as sodium hydride or potassium t-butoxide in an
appropriate solvent and conducted at temperature. The olefin compound compound 21-1 may be
reduced to the saturated compound 21-2, for example, using hydrogenation conditions well known in
the literature, e.g., hydrogen in the presence of palladium on carbon in a solvent such as methanol.
The acetylenic compound 21-3 may be prepared by methods previously described, or by reaction of
the aldehyde 20-5 with Bestmann-Ohira reagent (E. Quesada et al, Tetrahedron, 62 (2006) 6673-
6680) as described in the literature. Alternatively the alcohol compound 20-6 in Scheme 20 may be
oxidized to the aldehyde 20-5 with methods well known in the literature, e.g., Swem oxidation
conditions, followed by reaction with the Bestmann-Ohira reagent, wherein this reaction sequence
may be carried out either as a one pot two-step reaction sequence, or in two separate reaction steps.

. The compounds 22-1 and 22-3 may be prepared by using a variety of methods in the
literature, for example, via methods outlined in Scheme 22. The oxygen-substituted compound 22-1
may be prepared, for example, by reaction of an appropriately substituted alcohol 20-6 (in Scheme
20), wherein X is N or C, and P is a protecting group, with a base such as sodium hydride and an
appropriate agent such as an alkyl iodide, carbonate, or isocyanate, carried out in a suitable solvent
and at a suitable temperature. Alternatively, the alcohol group on the compound 20-6 may be
converted to a leaving group LG, as in compound 22-2, where the leaving group can be, for example,
bromide or mesylate. The compound 22-2 serves as a substrate for subsequent reaction with a
nucleophile, such as, for example, sodium ethoxide (Nuc = ethoxy).

It should noted that in all of the Schemes described herein, if there are functional groups
present on a substituent group such as Y, Z, R, R1, R2, R5, etc., further modification can be made if
appropriate and desired. For example, a CN group can be hydrolyzed to afford an amide group; a
carboxylic acid can be converted to a ester, which in turn can be reduced to an alcohol, which in turn
can be further modified. In another example, an OH group can be converted into a better leaving
group such as mesylate, which in turn is suitable for nucleophilic substitution, such as by CN. One
skilled in the art will recognize such further modifications.
Methods
Compounds of the invention can modulate activity of one or more Janus kinases (JAKs). The
term "modulate" is meant to refer to an ability to increase or decrease the activity of one or more
members of the JAK family of kinases. Accordingly, compounds of the invention can be used in
methods of modulating a JAK by contacting the JAK with any one or more of the compounds or
compositions described herein. In some embodiments, compounds of the present invention can act as
inhibitors of one or more JAKs. In some embodiments, compounds of the present invention can act to
stimulate the activity of one or more JAKs. In further embodiments, the compounds of the invention

can be used to modulate activity of a JAK in an individual in need of modulation of the receptor by
administering a modulating amount of a compound of Formula la, Ib, or Ic.
JAKs to which the present compounds bind and/or modulate include any member of the JAK
family. In some embodiments, the JAK is JAK1, JAK2, JAK3 or TYK2. In some embodiments, the
JAK is JAK1 or JAK2. In some embodiments, the JAK is JAK2. In some embodiments, the JAK is
JAK3.
The compounds of the invention can be selective. By "selective" is meant that the compound
binds to or inhibits a JAK with greater affinity or potency, respectively, compared to at least one other
JAK. In some embodiments, the compounds of the invention are selective inhibitors of JAK 1 or JAK2
over JAK3 and/or TYK2. In some embodiments, the compounds of the invention are selective
inhibitors of JAK2 (e.g., over JAK1, JAK3 and TYK2). Without wishing to be bound by theory,
because inhibitors of JAK3 can lead to immunosuppressive effects, a compound which is selective for
JAK2 over JAK3 and which is useful in the treatment of cancer (such as multiple myeloma, for
example) can offer the additional advantage of having fewer immunosuppressive side effects.
Selectivity can be at least about 5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at least
about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. Selectivity
can be measured by methods routine in the art. In some embodiments, selectivity can be tested at the
Km of each enzyme. In some embodiments, selectivity of compounds of the invention for JAK2 over
JAK3 can be determined by the cellular ATP concentration.
Another aspect of the present invention pertains to methods of treating a JAK-associated
disease or disorder in an individual (e.g., patient) by administering to the individual in need of such
treatment a therapeutically effective amount or dose of a compound of the present invention or a
pharmaceutical composition thereof. A JAK-associated disease can include any disease, disorder or
condition that is directly or indirectly linked to expression or activity of the JAK, including over-
expression and/or abnormal activity levels. A JAK-associated disease can also include any disease,
disorder or condition that can be prevented, ameliorated, or cured by modulating JAK activity.
Examples of JAK-associated diseases include diseases involving the immune system
including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host
disease).
Further examples of JAK-associated diseases include autoimmune diseases such as multiple
sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel
disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies,
autoimmune thyroid disorders, and the like. In some embodiments, the autoimmune disease is an
autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).
Further examples of JAK-associated diseases include allergic conditions such as asthma, food
allergies, atopic dermatitis and rhinitis. Further examples of JAK-associated diseases include viral

diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster
Virus (VZV) and Human Papilloma Virus (HPV).
Further examples of JAK-associated diseases or conditions include skin disorders such as
psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin
sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances
including some Pharmaceuticals when topically applied can cause skin sensitization. In some
embodiments, co-administration or sequential administration of at least one JAK inhibitor of the
invention together with the agent causing unwanted sensitization can be helpful in treating such
unwanted sensitization or dermatitis. In some embodiments, the skin disorder is treated by topical
administration of at least one JAK inhibitor of the invention.
In further embodiments, the JAK-associated disease is cancer including those characterized
by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer,
breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's
sarcoma, Castleman's disease, melanoma etc.), hematological cancers (e.g, lymphoma, leukemia such
as acute lymphoblastic leukemia, or multiple myeloma), and skin cancer such as cutaneous T-cell
lymphoma (CTCL) and cutaneous B-cell lymphoma. Example cutaneous T-cell lymphomas include
Sezary syndrome and mycosis fungoides.
JAK-associated diseases can further include those characterized by expression of a mutant
JAK2 such as those having at least one mutation in the pseudo-kinase domain (e.g., JAK2V617F).
JAK-associated diseases can further include myeloproliferative disorders (MPDs) such as
polycythemia vera (PV)» essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis
(MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML),
hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like.
Further JAK-associated diseases include inflammation and inflammatory diseases. Example
inflammatory diseases include inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis,
conjunctivitis, or related disease), inflammatory diseases of the respiratory tract (e.g., the upper
respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower respiratory
tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory
myopathy such as myocarditis, and other inflammatory diseases.
The JAK inhibitors described herein can further be used to treat ischemia reperfusion injuries
or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest.
The JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as
that resulting from or associated with cancer. The JAK inhibitors described herein can further be used
to treat restenosis, sclerodermitis, or fibrosis. The JAK inhibitors described herein can further be used
to treat conditions associated with hypoxia or astrogliosis such as, for example, diabetic retinopathy,
cancer, or neurodegeneration. See, e.g., Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427-36 and
Sriram, K. et al. J. Biol. Ckem. 2004, 279(19):19936-47. Epub 2004 Mar 2.

As used herein, the term "contacting" refers to the bringing together of indicated moieties in an
in vitro system or an in vivo system. For example, "contacting" a JAK with a compound of the
invention includes the administration of a compound of the present invention to an individual or
patient, such as a human, having a JAK, as well as, for example, introducing a compound of the
invention into a sample containing a cellular or purified preparation containing the JAK.
As used herein, the term "individual" or "patient," used interchangeably, refers to any animal,
including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,
horses, or primates, and most preferably humans.
As used herein, the phrase "therapeutically effective amount" refers to the amount of active
compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system,
animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other
clinician, which includes one or more of the following:
(1) preventing the disease; for example, preventing a disease, condition or disorder in an
individual who may be predisposed to the disease, condition or disorder but does not yet experience or
display the pathology or symptomatology of the disease;
(2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an
individual who is experiencing or displaying the pathology or symptomatology of the disease,
condition or disorder {i.e., arresting further development of the pathology and/or symptomatology),
and
(3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an
individual who is experiencing or displaying the pathology or symptomatology of the disease,
condition or disorder {i.e., reversing the pathology and/or symptomatology).
Combination Therapies
One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-
inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinase
inhibitors such as, for example, those described in WO 2006/056399, or other agents can be used in
combination with the compounds of the present invention for treatment of JAK-associated diseases,
disorders or conditions. The one or more additional pharmaceutical agents can be administered to a
patient simultaneously or sequentially.
Example chemotherapeutic include proteosome inhibitors {e.g., bortezomib), thalidomide,
revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine,
etoposide, cannustine, and the like.
Example steroids include coriticosteroids such as dexamethasone or prednisone.
Example Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts
thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281,
EP2005/009967, EP2005/010408, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable
salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.
Example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable
salts, as disclosed in WO 00/09495 and WO 05/028444.
Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable
salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO
00/053595, and WO 01/014402.
In some embodiments, one or more JAK inhibitors of the invention can be used in
combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may
improve the treatment response as compared to the response to the chemotherapeutic agent alone,
without exacerbation of its toxic effects. Examples of additional pharmaceutical agents used in the
treatment of multiple myeloma, for example, can include, without- limitation, melphalan, melphalan
plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional
agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK kinase
inhibitors. Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of the
present invention with an additional agent. Furthermore, resistance of multiple myeloma cells to
agents such as dexamethasone may be reversible upon treatment with a JAK inhibitor of the present
invention. The agents can be combined with the present compounds in a single or continuous dosage
form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in
combination with at least one JAK inhibitor where the dexamethasone is administered intermittently
as opposed to continuously.
In some further embodiments, combinations of one or more JAK inhibitors of the invention
with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone
marrow transplant or stem cell transplant.
Pharmaceutical Formulations and Dosage Forms
When employed as Pharmaceuticals, the compounds of the invention can be administered in
the form of pharmaceutical compositions. These compositions can be prepared in a manner well
known in the pharmaceutical art, and can be administered by a variety of routes, depending upon
whether local or systemic treatment is desired and upon the area to be treated. Administration may be
topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal,
vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols,
including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration
includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or
infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration
can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.

Pharmaceutical compositions and formulations for topical administration may include transdermal
patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be
"i
necessary or desirable. Coated condoms, gloves and the like may also be useful.
This invention also includes pharmaceutical compositions which contain, as the active
ingredient, one or more of the compounds of the invention above in combination with one or more
pharmaceutically acceptable carriers (excipients). In making the compositions of the invention, the
active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such
a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient
serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or
medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in
a liquid medium), ointments containing, for example, up to 10% by weight of the active compound,
soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged
powders.
In preparing a formulation, the active compound can be milled to provide the appropriate
particle size prior to combining with the other ingredients. If the active compound is substantially
insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is
substantially water soluble, the particle size can be adjusted by milling to provide a substantially
uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol,
starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,
microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as talc, magnesium stearate, and
mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention
can be formulated so as to provide quick, sustained or delayed release of the active ingredient after
administration to the patient by employing procedures known in the art.
The compositions can be formulated in a unit dosage form, each dosage containing from
about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The
term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical
excipient.
The active compound can be effective over a wide dosage range and is generally administered
in a pharmaceutically effective amount. It will be understood, however, that the amount of the
compound actually administered will usually be determined by a physician, according to the relevant

circumstances, including the condition to be treated, the chosen route of administration, the actual
compound administered, the age, weight, and response of the individual patient, the severity of the
patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with
a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous
mixture of a compound of the present invention. When referring to these preformulation compositions
as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so
that the composition can be readily subdivided into equally effective unit dosage forms such as
tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the
type described above containing from, for example, about 0.1 to about 1000 mg of the active
ingredient of the present invention.
The tablets or pills of the present invention can be coated or otherwise compounded to
provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric layer which serves to resist
disintegration in the stomach and permit the inner component to pass intact into the duodenum or to
be delayed in release. A variety of materials can be used for such enteric layers or coatings, such
materials including a number of polymeric acids and mixtures of polymeric acids with such materials
as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the compounds and compositions of the present invention can be
incorporated for administration orally or by injection include aqueous solutions, suitably flavored
syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil,
sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in
pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The
liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described
supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route
for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized
solutions may be breathed directly from the nebulizing device or the nebulizing device can be
attached to a face masks tent, or intermittent positive pressure breathing machine. Solution,
suspension, or powder compositions can be administered orally or nasally from devices which deliver
the formulation in an appropriate manner.
The amount of compound or composition administered to a patient will vary depending upon
what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state
of the patient, the manner of administration, and the like. In therapeutic applications, compositions
can be administered to a patient already suffering from a disease in an amount sufficient to cure or at
least partially arrest the symptoms of the disease and its complications. Effective doses will depend on

the disease condition being treated as well as by the judgment of the attending clinician depending
upon factors such as the severity of the disease, the age, weight and general condition of the patient,
and the like.
The compositions administered to a patient can be in the form of pharmaceutical
compositions described above. These compositions can be sterilized by conventional sterilization
techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized,
the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The
pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and
most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients,
carriers, or stabilizers will result in the formation of pharmaceutical salts.
The therapeutic dosage of the compounds of the present invention can vary according to, for
example, the particular use for which the treatment is made, the manner of administration of the
compound, the health and condition of the patient, and the judgment of the prescribing physician. The
proportion or concentration of a compound of the invention in a pharmaceutical composition can vary
depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity),
and the route of administration. For example, the compounds of the invention can be provided in an
aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for
parenteral administration. Some typical dose ranges are from about 1 jag/kg to about 1 g/kg of body
weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg
of body weight per day. The dosage is likely to depend on such variables as the type and extent of
progression of the disease or disorder, the overall health status of the particular patient, the relative
biological efficacy of the compound selected, formulation of the excipient, and its route of
administration. Effective doses can be extrapolated from dose-response curves derived from in vitro
or animal model test systems.
The compositions of the invention can further include one or more additional pharmaceutical
agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant,
examples of which are listed hereinabove.
Labeled Compounds and Assay Methods
Another aspect of the present invention relates to labeled compounds of the invention (radio-
labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in
assays, both in vitro and in vivo, for localizing and quantitating JAK in tissue samples, including
human, and for identifying JAK ligands by inhibition binding of a labeled compound. Accordingly,
the present invention includes JAK assays that contain such labeled compounds.
The present invention further includes isotopically-labeled compounds of the invention. An
"isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms
are replaced or substituted by an atom having an atomic mass or mass number different from the

atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable
radionuclides that may be incorporated in compounds of the present invention include but are not
limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), "C, 13C, 14C, 13N,
15N, I5O, 17O, 18O, I8F, 35S, 36C1, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and I31I. The radionuclide that is
incorporated in the instant radio-labeled compounds will depend on the specific application of that
radio-labeled compound. For example, for in vitro metalloprotease labeling and competition assays,
compounds that incorporate 3H, 14C, 82Br, I25I, I31I, 35S or will generally be most useful. For radio-
imaging applications nC, 18F, I25I, I23I, I241,1311,75Br, 76Br or 77Br will generally be most useful.
It is understood that a "radio-labeled " or "labeled compound" is a compound that has
incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the
group consisting of 3H, I4C, 1251,35S and 82Br.
The present invention can further include synthetic methods for incorporating radio-isotopes
into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic
compounds are well known in the art, and an ordinary skill in the art will readily recognize the
methods applicable for the compounds of invention.
A labeled compound of the invention can be used in a screening assay to identify/evaluate
compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is
labeled can be evaluated for its ability to bind a JAK by monitoring its concentration variation when
contacting with the JAK, through tracking of the labeling. For example, a test compound (labeled)
can be evaluated for its ability to reduce binding of smother compound which is known to bind to a
JAK (i.e., standard compound). Accordingly, the ability of a test compound to compete with the
standard compound for binding to the JAK directly correlates to its binding affinity. Conversely, in
some other screening assays, the standard compound is labeled and test compounds are unlabeled.
Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the
competition between the standard compound and the test compound, and the relative binding affinity
of the test compound is thus ascertained.
Kits
The present invention also includes pharmaceutical kits useful, for example, in the treatment
or prevention of JAK-associated diseases or disorders, such as cancer, which include one or more
containers containing a pharmaceutical composition comprising a therapeutically effective amount of
a compound of the invention. Such kits can further include, if desired, one or more of various
conventional pharmaceutical kit components, such as, for example, containers with one or more
pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those
skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to
be administered, guidelines for administration, and/or guidelines for mixing the components, can also
be included in the kit.

The invention will be described in greater detail by way of specific examples. The following
examples are offered for illustrative purposes, and are not intended to limit the invention in any
manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can
be changed or modified to yield essentially the same results. The compounds of the Examples
have been found to be JAK inhibitors according to at least one assay described herein.

Step 1. lH-Pyrrolo[2,3-b]pyridine 7-oxide
To a solution of lH-pyrrolo[2,3-b]pyridme (4.90 g, 0.0415 mol) in ethyl acetate (41 mL, 0.42
mol) was added a solution of meta-chloroperbenzoic acid (MCPBA; 9.3 g, 0.054 mol) in ethyl acetate
(27 mL, 0.28 mol) at 0 °C. The reaction mixture was solidified when -20 mL solution of MCPBA
was added. An additional ~10 mL of ethyl acetate was added so that a solution resulted. The reaction
mixture was allowed to warm to room temperature (rt) and stirred overnight, then was cooled at 0 °C,
filtered and washed with ethyl acetate three times to give 10.94 g wet solid. The wet solid (8.45 g)
was then suspended in water (35 mL), and to the suspension was added 13 mL of sat. Na2CO3
dropwise, and the resulting mixture was stirred at room temperature overnight. The mixture was then
cooled at 0° C, filtered and washed with water (x4) to give 3.55 g of pale purple solid which was dried
at 40° C overnight to give the desired product (2.47 g, 44.4% yield).
'H NMR (400 MHz, CD3OD): 5 8.2 (1H, d); 7.95 (1H, d); 7.5 (1H, d); 7.2 (1H, m); 6.65 (1H, d). MS
(M+H)+: 136.
Step 2. 4-Chloro-lH-pyrrolo[2,3-b]pyridine
To a pink solution of 1H-pyrrolo[2.3-b]pyridine 7-oxide (2.47 g, 0.0184 mol) in
dimethylformamide (DMF) (13.3 mL, 0.172 mol) was added methanesulfonyl chloride (4.0 mL, 0.052
mol) at 50 °C, and the pink color changed to orange. The reaction mixture was heated at 73 °C for 2h,
then cooled to 40 °C. Water (35 mL) was added, and the resulting suspension was cooled at 0 °C.
NaOH was added to adjust the pH of the mixture to about 7. The mixture was filtered and washed

with water (x3) to give 3.8 g of a wet pale orange solid that was dried at 40 °C overnight to give the
product (2.35 g, 82.2% yield).
1H NMR (400 MHz, CDC13): 6 10.8 (1H, br); 8.21 (1H, d); 7.41(1H, d); 7.18 (1H, d); 6.61 (1H, d).
MS (M+H)+: 153.

A mixture of 4-chloro-lH-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) and 4-bromo-3-
methyl-lH-pyrazole (0.10 g, 0.00066 mol) was heated at 130 °C overnight. The reaction mixture then
was subjected to column chromatography (eluting with 5% MeOH/DCM, 0.5% NH4OH, on silica gel)
to give 80 mg pale yellow solid which was triturated with MeOH (1.5 mL) to yield the product as a
pale yellow solid (44 mg, 44% yield).
1H NMR (400 MHz, CD3OD): 5 8.32 (1H, s); 8.25 (1H, d); 7.6 (1H, s); 7.45 (1H, d); 7.37 (1H, d);
6.96 (1H, d); 2.4 (3H, s). MS (M+H)+: 276.
Step 4. 3-[3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]benzonitrile
A mixture of 4-(4-bromo-3-methyl-lH-pyrazol-l-yl)-lH-pyrrolo[2,3-b]pyridine (0.032 g,
0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodium carbonate (0.032 g,
0.00030 mol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in 1,2-
dimethoxyethane (0.3 mL, 0.003 mol) and water (0.3 mL, 0.02 mol) was heated at 130 °C (a liquid
resulted, but with two layers) for 4 h. The reaction mixture then was cooled to room temperature (rt),
filtered and was washed with water (x2) and dimethyl ether (DME) (x2) to give the product as a pale
orange solid (15 mg, 44% yield).
'H NMR (400 MHz, CD3OD): 5 8.57 (1H, s); 8.31 (1H, d); 7.8 (2H, m); 7.75 (2H, m); 7.55 (1H, s);
7.45 (2H, m); 7.01 (1H, d); 2.6 (3H, s). MS (M+H)+: 299.
Example 2: (2E)-3-[3-Methyl-l-(lH-pyrrolo[2^-b]pyridin-4-yl)-lH-pyrazol-4-yl]acrylonitrile
trifluoroacetate salt

Step 1. 4-Bromo-lH-pyrrolo[2,3-b]pyridine
To a solution of lH-pyrrolo[2,3-b]pyridine 7-oxide (8.0 g, 0.060 mol), prepared by the
procedure outlined in Example 1, Step 1 in DMF (100 mL, 1 mol) was added methanesulphonic
anhydride (20.8 g, 0.119 mol, in four portions) at 0 °C. The mixture was stirred at 0 °C for an
additional 20 min followed by an addition of tetramethylammoniuni bromide (23.0 g, 0.149 mol). The
resulting mixture was stirred overnight. Water (0.1 L) was added, and a slight exotherm was
observed. A solution of sodium hydroxide in water (12.5 M, 12 mL) was added to adjust the pH of
the mixture to about 8, followed by an addition of ~0.25 L of water. The resulting mixture was
stirred for additional 2 h then filtered. The solid obtained was washed with water x3 to give 6.72 g of
a reddish solid which was dried at 50 °C over a weekend to give the product (5.75 g, 49% yield).
'HNMR (400 MHz, CDC13): 510.8 (1H, br); 8.2 (1H, d); 7.41 (1H, d); 7.19 (1H, d); 6.61 (1H, d). MS
(M+H)+: 196.
Step 2. 4-Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine
To a solution of 4-bromo-lH-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol) and [/3-
(trimethylsilyl)ethoxy]methyl chloride (6.7 mL, 0.038 mol) in DMF (62 mL, 0.80 mol) was added
sodium hydride (1.5 g, 0.038 mol) at 0 °C, and the resulting solution turned opaque. The mixture was
stirred for additional 4 h, then diluted with methyl tert-butyl ether (MTBE). The organic layer was
separated and washed with water (x2) and brine aqueous solution successively. The organic phase was
dried and concentrated in vacuo to give 14.1 g of a product as a pale orange oil. The oil was purified
by column chromatography eluting with 5-20% ethyl acctate/hexanes to give the purified product as a
colorless oil (9.66 g , 94% yield).
'H NMR (400 MHz, CDCL,): 8 8.2 (1H, d); 7.49 (1H, d); 7.19 (1H, d); 6.62 (1H, d); 5.78 (2H, s); 3.6
(2H, t); 0.98 (2H, t); 0.0 (9H, s). MS (M+H)+: 326.
Step 3. (2E)-3-[3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4~yl)-lH-pyrazol-4-yl]acrylonitrile
A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II)
chloride (0.0091 g, 0.000013 mol), 4-(4-bromo-3-methyHH-pyra2ol-l-yl>lH-pyrrolo[2,3-b]pyridine
(0.036 g, 0.00013 mol), and tetraethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019
mol) was microwaved at 120 °C for 2 h. The solution was then diluted with ethyl acetate and washed

with water (x2) and brine successively. The organic phase was dried and concentrated in vacuo to
give 62 mg of the product as an orange solid. The orange solid was purified by prep-LCMS to give 12
mg of an off-white solid as a trifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL)
to provide the purified product as a pale green solid, (dried at 60 °C for 4 h, 9 mg , 28% yield).
1HNMR (400 MHz, CD3OD): 2 :1 of trans : cis isomers. For trans: 8 8.95 (NH.1H, s); 7.75 (olefin,
1H, d); 6.1 (olefin, 1H, d); 2.45 (Me, 3H, s). MS (M+H)+: 249.

A mixture of (2E)-3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]acrylo-
nitrile, TFA salt, (0.0050 g, 0.000020 mol, prepared according to Example 2) and palladium (5.8 mg,
0.0000054 mol) in methanol (1 mL, 0.02 mol) and 1,2-dichloroethane (1 mL, 0.01 mol) was degassed
and then was stirred under an atmosphere of hydrogen for 3 h. The reaction mixture then was filtered
and the filtrate was concentrated in vacuo to give 8 mg of the product as an off-white solid. The crude
material was purified by prep-LCMS to give 5.1 mg of a white solid as a TFA salt which was
triturated with MTB (1 mL) to give the product as a white solid (1.7 mg, 34% yield).
'H NMR (400 MHz, CD3OD): 5 8.52 (1H, s); 8.35 (1H, d); 7.72(1H, d); 7.6 (1H, s); 7.38 (1H, d);
6.96 (1H, d); 2.7-2.9 (4H, m); 2.4 (3H, s). MS (M+H)+: 251.

A melt oi 4-chloro-lH-pyrroIo[2,3-b]pyridine (0.050 g, 0.00033 mol) in 4-pnenyl-1H-
imidazole (0.24 g, 0.0016 mol) was heated at 200 °C overnight. The reaction was partitioned between
ethyl acetate and saturated NaHCO3, separated and the organic phase was washed with brine. The

organic layer was then dried and evaporated to give 250 mg of an orange oil. The oil was
chromatographed with 7% MeOH/DCM, 0.7% NH4OH, sample in solvent system. Collected 74 mg of
the product as an orange glass. The glass was triturated with hot DCE (1.5 mL) to give 51 mg of a
brown solid which was dried at 60 °C for 4 h to afford the desired product (50 mg, 59 yield).
1H NMR (400 MHz, dimethylsulxoxide (DMSO)): 8 12.5 (1H, s); 8.5 (1H, s); 8.4 (1H, s); 8.38 (1H,
d); 7.8 (2H, m); 7.62 (1H, d); 7.4 (3H, m); 7.3 (1H, m); 6.81 (1H, d). MS (M+H)+: 260

Step 1. 3-Methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazole-
4-carboxylic acid
To a -70 °C solution of 4-(4-bromo-3-methyl-lH-pyrazol-l-yl)-l-[2-(trimethylsilyl)ethoxy]-
methyHH-pyrrolo[2,3-b]pyridine (0.107 g, 0.000263 mol) in THF (1 mL, 0.01 mol), and n-
butyllithium in hexane (0.23 mL of 1.6M), 0.5g of CO2 solid was added. After 15 min, the reaction
was quenched with NH4CI. Ethyl acetate and water were added. The organic phase was washed with
brine, and was evaporated to give 84 mg of an off-white glass/solid. The solid was chromatographed
with 50% ethyl acetate/hexanes, 0.5% AcOH, sample on silica gel to give 40 mg of a purified product
as a white solid (37% yield).
'H NMR (400 MHz, CDC13): 5 8.5 (1H, d); 7.45 (1H, d); 7.25 (1H, d); 7.02 (1H, s); 6.6 (1H, d); 5.75
(2H, s); 3.6 (2H, t); 2.48 (3H, s); 0.98 (3H, t); 0.0 (9H, s). MS (M+H)+: 372.
Step 2. 4-[3-Methyl-4-(piperidin-l-ylcarbonyl)-lH-pyrazol-l-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-
1 H-pyrrolo[2,3-bJpyridine
A solution of 3-methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-
lH-pyrazole-4-carboxylic acid (0.040 g, 0.00011 mol) (1:1 of AcOH) and N,N-carbonyldiimidazole
(0.035 g, 0.00021 mol) in THF (1 mL, 0.01 mol) was stirred for 1.2h, after which time piperidine (32
uL, 0.00032 mol) was added. After another 2h, another portion of piperidine (15 L) was added and
the resulting mixture was stirred overnight. The reaction mixture was then partitioned between ethyl
acetate and water, and washed sequentially with sat. NaHCO3 and brine. The organic phase was dried

and evaporated to give 49 mg of the crude product as an orange oil/glass. The crude product was
chromatographed with 75-100% ethyl acetate/hexanes, sample in DCM. Collected 25 mg of the
purified product as a colorless glass/oil (50% yield).
1H NMR (400 MHz, CDCl3): 5 8.45 (1H, d); 8.23 (1H, s); 7.5 (1H, d); 7.4 (1H, d); 7.05 (1H, d); 5.8
(2H, s); 3.7 (4H, br); 3.6 (2H, t); 2.55 (3H, s); 1.7 (6H, br); 1.0 (3H, t); 0.0 (9H, s). MS (M+H)+: 439.
Step 3. 3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-piperidin-l-yl-methanone
A solution of 4-[3-methyl-4-(piperidin-l-ylcarbonyl)-lH-pyrazol-l-yl]-l-[2-(trimethylsilyl)-
ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.025 g, 0.000057 mol) in TFA (1 mL, 0.01 mol) was
stirred for 1.5 h. The reaction mixture was then concentrated and partitioned between DCM and sat.
NaHCO3 x2, and brine. The organic layer was then dried and concentrated to give 28 mg of the
product as a white foam. The foam was dissolved in methanol (1 mL, 0.02 mol) and treated with
ammonium hydroxide in water (8.0M, 1 mL) for 1.5h. The reaction was concentrated using a rotary
evaporator to give 24 mg of a pale yellow glass. The glass was triturated with methyl t-butyl ether
(MTBE) to give 13 mg of a white solid which was dried at rt over a weekend. A total of 8 mg of the
product was obtained after drying (45% yield).
1H NMR (400 MHz, CDC13): 5 9.7 (1H, s); 8.4 (1H, d); 8.2 (1H, s); 7.42 (1H, d); 7.4 (1H, d); 6.99
(1H, d); 3.4-3.8 (4H, br); 2.47 (3H, s); 1.5-1.8 (6H, br). MS (M+H)+: 309.

Step 1. 3-Methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin~4-yl)-lH-pyrazole-
4'Carbaldehyde
To a -70 °C solution of 4-(4-bromo-3-methyl-lH-pyrazol-l-yl)-l-[2-(trimethylsilyl)ethoxy]-
methyl-lH-pyrrolo[2,3-b]pyridine (0.25 g, 0.00061 mol) in THF (2 mL, 0.03 mol), 1.6 M n-
butyllithium in hexane (0.54 mL). After 10 min, DMF (120 L, 0.0015 mol) was added. The reaction
was allowed to warm to rt and stirred overnight. The reaction was then quenched with NH4CI. Ethyl
acetate/water was added. The organic phase was separated and washed with brine, then dried and

concentrated to give 180 mg of an orange oil. The crude product was chromatographed with 25%
ethyl acetate/hexanes, sample in DCM. Collected 40 mg of a pale yellow oil (18% yield).
1H NMR (400 MHz, CDC13): 8 10.15 (1H, s); 8.7 (1H, s); 8.47 (1H, d); 7.58 (1H, d); 7.5 (1H, d); 7.05
(1H, d); 5.8 (2H, s); 3.63 (2H, t); 2.7 (3H, s); 0.98 (3H, t); 0.0 (9H, s). MS (M+H)+: 356.
Step 2.N-[3-Methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-
pyrazol-4-yl] methylaniline
A solution of 3-methyl-l-(l-[2-(trimethylsiIyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-
lH-pyrazole-4-carbaldehyde (0.025 g, 0.000070 mol) and aniline (1M in DCM, 0.070 mL), in DCM
(1 mL, 0.02 mol) was stirred for 1 min. Acetic acid (20 L, 0.0004 mol), aniline (1M in DCM, 140
L) and sodium triacetoxyborohydride (0.022 g, 0.00010 mol) were added. The reaction was stirred
overnight and partitioned between DCM and sat. NaHCO3, washed with brine. The organic phase was
dried and evaporated to give 21 mg of a product as a pale orange glass (70% yield).
'H NMR (400 MHz, CDC13): 5 8.4 (1H, d); 8.15 (1H, s); 7.65 (1H, d); 7.35 (3H, m); 7.09 (1H, d);
6.82 (1H, m); 6.89 (2H, m); 5.8 (2H, s); 4.35 (2H, s); 3.6 (2H, t); 2.5 (3H, s); 0.99 (3H, t); 0.0 (9H, s).
MS (M+H)+: 433.
Step 3. [3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-ylmethyl]-phenyl-amine
Deprotection of N-[3-methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-
4-yl)-lH-pyrazol-4-yl]methylaniline was carried out according to the procedures of Example 14, Step
3 to give the desired product (58% yield).
1H NMR (400 MHz, CDC13): 5 9.9 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.4 (1H, d); 7.35 (1H, d); 7.3
(2H, m); 7.0 (1H, d); 6.79 (1H, m); 6.77 (2H, m); 4.25 (2H, s); 3.81 (1H, s); 2.41 (3H, s). MS
rM+H)+: 303.

To a -75 °C solution of 4-(4-bromo-3-methyl-lH-pyrazol-l-yl)-l-[2-(trimethylsilyl)ethoxy]-
methyl-lH-pyrrolo[2,3-b]pyridine (0.11 g, 0.00027 mol) in THF (1.5 mL, 0.018 mol) was added 1.6
M n-butyllithium in hexane (0.22 mL). The reaction mixture turned dark orange. After ~10 min, 1.0
M magnesium dibromide in ether (0.35 mL) was added. After another 50 min, a solution of 3-ethoxy-
2-cyclohexen-l-one (41.5 L, 0.000308 mol) in THF (-0.3 mL) was added. The resulting mixture
was warmed to -40 °C over ~lh and quenched with NH4CI. Then ethyl acetate/water was added. The
organic phase was washed with brine, and concentrated to give 145 mg of an orange oil. The crude
product was chromatographed with 0-50% ethyl acetate/hexane gradient, sample in DCM. Collected
35 mg of the produce as an oil (30% yield).
1H NMR (400 MHz, CDC13): 5 8.49 (1H, d); 8.38 (1H, s); 7.55 (1H, d); 7.4 (1H, d); 7.1 (1H, d); 6.0
(2H, s); 3.6 (2H, t); 2.81 (2H, m); 2.62 (3H, s); 2.58 (2H, m); 2.27 (2H, m); 1.0 (3H, t); 0.0 (9H, s).
MS (M+H)+: 422.
Step 2. 3-[3-Methyl-l-(l-[2-(trimeihylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-
pyrazol-4-yl] cyclohexanol
A mixture of 3-[3-methyl-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-
yl)-lH-pyrazol-4-yl]cyclohex-2-en-l-one (0.019 g, 0.000045 mol) and palladium on carbon (Pd/C)
(0.018 g, 0.000017 mol) in methanol (2 mL, 0.05 mol) was degassed and was stirred under a
hydrogen atmosphere overnight. An additional 48 mg of 10% Pd/C was added and stirred under a
hydrogen atmosphere for 8h. The palladium was filtered and the filtrate was stirred with sodium
tetrahydroborate (0.032 g, 0.00084 mol) for 5h. The reaction was purified by prep-HPLC to give 5 mg
of the desired product. MS (M+H)+: 426.
Step 3. 3-[3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-cyclohexanol
Deprotection of 3-[3-methyl-l -(1 -[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-
4-yl)-lH-pyrazol-4-yl]cyclohexanol was carried out according to the procedures of Example 14, Step
3 to give the desired product (40% yield).
'H NMR (400 MHz, CDC13): 5 9.72 (1H, s); 8.35 (1H, d); 7.95 (1H, s); 7.41 (1H, d); 7.35 (1H, d);
7.02 (1H, d); 3.78 (1H, m); 2.6 (1H, m); 2.4 (3H, s); 1.2-2.4 (8H, m). MS (M+H)+: 296.

Step 1. 4-[l-(3-Methoxy-l-methylpropyl)-lH-pyrazoJ-4-yl]-l-[2-(trimethylsilyl)ethoxy]-methyl-lH-
pyrrolo[2,3-bJpyridine
To a 0 °C solution of 3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-
yl)-lH-pyrazol-l-yl]butan-l-ol (the alcohol was made by DIBAL reduction of the ester in Example
58) (0.056 g, 0.00014 mol)) in DMF (1 mL, 0.01 mol), was added sodium hydride (0.0107 g,
0.000268 mol). After 5 min, methyl iodide (18 L, 0.00029 mol) was added and the resulting mixture
was stirred over a weekend. The mixture was then partitioned between ethyl acetate and water,
separated and the organic phase was washed with brine. The organic phase was concentrated to give a
pale orange oil.
'H NMR (400 MHz, CDC13): 5 8.4 (1H, d); 8.3 (1H, s); 8.0 (1H, s); 7.65 (1H, d); 7.27 (1H, d); 6.8
(1H, d); 5.8 (2H, s); 4.7 (1H, m); 3.63 (2H, t); 3.2-3.4 (2H, m); 3.38 (3H, s); 2.1-2.3 (2H, m); 1.7 (3H,
d); 1.0 (2H, t); 0.0 (9H, s). MS (M+H)+: 400.
Step 2. 4-[l -(3-Methoxy-l-methyl-propyl)- lH-pyrazol-4-yl]-lH-pyrrolo[2,3-bJpyridine
Deprotection of 4-[l -(3-methoxy-l -methylpropyl)-lH-pyrazol-4-yl]-l -[2-(trimethylsilyl)-
ethoxy]-methyl-lH-pyrrolo[2,3-b]pyridine was carried out according to the procedures of Example
14, Step 3 to give the desired product (25% yield).
'H NMR (400 MHz, CDC13): 5 10.0 (1H, s); 8.35 (1H, d); 8.18 (1H, s); 7.95 (1H, s); 7.41 (1H, d);
7.21 (1H, d); 6.75 (1H, d); 4.63 (1H, m); 3.15-3.4 (2H, m); 3.35 (3H, s); 2.21-2.05 (2H, m); 1.6 (3H,
d). MS (M+H)+: 270.

Step 1. 4-l-[l-Methyl-3-(lH-pyrazol-l-yl)propyl]-lH-pyrazol-4-yl-l-[2-(trimelhylsilyl)ethoxy]methyl-
lH-pyrrolo[2,3-bJpyridine
To a 0 °C solution of 3-[4-(l-[2-(trimethylsayl)ethoxy]methyl-lH-pyiTolo[2,3-b]pyridin-4-
yl)-lH-pyrazol-l-yl]butyl methanesulfonate (prepared by raesylation of the alcohol as in Example 59,
Step 1) (0.055 g, 0.00012 mol) and lH-pyrazole (0.025 g, 0.00036 mol) in DMF (1 mL, 0.01 mol)
was added sodium hydride (0.014 g, 0.00036 mol). The resulting solution was stirred overnight and
then partitioned between ethyl acetate and 0.1 N HC1, water, the organic phase was separated and
washed with brine. The organic layer was then concentrated to give 49 mg of a pale orange glass
(87% yield).
1H MMR (400 MHz, CDCl3): S 8.4 (1H, d); 8.18 (1H, s); 7.99 (1H, s); 7.6 (1H, t); 7.5 (1H, d); 7.4
(1H, t); 7.27 (1H, d); 6.8 (1H, d); 6.3 (1H, m); 5.8 (2H, s); 4.2 (1H, m); 4.0-4.2 (2H, m); 3.61 (2H, t);
2.58 (2H, m); 1.65 (3H, d); 1.0 (2H, t); 0.0 (9H, s). MS (M+H)+: 436.
Step 2. 4-[l-(l-Methyl-3-pyrazol-l-yl-propyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine
Deprotection of 4-l-[l-methyl-3-(lH-pyrazol-l-yl)propyl]-lH-pyrazol-4-yl-l-[2-(trimethyl-
.silyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine was carried out according to the procedures of
Example 14, Step 3 to give the desired product (38% yield).
1H NMR (400 MHz, CDC13): 8 9.7 (IH, s); 8.38 (1H, d); 8.1 (1H, s); 7.7(1H, s); 7.59 (1H, t); 7.4 (1H,
d); 7.35 (1H, t); 7.21 (IH, d); 6.75 (IH, d); 6.25 (IH, m); 4.4 (1H, m); 3.9-4.15 (2H, m); 2.55 (2H, m);
1.63 (3H, d). MS (M+H)+: 306.
The following compounds in Table 1 were made by methods analogous to the procedures
above as indicated. "Purification A" indicates that the product following deprotection was purified by
preparative-HPLC under the following conditions: C18 eluting with a gradient of MeCN/H2O
containing 0.15% NH4OH.

Step 1. 4-(2-tert-butyl-lH-imidazol-5-yl)-l-[2-(tnmetoylsilyl)ethoxy]methyl-IH-pyrrolol2J-
bjpyridine
To a solution of trimethylacetic acid (0.169 mL, 0.00147 mol) in ethanol (6 mL, 0.1 mol) was
added cesium carbonate (0.24 g, 0.00073 mol), and the resulting mixture was stirred for 2 hours. The
solvent was removed in vacuo to afford cesium pivalate.
To a solution of 2-chloro-l-(l-[2-(trimethylsiIyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-
yl)ethanone (prepared, e.g., as in Ex. 50, Step 1) (0.054 g, 0.00017 mol) in DMF (1.8 mL, 0.023 mol)
was added cesium pivalate (0.0389 g, 0.000166 mol) and the reaction was stirred at room temperature
for 16 hours. Ammonium acetate (0.45 g, 0.0058 mol) was added, and the reaction was heated in the
microwave to 170 °C for 5 minutes. Water was added and the product was extracted with MTBE. The
combined organic extracts were dried over sodium sulfate, then filtered and concentrated. The crude
residue was purified by flash column chromatography (2.5% MeOH/DCM) to yield 4-(2-tert-butyl-
lH-imidazol-5-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (32 mg, 52%). 'H
NMR (400 MHz, CDC13): § 8.31 (d, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 7.37 (d, 1H), 6.94 (d, 1H), 5.69
(s, 2H), 3.52 (dd, 2H), 1.46 (s, 9H), 0.90 (dd, 2H), -0.08 (s, 9H); MS(ES):371(M+1).

Step 2. 4-(2-tert-butyl-l-methyl-lH-imidazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo-
[2,3-bJpyridine
To a mixture of 4-(2-tert-butyl-lH-imidazol-5-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-
pyrrolo[2,3-b]pyridine (0.019 g, 0.000051 mol) and potassium carbonate (0.15 g, 0.0011 mol) in
DMF (3 mL, 0.04 mol) was added methyl iodide (0.01 mL, 0.00015 mol) in two portions over 48
hours. Water was then added and the product was extracted with MTBE. The combined extracts were
dried with sodium sulfate, filtered, and concentrated in vacuo, then purified by silica gel
chromatography (20% ethyl acetate/hexanes) to afford 4-(2-tert-butyl-l-methyl-lH-imidazol-4-yl)-l-
[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (10 mg, 51%).
1H NMR (400 MHz, CDC13): § 8.37 (d, 1H), 7.54 (d, 1H), 7.44-7.22 (m, 2H), 7.19 (d, 1H), 5.78 (s,
2H), 3.93 (s, 3H), 3.60 (dd, 2H), 1.61 (s, 9H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):385(M+1).
Step 3.
A solution of . 4-(2-tert-butyl-l-methyl-lH-imidazol-4-yl)-l-[2-(trimethylsilyl)-ethoxy]-
methyl-lH-pyrrolo[2,3-b]pyridine (0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2
hours. Then the excess TFA was evaporated and the residue was stirred in methanol (3 mL, 0.07 mol)
and NH4OH (1 mL) for 16 hours. The solvents were removed and the product was purified by
preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-(2-
tert-butyl-l-methyl-lH-imidazol-4-yl)-lH-pyrrolo[2,3-b]pyridine, trifluoroacetate salt (9 mg, 90%).
'H NMR (400 MHz, de-DMSO): § 12.24 (s, 1H), 8.38 (br s, 1H), 8.24 (s, 1H), 7.70-7.63 (m, 2H), 7.08
(br s, 1H), 2.55 (s, 3H), 1.51 (s, 9H); MS(ES):255(M+1).
Additional analogs were prepared as shown in Table 2 using analogous procedures to those
described in Example 46 with different starting materials such as alternative carboxylic acids in Step
1. When the analogs were obtained as the free base, the product was obtained by preparative-HPLC
(Cl 8 eluting with a gradient of ACN/H2O containing 0.15% NH4OH). The results are summarized in

Step 1. 2-Chloro-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)ethanone
To a solution of 4-bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (2.05
g, 0.00626 mol) in THF (10 mL, 0.123 mol) at 0 °C was added dropwise a solution of
isopropylmagnesium chloride in ether (2.0 M, 9.4 mL). The mixture was allowed to warm to room
temperature and stirred for 4 hours. This mixture was then transferred via cannula to a solution of 2-
chloro-N-methoxy-N-methylacetamide (2.84 g, 0.0207 mol) in THF (10 ml). After 30 minutes
reaction time, the solution was quenched by the addition of saturated ammonium chloride aqueous
solution. The product was extracted with ethyl acetate, the combined organic extracts were washed
with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash
column chromatography (0-20% ethyl acetate/hexanes) to afford 2-chloro-l-(l-[2-(trimethylsilyl)-
ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)ethanone (711 mg, 35%). 1H NMR (400 MHz, CDC13):
5 8.56 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H), 0.98
(dd, 2H), 0.01 (s, 9H); MS(ES):325(M+1).
Step 2. 4-(2-Phenyl-l,3-thiazol-4-yl)-lH-pyrrolo[2,3-b]pyridine trifluoroacetate salt
A solution of 2-chloro-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridbi-4-yl)-
ethanone (0.050 g, 0.00015 mol) and benzenecarbothioamide (0.031 g, 0.00022 mol) in ethanol (2
mL, 0.03 mol) was heated to reflux for I hour. The solvent was removed in vacuo. Ethyl acetate was
added, and the resulting solid was isolated by filtration. The crude solid was stirred with TFA for 1
hour, then excess TFA was removed in vacuo. The crude residue was then stirred with aq. NH4OH
and MeOH for 16 hours. The solvent was removed and the product was purified by preparative-HPLC
(C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-(2-phenyl-l,3-thiazol-4-

yl)-lH-pyrrolo[2,3-b]pyridine as the trifluoroacetate salt (11 mg, 18%). 'H NMR (400 MHz, d6-
DMSO): q 12.01 (s, 1H), 8.58 (s, 1H), 8.39 (br s, 1H), 8.13-8.07 (m, 2H), 7.81 (d, 1H), 7.67-7.64 (m,
1H), 7.62-7.52 (m, 3H), 7.22 (d, 1H); MS(ES):278(M+1).

Step 1. N-Methyl-N-propylthiourea
N-Methyl-N-propylamine (0.501 mL, 0.00488 mol) was added to a solution of 1,1'-
thiocarbonyldiimidazole (0.957 g, 0.00537 mol) in THF (9 mL, 0.1 mol), and the resulting solution
was stirred for 16 hours. The intermediate from the reaction mixture was isolated by silica gel
chromatography (5% MeOH in DCM) and this intermediate was stirred with ammonia (7M solution
in MeOH) (6 mL) for 48 hours. The solvent was removed in vacua. N-methyl-N-propylthiourea was
obtained after flash column chromatography (4% MeOH in DCM).
Step 2.
A solution of 2-chloro-l-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-
ethanone (0.050 g, 0.00015 mol) and N-methyl-N-propylthiourea (0.030 g, 0.00022 mol) in ethanol (2
mL, 0.03 mol) was heated to reflux for 2 hours. Then, the ethanol was removed in vacuo and the
residue was dissolved in 2 mL TFA and stirred for 40 minutes. The excess TFA was removed in
vacuo and the residue was dissolved in 3 mL of MeOH. To this was added 0.5 mL of NH4OH and 100
uL of ethylenediamine, and the resulting solution was stirred for 16 hours. Solvent was removed, then
water was added to give a white precipitate which was purified by preparative-HPLC (C18 eluting
with a gradient of ACN/H2O containing 0.1% TFA) to afford N-methyl-N-propyl-4-(lH-pyrrolo[2,3-
b]pyridin-4-yl)-l,3-thiazol-2-amine as the trifluoroacetate salt (39 mg, 67%). *H NMR (300 MHz,
CD3OD): § 8.46-8.12 (br s, 1H), 7.92 (br s, 1H), 7.72 (s, 1H), 7.63 (d, 1H), 7.45 (br s, 1H), 3.56 (t,
2H), 3.20 (s, 3H), 1.78 (dq, 2H), 1.00 (t, 3H); MS(ES):273(M+1).
Additional aminothiazole analogs were prepared by procedures analogous to those described
in Example 51, using different starting materials such as alternative thioureas in Step 2. In Examples
52 and 53, the white precipitate obtained by the procedure of Example 51 was isolated by filtration,

washed with water and dried under high vacuum to afford the analogs as the free amine. The results
are summarized in Table 3 according to the following structure:

Step 1. (2-Phenyl-l,3-thiazol-5-yl)boronic acid
To a solution of n-butyllithium in hexane (1.6 M, 2.1 mL) in ether (20 mL) at -78 °C, a
solution of 2-phenyl-l,3-thiazole (449 mg, 0.00278 mol) in ether (5 mL) was added dropwise. The
mixture was stirred for one hour at -78 °C followed by the addition of boric acid trimethyl ester (0.949
mL, 0.00835 mol). The mixture was stirred at -78 °C for 15 minutes, then was allowed to warm to
room temperature and stirred for an additional 40 minutes. Saturated NH4CI aqueous solution was
added, followed by 1.0 N aqueous HC1. The acidified mixture was stirred for 15 minutes, and the
desired product was extracted with four portions of DCM containing 15% isopropanol. The combined
organic extracts were dried over sodium sulfate and concentrated to give 566 mg of a white solid
containing the desired (2-phenyl-l,3-thiazol-5-yl)boronic acid as a mixture with 2-phenyl-l ,3-
thiazole. This mixture was used in Step 2 without further purification. MS(ES):206(M+l).

Step 2.
To a mixture of (2-phenyl-l,3-thiazol-5-yl)boronic acid (75.0 mg, 0.000366 mol) and 4-
bromo-l-[2-(trimethyIsilyl)ethoxy]methyl-lH-pynrolo[2,3-b]pyridine (80 mg, 0.000244 mol) in DMF
(4 mL, 0.0516 mol) was added a solution of potassium carbonate (101 mg, 0.000732 mol) in water (1
mL, 0.0555 mol). The mixture was purged with a steady stream of nitrogen for 15 minutes.
Tetrakis(triphenylphospbine)palladium(0) (20 mg, 0,000018 mol) was added and the resulting
mixture was heated to 125 °C for 30 minutes. The product was purified by preparative-HPLC (C18
eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 12 mg of a yellow solid
containing the desired product as the major component. The mixture was stirred in TFA (1 mL) for 1
hour. Then excess TFA was removed in vacuo and the resulting residue was stirred with 2 mL MeOH,
0.5 mL NH4OH and 100 uL ethylenediamine for 16 hours. The product was isolated by preparative-
HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-(2-phenyl-l ,3-
thiazol-5-yl)-lH-pyrrolo[2,3-b]pyridine trifluoroacetate salt (5 mg, 5%). 1H NMR (400 MHz,
CD3OD): 5 8.64 (s, 1H), 8.34 (d, 1H), 8.10-8.04 (m, 2H), 7.73 (d, 1H), 7.71 (d, 1H), 7.56-7.51 (m,
3H), 7.14 (d, 1H); MS(ES):278(M+1).

4-(lH-Pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pvridine (60 mg,
0.00019 mol) was dissolved in DMF (1.5 mL), and the solution was cooled to 0 °C with a cold bath.
Sodium hydride (15 mg, 0.00038 mol) was added. After stirring for 10 min, 2-bromo-2-methyl-
propanoic acid ethyl ester (42 L, 0.00028 mol) was added. The cold bath was then removed and the
reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was
quenched with saturated ammonium chloride solution. More water was added, and the product was
extracted with MTBE. The combined extracts were dried over sodium sulfate, filtered and
concentrated. The residue was dissolved in 2 mL TFA and stirred for 1 h. Then excess TFA was
removed in vacuo and the resulting residue was stirred in 2 mL EtOH containing 0.6 mL NH4OH
solution for 16 hours. Volatiles were removed, and purification of the mixture was carried out via
preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) afforded ethyl 2-

methyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yI]propanoate trifluoroacetate salt (13 mg,
17%): 'HNMR (300 MHz, dVDMSO): 5 12.03 (s, 1H), 8.67 (s, 1H), 8.31-8.19 (m, 2H), 7.59 (t, 1H),
7.48 (d, 1H), 6.98 (br s, 1H), 4.10 (q, 2H), 1.84 (s, 6H), 1.12 (t, 3H); MS(ES):299(M+1) and 2-
methyl-2-[4-(lH-pyrrolot2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanoic acid (27 mg, 53%): 'H NMR
(300 MHz, de-DMSO): 5 12.04 (s, 1H), 8.64 (s, 1H), 8.26 (s, 2H), 7.59 (br s, 1H), 7.48 (d, 1H), 6.99
(br s, 1H), 1.83 (s, 6H); MS(ES):271(M+H).

A mixture of 2-methyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanoic acid
(23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CD1) (21 mg, 0.00013 mol) in 2 mL of DMF
was stirred for 3 hours. An excess of solid NH4CI and TEA was added to the mixture and this was
stirred for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified
by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) followed by
re-purification via preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15%
NH4OH) to afford 2-methyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanamide (6
mg, 26%). 'H NMR (400 MHz, d6-DMSO): § 11.63 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H),
7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS(ES):270(M+l).

4-(lH-Pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (220 mg,
0.0006996 mol) and 3-methyl-2-butenoic acid ethyl ester (292 L, 0.00210 mol) were dissolved in
DMF (10 mL). Cesium carbonate (912 mg, 0.00280 mol) was added and the resulting mixture was
stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the product
was extracted with MTBE several times. The combined extracts were dried over sodium sulfate and
concentrated. The crude residue was purified by flash column chromatography (0-60%
EtOAc/Hexanes) to afford ethyl 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2>3-
b]pyridin-4-yl)-lH-pyrazol-l-yl]butanoate (244 mg, 79%). 1H NMR (300 MHz, CDCl3): §8.37 (d,
1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H),
3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):443(M+1).
Step 2.
Ethyl 3-meAyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-
pyrazol-l-yl]butanoate (20 mg, 0.0000452 mol) was stirred in 1 mL TFA for 1 hour. Then excess
TFA was removed in vacuo. The residue was stirred for 16 hours in 2 mL MeOH containing 0.5 mL
NH4OH. Evaporation of the volatiles was followed by purification by preparative-HPLC (C18 eluting
with a gradient of ACN/H2O containing 0.1% TFA) to afford ethyl 3-methyl-3-[4-(lH-pyrrolo[2,3-b]-
pyridin-4-yl)-lH-pyrazol-l-yl]butanoate, trifluoroacetate salt (5 mg, 26%). 1H NMR (400 MHz, d6-
DMSO): § 12.19 (s, 1H), 8.61 (br s, 1H), 8.34-8.22 (br m, 2H), 7.62 (br s, 1H), 7.51 (br d, 1H), 7.02
(br s, 1H), 3.91 (q, 2H), 2.96 (s, 2H), 1.70 (s, 6H), 1.02 (t, 3H); MS(ES):313(M+1).

To a solution of ethyl 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]-
pyridin-4-yl)-lH-pyrazol-l-yl]butanoate (213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at
-78 °C was added diisobutylaluminum hydride in DCM (1.00 M, 1.1 mL) dropwise. The reaction
mixture was stirred for 3 hours during which time the reaction slowly wanned to -10 °C. To the
mixture at -10 °C was carefully added K/Na tartrate tetrahydrate in water. The mixture was stirred for
2 hours, then was extracted with three portions of ethyl acetate. The combined organic extracts were
washed with two portions of water and one portion of brine, then dried over sodium sulfate, filtered

and concentrated to afford 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]-
pyridin-4-yl)-lH-pyrazol-l-yl]butan-l-ol (185 mg, 96%), which was used without further
purification. A portion of the alcohol so obtained (15 mg, 0.000037 tnol) was stirred in TFA (1 mL)
for 2 hours. The TFA was removed in vacuo and the residue was stirred with 2 mL MeOH containing
0.5 mL NH4OH for 16 hours. Volatiles were removed and the product was purified by preparative-
HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 3-methyl-3-[4-(lH-
pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butan-l-ol as the trifluoroacetate salt (8.0 mg, 57%). 'H
NMR (300 MHz, de-DMSO): § 12.17 (s, 1H), 8.58 (br s, 1H), 8.32-8.22 (br m, 2H), 7.62 (br s, 1H),
7.53 (br d, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 2H), 1.62 (s, 6H); MS(ES):271(M+1).

Step 1. 4-Methyl-4-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-
pyrazol-1 -yljpentanenitrile
TEA (38.0 L, 0.000273 mol) and methanesulfonyl chloride (21.1 L, 0.000273 mol) were
added sequentially to a solution of 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-
b]pyridin-4-yl)-lH-pyrazol-l-yl]butan-l-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in
DCM (4 mL, 0.05 mol) at 0° C. The reaction mixture was held at this temperature for 1.5 hours, then
was quenched by the addition of water. The reaction mixture was extracted with DCM four times. The
combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude 3-methyl-
3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butyl
methanesulfonate (87 mg). MS(ES):479(M+1).
A mixture of 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-
yl)-lH-pyrazol-l-yl]butyl methanesulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg,
0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30 min at 125 °C followed by
additional 30 min at 135 °C. The mixture was then diluted with water, and the product was extracted
with three portions of MTBE. The combined extracts were dried over sodium sulfate, filtered and
concentrated to give 61 mg of crude 4-methyl-4-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo-
[2,3-b]pyridin-4-yl)-lH-pvrazol-l-yl]pentanenitrile, which was used without further purification.
MS(ES):410(M+l).

Step 2.
4-MethyM-[4-(l-[2-(1ximethylsilyl)ethoxy]methyl-lH-pyirolo[2,3-b]pyridin-4-yl)-lH-
pyrazol-l-yl]pentanenitrile (57 mg, 0.00014 mol) was stirred in DCM (4 ml) and TFA (1 mL) for 2
hours. The solvents were removed in vacuo and the residue was stirred in 2 mL MeOH containing 0.2
mL ethylenediamine for 16 hours. The volatiles were evaporated and the product was isolated from ....
the reaction mixture by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1%
TFA) affording 4-methyl-4-[4-(lH-pyrrolo[2]3-b]pyridin-4-yl)-lH-pyrazol-l-yl]pentanenitri]e as the
trifluoroacetate salt (10 mg, 18%). 1HNMR (400 MHz, ds-DMSO): 5. 12.09 (s, 1H), 8.58 (s, 1H), 8.29
(s, 1H), 8.25 (d, 1H), 7.60 (t, 1H), 7.48 (d, 1H), 7.00 (br s, 1H), 2.33-2.21 (m, 4H), 1.61 (s, 6H);
MS(ES):280(M+l).

The crude 4-methyl-4-[4-(l-[2-(trimethylsilyl)ethoxylmethyl-lH-pyrrolo[23-b]pyridin-4-yl)-
lH-pyrazol-l-yl]pentanenitrile (36 mg, 0.000088 mol, see preparation in Example 59), was stirred in
TFA (2 mL) for 1 hour. The mixture was concentrated to remove excess TFA, and the resulting
residue was stirred in 2 mL methanol containing 0.5 mL NH4OH for 16 hours. The product was
purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to
afford 4-methyl-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pvrazol-l-yl]pentanamide as the trifluoro-
acetate salt (21 mg, 58%). lH NMR (400 MHz, da-DMSO): 5 12.18 (s, 1H), 8.60 (s, 1H), 8.33-8.21
(m, 2H), 7.62 (br s, 1H), 7.53 (d, 1H), 7.22 (br s, 1H), 7.04 (br s, 1H), 6.71 (br s, 1H), 2.14-2.07 (m,
2H), 1.86-1.79 (m, 2H), 1.58 (s, 6H); MS(ES):298(M+1).
Example 61: (3S)-3-[4-(lH-PyrroIo[2r3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile trifluoro-
acetate salt,
AND
(3R)-3-[4-(lH-Pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile trifluoroacetate salt

To a solution of 4-(lH-pyrazoI-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolot2,3-
b]pyridine (0.050 g, 0.00016 mol) in ACN were added 2-butenenitrile (0.014 mL, 0.00017 mol) and
DBU (0.029 mL, 0.00020 mol). The resulting mixture was stirred for 16 hours. Then the volatiles
were evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed
successively with 1.0 N HC1, water, and brine, then was dried over sodium sulfate, filtered and
concentrated. To obtain the enantiomers in substantially pure form, Method A (vide infra) was used.
The crude residue was dissolved in TFA (7 mL, 0.09 mol) and the solution was stirred for 1
hour. Then excess TFA was evaporated and the residue was then stirred with ethylenediamine (0.1
mL, 0.001 mol) in methanol (4 mL, 0.09 mol) for 16 hours. The mixture was concentrated, and the
product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1%
TFA) to afford 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile trifluoroacetate
salt (35 mg, 61%). 'H NMR (300 MHz, d6-DMSO): 8 12.16 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 8.28
(d, 1H), 7.65-7.61 (m, 1H), 7.48 (d, 1H), 6.99 (d, 1H), 4.86 (q, 1H), 3.17 (d, 2H), 1.57 (d, 3H);
MS(ES):252(M+1).
Additional analogs were prepared by procedures analogous to those described in Example 61
using different starting materials for alleviation of the pyrazole ring. For example, the ,-unsaturated
nitriles were prepared by procedures analogous to the following, illustrated for (2E)- and (2Z)-
hexenenitrile: To a solution of 1.00 M potassium tert-butoxide in THF at 0 °C (24.2 mL) was added a
solution of diethyl cyanomethylphosphonate (4.10 mL, 0.025 mol) in THF (30 mL) dropwise. The
bath was removed and the solution was allowed to warm to room temperature. After reaching room
temperature, the solution was re-cooled to 0° C and a solution of butanal (2.00 mL, 0.023 mol) in
THF (7 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature
and stir overnight. The mixture was diluted with ethyl acetate and water. The layers were separated
and the aqueous layer was extracted with three portions of ethyl acetate. The combined organic
extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. This afforded
1.6 g of a crude mixture containing both (2E)- and (2Z)-hexenenitrile, which was used without further
purification in the subsequent alkylation step. 1H NMR (400 MHz, CDC13): § 6.72 (dt, 1H trans
olefin), 6.48 (dt, 1H cis olefin), 5.34 (dt, 1H trans olefin), 5.31-5.30 (m, 1H cis olefm).
Where it was desirable to obtain the enantiomers in substantially pure form, chiral separation
was performed by one of the following methods:

A) The separation was performed on the SEM-protected intermediate after silica gel
chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with
15% ethanol in hexanes);
B) The separation was performed on the deprotected free base by preparative chiral HPLC
(OD-H column, eluting with 15% ethanol in hexanes);
C) The separation was performed on the SEM-protected intermediate after silica gel
chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with
10% ethanol in hexanes);
D) The separation was performed on the SEM-protected intermediate after silica gel
chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with
15% ethanol in hexanes);
E) The separation was performed on the SEM-protected intermediate after silica gel
chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with
20% ethanol in hexanes; or
F) The separation was performed on the SEM-protected intermediate after silica gel
chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with
30% ethanol in hexanes. An OD-H column refers to Chiralcel OD-H from Chiral Technologies, Inc
3x25 cm, 5 m. An AD-H column refers to ChiralPak AD-H from Chiral Technologies, Inc. 2x25
cm, 5 m. The results are summarized for compounds in Table 4 below.

Step 1. 4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine
To a solution of 4-chloropyrrolo[2,3-d]pyrimidine (0.86 g, 0.0056 mol) in DMF (20 mL, 0.2
mol) at 0 °C was added sodium hydride (0.27 g, 0.0067 mol) in several portions. The reaction mixture
was stirred for an additional 45 minutes followed by a dropwise addition of -(trimethylsilyl)ethoxy]-
methyl chloride (1.2 mL, 0.0067 mol). The resulting reaction mixture was stirred at 0 °C for 45 min,
then was quenched with water and extracted with ethyl acetate. The organic extract was washed with
water, brine, dried over sodium sulfate, filtered and concentrated to give an oil. The crude residue was
purified by flash column chromatography (0-15% ethyl acetate/hexanes) to yield 4-chloro-7-[2-
(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pvrimidine (1.40 g, 88%).
1HNMR (400 MHz, CDC13): § 8.71 (s, 1H), 7.46 (d, 1H), 6.72 (d, 1H), 5.71 (s, 2H), 3.59 (dd, 2H),
0.97 (dd, 2H), 0.00 (s, 9H); MS(ES):284(M+1).
Step 2. 4-(lH-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine
To a mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine
(1.4 g, 0.0049 mol) and 4-(4>4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.4 g, 0.0074

mol) in DMF (40 mL} 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water.
The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(triphenyl-
phosphine)palladium(O) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125 °C for 30
min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture
was washed with water, brine, dried over Na2SO4 and concentrated to give a solution in a small
volume of DMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of
the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was
dried over Na2SO4, and concentrated in vacuo to afford a yellow solid. The product was triturated
with ethyl ether to yield 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[233-
d]pyrimidine as a white powder which was dried under vacuum (lg, 60%). 1H NMR (300 MHz,
CDC13): 5 10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61
(dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):316(M+1).
Step 3.
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidine (0.050 g, 0.00016 mol) in ACN (1 mL, 0.02 mol) was added hex-2-enenitrile (0.100 g,
0.00105 mol) (as a mixture of cis and trans isomers), followed by DBU(60 L, 0.0004 mol). The
resulting mixture was stirred at room temperature for 16 hours. The ACN was removed in vacuo. The
crude residue was dissolved in ethyl acetate, and was washed with 1.0 N HC1, brine, dried over
Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (0-70%
EtOAc/Hexane) to afford 56 mg of product, which was stirred with 1:1 TFA/DCM for 1 hour and the
solvents were evaporated. The resulting product was stirred with methanol (4 mL, 0.1 raol) containing
ethylenediamine (0.1 mL, 0.001 mol) overnight. The solvent was evaporated and the product was
purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to
afford 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]hexanenitrile as the trifluroacetate
salt. Where desired, the enantiomers were isolated in substantially pure form by Method A described
above for Example 61. 'H NMR (300 MHz, CD3OD): 8 8.93 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.85
(d, 1H), 7.28 (d, 1H), 4.87-4.77 (m, 1H), 3.26-3.05 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.86 (m, 1H),
1.40-1.10 (m, 2H), 0.95 (t, 3H); MS(ES):281(M+1).
Example 67: (3R-) and (3S)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-
1 -yl|propanenitrile

step i. (2E)- ana (22)-3-Cyclopentylacrylonitnle
To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0 °C was added dropwise
a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath
was removed and the reaction was warmed to room temperature followed by recooling to 0 °C, at
which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added
dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64
hours. The mixture was partitioned between diethyl ether and water, the aqueous was extracted with
three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washed
with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture
containing 24.4 g of olefin isomers which was used without further purification (89%).
1H NMR (400 MHz, CDC13): 8 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans
olefin), 5.20 (d, 1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98-
1.26 (m, 16H).
Step 2. (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethyIsilyl)ethoxy]methyl-7H-pyiTolo[2,3-d]-
pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added 3-cyclopentylacrylonitrile (15 g, 0.12
mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting
mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was
diluted with ethyl acetate, and the solution was washed with 1.0 N HC1. The organic layer was back-
extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine,
dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel
chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was
dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic
adduct (93%). The enantiomers were separated by preparative-HPLC, (OD-H, 15% ethanol/hexanes)
and used separately in the next step to generate their corresponding final product. The final products
(see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors;
however, the final product stemming from the second peak to elute from the preparative-HPLC was
more active than its enantiomer.

1H NMR (300 MHz, CDC13): 5 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H),
4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H), 1.80-
1.15 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):437 (M+l).
Step 3.
To a solution of 3-cycIopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated
above) in DCM (40 mL) was added TFA (16 mL) and this was stirred for 6 hours. The solvent and
TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary
evaporator two further times to remove as much as possible of the TFA. Following this, the residue
was stirred with ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. The solvent was
removed in vacuo, water was added and the product was extracted into three portions of ethyl acetate.
The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated
to afford the crude product which was purified by flash column chromatography (eluting with a
gradient of methanol/DCM). The resulting mixture was further purified by preparative-HPLC/MS
(C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford product (2.68 g, 58%).
1H NMR (400 MHz, D6-dmso): 5 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d,
1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36 (m, 1H), 1.86-1.76 (m, 1H),
1.68-1.13 (m, 7H); MS(ES):307(M+l).
Additional analogs provided in the following Tables were prepared by procedures analogous
to those described in, for example, Examples 61 and 65, using different starting materials such as
different ,-unsaturated nitriles in Step 3. Isolation of the enantiomers in substantially pure form
was achieved by the indicated chiral separation method described above (A-F) preceding Table 4.
Where the product was isolated as the free amine, the product following deprotection was purified by
preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) instead of
preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA). This is referred
to as "modification G". The results are summarized in Table 5 according to the following structure:

A solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyirolo[2,3-d]-
pyrimidine (0.050 g, 0.00016 mol) in DMF (2 mL, 0.02 mol) was cooled in an ice bath and to this was
added sodium hydride (0.013 g, 0.00032 mol). The resulting mixture was stirred for 10 minutes,
followed by an addition of 2-bromopentane (0.030 mL, 0.00024 mol). The cooling bath was then
removed and the reaction was stirred at room temperature for 3 hours, at which time a further portion
of 2-bromopentane (0.015 mL, 0.00012 mol) was added. After 45 minutes, water was added and the
reaction mixture was extracted with three portions of ethyl acetate. The combined extracts were
washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was stirred with
TFA (3 mL, 0.04 mol) and DCM (3 mL, 0.05 mol) for 3.5 hours, then the solvent was removed in
vacuo. The residue was then stirred with NH4OH (1.5 mL) in MeOH (4 mL) for 16 hours. The solvent
was evaporated and the product was purified by preparative-HPLC (C18 eluting with a gradient of
ACN/H2O containing 0.1% TFA) to afford 4-[l-(l-methylbutyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-
d]pyrimidine as the trifluoroacetate salt (25 mg, 44%). 'H NMR (300 MHz, CD3OD): 5 8.83 (s, 1H),
8.75 (s, 1H), 8.43 (s, 1H), 7.77 (d, 1H), 7.24 (d, 1H), 4.63-4.50 (m, 1H), 2.07-1.91 (m, 1H), 1.88-1.74
(m, 1H), 1.58 (d, 3H), 1.38-1.09 (m, 2H), 0.93 (t, 3H); MS(ES):256(M+1).
Isolation of the enantiomers in substantially pure form was achieved by separation of the
racemic free base (isolated by flash column chromatography after deprotection, eluting with a
MeOH/DCM gradient) using HPLC (OD-H, eluting with 5% isopropanol/hexanes).

Step 1. Ethyl 3-methy!-3-f4-(7-f2-(trimethylsilyl)etho^Jmethyl-7H-pyrrolof2,3d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]butanoate
A solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (12.1 g, 0.0384 mol), 2-butenoic acid, 3-methyl-, ethyl ester (16.0 mL, 0.115 mol) and
DBU (14.3 mL, 0.0959 mol) in ACN (100 mL) was heated at reflux for 3.5 hours. The solvent was

removed in vacuo. The residue was diluted with water, extracted with ethyl acetate, and the combined
organic extracts were washed with saturated-ammonium chloride, dried over sodium sulfate, and
concentrated. The crude residue was purified by flash column chromatography (ethyl acetate/hexanes)
to yield the desired product (15.5 g, 91%).
1H NMR (400 MHz, CDC13): 5. 8.83 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 7.37 (d, 1H), 6.80 (d, 1H),
5.66 (s, 2H), 4.03 (q, 2H), 3.54 (dd, 2H), 2.98 (s, 2H), 1.80 (s, 6H), 1.13 (t, 3H), 0.91 (dd, 2H), -0.07
(s, 9H); MS(ES):444(M+1).
Step 2. 3-Methyl-3-[4-(7-[2-(trimelhylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]butan-l-ol
To a solution of ethyl 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]butanoate (15.4 g, 0.0347 mol) in THF (151 mL) at -78 °C was
added 1.00 M diisobutylaluminum hydride in DCM (84.5 mL) dropwise. The reaction was stirred for
2 hours with slow wanning to -10 0C. The mixture was quenched with water, then was treated with
potassium sodium tartrate tetrahydrate and water. The mixture was stirred for 1 hour, then was
extracted with ethyl acetate. The extracts were washed with water and brine, then dried with sodium
sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column
chromatography to yield the desired product (13.8 g, 99%).
'H NMR (300 MHz, CDC13): 8 8.83 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.38 (d, 1H), 6.80 (d, 1H),
5.67 (s, 2H), 3.65 (dd, 2H), 3.54 (dd, 2H), 2.21 (t, 2H), 1.72 (s, 6H), 0.91 (dd, 2H), -0.07 (s, 9H);
MS(ES):402(M+l).
Step 3. 3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butan-l-ol
A solution of 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrTolo[2,3-d]pyrimidin-
4-yl)-lH-pyrazol-l-yl]butan-l-ol (13.8 g, 0.0344 mol) in TFA (20 mL) was stirred for 1 hour. The
mixture was then concentrated in vacuo and the residue was stirred for 2 hours in a mixture of
methanol (30 mL), ammonium hydroxide (30 mL), and ethylenediamine (8 mL). The mixture was
then concentrated, and the residue was diluted with water and extracted with several portions of 15%
IPA/CH2CI2. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give
20 g of white solid. The solid was triturated with ether and the product was isolated by filtration to
give the product as a white solid (7.75 g, 83%).
'H NMR (400 MHz, CDC13): 5. 9.99 (s, 1H), 8.83 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.38 (dd, 1H),
6.80 (dd, 1H), 3.66 (t, 2H), 2.72 (br s, 1H), 2.22 (t, 2H), 1.74 (s, 6H); MS(ES):272(M+1).
Step 4. 3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-I-ylJbutyl methanesulfonate

A solution of 3-methyl-3-[4-(7H-pyrroIo[2J3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]butan-l-ol
(6.61 g, 0.0244 mol) in DCM (300 mL) at 0 °C was treated with TEA (3.74 mL, 0.0268 mol),
followed by methanesulfonyl chloride (2.07 mL, 0.0268 mol). The reaction was stirred for 1 hour,
and was then concentrated in vacuo. The crude residue was purified by flash column chromatography
to afford the desired product (4.9 g, 57%).
1H NMR (400 MHz, ds-dmso): 5. 12.45 (s, 1H), 9.50 (s, 1H), 9.35 (s, !H), 8.83 (s, 1H), 7.79 (dd, 1H),
7.11 (dd, 1H), 4.75 (t, 1H), 3.30 (s, 3H), 2.85 (t, 1H), 1.75 (s, 6H); MS(ES):254(M-CH3SO3H+1).
Step 5: 4-Methyl-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile
3-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]butyl methanesulfonate
(2.97 g, 8.50 mmol), DMF (120 mL) and sodium cyanide (6.21 g, 0.127 mol) were distributed
evenly into six 20 mL microwavable vessels, each of which was heated in the microwave reactor for
4000 seconds at 125 °C. The contents of the vials were combined and were diluted with 400 mL water
and extracted with five 150 mL portions of ethyl acetate. The combined extracts were dried over
sodium sulfate, and the solvent was removed in vacuo. The crude residue was purified by flash
column chromatography to yield the desired product (1.40 g, 59%).
'H NMR (400 MHz, CDC13): 6 9.52 (br s, 1H), 8.83 (s, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 7.39 (dd, 1H),
6.81 (dd, 1H), 2.38 (dd, 2H), 2.16 (dd, 2H), 1.73 (s, 6H); MS(ES):281(M+1).
The analogs in Table 5a were prepared according to the above method described for Example
69a. For Example 69b, a conjugate acceptor was used and prepared as described in Perkin Trans. 1,
2000, (77), 2968-2976, and Steps 4&5 were performed before Step 3.

Step 1. Senecionitrile
To a solution of 1.0 M potassium tert-butoxide in THF (2.0 mL) at 0 °C was added a solution
of diethyl cyanomethylphosphonate (0.33 mL, 2.06 mmol) in THF (4 mL) dropwise. The cold bath
was removed and the reaction was wanned to room temperature. The reaction was then re-cooled to
0 °C and acetone (0.20 mL, 2.81 mmol) was added dropwise. The cooling bath was then removed and
the reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted
with water, the layers separated, and the aqueous extracted with ethyl acetate. The extracts were
washed with brine, dried over sodium sulfate, filtered and concentrated. The product was used without
further purification (339 mg, 67%).
1H NMR (300 MHz, CDC13): 5. 5.10 (br s, 1H), 2.05 (s, 3H), 1.92 (s, 3H).
Step 2. 3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljbutanenitrile
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]niethyl-7H-pvrrolo[2,3-d]-
pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g,
1.37 mmol), followed by DBU (200 L, 0.002 mol) and the resulting mixture was heated to 60 °C for
23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture
was diluted with ethyl acetate and washed with dilute HC1 and brine. The organic solution was dried
over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl
acetate/hexanes) afforded the desired product.
'H NMR (300 MHz, d6-dmso): 5 8.83 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H),
5.66 (s, 2H), 3.54 (dd, 2H), 3.08 (s, 2H), 1.84 (s, 6H), 0.91 (dd, 2H), -0.07 (s, 9H);
MS(ES):397(M+1).
To a solution of this product in DCM at 0 °C was added TFA sufficient to comprise 20% of
the total volume. The solution was stirred at this temperature for 30 min, then at ambient temperature
for 2 hours and 15 minutes. The solvents were removed in vacuo and the residue was stirred with
methanol (10 mL) and ethylenediamine (0.4 mL, 0.006 mol) overnight. The solvent was evaporated

arid the product was purified by preparative-HPLCAMS (C18 column eluting with a gradient of
ACN/H2O containing 0.15% MH4OH) to afford the product (25 mg, 14%).
1HNMR (300 MHz, ds-dmso): $ 12.08 (s, 1H), 8.68 (s, 2H), 8.39 (s, 1H), 7.59 (d, 1H), 7.05 (d, 1H),
3.32 (s, 2H), 1.73 (s, 6H); MS(ES):267(M+1).
Examples 69e and 69f in Table 5b were prepared by a method analogous to that described
above for Example 69d, with unsaturated nitriles prepared either according to published literature
procedures, or by the method in Step 1.

Additional analogs were prepared by procedures analogous to those described in Example 69,
using different starting materials such as alternative bromide or mesylate compounds for the
nucleophilic substitution step. Where the free amine was obtained as the product, the product was
purified after deprotection either by silica gel chromatography (eluting with 5% methanol in DCM) or
by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH). The
results are summarized for compounds listed in Table 6.

Step 1. 3-Cyclopentylprop-2-ynenitrile
To a solution of cyclopentylacetylene (0.50 g, 5.3 mmol) in THF (5 mL) at -78 °C was added
2.5 M n-butyllithium in hexane (2.23 mL). The mixture was stirred for 15 min followed by the
dropwise addition of phenyl cyanate (0.70 g, 5.8 mmol) in THF (3 mL). The reaction was wanned to
room temperature. Into the reaction mixture was poured 6 N NaOH, and the mixture was stirred for 5
minutes. The product was extracted with diethyl ether. The extracts were washed with 6 N NaOH and
with brine, then dried over sodium sulfate, decanted and the solvent was removed in vacuo to afford
product (600 mg, 95%). 'H NMR (300 MHz, CDC13): 5 2.81-2.68 (m, 1H), 2.07-1.54 (m, 8H).
Step 2. (2Z)-3-Cyclopentyl-3-[4-(7-[2~(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)-lH-pyrazol-l-yl]acrylonitrile
To a mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (0.40 g, 1.2 mmol) and 3-cyclopentylprop-2-ynenitrile (0.30 g, 2.5 mmol) in DMF (8 mL)
was added potassium carbonate (0.09 g, 0.6 mmol). The mixture was stirred for 35 min. The reaction
was diluted with ethyl acetate and brine, and the aqueous portion extracted with three volumes of

ethyl acetate. The combined organic extracts were washed with brine again, then were dried over
sodium sulfate, decanted and concentrated in vacua. The crude residue was purified by flash column
chromatography (ethyl acetate/hexanes) to yield the desired product (290 mg, 53%).
'H NMR (400 MHz, CDC13): 5. 8.98 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 7.42 (d, 1H), 6.84 (d, 1H),
5.67 (s, 2H), 5.21 (s, 1H), 3.64-3.55 (m, 1H), 3.53 (t, 2H), 2.13-2.01 (m, 2H), 1.83-1.66 (m, 4H),
1.57-1.46 (m, 2H), 0.91 (t, 2H), -0.07 (s, 9H); MS(ES):435(M+1).
Step 3. (2Z)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]actylonitrile
A solution of (2Z)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]acrylomtrile (0.030 g, 0.069 mol) in DCM (3 mL) and TFA (2 mL)
was stirred for 1 hour. The solvents were removed in vacuo and the product was stirred with THF (1.5
mL), sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) for 2 hours. The
reaction mixture was neutralized by the dropwise addition of cone. HC1. The product was extracted
with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated in
vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient
of ACN/H2O containing 0.15% NH4OH) to afford the desired product (16 mg, 76%).
'H NMR (400 MHz, d6-dmso): 5 9.08 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 7.66 (d, 1H), 7.05 (d, 1H),
5.82 (d, 1H), 3.62-3.54 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.48 (m, 6H); MS(ES):305(M+l).
Example 75 : 3-Cyclopentylidene-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile

Step 1. 3-Cyclopentylidene-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-
yl)-l H-pyrazol-1 -yljpropanenitrile
To a suspension of 3-cyclopentylprop-2-ynenitrile (0.4 g, 0.003 mol) in ACN (10 mL) was
added 4-(lH-pyraz»l-4-yl)-7-[2-(timethylsilyl)ethoxy]methyl-7H-pyn"olo[2,3-d]pyriinidine (0.53 g,
1.7 mmol) and DBU (0.33 mL, 2.2 mmol). This mixture was stirred at room temperature for 50
minutes. The reaction mixture was partitioned between ethyl acetate and dilute HC1. The aqueous
portion was separated and extracted with ethyl acetate. The combined organic extracts were washed
with dilute HC1 and brine, were dried over sodium sulfate, filtered and concentrated in vacuo. The

erode residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the
desired product (540 mg, 74%).
1H NMR (300 MHz, CDC13): 8. 8.85 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.40 (d, 1H), 6.78 (d, 1H),
5.67 (s, 2H), 3.70 (s, 2H), 3.54 (dd, 2H), 2.55 (t, 2H), 2.45 (t, 2h), 1.85 (dddd, 2H), 1.73 (dddd, 2H),
0.91 (dd, 2H), -0.06 (s, 9H); MS(ES):435(M+1).
Step 2. 3-Cyclopentylidene-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile
A solution of 3-cyclopentylid6ne-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (0.030 g, 0.069 mmol) in DCM (3 mL) and TFA (2
mL) was stirred for 1 hour. The solvents were evaporated in vacuo and the product was stirred with
sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) and THF (1.5 mL) for 2
hours. The reaction mixture was neutralized by dropwise addition of concentrated HC1. The product
was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate,
filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18
column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product
(7 mg, 33%).
1H NMR (400 MHz, d6-dmso): 5. 12.23-12.01 (br s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 7.60
(d, 1H), 7.04 (d, 1H), 3.95 (s, 2H), 2.53 (t, 2H), 2.42 (t, 2H), 1.76 (dddd, 2H), 1.65 (dddd, 2H);
MS(ES):305(M+l).

Step 1. 4- (1,3-Thiazol-S-yl)- 7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidine
4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 0.0106
mol), and 1,3-thiazole (7.50 mL, 0.106 mol) were dissolved in N,N-dimethylacetamide (40.0 mL).
The solution was distributed in equal portions into four 20 mL microwavable vessels. Into each
reaction vessel was then added potassium acetate (0.777 g, 7.93 mmol) followed by tetrakis(triphenyl-
phosphine)palladium(0) (0.60 g, 2.1 mmol). Each reaction vessel was heated at 200 °C in the
microwave reactor for 30 minutes. The reactions were combined and most of the solvent was removed
in vacuo. The residue was diluted with DCM, filtered and concentrated. Purification by flash column
chromatosranhv (ethvl acetate/hexanesi afforded the desired nroduct (1.15 e. 64%).

1H NMR (300 MHz, CDCI3): 8 8.99 (s, 1H), 8.90 (s, 1H), 8.72 (s, 1H), 7.49 (d, 1H), 6.91 (d, 1H),
5.70 (s, 2H), 3.56 (dd, 2H), 0.93 (dd, 2H), -0.05 (s, 9H); MS(ES):333(M+1).
Step 2. 4-(2-Bromo-l,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine
2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a -78 °C solution of 4-
(ls3-thiazoi-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2)3-d]pyrimidine (550 nag, 0.0016
mol) in THF (20 mL). The mixture was stirred for 30 minutes at -78 °C, followed by the slow addition
of carbon tetrabromide (658 mg, 0.00198 mol) as a solution in THF (10 mL). After 30 minutes, the
mixture was quenched with a small amount of saturated ammonium chloride, diluted with ether, and
dried over sodium sulfate. The residue obtained after filtration and concentration was purified by flash
column chromatography (ethyl acetate/hexanes) to afford the desired product (387 mg, 57%).
1H NMR (300 MHz, CDCl3): 5 8.85 (s, 1H), 8.33 (s, 1H), 7.49 (d, 1H), 6.83 (d, 1H), 5.69 (s, 2H),
3.55 (dd, 2H), 0.92 (dd, 2H), -0.05 (s, 9H); MS(ES):411, 413(M+1).
Step 3. 4-(2-Bromo-l,3-thiazol-5-yl)-7H-pyrrolo[2,3-dJpyrimidine
A solution of 4-(2-bromo-l,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-
[2,3-d]pyrimidine (370 mg, 0.90 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at room
temperature for 7 hours. The mixture was then concentrated, re-dissolved in methanol (2 mL), and
ethylenediamine (0.5 mL) was added. The mixture was stirred for 6 hours at room temperature. The
mixture was diluted with DCM (10 mL), and the precipitate was isolated by filtration and washed
with a small amount of DCM to afford desired product (182 mg, 72%).
'H NMR (300 MHz, dVdmso): 8.8.74 (s, 1H), 8.70 (s, 1H), 7.76 (d, 1H), 7.15 (d, 1H);
MS(ES):281,283(M+1).
Step 4. 3-Methyl[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l, 3-thiazol-2-yl]aminopropanenitrile
A solution of 4-(2-bromo-l,3-thiazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (31 mg, 0.11 mmol)
and 3-(methylamino)propionitrile (103 L, 0.00110 mol) in DMF (1.0 mL, 0.013 mol) was stirred at
90 °C for 2 hours. The crude reaction mixture was purified by preparative-HPLC/MS (C18 column
eluting with a gradient of ACN/H2O containing 0.15% NH4OH) and again by preparative-HPLC/MS
(C18 column eluting with a gradient of ACN/H2O containing 0.1% TFA) to yield the desired product
as the trifluoroacetate salt (30 mg, 68%).
1H NMR (300 MHz, d6-DMSO): 8. 12.25 (s, 1H)5 8.60 (s, 1H), 8.31 (s, 1H), 7.60 (dd, 1H), 7.00 (dd,
1H), 3.89 (t, 2H), 3.20 (s, 3H), 2.94 (t, 2H); MS(ES):285(M+1).
Example 77: (3S)- and (3R)-3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]hexane-
nitrile

Step 1. N-Methoxy-N-methylbutanamide
To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydro-
chloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-l-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). The mixture was
stirred overnight at room temperature. The solution was then washed with water and brine, dried over
sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column
chromatography (ether/hexanes). The solvent was removed (235 mbar/40 °C) to afford the product
(1.33g, 88%). lH NMR (300 MHz, CDC13): 8. 3.68 (s, 3H), 3.18 (s, 3H), 2.40 (t, 2H), 1.74-1.59 (m,
2H), 0.96 (t, 3H).
Step 2. l-[5-(7-[2-(Trimethylsilyl)ethoxy]methyI- 7H-pyrrolo[2,3-dJpyrimidin-4-yl)-J, 3-thiazol~2-yl]-
butan-1-one
2.5 M n-Butyllithium in hexane (878 uL) was added slowly dropwise to a -78 °C solution of
4-(l,3-thiazol-5-yl)-7-[2-(trimethyIsilyl)ethoxy]memyl-7H-pyirrolo[2,3-d]pyrimidine (501 mg, 1.37
mmol) in THF (20 mL). After 45 minutes, N-methoxy-N-methylbutanamide (0.360 g, 2.74 mmol)
was added. The reaction was continued at -78 °C for 30 man, and was then allowed to reach room
temperature. The reaction was quenched with saturated ammonium chloride, and was extracted with
ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate and
concentrated in vacuo. Flash column chromatography (ethyl acetate/hexanes) afforded the product
(235 mg, 42%).
1H NMR (300 MHz, CDC13): 8 8.93 (s, 1H), 8.76 (s, 1H), 7.52 (d, 1H), 6.92 (d, 1H), 5.71 (s, 2H),
3.56 (dd, 2H), 3.19 (t, 2H), 1.92-1.77 (m, 2H), 1.05 (t, 3H), 0.93 (dd, 2H), -0.05 (s, 9H);
MS(ES):403(M+l).
Step 3. (2E)- and (2Z)-3-[5-(7-[2-(Trimethylsilyl)eth(^]methyl-7H-pyrrolo[2,3-dJpynmidin-4-yl)-
l,3-thiazol-2-yl]hex-2-enenitrile
To a solution of 1.0 M potassium tert-butoxide in THF (0.605 mL) in THF (4,0 mL) at
0° C was added diethyl cyanomethylphosphonate (0.102 mL, 0.634 mmol) dropwise. The cooling bath
was removed and the reaction was wanned to room temperature. After 30 minutes, a solution of l-[5-

(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyiTolo[23-d]pyrimidih-4-yl)-l,3-thiazol-2-yl]butan.-l-one
(232 mg, 0.576 mmol) in THF (3.0 mL) was added dropwise. The reaction was stirred for 2 hours,
and the crude mixture was then adsorbed onto silica gel'and purified by flash column chromatography
(ethyl acetate/hexanes) to afford the product as a mixture of olefin isomers (225 mg, 92%).
'H NMR (300 MHz, CDC13), major isomer: £ 8.89 (s, 1H), 8.65 (s, 1H), 7.52 (d, 1H), 6.89 (d, 1H),
6.35 (s, 1H), 5.70 (s, 2H), 3.56 (dd, 2H), 2.96 (t, 2H), 1.88-1.72 (m, 2H), 1.08 (t, 3H), 0.93 (dd, 2H), -
0.07 (s, 9H); MS(ES):426(M+1).
Step 4. (3SJ- and (3R)-3-[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2.3-d]pyrimidin-4-yl)-
1,3-thiazol-2-yl]hexanenitrile
Cupric acetate, monohydrate (0.7 mg, 0.004 mmol) and (oxydi-2,l-phenylene)bis(diphenyl-
phosphine) (2 mg, 0.004 mol) was mixed in toluene (0.24 mL). PMHS (30 L) was added. The
mixture was stirred for 25 minutes at room temperature followed by the addition of (2E)-3-[5-(7-[2-
(trimethylsilyl)ethoxy]methyI-7H-pyrrolo[2,3-d]pyrirnidin-4-yl)-l,3-thiazol-2-yl]hex-2-enenitrile (51
mg, 0.12 mol) in toluene (0.24 mL) and finally, tert-butyl alcohol (0.043 mL). The resulting mixture
was stirred overnight. The crude mixture was purified directly by flash column chromatography (ethyl
acetate/hexanes) to afford the desired product (39 mg, 76%).
'H NMR (300 MHz, CDC13): 8. 8.87 (s, 1H), 8.52 (s, 1H), 7.48 (d, 1H), 6.87 (d, 1H), 5.69 (s, 2H),
3.60-3.46 (m, 3H), 2.99-2.82 (m, 2H), 2.05-1.89 (m, 2H), 1.50-1.34 (m, 2H), 0.97 (t, 3H), 0.92 (t,
2H), -0.06 (s, 9H); MS(ES):428(M+1).
Step 5. (3S)~ and (3R)-3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1.3-thiazol-2-yl]hexanenitrile
TFA (1.0 mL) was added to a solution of 3-[5~(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]hexanenitrile (36 mg, 0.084 mmol) in DCM (4.0 mL)
and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated, and re-
dissolved in methanol (3 mL), to which ethylenediamine (0.1 mL) was added. After 2 hours reaction
time, the mixture was concentrated and directly purified by preparative-HPLC/MS (C18 column
eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (10 mg,
40%). 1H NMR (300 MHz, CDC13): 5 9.96 (br s, 1H), 8.87 (s, 1H), 8.54 (s, 1H), 7.51-7.45 (m, 1H),
6.90-6.86 (m, 1H), 3.59-3.44 (m, 1H), 3.01-2.82 (m, 2H), 2.06-1.87 (m, 2H), 1.51-1.34 (m, 2H), 0.98
(t, 3H); MS(ES):298(M+1).
Example 78: (3R)- and (3S)-3-Cyclopentyl-3-l5-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-l,3-thiazoI-2-
yllpropanenitrile

To a solution of (2E)- and (2Z)-3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrirnidin-4-yl)-l,3-thiazol-2-yl]acrylonitrile (199 mg, 0.440 mmol) (prepared, for
example, as in Example 77, steps 1 through 3) in a mixture of ethanol (10 mL) and ethyl acetate (10
mL) was added a catalytic amount of 10% palladium on carbon. The mixture was stirred at room
temperature under one atmosphere of hydrogen overnight. It was then subjected to 50 PSIH2 until the
reaction was complete. Filtration and removal of solvent afforded an oil which was dissolved in DCM
(4 mL) and TFA (1 mL). The solution was stirred until starting material was consumed and the
mixture was then concentrated and re-dissolved in methanol (3 mL), to which ethylenediamine (0.4
mL) was added. The solution was stirred at room temperature for one hour, and was concentrated in
vacuo. The crude mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient
of ACN/H2O containing 0.15% NH4OH) to afford the desired product (36 mg, 25%).
1H NMR (400 MHz, CDC13): 8 10.44 (br s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 7.50 (dd, 1H), 6.89 (dd,
1H), 3.34 (dt, 1H), 2.98 (dd, 1H), 2.89 (dd, 1H), 2.44-2.31 (m, 1H), 2.07-1.96 (m, 1H), 1.80-1.52 (m,
5H), 1.40-1.24 (m, 2H); MS(ES):324(M+1).
The following compounds of Table 5c were prepared (as racemic mixtures) as described by
Example 77, 78 or 86, as indicated in the following table, by using different Weinreb amides (as
prepared in Example 77, Step 1):

Step 1. (2S)- and (2R)-2-[5-(7-[2-(Trimethylsifyl)ethoxy]methyl-7H-pyrrolo[2,3-dJpyrimidin-4-yl)-
1 r3-thiazol-2-yl]pentanenitrile
To a mixture of l-fS-Cy-P-CtrimethylsUyOethoxyjmethyl-TH-pyrrolop^-dJpyrimidin^-yl)-
l,3-thiazol-2-yl]butan-l-one (prepared as in Example 77) (101 mg, 0.251 mmol) and p-tolylsulfonyl-
methyl isocyanide (147 mg, 0.753 mmol) in a mixture of DMSO (5.0 mL) and ethanol (61 |jL) was
added 1.0 M potassium tert-butoxide in THF (753 \\L). The mixture was then heated to 45 °C for 2
hours. Upon cooling to room temperature, the mixture was quenched by the addition of saturated
ammonium chloride, followed by water. The product was extracted with ether, and the extracts were
washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacua. Flash
column chromatography (ethyl acetate/hexanes) afforded the product (39 mg, 25%).
'H NMR (400 MHz, CDC13): 5 8.88 (s, 1H), 8.52 (s, 1H), 7.50 (d, 1H), 6.87 (d, 1H), 5.70 (s, 2H),
4.32 (dd, 1H), 3.55 (dd, 2H), 2.20-2.11 (m, 2H), 1.71-1.57 (m, 2H), 1.03 (t, 3H), 0.93 (dd, 2H);
MS(ES):414(M+1).
Step 2. (2S)- and (2R)-2-[5-(7H-PyrroJo[2l3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]pentanenitrile
A solution of 2-[5-(7-[2-(trimethyIsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-
thiazol-2-yl]pentanenitrile (59 mg, 0.093 mmol) in DCM (3 mL) and TFA (0.5 mL) was stirred at
room temperature for 4 hours. The mixture was then concentrated, and the residue was then dissolved
in methanol (3 mL) to which ethylenediamine (0.3 mL) was then added. The solution was stirred at
room temperature for 40 minutes. The solvent was removed in vacuo, and the crude mixture was
purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing
0.15% NH,OH) to afford the desired product (20 mg, 76%).
'H NMR (400 MHz, CDC13): 8. 9.66 (br s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 7.49 (dd, 1H), 6.88 (dd,
1H), 4.33 (dd, 1H), 2.23-2.12 (m, 2H), 1.75-1.60 (m, 2H), 1.04 (t, 3H); MS(ES):284(M+1).
Example 85: (4S)- and (4R)-4-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl>l^-ttiiazol-2-yl]heptane-
nitrile

To a solution of triethyl phosphonoacetate (188 nig, 0.838 mmol) in THF (6.0 mL) at 0 °C
was added 1.0 M potassium tert-butoxide in THF (840 L). The mixture was then allowed to warm to
room temperature followed by re-cooling to 0 °C, at which time l-[5-(7-[2-(trimethylsilyl)ethoxy]-
methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]butan-l-one (prepared as in Example 77)
(225 mg, 0.559 mmol) in THF (4.0 mL) was added. The mixture was stirred at room temperature for
1.5 hours, at which time it was quenched with water and extracted with ethyl acetate. The combined
extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacua.
Flash column chromatography afforded the product as a mixture of olefin isomers (222 mg, 84%).
MSQES):473(M+1).
Ethyl 3-[5-(7-[2-(trimethylsilyl)emoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-
2-yl]hex-2-enoate as a mixture of (2E)- and (2Z)- isomers (222 mg, 0.470 mmol) was dissolved in
ethanol (10 mL), and a catalytic amount of 10% Pd-C was added. The mixture was stirred under an
atmosphere of hydrogen, provided by a balloon, for 16 hours. Filtration and concentration in vacuo
afforded the desired product (201 mg, 90%). MS(ES):475(M+1).
To a solution of ethyl 3-t5-(7-[2-(trimethylsiIyI)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)-l,3-thiazol-2-yl]hexanoate (201 mg, 0.423 mmol) in THF (5.0 mL) at -78 °C was added 1.00 M
diisobutylaluminum hydride in DCM (1.06 mL). The mixture was allowed to warm to -10 °C slowly
over 1.5 hours, followed by the addition of potassium sodium tartrate tetrahydrate, water, and ether.
The mixture was stirred for 1 hour, then layers were separated, and the aqueous layer was extracted
further with ethyl acetate. The organic extracts were washed with water and brine, dried over sodium
sulfate and concentrated in vacuo to afford desired product (176 mg, 96%). MS(ES):433(M+1).
A solution of 3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-
thiazol-2-yl]hexan-l-ol (88 mg, 0.20 mmol) in TFA (2 mL) was stirred for 30 minutes. The TFA was
then evaporated and the residue was stirred in methanol (2 mL) containing ethylenediamine (0.2 mL)
and a drop of water for 30 minutes. Purification via preparative-HPLC/MS (C18 eluting with a
gradient of ACN/H2O containing 0.15% NH4OH) afforded the desired product (36 mg, 58%).
MS(ES):303(M+l).
To a mixture of 3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]hexan-l-ol (36 mg,
0.12 mmol) and TEA (19.9 L, 0.143 mmol) in DCM (5 mL) at 0 °C was added methanesulfonyl
chloride (11.0 L, 0.143 mmol). After stirring for 10 minutes, the solution was concentrated and

dissolved in DMSO (1.6 mL) and sodium cyanide (23 mg, 0.48 mmol) was added. The mixture was
then heated at 125 °C in the microwave for 30 minutes. The mixture was then purified directly using
preparative-HPLC/MS (CIS eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford
the desired product (10 mg, 27%).
1H NMR (400 MHz, CDC13): 5. 9.37 (br s, 1H), 8.86 (s, 1H), 8.52 (s, IH), 7.46 (dd, 1H), 6.88 (dd,
1H), 3.34-3.25 (m, 1H), 2.47-2.30 (m, 2H), 2.22-2.12 (m, 2H), 1.95-1.71 (m, 2H), 1.44-1.31 (m, 2H),
0.94 (t, 3H); MS(ES):312(M+1).

Step 1. N-Methoxy-2-[(4-methoxybenzyl)oxy]-N-methylacetamide
To a mixture of [(4-methoxybenzyl)oxy]acetic acid (Bioorganic and Medicinal Chemistry
Letters, 2001, pp. 2837-2841) (6.86 g, 0.0350 mol) and N,O-dimethylhydroxylamine hydrochloride
(3.41 g, 0.0350 mol) in DCM (100 mL) was added benzotriazol-l-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate (17 g, 0.038 mol) foEowed by TEA (9.7 mL, 0.070 mol). The
resulting mixture was stirred overnight at room temperature. The solution was then washed with
water, 0.5 M HC1, saturated NaHCO3, and brine, then was dried over sodium sulfate, filtered and
concentrated in vacuo. Flash column chromatography (ether/hexanes) afforded the desired product
(5.75 g, 69%).
Step 2. 2-[(4-MethoxybenzyI)oxy]-l-[5-(7-[2-(trimethytsilyt)ethoxy]methyl-7H-pyrrolo[213-d]-
pyrimidin-4-yl)-l,3-thiazol-2-yl]ethanone
To a solution of 4-(l,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (2.12 g, 6.38 mmol) in THF (70 mL) at -78 °C was added 2.5 M n-butyllithium in hexane
(3.06 mL) slowly dropwise. After stirring for 30 minutes, N-methoxy-2-[(4-methoxybenzyl)oxy]-N-
methylacetamide (2.29 g, 9.56 mmol) was added. The reaction was continued for 30 minutes
following the addition, at -78 °C, then the cooling bath was removed and the reaction was quenched
with saturated ammonium chloride and extracted with ether. The extracts were dried with sodium
sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography
(ethyl acetate/hexanes) to afford desired product (2.16 g, 66%).

1H NMR (300 MHz, CDC13): 5. 8.93 (s, 1H), 8.72 (s, 1H), 7.53 (d, 1H), 7.37 (d, 2H), 6.91 (d, 2H),
6.89 (d, 1H), 5.70 (s, 2H), 5.00 (s, 2H), 4.70 (s, 2H), 3.81 (s, 3H), 3.56 (dd, 2h), 0.93 (dd, 2H), -0.05
(s, 9H); MS(ES):511(M+1).
Step 3. (2E)- and (2Z)^-[(4-Methoxyberizyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H~
pyrrolo[2,3-dJpyrimidin-4-yl)-l,3-thiazol-2-yl]but-2-enenitrile
To a solution of 1 M potassium tert-butoxide in THF (4.44 mL) in THF (30 mL) at 0° C was
added diethyl cyanomethylphosphonate (820 mg, 0.0046 mol) dropwise. The bath was removed and
the reaction was wanned to room temperature. After 30 minutes, a solution of 2-[(4-methoxybenzyl)-
oxy]-l-[5-(7-[2-trimethylsayl)emoxy]methyl-7H-pyrrolo[2,3-d]pyrmidin-4-yl)-l,3-thiazol-2-yl]-
ethanone (2.16 g, 0.00423 mol) in THF (20 mL) was added dropwise. The reaction was stirred for 1
hour, and was then quenched with a small amount of saturated ammonium chloride, diluted with
ether, dried over sodium sulfate and concentrated in vacuo. Purification by flash column
chromatography, eluting with a gradient of 0-35% ethyl acetate/hexanes afforded the desired product
as a mixture of olefin isomers in nearly equal amounts (1.76 g, 78%).
1HNMR (400 MHz, CDC13): 8 8.90 (s, 1H), 8.88 (s, 1H), 8.71 (s, 1H), 8.67 (s, 1H), 7.50 (d, 2H), 7.35
(dd, 2H), 7.31 (dd, 2H), 6.92 (dd, 2H), 6.90 (dd, 2H), 6.86 (d3 2H), 6.62 (s, 1H), 6.10 (t, 1H), 5.70 (s,
4H), 4.75 (s, 2H), 4.72 (d, 2H), 4.64 (s, 4H), 3.82 (s, 3H), 3.81 (s, 3H), 3.56 (dd, 2H), 3.55 (dd, 2H),
0.96-0.90 (m, 4H), -0.05 (s, 9H), -0.054 (s, 9H); MS(ES):534(M+1).
Step 4. 4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-l,3-thiazol-2-yl]butanenitrile
(2E)- and (2Z)-4-[(4-Methoxyben2yl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d3pyrimidin-4-yl)-l,3-thiazol-2-yl]but-2-enenitri]e (880 mg, 1.6 mmol) was dissolved in a
mixture of ethanol (20 mL) and ethyl acetate (20 mL). A catalytic amount of 10% Pd-C was added.
The mixture was shaken under 50 PSI of hydrogen. The mixture was filtered and concentrated in
vacuo to afford the desired product (0.85 g, 99%). MS(ES):536(M+1).
Step 5. 3-[5-(7H-PyrroIo[2,3-d]pyrimidin-4-yl)-lt3-thiazol-2-yl]pentanedinUrile
4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-l,3-thiazol-2-yl]butanenitrile (251 mg, 0.468 mmol) in DCM (10 mL) was treated
with dichlorodicyanoquinone (DDQ) (434 mg, 1.87 mmol), followed by water (376 L). After 1.5
hours, saturated sodium bicarbonate and water were added, and the reaction was extracted with ethyl
acetate three times. The extracts were washed with water, brine, dried over sodium sulfate, filtered
and concentrated in vacuo to afford the crude product which was used without further purification.

A solution of the above prepared 4-hydroxy-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]butanenitrile in DCM (12 mL) at 0 °C was treated
sequentially with TEA (130 L, 0.94 mmol) and methanesulfonyl chloride (73 L, 0.94 mmol). After
1 hour reaction time, the mixture was diluted with water and extracted with ethyl acetate three times.
The extracts were washed with water and brine, dried over sodium sulfete, filtered and concentrated in
vacuo. The residue was then dissolved in DMSO (5 mL) and sodium cyanide (110 mg, 2.3 mmol) was
added. After 30 minutes, the mixture was diluted with water, extracted with ether, washed with water,
brine and dried over sodium sulfate. Concentration and purification by flash column chromatography
(ethyl acetate/hexanes) afforded the desired product (14 mg, 7%). MS(ES):425(M+1).
A solution of 3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-
thiazol-2-yl]pentanedinitrile (14 mg, 0.033 mmol) in DCM (3 mL) containing TFA (0.6 mL) was
stirred for 4 hours. The mixture was then concentrated and the residue was redissolved in methanol (2
mL) to which ethylenediamine (0.4 mL) was then added. After 1 hour reaction time, the product was
purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O containing 0.15%
NK4OH) to afford the desired product (6 mg, 62%).
1H NMR (400 MHz, d6-dmso): 5 12.27 (br s, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 7.75 (d, 1H), 7.14 (d,
1H), 4.14 (m, 1H), 3.17 (d, 4H); MS(ES):295(M+1).
Example 87: (3R)-3-CycIopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-oxazol-2-ylI-
propanenitrile,
and
(3S)3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-l,3-oxazol-2-yl]propanenitrile

Step I. 4-(l,3-Oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine
A mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine
(0.440 g, 1.55 mmol), 1,3-oxazole (0.306 mL, 4.65 mmol), potassium acetate (0.456 g, 4.65 mmol)
and tetrakis(triphenylphosphine)palladium(0) (0.179 g, 0.155 mmol) in N,N-dirnethylacetamide (8.0
mL) was heated to 200 °C in the microwave reactor for 30 minutes. Most of the solvent was removed
in vacuo. The resulting residue was diluted with DCM, and was filtered and concentrated. Flash
column chromatography (ethyl acetate/hexanes) afforded the product (330 mg, 67%).

1H NMR (400 MHz, CDCI3): 6 8.96 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.54 (d, 1H), 7.08 (d, 1H),
5.76 (s, 2H), 3.60 (t, 2H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):317(M+1).
Step 2. Cyclopentyl[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3~
oxazol-2-yl] methanone
n-Butyllithium in hexane (1.6 M, 0.30 mL) was added slowly dropwise to a -78 °C solution of
4-(13-oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrinudine (140.0 mg, 0.44
mmol) in THF (10.0 mL). After 20 minutes, 1.0 M zinc dichloride in ether (0.53 mL) was added. The
reaction mixture was then stirred for 60 min at 0 °C. Following this, copper© iodide (84 mg, 0.44
mmol) was added, and this mixture was allowed to stir for 10 minutes. Cyclopentanecarbonyl chloride
(108 L, 0.885 mmol) was then added. The reaction was stirred at 0 °C for a further 1 hour, at which
time it was allowed to warm to room temperature. The reaction was quenched by the addition of
saturated NH4CI solution, and was extracted with ethyl acetate. The extracts were washed with water
and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash column
chromatography (ethyl acetate/hexanes) afforded the product (97 mg, 53%).
1H NMR (400 MHz, CDC13): 5 8.96 (s, 1H), 8.21 (s, 1H), 7.56 (d, 1H), 7.22 (d, 1H), 5.76 (s, 2H),
3.60 (t, 2H), 3.56 (t, 1H), 2.23-1.56 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):413(M+1).
Step 3. (3R)- and (3S)-3-Cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4~yl)'l,3-oxazol-2-yl]propanenitrile
To a solution of 1.0 M potassium tert-butoxide in THF (0.355 mL) and THF (3 mL) at 0° C
was added diethyl cyanomethylphosphonate (66 mg, 0.37 mmol) dropwise. The cold bath was
removed and the reaction was warmed to room temperature. After 30 minutes, a solution of
cyclopentyl[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-oxazol-2-
yl]methanone (1.40E2 mg, 0.338 mmol) in THF (2.0 mL) was added dropwise. After 3 hours reaction
time, the mixture was adsorbed onto silica gel, and flash column chromatography (ethyl
acetate/hexanes) afforded the desired product as a mixture of olefin isomers (89 mg, 60%).
MS(ES):436(M+1).
To a mixture of cupric acetate, monohydrate (4.0 mg, 0.020 mmol) and (oxydi-2,1-
phenylene)bis(diphenylphosphine) (11 mg, 0.020 mmol) in toluene (0.40 mL, 0.0038 raol) was added
PMHS (50 jiL). The resulting mixture was stirred for 25 minutes at room temperature, followed by
the addition of (2E)- and (2Z)-3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-l,3-oxazol-2-yl]acrylonitrile (88 mg, 0.20 mmol) in toluene (0.40 mL), and
then tert-butyl alcohol (0.072 mL). After failure to react at room temperature over 16 hours,
additional cupric acetate, monohydrate and (oxydi-2,l-phenylene)bis(diphenylphosphine) (0.10 mol
equivalent each) were added and the reaction mixture was heated at 60 °C for 16 hours. The crude

mixture was subjected to flash column chromatography (ethyl acetate/hexanes) to afford the desired
product (21 mg, 23%).
1H NMR (400 MHz, CDC13): 8 8.96 (s, 1H), 8.02 (s, 1H), 7.56 (d, 1H), 7.10 (d, 1H), 5.76 (s, 2H),
3.60 (t, 2H), 3.38-3.30 (m, 1H), 3.03 (dd, 1H), 2.95 (dd, 1H), 2.60-2.40 (m, 1H), 2.10-2.00 (m, 1H),
1.85-1.15 (m, 7H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):438(M+1).
Step 4. (3R)- and (3S)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-oxazol-2-yl]-
propanenitrile
A solution of 3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyn-olo[2,3-d)-
pyrimidin-4-yl)-l,3-oxazol-2-yl]propanenitrile (20.0 mg, 0.0457 mmol) was stirred with TFA (0.1
mL) in DCM (0.2 mL) for 6 hours. The solvent was removed, and the resulting residue was stirred
overnight with ethylenediamine (0.1 mL) in methanol (0.2 mL). The solvent was removed in vacuo.
The desired product was obtained via preparative-HPLC/MS (C18 column eluting with a gradient of
ACN/H2O containing 0.15% NH4OH) (5.3 mg, 38%).
'H NMR (400 MHz, CDC13): 5 10.25 (br s, 1H), 8.90 (s, 1H), 8.00 (s, 1H), 7.50 (d, 1H), 7.06 (d, 1H),
3.36-3.28 (m, 1H), 2.98 (dd, 1H), 2.90 (dd, 1H), 2.51-2.38 (m, 1H), 2.08-1.96 (m, 1H), 1.80-1.51 (m,
5H), 1.44-1.30 (m, 2H); MS(ES):308(M+l).
The following compound of Table 5d was also prepared as a racemic mixture, according to
the procedure of the above Example 87.

Step 1. (2E)-5-(Methyltyio)pent-2-enenitrile
To a 0 °C mixture of [chloro(triphenyl)phosphoranyl]ACN (2.5 g, 0.0073 mol) in THF (10
mL, 0.1 mol) was added TEA (2.0 mL, 0.014 mol), and the resulting mixture was stirred for 30 min.
The ice bath was removed for 30 min, then the mixture was re-cooled back to 0 °C, A solution of 3-
(methylthio)-propanol (0.68 mL, 0.0072 mol) in THF (1 mL, 0.02 mol) was added and the mixture
was stirred overnight. Water was added and the mixture was filtered. The filtrate was washed with
water x3 and brine. The organic phase was dried and the solvent was removed by rotary evaporation
to give 2.1 g of an off-white solid. The solid was triturated with MTBE and was filtered. The filtrate
was washed with IN HC1, water, sat. NaHCO3 and brine. The organic phase was dried and was
concentrated using a rotary evaporator to give 0.62 g orange oil (44% yield, trans : cis ~ 2 : 1).
1H NMR for trans (400 MHz, CDC13): 5 6.68 (1H, m); 5.14 (1H, d); 2.6 (2H, m); 2.55 (2H, t); 2.1
(3H, s).
Step 2. 5-(Methylthio)-3-[4-(7-[2-(trimethyhilyl)ethoxy]methyl-7H-pyrrolo[2t3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]pentanenitrile
A mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (0.30 g, 0.00095 mol), (2E)-5-(methylfhio)pent-2-enenitrile (0.28 g, 0.0016 mol) and DBU
(45 L, 0.00030 mol) in ACN (3 mL, 0.06 mol) was stirred at rt for 5 days. The solvent was removed
by rotary evaporation to give an orange oil. The crude oil was chromatographed with 30-70 ethyl
acetate/hex, to give 0.35 g of a colorless oil (83% yield).
1H NMR (400 MHz, CDC13): 5 8.95 (1H, s); 8.41 (1H, s); 8.4 (1H, s); 7.48 (1H, d); 6.84 (IH, d); 5.75
(2H, s); 4.95 (IH, br); 3.6 (2H, t); 3.1 (2H, m); 2.58 (2H, m); 2.28 (2H, m); 2.1 (3H, s); 1.99 (2H, t);
0.0 (9H, s). MS (M+H): 443.
Step 3. 5-(Methylthio)-3'[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrlle
A solution of 5-(methylthio)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile (0.35 g, 0.00079 mol) in THF (4 mL, 0.05 mol) and
3.0 M HCI (HC1) in water (4 mL) was heated to reflux overnight. The solvent was removed by rotary
evaporation to give a pale orange oil. The oil was stirred in ethanol (3 mL, 0.05 mol) and 8.0 M

ammonium hydroxide in water (1 mL) overnight. The reaction was concentrated and purified by prep
LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give 125 mg
of a white foam. The white foam was triturated with MTBE (~ 1.5 mL). The resulting solid was
filtered, washed and dried to give 80 mg of the product (32% yield).
1H NMR (400 MHz, CDCI3): 5 10.38 (1H, s); 8.88 (1H, s); 8.39 (1H, s); 8.38 (1H, s): 7.44 (1H, d);
6.8 (1H, d); 5.75 (2H, s); 4.9 (1H, br); 3.05 (2H, m); 2.5 (2H, m); 2.23 (2H, d); 2.1 (3H, s). MS
(M+H): 313.

A solution of 5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
pentanenitrile (0.065 g, 0.00021 mol) and hydrogen peroxide (0.022 mL, 0.00023 mol) in ACN (1
mL, 0.02 mol) was stirred overnight. The reaction was concentrated and purified by HPLC to give 21
mg of a solid. The solid was triturated with MTBE (1 mL)/DCM (10 drops). The solid was filtered
and washed to give 13 mg of a white solid (20% yield) which was dried rt to 50 °C for 2 h.
1H NMR (400 MHz, CDCl3): 5 9.95 (1H, s); 8.85 (1H, s); 8.4 (2H, m); 7.4 (1H, d); 6.8 (1H, s); 4.9
(1H, br); 3.15 (2H, m); 3.0 (2H, m); 2.8-2.5 (2H, m); 2.6 (3H, s). MS (M+H): 329.
Example 92: 5-(Methylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-l-yI]-
pentanenitrile

A solution of 5-(Jnethylthio)-3-[4-(7H-pyrrolo[2,3-d]pynmidin-4-yl)-lH-pyrazol-l-yl]-
pentanenitrile (0.040 g, 0.00013 mol) and hydrogen peroxide (0.5 mL, 0.005 mol) in ACN (1 mL,

0.02 mol) was refluxed overnight. The reaction was purified by HPLC to give 16 mg of a white
glass/solid which was triturated with EtOH (~0.8 mL) to give 13 mg of a white solid (30% yield).
1HNMR (400 MHz, CDC13): 8 8.75 (1H, s); 8.48 (1H, d); 8.4 (1H, d); 7.43 (1H, d); 6.8 (1H, s); 5.0
(1H, br); 3.4 (2H, m); 3.2-3.0 (2H, m); 2.8-2.5 (2H, m); 2.95 (3H, s). MS (M+H): 345.

Step 1. 4,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
IH-pyrazol-l-ylJbutanenitrile
A mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (6.9 g, 0.022 mol), (2E)-4,4,4-trifluorobut-2-enenitrile (2.8 g, 0.023 mol) and DBU (0.18
mL, 0.0012 mol) in ACN (70 mL, 1 mol) was stirred for 20 min. The reaction was filtered and filtrate
was removed by rotary evaporation to give an orange oil. The crude oil was chromatographed with
20-50% ethyl acetate/hex to give to give 9.1 g of a solid/oil (96% yield). A single enantiomer (peak 2)
was separated by chiral column chromatography (OD-H column, 30%EtOH/hex) as a greenish
solid/glass (3.3 g, 32% yield).
lHNMR(400 MHz, CDC13): 5 8.93 (1H, s); 8.46 (1H, s); 8.45 (1H, s); 7.5 (1H, d); 6.85 (1H, d); 5.75
(2H, s); 5.2 (1H, m); 3.6 (2H, t); 3.7-3.3 (2H, m); 1.99 (2H, t); 0.0 (9H, s). MS (M+H): 438.
Step 2. 4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-l-ylJ-butyronitrile
A solution of 4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyra2X)l-l-yl]butanenitrile (3.1 g, 0.0071 mol) from Step 1 in THF (35 mL, 0.43
mol) and 3.0 M HC1 in water (35 mL) was heated to reflux overnight. The solvent was removed by
rotary evaporation to give a greenish orange oil/glass. The oil was stirred with ethyl acetate and sat.
NaHCO3 (50 mL). The aqueous phase was extracted with ethyl acetate. The organic layers were
washed with brine and reduced by rotary evaporation to give an oil/glass residue. The residue was
stirred in ethanol (20 mL, 0.3 mol) and 8.0 M ammonium hydroxide in water (10 mL) over a
weekend. The solvent was removed by rotary evaporation to give a pale orange foam/solid. The crude
was chromatographed with 0-7% MeOH/DCM, O-O.7% NH4OH to give 3 g of a pale orange
paste/solid. The solid was recrystallized from EtOH to give 1.6 g of an off-white crystals (74% yield).

Step 1: 3-(Dimethoxymethyl)cyclopentanecarbaldehyde.
Into a 3-neck round bottom flask 2-norbomene (5.500 g, 0.05841 mol) was dissolved in DCM
(198.0 mL,) and raethanol (38.5 mL) and was cooled at -78 °C. Ozone was passed through the
reaction until it turned blue and was stirred at -78 °C for 30 minutes. Then nitrogen was passed
through for 20 minutes and p-toluenesulfonic acid (0.95 g, 0.0055 mol) was added The reaction was
allowed to warm at 20 °C and was stirred for 90 minutes. Into the reaction was added sodium
bicarbonate (1.67 g, 0.0199 mol) and the resulting mixture was stirred at 20 °C for 30 minutes and
dimethyl sulfide (9.4 mL, 0.13 mol) was added. The reaction was stirred for 16 hours and was
reduced by rotary evaporation to ~50 mL The reaction was extracted with DCM and the organic
extracts were washed with water and brine, dried (MgSO4), and stripped in vacuo. The reaction was
distilled at 135 °C (bath temperature) at high pump vacuum to give the product (7.5,g) as a ~2:1
mixture of diastereomers. 1HNMR (300 MHz, CDC13): 9.64 & 9.62 (d, 1H), 4.i5 & 4.12 (s, 1H), 3.35
& 3.34 (s, 6H), 2.77 m, 1H), 2.34 (m, 1H), 1.35-2.00 (m, 6H).
Step 2. (2E,Z)-3-[3-(Dirnethoxymethyl)cyclopentyl]acrylonitrile.
Into a flask containing a 0 °C solution of t-BuOK in THF (1.0 M, 6,10 mL) was added a
solution of diethyl cyanomethylphosphonate (1.1 g, 6.4 mmol) in THF (8 mL). The cooling bath
was removed and the reaction was warmed to ambient temperature, then a solution of 3-(dimethoxy-
methyl)cyclopentanecarbaldehyde (1.00 g, 5.81 mmol) in THF (2 mL) was added dropwise. Shortly
after completion of the addition orange gel-like particulates began to form, after approximately 1 hour
the reaction was gelatinous. The reaction was held with stirring at ambient temperature for 16 hours
at which time tic indicated complete reaction. The reaction was partitioned between water and EtOAc
and the aqueous phase was washed with additional EtOAc. The combined organic phase was washed
with water, then satd NaCl, and then was dried over MgSO4 and reduced in vacuo, and the resulting
residue was purified by column chromatography with 6:1 hexanes:EtOAc +1% TEA to obtain the
product as a 1:1 mixture of E/Z isomers (760 mg, 61%). 1H NMR (400 MHz, CDC13): 8 vinylic
protons at 6.69 (m, 0.5H), 6.37 (m, 0.5H), 5.32 (m, 0.5H), 5.23 (m, 0.5H), acetal methine proton at
4.14 (m, 1H), methyl protons at 3.34 (s, 6H).

Step 3. 3-[3-(Dimethoxyrnethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile.
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyI-7H-pyrrolo[2,3-
d]pyrimidine (230 mg, 0.74 mmol) in ACN (5 mL) was added (2E,Z)-3-[3-(dimethoxymethyl)cyclo-
pentyl]acrylonitrile (289 mg, 1.48 mmol), followed by DBU (300 L, 2.0 mmol). The mixture was
stirred at ambient temperature for 16 hours, at which point LCMS and TLC indicated complete
reaction. The reaction was reduced to dryness in vacuo, and the residue was purified by column
chromatography to obtain the product as a mixture of diastereomers (293 mg, 77%). 1HNMR (400
MHz, CDC13): 8 8.85 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.28 (m, 1H), 4.11
(m, 1H), 3.54 (t, 2H), 3.36 (s, 1.5H), 3.34 (s, 1.5H), 3.30 (s, 1.5H), 3.26 (s, 1.5H), 3.12 (m, 1H), 2.94
(m, 1H), 2.65 (m, 1H), 2.34 (m, 1H), 2.0-1.0 (m, 6H), 0.92 (t, 2H), -0.56 (s, 9H). MS (El) m/z = 511.3
(M+H).
Step 4. 3-(3-Formylcyclopentyl)-3-[4-(7-[2-(trimethyIsilyl)ethaxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile.
To a solution of 3-[3-(dimethoxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]-
methyl-7H-pyrrolo[2,3-d]pyrimidinr4-yl)-lH-pyrazol-l-yl]propanenitrile (293 mg, 0.574 mmol) in
THF (4.5 mL) was added aqueous HC1 (1.0 M, 1.5 mL). The reaction was held at ambient
temperature for 2.5 hours at which point TLC and LCMS indicated complete deprotection to the
corresponding aldehyde. The reaction was partitioned between water and EtOAc and the aqueous
phase was extracted with additional EtOAc. The combined organic phase was washed with water,
then sat'd NaHCO3, then sat'd NaCl, and then was dried over MgSO4 and filtered and stripped to
dryness to leave the crude product as a mixture of diastereomers. 'H NMR (400 MHz, CDC13): 5 9.69
(d, 0.5H), 9.64 (d, 0.5H), 8.85 (s, 0.5H), 8.84 (s, 0.5H), 8.35 (s, 0.5H), 8.34 (s, 0.5H), 8.32 (s, 0.5H),
8.30 (s, 0.5H), 7.41 (d, 0.5H), 7.40 (d, 0.5H), 6.80 (d, 0.5H), 6.79 (d, 0.5H), 5.68 (s, 1H), 5.67 (s, 1H),
4.32 (m, 1H), 3.54 (m, 2H), 3.14 (m, 1H), 2.96 (m, 2H), 2.76 (m, 1H), 2.1-1.1 (m, 6H), 0.92 (m, 2H),
-0.058 (s, 9H). MS (El) m/z = 465.1 (M+H).
Step 5. 3-3-f(E, Z)-(Hydroxyimino)methyl]cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljpropanenitrile.
To a solution of 3-(3-formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yljpropanenitrile (336 mg, 0.000723 mol) in CH3OH (5.0
mL, 0.12 mol) was added hydroxylamine hydrochloride (60 mg, 0.00087 mol) and KHCO3 (110 mg,
0.0011 mol) and the reaction was held at ambient temperature for 16 hours, at which point LCMS
indicated complete reaction. The reaction was reduced to dryness in vacuo and the residue was
partitioned between water and EtOAc, and the aqueous phase was extracted with additional EtOAc.

The combined organic phase was washed with water, then sat'd NaCl, then was dried over MgSO4 and
concentrated to leave the crude product, which was carried forward to the subsequent reaction without
purification. NMR indicated disappearance of aldehydic protons. MS (El) m/z = 480.2 (M+H).
Step 6. 3-(2-Cyano-l -[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]ethyl)cyclopentanecarbonitrile.
To a solution of 3-3-[(E,Z)-(hydroxyimino)methyl]cyclopentyl-3-[4-(7-[2-(trimethylsiIyI)-
ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (324 rag, 0.67
mmoJ) in pyridine (1.2 mL), was added methanesulfonyl chloride (210 L, 2.7 mmol) dropwise. The
reaction was heated to 60 °C for 2.5 hours, at which point LCMS indicated complete reaction. The
reaction was partitioned between water and EtOAc, and the aqueous phase was extracted with
additional EtOAc. The combined organic phase was washed with water, then 0.1N HC1, then sat'd
NaCl, and then was dried over MgSO4. The crude product was purified by column chromatography to
obtain the product as a mixture of diastereomers (164 mg, 52%). The diastereomers were then
separated by chiral HPLC to provide four distinct diastereomers, which were taken directly on to the
deprotection step. MS (El) m/z = 462.1 (M+H).
Step 7. 3-(2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)-cyclopentane-
carbonitrile trifluoroacetate.
The four diastereomers were then separately deprotected in this representative manner. To 3-
2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]ethylcyclopentanecarbonitrile (35 mg, 0.076 mmol) dissolved in CH2C12 (2.0 mL) was added TFA
(1.0 mL) and the reaction was stirred for 2 hours at ambient temperature at which point LCMS
indicated complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to
the residue was added methanol (1.0 mL) followed by ethylenediamine (40 uL, 0.61 mmol), the
reaction was stirred for 16 hours at which point LCMS indicated complete reaction. The solvent was
removed and the residue was purified by preparative LCMS to provide the product as a TFA salt.
NOE experiments confirm that all isomers have cis geometry on cyclopentyl ring. Isomers 1 and 2:
'H NMR (400 MHz, CD3OD): 5 8.95 (s, 1H), 8.89 (s, 1H), 8.54 (s, 1H), 7.86 (d, 1H), 7.29 (d, 1H),
4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 2.95 (m, 1H), 2.72 (m, 1H), 2.2-1.9 (m, 4H), 1.67 (m, 2H).
Isomers 3 and 4: "H NMR (400 MHz, CD3OD): 5 8.95 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.85 (d,
1H), 7.28 (d, 1H), 4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.71 (m, 1H), 2.44 (m,
1H), 2.05 (m, 1H), 1.92 (m, 1H), 1.72 (m, 1H), 1.58 (m, 2H).MS (El) m/z = 332.2 (M+H).
Example 98: 3-[3-(Hydroxymcthy0cycIopentyll-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]propanenitrile

Step 1: 3-[3-(Hydroxymethyt)cyclopentyl]-3-(4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile
A solution of 3--3-fonnylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (50.0 mg, 0.108 mmol) in methanol (280 L)
was cooled to 0 °C, then sodium tetrahydroborate (14 mg, 0.37 mmol) was added. The reaction was
held at 0 °C for 10 minutes, at which point LCMS and TLC indicated complete reaction. The reaction
was quenched by cautious addition of IN HC1 (3 drops) and methanol (1 mL), followed by addition of
aqueous NaHCO3 and CHC13. The phases were separated and the aqueous phase was washed with
additional CHC13. The combined organic phase was washed with sat'd NaCl, dried over MgSO4 and
reduced to dryness. The residue was purified by column chromatography to obtain the product as a
mixture of diastereomers (37.4 mg, 74%). 1HNMR (400 MHz, CDC13): 5 8.84 (s, 1H), 8.31 (s, 2H),
7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, 1H), 3.53 (m, 1H), 3.53 (t, 2H), 3.14 (m, 1H), 2.95
(m, 1H), 2.68 (m, 1H), 2.2-1.0 (m, 9H), 0.92 (t, 2H), -0.059 (s, 9H). MS (El) m/z = 467.2 (M+H).
Step 2. 3-[3-(Hydroxymethyl)cyclopentyl]-3'[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH--pyrazol-l -
yljpropanenitrile
To 3-[3-(hydroxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (60.4 mg, 0.129 mmol) dissolved in CH2C12
(2.0 mL) was added TFA (1.0 mL) and the reaction was stirred for 1 hour at which point LCMS
indicated complete cleavage to the N-hydroxymethyl intermediate (m/z = 367). The trifluoroacetate
ester of the hydroxymethyl of the cyclopentyl ring was also observed (m/z = 463). The solvent was
removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (80 uL, 1.19
mmol). The resulting mixture was stirred for 16 hours at which point LCMS indicated complete
reaction to the desired product. The solvent was removed and the residue was purified by chiral
HPLC to provide four distinct diastereomers (20.2 mg total of four isomers, 46%). NOE experiments
suggest that all isomers have cis geometry on the cyclopentyl ring. Isomers 1 and 2: 1H NMR (400
MHz, CD3OD): 8 8.65 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H),
3.40 (m, 2H), 3.22 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.82 (m, 1H),
1.6-1.4 (m, 3H), 1.03 (m, 1H). Isomers 3 and 4: 'H NMR (400 MHz, CD3OD): S 8.66 (s, 1H), 8.62

(s, 1H), 8.37 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 3.11 (m,
1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.09 (m, 1H), 1.71 (m, 1H), 1.55-1.25 (m, 3H),' 1.04 (m, 1H). MS
(EI)m/z = 337.1(M+H).

4-Bromo-lH-pyrrolo[2,3-b]pyridine (0.078 g, 0.00040 mol) and lH-indazole (0.283 g,
0.00240 mol) was heated neat in a sealed tube at 200 °C (an oil bath) overnight with stirring. The
reaction was allowed to cool to it and the crude product was purified by prep LC-MS on a C-18
column during with a water/ACN gradient containing 0.2% TFA to give the title compound (0.015
gm, 15%), as an amorphous white solid, LC /MS (M+H)+ 235, 'H NMR (DMSO-cfe) 8 12.01 (bs, 1H),
9.17(s, 1H), 8.31(s, 1H), 7.73(d, 1H, J=9.0), 7.67(m, 2H), 7.58(m, 1H), 7.28(m, 1H), 7.07(m, 2H).

4-Bromo-l-t2-(trimethyIsilyl)ethoxy]methyl-lH-pyrroloE2,3-b]pyridine (0.300 g, 0.000917
mol) was dissolved in DMF (6.5 mL, 0.084 mol) and then zinc cyanide (0.30 g, 0.0026 mol) was
added. The solution was degassed with nitrogen and then bis(tri-t-butylphosphine)palladium (0.1 g,

0.0002 mol) was added. The reaction was sealed and heated in the microwave to 100 °C for 30
minutes. The reaction was allowed to cool to rt, taken up in ethyl acetate and washed with water
saturated sodium carbonate, brine, dried over magnesium sulfate and concentrated to give an oil. The
crude product was purified by flash column chromatography (FCC) on silica gel, eluting with a
hexane: ethyl acetate gradient to give the product (0.25 gin) as a colorless oil. LC/M S (M+H)+ 274,
lH NMR (CDC13) 5 8.22 (d, 1H), 7.53(d, 1H), 7.40(d, 1H), 6.73(d, 1H), 5.65(s, 2H), 3.50(m, 2H),
0.90(m, 2H), 0.0(s, 9H).

l-[2-(Trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.05 g, 0.0002
mol) was dissolved in ethanol (2.0 mL, 0.034 mol), and then hydroxylamine hydrochloride (0.023 g,
0.00033 mol) and potassium carbonate (0.10 g, 0.00073 mol) were added. The reaction was heated to
reflux for 5 h, and the reaction was then allowed to cool to rt and filtered to remove the solids. The
filtrate was concentrated to give the product 0.06 g as yellow oily residue, LC/MS (M+H)+ 307.
Step3.3-[3-(l-[2-(Trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxadiazol-5-
yl] benzonitrile

The crude product N-hydroxy-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine-
4-carboximidamide (0.06 gm, 0.0002 mol) was dissolved in pyridine (1.0 mL, 0.012 mol) and then 3-
cyanobenzoyl chloride (0.040 g, 0.00024 mol) was added at rt. This mixture was stirred for 1 h and
heated to 80 °C in an oil bath. After heating for 18 h the reaction was allowed to cool to rt and then
diluted with ACN and concentrated in vacuo to give 3-[3-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-
pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxadiazol-5-yl]benzonitrile 0.08 gm as an off white residue, LC/M
S(M+H)+ 418.

Step4.3-[3-(lH-Pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxadiazol-5-yl]benzonitrile
Thecmde 3-[3-l-t2^trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxa-
diazol-5-yl]benzonitrile (0.08 g, 0.0002 mol) was dissolved in TFA (3.0 mL, 0.039 mol) under
nitrogen and then heated to 60 °C. After heating for 2 h the reaction was allowed to cool to rt and
concentrated in vacuo. The resulting residue was taken up in methanol and concentrated to remove as
much of the TFA as possible. The residue was taken up in methanol (2.0 mL, 0.049 mol) and
ammonium hydroxide (I mL). This mixture was stirred at rt for 2 h and the reaction was then
complete. The reaction was concentrated in vacuo to give the crude product which was purified by
prep HPLC on a C-18 column eluting with a ACNiwater gradient with 0.2% TFA to give the title
compound (0.025 gm, 43%) (M+H)= 288. 1H NMR (DMSOd6) 8 12.1 (bs, 1H), 8.65(s, 1H), 8.48(d,
1H,J=6.4), 8.39(d, 1H, J=4.8), 8.16(d, 1H, J=6.4), 7.84(t, 1H, J=6.4), 7.75(d, 1H, J=4.8), 7.68(m, 1H),
6.99 (m, 1H).

l-Benzothien-2-ylboronic acid (0.05 g, 0.0003 mol) and 4-bromo-l -[2-(trimethylsilyl)-
ethoxy]methyl-lH-pyrroIo[2,3-b]pyridine (0.10 g, 0.00031 mol) were combined in toluene (3.0 mL,
0.028 mol) and ethanol (1.0 mL, 0.017 mol). Potassium carbonate (0.085 g, 0.00062 mol) dissolved
in water (1.0 mL) then was added and the reaction was degassed with nitrogen. Then
tetrakis(triphenylpnosphine)palladhim(0) (0.05 g, 0.00004 mol) was added and the reaction was
heated to 120 °C in a sealed tube in the microwave for 60 minutes. This was allowed to cool to rt,
taken up in ethyl acetate and washed with water 2X, brine, dried over magnesium sulfate and

concentrated to give 4-(l-benzothien-2-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]-
pyridine (0.10 gm) as an oil, LC /MS (M+H)+ 381.
Step 2. 4-(l-Benzothien-2-yl)-lH-pyrrolo[2,3-b]pyridine
Using a procedure analogous to Example 106, Step 4, but using 4-(l-benzothien-27yl)-l-[2-
(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was prepared as a
yellow powder (0.015 g, 18%), LC /MS (M+H)+: 251, 1H NMR (DMSO-d6) 5 11.95 (bs, 1H), 8.28(d,
1H, J=5.4), 8.l5(s, 1H), 8.03(m, 1H), 7.96(m, 1H), 7.64(m, 1H), 7.42(m, 2H), 7.39(d, 1H, J=5.4),
6.95(m, 1H).

4-Bromo-lH-pyrrolo[2,3-b]pyridine (0.050 g, 0.00025 mol) and 4-fluoro-2-(lH-pyrazol-3-
yl)phenol (0.150 g, 0.000842 mol) were heated neat to 160 °C for 5 h. The reaction was allowed to
cool to rt and the residue was purified by prep LC-MS on a C-18 column eluting with a water/ACN
gradient containing 0.2% TFA to give the title compound, (0.052 g, 20%, as an amorphous white
solid, LC IMS (M+H)+ 295, 'H NMR (DMSO-d6) 5 12.01 (bs, 1H), 10.25(bs, 1H), 8.81(s,lH), 8.35(d,
1H, J= 5.5), 7.77(d, 1H, J=9.5), 7.64(m, 1H), 7.59(d, 1H, J=5.5), 7.32(s, 1H), 7.09(m, 1H), 7.05(m,
1H), 7.01(m, 1H).

l-[5-(Trifluoromethyl)phenyl]ethanone (0.20 mL, 0.0013 mol) and l,l-dimethoxy-N,N-
dimethylmethanamine (0.17 mL, 0.0013 mol) were combined in a sealed tube and heated in a
microwave to 120 °C for 15 minutes, the reaction was allowed to cool and was concentrated to
remove the residual DMF acetal, to give (2E)-3-(dimethylamino)-l-[3-(trifluoromethyl)phenyl]prop-
2-en-l-one, 0.32 gm, as a red oil, LC /MS (M+H)+: 244.

The (2E)-3-(dimethylamino)-l-[3-(trifluoromethyl)phenyl]prop-2-en-l-one (0.32 g, 0.0013
mol) was dissolved in ethanol (10.0 mL, 0.171 mol) and hydrazine (0.24 mL, 0.0078 mol) under
nitrogen and heated to reflux. The reaction was monitored by HPLC and was complete almost
immediately. The mixture was allowed to cool to rt and concentrated to give the crude product as an
oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to
give 3-[3-(trifluoromethyl)phenyl]-lH-pyrazole as an oil (0.25 g, 89% ), LC /MS (M+H)+: 213, 'H
NMR (CDC13) 5 8.06 (s, 1H), 7.99(d, 1H, J=7.5), 7.66(d, 1H, J= 2.4), 7.57(m, 1H), 7.55(d, 1H,
J=7.5), 6.69(d, 1H, J= 2.4).
Step 3. 4-3-[3-(Trifluoromethyl)phenyl]-lH-pyrazol-l-yl-lH-pyrrolo[2,3-b]pyridine
4-Bromo-lH-pyrrolo[2,3-b]pyridine (0.028 g, 0.00014 mol) and 3-[3-(trifluoromethyl)-
phenyl]-lH-pyrazole (0.03 g, 0.0001 mol) were combined neat. The reaction was heated in a sealed
tube in an oil bath to 175 °C for 20 to produce a crude product that was a black viscous gum. The
crude product was purified by HPLC on a C-18 column eluting with a waterACN gradient with 0.2%
TFA to give the title product (0.025 gm, 50%) as a white amorphous solid, LC /MS (M+H)+: 329, 'H
NMR (DMSO-rf6) 5 11.95 (bs, 1H), 8.83(d, 1H, J=2.7), 8.31(m, 3H), 7.75(m, 2H), 7.60(m, 2H),
7.35(d, 1H, J=2.7), 7.14(m, 1H).
Example 128: 3-[l-(lH-Pyrrolo[2,3-blpyridin-4-yl)-lH-pyrazol-3-yl]benzonitrile

Step 1. 3-[(2E)-3-(Dimethylamino)prop-2-enoyl]benzonitrile
3-AcetylbenzonitriIe (0.435 g, 0.00300 mol) and l,l-dimethoxy-N,N-dimethylmethanamine
(0.400 mL, 0.00301 mol) were combined and heated in sealed tube to 120 °C in the microwave for 15
min. The reaction was then allowed to cool to rt giving the 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-
benzonitrile as a red-orange crystalline material, LC /MS (M+H)+: 201.
Step 2. 3-(lH-Pyrazol-3-yl)benzonitrile
The 3-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile (0.600 g, 0.00300 mol) was
dissolved in ethanol (20.0 mL, 0.342 mol) and hydrazine (0.56 mL, 0.018 mol) under an atmosphere
of nitrogen was stirred at room temperature for 1.5 h. The reaction was concentrated in vacuo to give
a dark product which was purified by FCC on silica gel, eluting with ethyl acetate-hexane 1:1 to give
3-(lH-pyrazol-3-yl)benzonitrile as an oil (0.430g, 84%), LC /MS (M+H)+: 170.
Step 3. 3-[l-(lH-Pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yl]benzonitrile
4-Bromo-lH-pyrrolo[2,3-b]pyridine (0.075 g, 0.00038 mol) and 3-(lH-pyrazol-3-yl)benzo-
nitrile (0.161 g, 0.000952 mol) were heated in sealed tube to 160 °C for 18 h. The resulting product,
dark viscous gum, was purified by HPLC on a C-l 8 column eluting with a water:ACN gradient with
0.2% TFA to give the title product (0.030 g, 27%) as a white amorphous solid, LC /MS (M+H)+: 286,
'H NMR (DMSO-d6) 6 11.95 (bs, 1H), 8.76(s, 1H), 8.36(s, 1H), 8.29(d, 1H, J=7.5), 8.25(d, 1H,
J=5.0), 7.79(d, 1H, J= 7.5), 7.62(t, 1H, J= 7.5), 7.53(m, 2H), 7.25(s, 1H), 7.1 l(m, 1H).

Stepl.4-(4A,5,S-Tetramethyl-l,3,2-(Uoxaborolan-2-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-
pyrazole
A solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyra2ole (2.0 g, 0.010 mol)
and DMF (30.0 mL, 0.387 mol) was cooled to 0 °C. Sodium hydride (320 mg, 0.013 mol) (60% in oil)
was added and the mixture was stirred for 10 min. [/3-(Trimethylsilyl)ethoxy]methyl chloride (2.4
mL, 0.013 mol) was added and the resulting mixture was stirred for 20 min at 0° C and 2 h at room
temperature. The reaction was partitioned between water and ethyl acetate. The organic layer was
washed with brine, dried over MgSO4 and concentrated to give 4-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrazole as a crude material. LC/MS
(M+H)+: 325, 1H NMR (CDC13) 6 7.85 (s, 1H), 7.80(s, 1H), 5.45(s, 2H), 3.55(t, 2H), 1.35(s, 12H),
0.95(t, 2H), 0.0(s, 9H).
Step 2. 3-(l-[2-(Trimethylsilyl)ethoxy]methyl-lH-pyrazol-4-yl)benzonitrile
A mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-[2-(trimethylsilyl)ethoxy]-
methyl-lH-pyrazole (150.0 mg, 0.0004625 mol) and 3-bromobenzonitrile (0.10 g, 0.00056 mol) in
toluene (2.0 mL, 0.019 mol) and ethanol (0.3 mL, 0.005 mol) was treated with sodium carbonate (98
mg, 0.00092 mol) in water (0.5 mL, 0.03 mol). The mixture was degassed by bubbling nitrogen.
Tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.000046 mol) was added and nitrogen was
bubbled for 3 min. The reaction was heated in a microwave at 80 °C for 30 min, then allowed to cool
to it and taken up in water and ethyl acetate. The organic layer was dried over MgSO4, filtered and
concentrated to give a crude product, which was purified by FCC on silica gel, eluting with
EtOAc/Hexanes (1:5) to give 3-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrazol-4-yl)benzonitrile, as
an oil, LC /MS (M+H)+: 300.

A solution of 3-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrazol-4-yl)benzonitrile (110.0 mg,
0.0003673 mol) was taken up in TFA (3.0 mL, 0.039 mol) and the mixture was heated in microwave
at 120 °C for 3 min. The reaction mixture was allowed to cool to rt, and then concentrated to give a
crude residue. The product was purified by HPLC on a C-l 8 column eluting with a water/ACN
gradient containing 0.2% TFA to give 3-(lH-pyrazol-4-yl)benzonitrile trifluoroacetate as an
amorphous white solid, LC /MS (M+H)+: 170.

Step 4. 3-[l-(lH-Pyrrolo[2,3-b]pyridin-4-yl)~lH-pyrazol-4-yl]benzonitrile
A mixture of 4-bromo-lH-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol) and 3-(lH-
pyrazol-4-yl)benzonitrile trifluoroacetate (23.6 mg, 0.0000833 mol) was heated at 180 °C, neat
overnight. The crude residue was purified by HPLC on a C-18 column eluting with a water; ACN
gradient containing 0.2% TFA to give the title compound as an amorphous white solid, LC/MS
(M+H)+: 286, 'H NMR (DMSCW6) 5 11.85 (bs, 1H), 9.18(s, 1H), 8.42(s, 1H), 8.28(s, 1H), 8.25(d,
1H, J=5.0), 8.07(d, 1H, J=7.0), 7.64(d, 1H, J=7.0), 7.56(t, 1H, J= 7.0), 7.51(m, 1H), 7.47(d, IH,
J=5.0), 7.03(m,lH).

To 4-bromo-l-t2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (1.98 g, 0.00605
mol) was added hydrazine (11.0 mL, 0.350 mol) followed by addition of methanol (1.0 mL, 0.025
mol) (to improve solubility). The reaction mixture was heated in a sealed tube at 97 °C (an oil bath)
for 18 h. The reaction mixture was cooled to rt and formed an off-white solid precipitate. The solid
was filtered off and rinsed with cold water and dried to give 4-hydrazino-l-[2-(trimethylsilyl)ethoxy]-
methyl-lH-pyrrolo[2,3-b]pyridine (1.55gm) as a light yellow solid, LC/MS (M+H)+:279, 1H NMR
(DMSO-d6) 8 7.98(d, 1H), 7.91(s, IH), 7.28(d, IH), 6.69(s, 1H), 6.61(d, IH), 5.58(s, 2H), 4.37(s, 2H),
3.56(t, 2H), 0.90(t, 2H), 0.0(s, 9H).
Step 2. 2-[l-(l-[2-(Trimethylsilyl)elhoyy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-
1,3-benzoxazole

To 4-hydrazino-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.083 g,
0.00030 mol) 3782-117-1 and l.S-benzoxazol^-ylmalonaldehyde (0.056 g, 0.00030 mol) in toluene
(1.5 mL, 0.014 mol) was added molecular sieves. The mixture was heated in a sealed tube at 70 °C
(an oil bath) with stirring for 2 h. The solvent was removed in vacuo and the crude product was
purified by FCC on silica using ethyl acetate:hexanes 3:7 to give 2-[l-(l-[2-(trimethylsilyl)ethoxy]-
methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-l,3-benzoxazole (0.090gm) as an oil,
LC/MS (M+H)+: 432.
Step 3.
Using a procedure analogous to Example 106, Step 4, but using 2-[l-(l-[2-(trimethylsilyl)-
ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-l,3-benzoxazole, the title compound
was prepared as a white amorphous powder (0.015 gm, 18%), LC /MS (M+H)+:302, 1H NMR
(DMSO-d6) 5 11.85 (bs, 1H), 9.45(s,lH), 8.53(s, 1H), 8.36(bs, 1H), 7.7-7.6(m, 2H), 7.65(d, 1H),
7.56(bs, 1H), 7.38-7.34(m, 2H),7.01(d,lH).

A mixture of 4-bromo-lH-pyrrolo[2,3-bJpyridine (1.10 g, 0.00558 mol) and 4-broroo-lH-
pyrazole (1.2 g, 0.0084 mol) was heated neat to 150 °C for 2 h. DMF was added to dissolve the
crude residue. This residue was taken up in EtOAc and washed with IN NaOH. The organic layer
was washed with brine, dried over MgSO4, filtered and concentrated to give a crude 4-(4-bromo-lH-
pyrazol-l-yl)-lH-pyrrolo[2,3-b]pyridine residue, LC /MS (M+H)+: 263,265.

A solution of 4-(4-bmma-lH-pyrazol-l--yl]-l-[2-(trimethylsiiyl)ethoxy]methyl chloride (1.4
mL, 0.0079 mol) was added and stirred for 20 min at 0 °C. The reaction was partitioned between ethyl
acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated to
give the crude material. The product was purified by FCC on silica gel (EtOAc/Hexanes, 1/10) to give
4-(4-bromo-lH-pyrazol-l-yl)-l-[2-(triinethyIsilyl)ethoxy]methyl-lH-pyrro/o/2,5-67]yarirfine as a
solid product, LC /MS (M+H)+: 393, 394, 1HNMR (CDC13) 8 8.47(d, 1H, J=7.0), 8.27(s, 1H), 7.88(s,
1H), 7.52(d, 1H, J=4.5), 7.39(d, 1H, J=7.0), 7.069(d, 1H, J=4.5), 5.80(s, 2H), 3.6(t, 2H), 1.95(t, 2H),
0.0(s, 9H).
Step 3. CyclohexyI[l-(l-[2-(trimethylsilyl)ethoty]methyI-lH-pyrrolo[2J-b]pyridin-4-yl)-1H-pyrazol
4-ylfmethanol

A mixture of 4-(4-bromo-lH-pyrazol-l-y])-l-[2-(trimethylsilyl)ethoxy]inethyl-lH-
pyrrolo[2>3-b]pyridine (50.0 mg, 0.000127 mol) in THF (2.0 mL, 0.025 mol) under a nitrogen
atmosphere was cooled to -78 °C and 1.6 M n-butyllithium in water (1.00 mL, 0.0555 mol). The
mixture was stirred for 3 rain. The reaction was partitioned between water and EtOAc. The organic
layer was dried over MgSO4, filtered and concentrated to give the cyclohexyl[l-(l:5) to give 4-yl)-
lH-pyrazol-4-yl]methanol as a crude residue, LC /MS (M+H)+: 417.
Step 4. Cyclohexyl[l-phenylvinyl)-lH-pyrazol-4-yl]methanol
Using a procedure analogous to Example 106, Step 4, but using cyclohexyl[l-(l-[2-
(trimethylsilyl)ethoxy]methyI-lH-pyrroIo[2)3-b]pyridine, the title compound was prepared as a white
amorphous powder (0.015 gm, 18%), LC /MS (M+H)+: 297. 1H NMR (DMSO-d6) S 11.85 (bs, 1H),
8.44(s, 1H), 7.74(s, 1H), 7.50(m, 1H), 7.44(d, 1H, J=6.5.70(s, 1H), 5.37(s, 1H).

A mixture of (l-phenylvinyl)boronic acid (24.0 mg, 0.000162 mol) and 4-(4-bromo-l H-
pyrazol-l-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol)
in toluene (2.00 mL, 0.0188 mol) and ethanol (0.50 mL, 0.0086 mol) was treated with potassium
5 carbonate (35 mg, 0.00025 mol) in water (1.00 mL, 0.0555 mol). The mixture was degassed by
bubbling nitrogen. Tetrakis(triphenylphosphine)palladiiim(0) (10 mg, 0.00001 mol) was added and
nitrogen was bubbled for 3 min. The reaction was heated in a sealed tube in the microwave at 100 °C

for 30 min. The reaction was allowed to cool to it and partitioned between ethyl acetate and water.
The combined organic layer was dried over MgSO4 filtered and concentrated to give the crude
material The crude product was purified by FCC on silica gel eluting with EtOAc/Hexanes (1:5) to
give 4-[4^1-phenylvnyl)-lH-pyrazol-l-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]-
pyridine as a solid residue, LC /MS (M+H)+: 417.
Step 2.
Using a procedure analogous to Example 106, Step 4, but using 4-[4-(l-phenylvinyl)- 1H-
pyrazol-l-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was
prepared as an white amorphous powder (0.015 gm, 31%), LC /MS (M+H)+: 287, 'H NMR (DMSO-
d6) 8 11.85 (bs, 1H), 8.63(s, 1H), 7.99(s, 1H), 7.55(bs, 1H), 7.48(m, 2H), 7.43-7.37(m, 5H),
7.01(m,lH), 5.70(s, 1H), 5.37(s, 1H).

4-Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyn-olo[2>3-b]pyridine (0.100 g, 0.000306
mol) was combined with l-benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole
(0.113 g, 0.000398 mol) in toluene (3.0 mL, 0.028 mol) and ethanol (0.5 mL, 0.008 mol). Potassium
carbonate (0.084 g, 0.00061 mol) dissolved in water (1.0 mL, 0.056 mol) was added and the reaction
mixture was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.000069
mol) was added, and again the mixture was degassed with nitrogen for 5 min. The reaction was heated
in sealed tube to 100 °C in a microwave for 30 minutes. The reaction was partitioned between ethyl
acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and

concentrated to give a crude residue. The product was purified by FCC on silica gel using ethyl
acetate:hexane 3:7, to give 4-(l-benzyl-lH-pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-
pyrrolo[2,3-b]pyridine 0.092g as a semisolid residue, LC /MS (M+H)+: 405.
Step 2. 4-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine
Using a procedure analogous to Example 106, Step 4, but using 4-(l-benzyl-lH-pyrazol-4-
yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was prepared as
a white amorphous powder (0.054 gm), LC /MS (M+H)+: 275, 'H NMR (DMSO-rf6) 5 12.21 (bs, 1H),
8.80(s, 1H), 8.25(vbs, 1H), 8.23(s, 1H), 7.63(s, 1H), 7.49(bs, 1H), 7.4-7.2(m, 5H), 6.99(s, 1H), 5.42(s,
2H).

Step 1. l-(2-Naphthylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole
The 4-(4J4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.10 g, 0.00052 mol) was
combined with naphthalene, 2-(bromomethyl)- (0.12 g, 0.00057 mol) in ACN (3.0 mL, 0.057 mol)
under nitrogen at rt. Then cesium carbonate (0.50 g, 0.0015 mol) was added and the reaction was
complete after stirring for 1 h. This was partitioned between ethyl acetate and brine. The organic
layer was washed with brine, dried over magnesium sulfate and concentrated to give l-(2-
naphthylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole 0.17 gm, as an oil,
LC/MS (M+H)+: 335, 'H NMR (CDC13) 5 7.89 (s, 1H), 7.79-7.84(m, 3H), 7.69(bs, 2H), 7.49-7.4(m,
2H), 7.46-7.33(m, 1H), 5.47(s, 2H), 1.31(s, 12H).

4-Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.06 g, 0.0002 mol)
and l-(2-naphthylmethyl)-4-(4,4,5,5-tetramethyl-l)3)2-dioxaborolan-2-yl)-lH-pyrazole (0.074 g,
0.00022 mol) were combined in toluene (2.0 mL, 0.019 mol) and ethanol (1.0 mL, 0.017 mol), and
then potassium carbonate (0.063 g, 0.00046 mol, in 1 mL water) was added. The reaction mixture
was degassed with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol) was
added, sealed in a tube and heated to 120 °C in a microwave for 30 minutes. This was allowed to
cool and then partitioned between ethyl acetate and brine. The organic layer was dried over
magnesium sulfate and concentrated to give 4-[l-(2-naphthylmethyl)-lH-pyrazol-4-yl]-l-[2-
(trimethylsilyl)ethoxy]methyl-lH-pyrroIo[2,3-b]pyridine 0.08 g, as an oily residue, LC /MS (M+H)+:
455.
Step 3
Using a procedure analogous to Example 106, Step 4, but using 4-[l-(2-naphthylmethyl)-lH-
pyrazol-4-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was
prepared as a white amorphous powder (0.053 g, 88%), LC /MS (M+H)+: 325, 1H NMR (DMSO-D6) 5 •
12.0(bs, 1H), 8.79(s, 1H), 8.24(s, 1H), 8.19(d, 1H, J=5.7), 7.82(m, 4H), 7.56(m, 1H), 7.43(m, 4H),
6.92(m, 1H), 5.54(s, 2H).

Step 1. l-phenyl-4-(4,4,5,5-Tetramethyl-l,3.2-dioxaborolan-2-yl)-lH-pyrazole
4-(4,4,575-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.07 g, 0.0003 mol) and
phenylboronic acid (0.083 g, 0.00068 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then
copper(Il) diacetate (0.010 g, 0.000055 mol) and pyridine (0.069 mL, 0.00085 mol) were added. The
reaction was heated in an open tube to 80 °C for 40 minutes. The reaction was complete by HPLC,
allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium
carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated
to give l-phenyl-4-(4,4,5,5-tetramethyl-l,332-dioxaborolan-2-yl)-lH-pyrazo, 0.09 gm as an oily
residue, LC/MS (M+H)+: 271.

Step 2. 4-(l-Phenyl-lH-pyrazol-4-yl)-l-f2-(trimethylsilyl)ethojty]methyl-lH-pyrrolof2,3-b]pyridine
Using a procedure analogous to Example 201, Steps B and C, but using 1 -phenyl-4-(4,4,5,5-
tetramethyl-l,3,2-dioxaborolan-2-yl)~lH-pyrazo, the title compound was prepared as an white
amorphous powder (0.015 gm, 18%), LC/MS (M+H)+: 261, 1H NMR (DMSO-d6) 5 12.05 (bs, 1H),
9.23(s, IH), 8.53(s, 1H), 8.31(m, 1H), 8.01(m, 2H), 7.63(m, 1H), 7.57-7.52 (m, 3H>, 7.36(m, 1H),
7.13(m, IH).

4-Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.20 g, 0.00061 mol)
and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.15 g, 0.00079 mol) were
combined in DMF (5.0 mL, 0.064 mol) and then potassium carbonate (0.25 g, 0.0018 mol) in 1 mL
water was added. The reaction was degassed with nitrogen, then tetrakis(triphenylphosphine)-
palladium(O) (0.08 g, 0.00007 mol) was added and in a sealed tube the reaction was heated to 120 °C
oil bath. The reaction was heated for 30 minutes, allowed to cool and then taken up in ethyl acetate.
The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated to give
an oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to
give 4-(lH-pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine (0.13 gm,
70%) as a crystalline white powder, LC /MS (M+H)+: 315, 1H NMR (DMSO-d6) 8 13.35 (bs, IH),
8.59(bs, IH), 8.32(d, 1H, J=8.5), 8.26(bs, IH), 7.76(d, IH, J=6.0), 7.45(d, 1H, J=8.5), 7.01 (d, IH,
J=6.0), 5.73(s, 2H), 3.6l(t, 2H), 0.92(t, 2H), 0.0(s, 9H).
Step2.3-[4-(l-[2-(Trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-
yljbenzonitrile

4-(lH-Pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyirolo[2,3-b]pyridine (0.025 g,
0.000080 mol) and (3-cyanophenyl)boronic acid (0.023 g, 0.00016 mol) were combined in DMF
(1.50 mL, 0.0194 mol). Then copper(H) diacetate (0.002 g, 0.00001 mol) and pyridine (0.019 mL,
0.00024 mol) were added. The reaction was heated in an open tube to 125 °C for 40 minutes,
allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium
carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated
to give 3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-
benzonitrile (0.025 gm, 92%) as an oily residue, LC /MS (M+H)+: 316.
Step 3
Using a procedure analogous to Example 106, Step 4, but using 3-[4-(l-[2-(trhnethylsilyl)-
ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile, the title compound was
prepared as an white crystalline powder (0.012 gm, 60%), LC/MS (M+H)+: 286, 1H NMR (DMSO-
d6) 5 12.05 (bs, 1H), 9.32(s, 1H), 8.59(m, 1H), 8.55(m, 1H), 8.36(m, 1H), 8.30(d, 1H, J=5.2), 7.83(m,
1H), 7.75(m, 1H), 7.63(m, 1H), 7.51(d, 1H, J=5.2), 7.12(m, 1H).

4-(lH-Pyra2zol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyirolo[2,3-b]pyridine (50 mg,
0.0002 mol) (see, Example 231, Step 1) was dissolved in DMF (2 mL, 0.02 mol) and cooled at 0 °C.
This solution was treated with sodium hydride (7.0 mg, 0.00029 mol) (60% in oil) and stirred for 15
min. The mixture was then treated with 2-bromopentane (40 mg, 0.0002 mol) and was stirred for 5 h.
The reaction was partitioned between ethyl acetate and water. The organic layer was washed with
brine, dried over MgSO4, filtered and concentrated to give the crude product 4-[l-(l-methylutyl)-lH-
pyrazol-4-yl]-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine as an oil, LC/MS
(M+H)+: 286.
Step 2. 4-[l-(l-Methylbutyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine
Using a procedure analogous to Example 106, Step 4, but using 4-[l-(l-methylbutyl)-lH-
pyrazol-4-yl]-l-[2-(trimethylsiIyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridine, the title compound was
prepared as an white amorphous powder (0.025 gm, 60%), LC /MS (M+H)+: 255, 1H NMR (DMSO-
d6) S 12.21 (bs, 1H), 8.66(s, 1H), 8.27(bs, 1H), 8.25(s, 1H), 7.62(m, 1H), 7.49(m, 1H), 7.02(m, 1H),
4.46(m, 1H), 1.9-1.8(m, 1H), 1.7-1.6(m, 1H), 1.47(d, 3H), 1.2-1.0(m, 2H), 0.83(t, 3H).
Step 3. Separation of Enantiomers
The separation of the enantiomers of 4-[l-(l-methylbutyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-
b]pyridine from Step 2 was performed by chiral column preparative HPLC separation using an OD-H
column eluting with an isopropanokhexane gradient to give the title compounds as amorphous white
residues, LC /MS (M+H)+: 255, 1H NMR (DMSO-d6) 6 12.21 (bs, 1H), 8.66(s, 1H), 8.27(bs, 1H),
8.25(s, 1H), 7.62(m, 1H), 7.49(m, 1H), 7.02(m, 1H), 4.46(m, 1H), 1.9-1.8(m, 1H), 1.7-1.6(m, 1H),
1.47(d, 3H), 1.2-1.0(m, 2H), 0.83(t, 3H).

To a mixture of 4-(lH-pyrazol-4-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]-
pyridine (0.050 g, 0.00016 mol) (see, Example 231, Step 1) and cesium carbonate (0.10 g, 0.00032
mol) in dry DMF (1.0 mL, 0.013 mol) was added 3-fluoro-4-methylbenzonitrile (0.043 g, 0.00032
mol). The reaction mixture was heated in sealed tube to 120 °C for 5.5 hours. The reaction was
allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with
water, brine, dried over magnesium sulfate, filtered, and concentrated to give 4-methyl-3-[4-(l-[2-
(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile as a crude
product, LC /MS (M+H)+: 430.
Step 2. 4-Methyl-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile
Using a procedure analogous to Example 106, Step 4, but using 4-methyl-3-[4-(l-[2-
(trimethyIsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-l-yl]benzonitrile, the title
compound was prepared as a white amorphous powder (0.037 gm, 88%), LC /MS (M+H)+: 300, 'H
NMR (DMSO-d6) 8 12.19 (bs, 1H), 8.98(s, 1H), 8.57(s, 1H), 8.31(d, 1H, J=7.0), 8.08(s, 1H), 7.89(d,
1H, J=10), 7.66(d, 1H, J=10), 7.63(m, 1H), 7.55(d, 1H), 7.07(m, 1H), 2.4(s, 3H).
Further example compounds of the invention are provided in Tables 7, 8,9,10, and 11 below.
The compounds listed in Tables 7, 8, 9, 10 and 11 are racemic unless the enantiomers are indicated
separately.

Step 1: Dimethyl 3~[4-(7-{[2-(tnmetkylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]pentanedioate
4^1H-PyrazoM-yl)-7-t2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (31.0 g,
0.0983 mol) was suspended in ACN (620 mL, 12 mol), and DBU (9.3 mL, 0.062 mol) was added
under nitrogen. The reaction was heated to 65 °C and dimethyl (2E)-pent-2-enedioate (16 mL, 0.12
mol) was added in 5 mL portions over 2 h. After stirring overnight, the reaction was complete. The
reaction was allowed to cool to room temperature and was concentrated in vacuo to give a dark oil.

The oil was partitioned between ethyl acetate and water. The organic layer was washed with 1.0 N
HC1, brine, dried over magnesium sulfate, and then concentrated to give a dark oil. The viscous oil
was-triturated with ethyl ether 3X 500 mL to give a dark precipitate. The oil was taken up in ethyl
acetate to form a solid. The solids were collected, washed with ethyl ether and dried to give dimethyl
3-[4-(7-{[2-(trimemylsilyl)ethoxy3methyl}-7H-pvrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]pentanedioate as a white powder (29.5 gm, 64%), LC /MS (M+H)+: 474, 'H NMR (DMSO-d6) 8
9.1 (s,lH), 9.02 (s,lH), 8.65 (s, 1H), 8.11 (d, 1H), 7.42(d, 1H), 5.78(s, 2H), 5.27(m, 1H), 3.65(m, 8H),
3.15(m, 4H), 0.95(t, 2H), 0.1(s, 9H).
Step 2: 3-[4-(7-[2-(Trimetf^lsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-dJpyrimidin-4-yl)-lH-pyrazol-J-ylJ-
pentanedioic acid
Dimethyl 3-[4 pyrazol-l-yl]pentanedioate (43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol)
and lithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125 mL) was added. The
reaction was stirred at rt for 2 h. The methanol was removed in vacuo and a resulting aqueous layer
was cooled in an ice bath. The solution was made acidic pH~4 with IN HC1 to give a white
precipitate. The solid precipitate was collected, washed with water, dried to give 3-[4-(7-[2-
(trimethylsilyl)ethoxy3methyl-7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yljpentanedioic acid as
a white crystalline powder (31.8 gm, 80%), LC /MS (M+H)+: 446, 'H NMR (DMSO-d6) 5 8.85s 1H),
8.75(s, 1H), 8.42(s, 1H), 7.85(d, 1H), 7.17(d, 1H), 5.71(s, 2H), 5.18(m,lH), 3.65(t, 2H), 3.05(m,4H),
0.92(t,2H),0.1(s,9H).
Step 3: 3-[4-(7-[2-(Trimethylsilyl)ethoy]methyl-7H-pyrrolo[2,3-d]pyHmidin-4-yl)-lH-pyrazol-l-yl]-
pentanediamide
3-[4 yl]pentanedioic acid (31.80 g, 0.07137 mol) was dissolved in DMF (636 mL, 8.21 mol) under
nitrogen cooled in an ice bath and CDI (34.7 g, 0.214 mol) was added. This mixture was allowed to
stir for 30 minutes and then allowed to warm to rt. After stirring for 2 h ammonia (12.2 g, 0.714 mol)
was bubbled through the solution for 30 minutes giving a cloudy suspension. The reaction mixture
was concentrated to remove some of the DMF (~200 mL) and then water was added slowly to give a
white precipitate. This mixture was cooled in an ice bath and the solid precipitate was collected,
washed with water and dried in vacuo to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pvrazol-l-yl]pentanediamide as a white powder (29.0 gm, 91%),
LC /MS (M+H)+: 444, 'H NMR (DMS0-d6) 8 8.85(s, 1H), 8.59(s, 1H), 8.40(s, 1H), 7.87(d,lH),
7.75(s,2H), 7.15(d, 1H), 6.95(s, 2H), 5.73(s, 2H), 5.29(m,lH), 3.63(t, 2H), 2.82(m, 2H), 2.73(m, 2H),
0.90(t,2H),0.1(s,9H).

Step 4: 3-[4-(7-[2-(Trimethylsilyl)etho^]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-
pentanedinitrile
3-[4-(7,[2-9Trimethylsllyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]pentanediamide (29.0 g, 0.0654 mol) was partially dissolved in DMF (200 mL, 2 mol), DCM (200
mL, 3 mol) and TEA (36 mL, 0.26 mol) and. cooled in an ice bath under nitrogen atmosphere. The
trichloroacetyl chloride (IS mL, 0.14 mol) was added dropwise turning the reaction to a dark solution.
This was stirred at 0 °C for 1/2 h. The reaction was then concentrated to remove the DCM and the
resulting DMF solution was diluted with water to precipitate the product. The solid precipitate was
collected and washed with water to give a dark solid. The solid was then dissolved in DCM and
washed with brine, dried over magnesium sulfate and concentrated to give a very dark oily residue.
The residue was taken up in DCM, and hexane was added until the solution became slightly cloudy.
This was stirred at it to precipitate 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanedinitrile as white needle-like crystals (22.7 gm, 85%), LC
/MS (M+H)+: 408, 'H NMR (DMSO-4;) 8 9.07(s, 1H), 8.87(s, 1H), 8.59(s, 1H), 7.88(d, 1H), 7.19(d,
1H), 5.75(s, 2H), 5.30(m,lH), 3.62(t, 2H), 3.40(m, 4H), 0.91(t, 2H), 0.10(s, 9H).
Step 5: 3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanedinitrile
3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l-
yl]pentanedinitrile (10.0 g, 0.0245 mol) was dissolved in ACN (200 mL, 3.83 mol) and water (20 g,
1.1 mol) at rt. To this lithium tetrafluoroborate (23.0 g, 0.245 mol) was added giving a cloudy
solution. The reaction was heated to reflux and monitored by HPLC. After heating for 24 h the
reaction was allowed to cool to rt and then cooled in an ice bath. To this, ammonium hydroxide (23
mL, 0.59 mol) was added slowly. The reaction was allowed to warm to rt. After stirring for 18 hs the
reaction was diluted with water and concentrated in vacuo to remove the ACN, giving a precipitate.
The solids were collected, washed with water and dried to give the title compound as an off-white
solid (6. 2 gm, 91%), LC /MS (M+H)+: 278, 'H NMR (DMSO-d6) S 8.9(s, 1H), 8.72(s,lH), 8.43(s,
1H), 7.59(d, 1H), 6.92(d, 1H), 5.21(m,lH), 3.25(m, 4H).
Example 421: 5-{2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]etnyl}-
pyridine-2-carbonitrile trifluoroacetate

Step J: 3-(6-Chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile
3-(6-Chloropyridin-3-yl)-3-[4-(7-[2-(trimethylsi!yl)ethoxy]methyI-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yI]propanenitrile (prepared by methods analogous to those described
for Example 61) (0.070 g, 0.00014 mol) in TFA (3.0 mL, 0.039 mol) and DCM (3.0 mL, 0.047 mol)
was stirred at room temperature for 1 hour. Solvent was removed in vacuo, and the residue was
dissolved in methanol (4.0 mL, 0.099 mol) and ethylenediamine (0.07 mL, 0.001 mol). The reaction
mixture was stirred at room temperature overnight. Solvent was removed in vacuo, the crude product
was purified by preparative HPLC eluting with an ACN; water gradient buffered with ammonium
hydroxide to pH=10, to give 3-(6-chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-
pyrazol-l-yl]propanenitrile as a white powder (35mg,69%), LCMS (M+l)+:350, 'H NMR (DMSO-d6)
6 12.21 (b,lH), 9.00 (s,lH), 8.78 (s,lH), 8.62 (s,lH), 8.58 (s,lH), 8.00(m,lH), 7.70(m,2H),
7.00(s,lH), 6.22(m,lH), 3.90(m,lH), 3.78(m,lH)
Step 2: 5-2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin~4-yl)-lH-pyrazol-l-yl]ethylpyridine-2-carbo-
nitrite trifluoroacetate
A mixture of 3-(6-cchloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]propanenitrile (0.025 g, 0.000071 mol) and zinc cyanide (0.08 g, 0.0007 mol) in DMF (1.0 mL,
0.013 mol) was degassed with nitrogen. To this mixture, tetralds(triphenylphosphine)palladium(0)
(0.04 g, 0.00004 mol) was added and the resulting mixture degassed again with dinitrogen. The
reaction mixture was heated in a sealed tube at 170 °C for 15 minutes in a microwave (Personal
Chemistry). After cooling to room temperature, the solids were filtered, rinsed with DMF and the
combined solvent was concentrated in vacuo. The residue was triturated with hexanes (3x), and
hexanes washes were discarded. The crude product was purified by preparative HPLC eluting with an
ACN; water gradient containing 0.2% TFA to give the title compound as. a white powder (16 mg,
49.27%), LCMS (M+l)+: 341, 1H NMR (DMSO-d6) 5 12.50(b,lH), 9.05(s,lH), 8,89(s,lH),
8,80(s,lH), 8.58(s,lH), 8.18(m,2H), 7.78(s,lH), 7.05(s,lH), 6.20(m,lH), 3.90(m,lH), 3.77(m,lH).
Example 428: 4-[4-(7H-PyrroloI2^-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]heptanedinitrile

Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yllpentane-l ,5-diol
Diethyl 3-[4-(7-[2-(1ximethylsilyl)ethoxy]methyl-7H-pynrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]pentanedioate, prepared substantially as described in Example 407 (0.80 g, 0.0016 mol),
was dissolved in THF (40 mL, 0.49 mol) and cooled in an ice bath under a nitrogen atmosphere. To
this mixture, 1.0 M lithium tetrahydroaluminate in THF (3.2 mL) was added slowly. The reaction
was stirred for lh, quenched with ice and partitioned between ethyl acetate and 1 N HC1. The organic
layer was washed with brine, dried over magnesium sulfate and concentrated to give an amber oil.
The product was purified by FCC on silica gel eluting with an ethyl acetate: methanol gradient to give
3-[4-(7-[2-(tiimethylsilyl)ethoxy]methyl-7H-pyn:olo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentane-
1,5-diol as a clear viscous oil (0.51 gm, 76%), LC /MS (M+H)+: 418, 1H NMR (DMSO-ds) 5, 8.85(s,
1H), 8.41(s, 1H), 8.37(s, 1H), 7.45(d,lH), 6.83(d, 1H), 5.73(s, 2H),4.91(m, 1H), 3.75(m,2H), 3.59(m,
2H), 3.45(m,2H), 2.18(m, 4H), 0.95(m,2H), 0.1(s, 9H).
Step 2: 3~[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
ylJpentane-J, 5-diyl dimethanesulfonate
A mixture of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]pentane-l,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0 °C. To
this mixture, TEA (50 \xL, 0.0004 mol) was added. The reaction was stirred for 15 minutes.
Methanesulfonyl chloride (23 L, 0.00030 mol) was added and the resulting mixture was stirred for 1
hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were
washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to
give 3-[4-(7-[2 pentane-1,5-diyl dimethanesulfonate (57 mg, 80 %) as an oil. MS(ES): 574 (M+l).
Step 3: 4-[4-(7-[2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]heptanedinitrile

To a mixture of S-[4-(7-[2-(trimethylsilyl)ethoxylmethyl-7H-pyrrolo[2,3-dlpyriraidin^4-yl)-
lH-pyrazol-l-yl]pentane-l,5-diyl dimethanesulfonate (57 mg, 0.000099 mol) in DMSO (1 mL, 0.01
mol), sodium cyanide (10 mg, 0.0003 mol) was added and the mixture was stirred for 2 hours. The
mixture was heated at 60 °C for 1 hour. Water was added and the product was extracted with ethyl
acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium
sulfate, filtered and concentrated to give 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]heptanedinitrile (40 mg, 90 %) as an oil. MS(ES): 436 (M+l).
Step 4: 4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]heptanedinitrile
Using a procedure analogous to Example 61 for the removal of the SEM protecting group, the
title compound was prepared as a white amorphous solid, (17 mg, 60%) 1H NMR (400 MHz,
DMSO): 5. 8.75 (s, 1H), 8.65 (s, 1H), 8.4 (s, 1H), 7.6 (d, 1H), 7.0 (d, 1H), 4.5 (m, 1H), 2.35 (m, 4 H),
2.2 (m, 4H). MS(ES): 306 (M+l).
Example 429: 3-(5-Bromopyridin-3-yl)-3-[4-(7H-pyrroIo[2,3-dlpyrimidin-4-yl)-lH-pyrazol-l-
yi]propaneni trite

To a mixture of 1.0 M potassium tert-butoxide in THF (2.7 mL) at 0 °C (water-ice bath, under
an atmosphere of nitrogen) was added diethyl cyanomethylphosphonate (0.48 mL, 0.0030 mol) in
THF (4.0 mL, 0.049 mol), dropwise. The reaction mixture was wanned to room temperature, and then
was cooled to 0 °C, followed by dropwise addition of 5-bromonicotinaldehyde (0.5 g, 0.003 mol) in
THF (1.0 mL, 0.012 mol). After stirring at room temperature for 20 hours, the reaction mixture was
quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate, filtered, and concentrated to give a crude product as a dark oil.
The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 3:7
as eluent to give a mixture of cis and trans isomers (2)-3-(5-bromopyridin-3-yl)acrylonitrile as an off-

white solid (268 mg, 47.69%). LCMS (M+l)+: 209,211, 1H NMR (400 MHz, CDC13): 5. 8.75(s,lH),
8.62(s,lH), 7.90(s,lH), 7.40(d,lH), 6.00(d, 1H).
Step 2: 3-(5-Bromopyridin-3-yl)-3-[4-(7-[2-(tnmethylsilyl)ethooy]rmthyl-7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-lH-pyrazol-l-yl]propanenitrile
To 4-(lH-pyrazol-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pjmrolo[2,3--di]pyrimidine
(0.200 g, 0.000634 mol) in 1.0 mL of dry ACN was added DBU (0.10 mL, 0.00067 mol), followed by
the addition of (2Z&E)-3-(5-bromopyridin-3-yl)actylonitrile (0.234 g, 0.00112 mol) in 1.0 mL of
ACN. The reaction mixture was stirred at 67 °C for 4 hours. Upon cooling, the mixture was
partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer was washed with
saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The crude product
was purified by flash chromatography on silica gel using ethyl acetate : hexanes (7:3) to give 3-(5-
bromopyridin-3-yl]-3-[4-7-[2-(trimethylsilyl)-ethoxy]-methyl-7H-pyrrolo[2,3-d]pyriniidin-4-yl)-1H-
pyrazol-l-yl]propanenitrile as an off-white solid (225 mg, 67.66%). LCMS (M+l)+:524,526: 'H
NMR (400 MHz, CDC13): § 8.90(s, 1H), 8.80(s, 1H), 8.70(s, 1H), 8.42(s, 1H), 8.40(s, 1H), 8.00(s,
1H), 7.50(d, 1H), 6.82(d, 1H), 5.81(m, 1H), 5.75(s, 2H), 3.70(m,lH), 3.60(m, 2H), 3.42(m, 1H),
1.00(m,2H),0.08(s,9H).
Step 3: 3-(5-Bromopyridin-3-yl)-3'[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-ylJpropane-
nitrite
The 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (0.220 g, 0.000419 mol) in DCM (9.0 mL, 0.14 mol)
and TFA (9.0 mL, 0.12 mol) was- stirred at room temperature for 1 hour. The reaction was
concentrated in to give a residue. This crude intermediate was dissolved in methanol (12 mL, 0.30
mol) and ethylenediamine (0.2 mL, 0.003 mol) and was stirred overnight at room temperature. The
reaction was concentrated in vacuo to give the crude product which was purified by preparative
HPLC eluting with a water : ACN gradient buffered with ammonium hydroxide (pH=10) to give 3-
(5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]propanenitrile as an
amorphous white powder (118 mg, 71.36%). LCMS (M+l)+:394,396, *H NMR (400 MHz, DMSO-
d6): 5. 12.05(bs,lH), 8.98(s, 1H), 7.0(s, 1H), 6.50(m, 2H), 8.50(s, 1H), 8.10(s, 1H), 7.80(s, 1H),
6.98(s, 1H), 6.21(m, 1H), 3.90(m, 1H), 3.70(m, 1H).
Example 430: 3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentane-l,5-diol

Using a procedure analogous to Example 61 for the removal of the SEM protecting group but
using 3-[4-(7-[2-(trimethylsilyI)ethoxy]methyl-7H-pyn-olo[2,3Hl]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
pentane-l,5-diol from Example 428, the title compound was prepared as a white amorphous solid, (25
mg, 70%) 1HNMR (400 MHz, DMSO): 5. 8.65 (s, 1H), 8.6 (s, 1H), 8.25 (s, 1H), 7.6 (d, 1H), 6.0 (d,
1H), 4.6 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 2.1 (m, 2H), 1.9_(m, 2H). MS(ES): 288 (M+l).
Example 431: 5-(2-Cyano-l-[4-(7H-pyrrolo[2^-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)-
nicotinonitrile bis(trifluoroacetate)

A slurry of 3-(5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-
yl]propanenitrile (0.050 g, 0.00013 mol) (from Example 429), DMF (2.0 mL, 0.026 mol) and zinc
cyanide (0.1 g, 0.001 mol) was degassed by purging with nitrogen. Then tetrakis(triphenyl-
phosphine)palladium(O) (0.07 g, 0.00006 mol) was added and the resulting slurry again was degassed
with nitrogen. The reaction was sealed and heated at 170 °C for 15 minutes in a microwave (Personal
Chemistry). The reaction was allowed to cool and the solids were filtered off. The combined DMF
fractions were concentrated in vacuo. The residue was triturated with ethyl acetate-hexanes 2:8, then
with ethyl ether to removed by-products. The crude product,was purified by preparative HPLC eluting
with a water : acetontrile gradient containing 0.2% TFA to give the racemic title compound (43 mg,
59.65%). LCMS (M+l)+:341, 1HNMR(400 MHz, DMSO-d6): 6. 12.60(bs, 1H), 9.10(s, 1H), 8.90(s,

1H), 8.80(s, 1H), 8.50(s, 1H), 8.42(s, 1H), 7.78(s, 1H), 7.10(s, 1H), 630(m, 1H), 3.90(m, 1H),
3.70(m, 1H).
Example 431R and Example 431S
The enantiomers R-5-(2-cyano-I -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]-
ethyl)nicotinonitrile and S-5-(2-cyano-l -[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl] -
ethyl)nicotinonitrile were separated by chiral column HPLC.
Example 467: 3-(3-Aminophenyl)-3-14-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l-yl]-
propanenitrile bis(trifluoroacetate)

Stepl: 3-(3-Nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]
1H-pyrazol-J-ylJpropanenitrile
To 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine
(0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL, 0.0016 mol) followed by
addition of (2Z)-3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction
mixture was heated at 67 °C for 18 hours. This was cooled to room temperature, and the mixture was
partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed with
saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude
product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 6:4, to give 3-
(3-nitropheny])-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-1 -yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+l)+:490
Step 2. 3-(3-Aminophenyl)-3-(4-7-[2-(trimethylsilyl)etho7y]-7H-pyrrolo[2,3-d]pyrimidin-4-yl-lH-
pyrazol-l-yl)propanenitrile
The 3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)-lH-pyrazol-l-yl]propanenitrile (0.630 g, 0.00129 mol) was dissolved in ethanol (65 mL, 1.1
mol), degassed with nitrogen, and then palladium (0.55 g, 0.0052 mol) (10% on carbon) was added.
The reaction mixture was again purged with nitrogen, and it was then charged at 50 psi hydrogen in a
Parr shaker for 60 minutes. The reaction mixture was filtered and concentrated to give 3-(3-amino-

phenyl)0-(4-7-[2-(trimethylsilyl)ethoxy]-7H-pyn-olo[2,3wi]pyrimidin--4-yl-lH-pyrazol-l-yl)propane-
nitrile as a colorless oil (550 mg, 95.92%), LCMS (M+l)+=460,
Step 3. 3-(3-Aminophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljpropanertitrile
his(trifluoroacetate)
Using a procedure analogous to that of Example 61 for the removal of the SEM protecting
group, the title compound was prepared as a white amorphous solid (18 mg, 38%), LCMS
(M+l)+=329: 1H NMDR. (DMSO-d6) 6 12.61 (b,lH), 9.00 (s,lH), 8.80 (s,lH), 8.50 (s,lH),7.78 (m,lH),
7.25( m,lH), 7.18(m,lH), 6.85(m,2H), 6.02 (m.lH), 3.78(m,lH), 3.60 (m,lH).

Step 1 -(3-2-Cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]ethylphenyl)acetamide
To 3-(3-aminophenyl)-3-[4^7-[2-(trimethylsllyl)ethoxy]memyl-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)-lH-pyrazol-l-yl]propanenitrile (0.070 g, 0.00015 mol) (from Example 467) in dry DCM (1.0
mL, 0.016 mol) was added TEA (0.042 mL, 0.00030 mol). The reaction was cooled in an ice bath
and acetyl chloride (0.016 mL, 0.00023 mol) was added. The reaction mixture stirred for 30 minutes
and was diluted with water and extracted with ethyl acetate (2x). The combined organic layers were
washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to give N-(3-2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pvrimidin-4-yl)-lH-pyrazol-l-yl]ethylphenyl)acetamide as a colorless oil, (65 mg, 85.08%),
LCMS(M+l)+= 502.
Step 2 N-(3-2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylphenyl)acetamide
trifluoroacetate
Using a procedure analogous to that of Example 61 for the removal of the SEM protecting
group, the title compound was prepared as a white amorphous solid (40 mg, 68.9%),

LCMS(M+l)+=372, 1H NMR (DMSO-ds) 5 12.61 (b.lH), 9.05 (s.lH), 8.79 (s,lH), 8.44 (s,lH):
(s,lH), 7.55 (s,lH), 7.48 (d,lH), 7.24 (m,lH), 7.10 (m,2H)), 6.05 (m,lH), 3.70 (m,lH), 3.48 (m
1.98 (s,3H).
Example 470: 4-(2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI]ethyl)-
thiophene-2-carbonitrile trifluoroacetate

Step 1 4-Bromo-2-(diethoxymethyl)thiophene
A mixture of 4-bromothiophene-2-carbaldehyde (1.2 g, 0.0063 mol) in ethanol (10 mL, 0.2
mol) was treated with ammonium chloride (0.42 g, 0.0078 mol) and ethyl orthoformate (1.2 g, 0.0078
mol). The mixture was stirred at 60 °C for 2 hours. The reaction was quenched with water and
extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride,
dried over magnesium sulfate, filtered and concentrated to give 4-bromo-2-(diethoxymethyl)thio-
phene as an oil (1.3 g, 81% ). 1H NMR (400 MHz, CDCI3): 5 7.22 (s, 1H), 6.99 (s, 1H), 5.68 (s, 1H),
3.63 (q,4H) 1.24 (t,6H).
Step 2 5-(Diethoyymelhyl)thiophene-3-carbaldehyde
A solution of 4-bromo-2-(diethoxymethyl)thiophene (500 mg, 0.002 mol) in ether (5 mL,
0.05 mol) was cooled at -78 °C. To this solution, 2.5 M n-butyllithium in hexane (0.83 mL) was
added dropwise. The reaction was stirred at -78 °C for 1 hour. To the reaction was added DMF (0.4
g, 0.006 mol) at -78 °C and the mixture was stirred for 30 minutes. The reaction was quenched with
water and extracted with ethyl acetate. The combined organic layers were washed with saturated
sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was
purified by flash column chromatography to yield the 5-(diethoxymethyl)thiophene-3-carbaldehyde as
an oil (170 mg, 42.0%). By lH NMR two different regioisomers of aldehydes were formed and were
not separated; (note: NMR shifts are for the major isomer only) ]H NMR (400 MHz, CDC13): § 9.85
(s, 1H), 8.05,7.7 (s, 1H), 7.45, 7.15 (s, 1H), 5.7 (s, 1H), 3.65 (m, 2H), 1.25 (m, 2H).
Step 3 (2E)-3-[5-(Diethoxymethyl)-3-thienyl]acrylonitrile
To a solution of diethyl cyanomethylphosphonate (100 mg, 0.0008 mol) in THF (2 mL, 0.02
mol) cooled at 0 °C and 1.0 M potassium tert-butoxide in THF (0.8 mL) was added dropwise. The

bath was removed and the reaction was warmed to room temperature for 30 minutes. The reaction
was cooled to 0 °C and a solution of 5-(diethoxymethyl)thiophene-3-carbaldehyde (170 mg, 0.00079
mol) in THF (2 mL, 0.02 mol) was added drop wise. The reaction was stirred overnight at room
temperature. The reaction was partitioned between water and ethyl acetate. The combined extracts
were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated.
The crude residue was purified by flash column chromatography on silica gel eluting (ethyl
acetate:hexane, 1:5) to give (2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile as an oil (160 mg,
84.9%). 'H NMR (300 MHz, CDC13): 8 7.4-7.0 (m, 3H), 5.65 (m 1H), 4.2 (m, 1H), 3.65 (m, 4H),
1.25 (m, 6H).
Step 4 3-[5-(Diethoxymethyl)-3-thienylJ-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4~yl)-lH-pyrazol-l-yl]propanenitrile
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (200 mg, 0.0007 mol) in ACN (2 mL, 0.04 mol) and (2E)-3-[5-(diethoxymethyl)-3-
thienyl]acrylonitrile (160 mg, 0.00067 mol) (mixture of regioisomers) DBU (80 uL, 0.0005 mol) was
added. The reaction was stirred overnight than water was added and the product was extracted with
ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over
magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column
chromatography on silica gel eluting (50% EtOAc/Hexane) to give 3-[5-(diethoxymethyl)-3-thienyl]-
3-[4-(7-[2-(trimethylsilyl)ethoxy]memyl-7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile (160 mg, 43%). 1H NMR (400 MHz, CDC13): 5 8.92 (s, 1H), 8.41 (s, 1H), 8.29 (b, 1H), 7.45(d,
1H), 7.41(d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.82 (m, 1H), 5.74 (d, 2H), 3.74 (m, 2H), 3.71 (m, 8H),
3.59 (m, 1H), 1.32 (m, 4H), 0.95 (m, 2H), -0.08 (s, 9H); MS(ES):553 (M+l).
Step 5 3-(5-Formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-dJpyrimidin-
4-yl)-lH-pyrazol-l-yl]propanenitrile
A solution of 3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (70 mg, 0.0001 mol) in THF (1 mL,
0.01 mol) was treated with 1 M HC1 in water (400 uL). The reaction was stirred at room temperature.
Water was added and the product was extracted with ethyl acetate. The combined extracts were
washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to
give 3-(5-foimyl-3-thienyl)-3-[4-(7-[2-(trunethylsilyl)ethoxy]m
yl)-lH-pyrazol-l-yl]propanenitrile as a semisolid residue (60 mg, 98%). 1H NMR (400 MHz,
CDC13): 8. 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, 1H), 3.73-3.43
(m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+l).

Step 6: 5-[(E)~(Hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethyhilyl)ethoxyJmethyl- 7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile
A solution of 3-(5-formyl-3-thienyl)-3-[4-(7-(2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (65 mg, 0.00014 mol) in methanol (2 mL, 0.05
mol) was treated with hydroxylarnine hydrochloride (11 mg, 0.00016 mol) and potassium bicarbonate
(23 mg, 0.00023 mol). The reaction was stirred at room temperature for 4 hours. Water was added
and the product was extracted with ethyl acetate. The combined extracts were washed with saturated
sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-5-[(E)-
(hydroxyimino)methy]]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yi)-lH-pyrazol-l-yl]propanenitrile as a semisolid oil (60 mg, 89.5%). (The crude product
contained both isomers of oxime and also both regioisomers of thiophene). MS (ES): 494 (M+l).
Step 7: 4-(2-Cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]ethyl)thiophene-2-carbonitrile
To a mixture of 3-5-[(E)-(hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]-
methyl-7H-pyn-olo[2,3-d]pyrknidin-4-yl)-lH-pyra2»l-l-yl]propanenitriIe (70 mg, 0.0001 mol) in
pyridine (1 mL, 0.01 mol), methanesulfonyl chloride (100 L, 0.001 mol) was added. The mixture
was stirred at 60 °C for 2 hours. Water was added and the product was extracted with ethyl acetate.
The combined extracts were washed with 0.1 N HC1, brine, dried over magnesium sulfate, filtered and
concentrated to give 4-(2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pvrimidin-4-yl)-lH-pyra2ol-l-yl]ethyl)thiophene-2-carbonitrile as a crude product (30 mg, 44%). MS
(ES): 476 (M+l).
Step 8: 4-(2-Cyano~l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)thiophene-2-
carbonitrile trifluoroacetate
A mixture of 4-(2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrroio[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)thiophene-2-carbonitrile (50 mg, 0.0001 mol) in DCM (2 mL,
0.03 mol) and TFA (1 mL, 0.01 mol) was stirred for 1 hour. The starting material was consumed and
the desired methyl hydroxy compound was formed. The mixture was concentrated in vacuo to
remove TFA. The crude intermediate was dissolved in methanol (3 mL, 0.07 mol) and was treated
with ethylenediamine (1 mL, 0.01 mol). The mixture was stirred overnight and concentrated in
vacuo. The products were purified by preparative HPLC eluting with ACN: water with 0.2% TFA to
give two regioisomers, the title compound as an amorphous white solid (30 mg, 60 %).
1H NMR (500 MHz, DMSO): $ 8.95 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H),
7.70 (d, 1H), 7.05 (d, 1H), 6.25 (m, 1H), 3.80-3.60 (m, 2H); MS (ES): 346 (M+l).

Isolated as the second regioisomer from Example 470, the title compound was isolated as an
amorphous white solid (4 mg, 8%). 1H NMR (500 MHz, DMSO): 8. 9.0 (s, 1H0, 8.75 (s, 1H), 8.50 (s,
1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.0 (d, 1H), 6.45 (m, 1H), 3.8 (dd, 2 H); MS (ES): 346
(M+l).
Example 472 : 3-[3-(Morpholin-4-yIcarbonyl)phenyll-3-[4-(7H-pyrrolo[2^-d]pyrimidin-4-yl)-
lH-pyrazol-l-yl]propanenitrile trifluoroacetate
Step 1: 3-(2-cyano-l-[4-(7-[2-(trimethylsilyI)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]ethyl)benzoic acid
To a solution of methyl 3-2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylbenzoate (50 mg, 0.0001 mol) (prepared as in Example 61) in
methanol (2 mL, 0.05 mol), lithium hydroxide (1 mg, 0.0001 mol) in water (1 mL, 0.06 mol) was
added slowly. Water was added and also some IN HC1 was added until the solution was slightly
acidic. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried over
magnesium sulfate, filtered and concentrated to give 3-(2-cyano-l-[4-(7-[2-(trimethylsiIyl)ethoxy]-
methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)benzoic acid as a crude residue (35
mg, 72.0%). MS (ES): 489 (M+l).

Step 2: 3-[3-(Morpholine-l-ylcarbonyl)phenyl]-3-[4-(7~{[2-(trimethylsilyl)ethoxy]methyl}- 7H-
pyrrolo[2,3-d]pyrimidine-4-yl)-lH-pyrazole-l-yl]propanenitrile
To a solution of 3-(2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl)benzoic acid (40 mg, 0.00008 mol) in DMF (1 mL, 0.01 mol),
N)N-N,N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluqrophosphate (36 mg, 0.000095
mol) and DIPEA (30 L, 0.0002 mol) were added. The reaction was stirred for 10 minutes and then
morpholine (10 mg, 0.00012 mol) was added and the resulting mixture was stirred for 3 hours. Water
was added and the product was extracted with ethyl acetate. The combined organic extracts were
washed with IN HC1, brine, dried over magnesium sulfate, filtered and concentrated to give 3-[3-
(morpholine-l-ylcarbonyl)phenyl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-
d]pyrimidine-4-yl)-lH-pyrazole-l-yl]propanenitrile as a crude (40 mg, 88%) product. MS (ES): 558
(M+l).
Step 3: 3-[3-(Morpholin-4-ylcarbonyI)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -
yl]propanenitrile trijluoroacetate
Using A procedure analogous to that of Example 61 for the removal of the SEM protecting
group, the title compound was isolated as an amorphous white solid (18 mg, 50 %). 1H NMR (400
MHz, DMSO): 5. 9.05 (s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 7.85 (b, 1H), 7.665 (s, 1H), 7.55- 7.35 (m,
3H), 7.15 (s, 1H), 6.15 (m, 1H), 3.85 (m, 1H), 3.65-3.4 (m, 6H), 3.25 (m, 2H), 3.05 (m, 1H); MS(ES):
428 (M+l).

Step 1: 3-(5-Phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsllyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yljpropanenitrile
To a solution of 3-(5-biomopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrunidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (from Example 429) (60 mg, 0.0001
mol) in 1,4-dioxane (2 mL, 0.02 mol), phenylboronic acid (15 mg, 0.00012 mol) and sodium
bicarbonate (30 mg, 0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resulting mixture was

degassed using nitrogen. Tetrakis(triphenylphosphine)palladiuni(0) (10 nig, 0.00001 mol) was added
and nitrogen was bubbled through the reaction again. The reaction was heated at 80 °C in oil bath for
lhour. Water was added and the product was extracted with ethyl acetate. The combined extracts
were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated
to give 3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522
(M+l).
Step 2: 3-(5-Phenylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile trifluoroacetate
Using a procedure analogous to that of Example 61 for the removal of the SEM protecting
group, the title compound was isolated as an amorphous white solid (20 rng, 40 %). 1H NMR (400
MHz, DMSO): 5. 9.15 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.22 (s.lH), 7.85
(b, 1H), 7.67 (m, 2H), 7.45(m 2 H), 7.43 (m, 1H), 7.15 (s, 1H), 6.25 (m 1H), 3.95 (dd, 1H), 3.80 (dd,
1H), 3.0 (m, 1H); MS (ES): 392.1 (M+l)

Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pytrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
3-5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitrile
To a solution of 3-(5-1bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (from Example 429) (0.080 g, 0.00015
mol) in TEA (0.300 mL, 0.00215 mol) was degassed with nitrogen, and then copper(I) iodide (0.005
g, 0.00003 mol), (trimethylsilyl)acetylene, and bis(triphenylphosphine)palladium(II)chloride were
added. The reaction mixture was sealed in a tube and stirred at room temperature overnight. The
resulting black solution was partitioned between water (10 mL) and ethyl ether. The organic layer was
washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to
give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pvrimidin-4-yl)-l H-pyrazol-1 -yl]-3-

5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitriie as a yellow oil (60 mg,72.6), LCMS
(M+1H:542).
Step 2: 3-(5-EthynyIpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4~yl)-lH-pyrazol-l-yl]propane-
nitrile trifluoroacetate
3-[4-(7-t2-(Trimethylsilyi)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-r-
yl]-3-5-[(trimethyIsilyl)ethynyl]pyridin-3-ylpropanenitrile (0.050 g, 0.000092 mol) was dissolved in
DCM (5.0 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol). The reaction mixture was stirred at room
temperature, for 90 minutes and was concentrated in vacuo. The dry residue dissolved in methanol
cooled in an ice bath and a solution of potassium hydroxide (0.482 g, 0.00859 mol) in methanol (10
mL, 0.2 mol) was added. The reaction solution was stirred for 30 mm was concentrated and the crude
product was purified by preparative HPLC eluting with a water: ACN gradient with 0.2% TFA, to
give the title compound as a white amorphous solid (15 mg, 35.85%). LCMS (M+l)+:340, 'H NMR
(400 MHz, DMSO-dg): 5. 12.1(bs, 1H), 9.02(s, 1H), 8.80(s, 1H), 8.70(m, 2H), 8.48(s, 1H), 8.00(s,
IH), 7.80(d, 1H), 7.15(d, 1H), 6.20(m, 1H), 4.82(s, 1H), 3.90(m, 1H), 3.70(m, 1H).

Stepl: 3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile
To the 3-(5-bromopyridm-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in
dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution
was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5-
diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), bis(dibenzylideneacetone)palladium(0) (0.0036
g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with
nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3h. The-reaction mixture was
diluted with ethyl acetate, washed with water (2X), brine (IX), dried over magnesium sulfate, filtered,
and the solvent was evaporated in vacuo. The crude product was triturated-with hexane-ethyl acetate

9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z = 554.2.
Step 2: 3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile trifluoroacetate
The 3-[5-(phenylthio)pyridin-3-yl]0-[4-(742-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (0.110 g, 0.000199 mol) was dissolved in DCM (5.0
mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol), and the mixture was stirred at room temperature for 1
hour. The solvent was removed in vacuo, and the resulting residue was dissolved in raethanol (5.0
mL, 0.12 mol), and ethylenediamine (0.1 mL, 0.002 mol) was added. This reaction mixture was
stirred at room temperature overnight. The mixture was concentrated in vacuo, and the crude product
was purified by LCMS ( pH=2) to yield the title compound as an amorphous solid (62 mg, 58.07%).
'H NMR (400 MHz, DMSO): 5. 12.80 (s), 9.10 (s) 8.87(d), 8.60 (s), 8.50 (s), 8.43 (s), 7.82 (s), 7.78
(m), 7.39 (m), 7.25 (m), 7.18 (d), 6.20 (m), 3.84 (m), 3.70 (m). LC/MS (M+H)+: m/z = 424.15

Step 1: 4-(5-Bromopyridin-3-yl)morpholine
To a solution of [3,5-dibromopyridine (1000 mg, 0.004 mol) in 1,4-dioxane (8 mL, 0.1 mol),
morpholine (400 mg, 0.004 mol) and sodium terf-butoxide (400 mg, 0.004 mol) were added. The
reaction was bubbled with nitrogen. Tetrakis(triphenylphosphine)palladiuin(0) (200 mg, 0.0002 mol)
was added and nitrogen was bubbled through for couple of minutes. The mixture was heated at 80 °C
overnight. The reaction was allowed to cool to rt and was then partitioned between water and ethyl
acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate,
filtered and concentrated to give a crude residue. The crude product was purified by FCC on silica gel
eluting with 1:1, EtOAC:Hexane gave to give 4-(5-bromopyridin-3-yl)morpholine as a viscous oil
(400 mg, 40 %). 'H NMR (400 MHz, CDC13): 6. 8.2 (s, 1H), 8.1 (s, 1H), 7.2 (s, 1H), 3.8 (m, 4H), 3.2
(m, 4H).

A solution of 4-(5-bromopyridin-3-yl)morpholine (100 mg, 0.0004 mol) in ether (2 mL, 0.02
mol) cooled at -78 "C was treated with 2.5 M n-butyllithium in hexane (0.2 mL) and was stiired for
lh. To this mixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction was quenched with
water and extracted with ethyl acetate. The combined organic layers were washed with saturated
sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 5-morpholin-4-
ylnicotinaldehyde (70 mg, 90%) as a crude product. 'H NMR (400 MHz, CDC13): £ 10.1 (s, 1H), 8.0
(s, 2H), 7.6 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).
Step 3: (2E)-3-(5-Morpholin-4-ylpyridin-3-yl)acrylonitrile
To a solution of diethyl cyanomethylphosphonate (70 mg, 0.0004 mol) in THF (2 mL, 0.02
mol) cooled at 0 °C was added 1.0 M potassium tert-butoxide in THF (0.50 mL) dropwise. The cold
bath was removed and the reaction was warmed to room temperature over 30 minutes. The reaction
was cooled to 0 °C and a solution of 5-morpholin-4-ylnicotinaldehyde (70 mg, 0.0004 mol) in THF (2
mL, 0.02 mol) was added dropwise. The reaction was stirred at room temperature for 4 h, quenched
with water and extracted with ethyl acetate. The combined organic layers were washed with saturated
sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (2E)-3-(5-
morpholin-4-ylpyridin-3-yl)acrylonitrile (75 mg, 100%) as a mixture of isomers; LC/MS: 216 (M+l).
Step 4: 3-(5-Morpholin-4-ylpyHdin-3-yl)-3-[4-(7-[2-(trimethyMlyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-JH-pyrazol-l-yl]propanenitrile
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3-(5-morpholin-4-yIpyridin-3-
yl)acrylonitrile (70 mg, 0.0003 mol) ( mixture of isomers), DBU (50 L, 0.0003 mol) was added and
the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl
acetate. The combined organic layers were washed with saturated sodium chloride, dried over
magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-
(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitriIe (200
mg, 100%) as a crude product; L/MS = 531 (M+l).
Step 5: 3-(5-Morpholin-4-ylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-ylJ-
propanen itrile
Using a procedure analogous to Example 61 for the removal of the SEM protecting the title
compound was isolated as an amorphous white solid (18 mg, 50 %). 1H NMR (400 MHz, DMSO): &
8.8 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.4 (m, 1H), 6.9 (d, 1H), 6 (m,
1H), 3.8 (dd, 1H), 3.7(m, 4H), 3.6 (dd, 1H), 3.1 (m, 4 H); LC/MS: 401(M+l).

Example 496: 3-[5-(PhenyIsuIfinyI)pyridin-3-yll-3-[4-(7H-pyrroIo[2^-d]pyriniidiii-4-yl)-lH-
pyrazol-1-yllpropanenitrile,
and
Example 497: 3-[5-(Phenylsulfonyl)pyridin-3-yI]-3-[4-(7H-pyrroIo [2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]propanenitrile

To the solution of 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyriraidin-4-yl)-lH-
pyrazo1-1-yl]propanenitrile trifluoroacetate (0.050 g, 0.000093 mol) from Example 488, Step 2, in
THF (1.0 mL, 0.012 mol) was added MCPBA (0.022 g, 0.00013 mol) (0.031g of 77% in water), in a
water ice bath. The reaction mixture was stirred for 1 h at room temperature. The crude products were
purified by LCMS (pH=10). Two peaks were collected :
# 1 - to yield 3-t5-(phenylsulfinyl)pyridin-3-yl]-344-(7H-pyrrolo[2)3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]propanenitrile (8 mg, 19.57%). 1H NMR (400 MHz, DMSO): 8. 12.1 (s), 8.89 (d), 8.80
(d), 8.70 (s), 8.62 (s), 8.40 (s), 8.19 (s), 7.70 (m), 7.58 (s), 7.42 (m), 6.90 (s), 6.20 (m), 3.82 (m), 3.65
(m). LC/MS(M+H)+:m/z = 440.0
# 2 - to yield 3-[5^henylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3Hl]pyrimidm-4-yl)-lH-
pyrazol-l-yl]propanenitrile (21 mg, 50%). 1H NMR (400 MHz, DMSO): 5. 12.1 (s), 9.10 (s),
8.86 (m), 8.6 l(s), 8.40 (m), 7.98 (m), 7.62 (m), 7.58 (m), 6.90 (s), 6.20 (m), 3.82 (m), 3.65
(m). LC/MS (M+H)+: m/z = 456.0

Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]pentanal
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (100 mg, 0.0003 mol) in ACN (2 mL, 0.04 mol) and DBU (50 L, 0.0003 mol), the (2E)-
pent-2-enal (4.0E1 mg, 0.00048 mol) in lml ACN was added drop wise. The reaction was stirred for 1
h, and then water was added and the resulting mixture extracted with ethyl acetate. The combined
organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered
and concentrated to give the crude as the hydrated product form. LC/MS (M+H)+: m/z = 400.
Step 2: 3-[4- (7-[2-(Trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -
yl]pentan-l-ol
A mixture of [3-[4-(7-[2-(trunethylsilyl)ethoxy]memyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]pentanal (50 mg, 0.0001 mol) in methanol (2 mL, 0.05 mol) was treated with sodium
tetrahydroborate (8 mg, 0.0002 mol). The mixture was stirred at room temperature for 1 h, and then
water was added and the product was extracted with ethyl acetate. The combined organic layers were
washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to
give the desired product as an oil. LC/MS (M+H)+: m/z = 402.
Step 3:
Using a procedure analogous to Example 61 for the removal of the SEM protecting group the
title compound was isolated as an amorphous white solid (6 mg, 20 %). 1H NMR (400 MHz,
DMSO): $ 8.65 (d, 1H), 8.60 (d, 1H), 7.55 (s, 1H), 6.95 (s, 1H), 4.50 (b, 1H), 4.4 (m, 1H), 3.4 (m,
1H), 3.2 (m, 1H), 2.1 (m, 1H), 1.8-2.0 (m, 3H), 0.7(t, 3H); LC/MS (M+H)+: m/z = 272.
Example 499: Methyl 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl]pentyl carbonate

Step 1: Methyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]pentyl carbonate
To a solution of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
lH-pyrazol-l-yl]pentan-l-ol (50 mg, 0.0001 mol) from Example 498 Step 2 in pyridine (1 mL, 0.01

mol), methyl chloroformate (30 L, 0.0003 mol) was added. The reaction was stirred for 3h, water
was added and the product was extracted with ethyl acetate. The combined organic layers were
washed IN HC1, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 3-[4-
(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pvn-olo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yljpentyl
carbonate as a semisolid residue (30 mg, 50%). LC/MS (M+H)+: m/z = 460.
Step 2:
Using a procedure analogous to Example 61 for the removal of the SEM protecting the title
compound was isolated as an amorphous white solid (8 mg, 20 %). 'H NMR (400 MHz, DMSO):
5 . 12.0 (b, 1H), 8.65 (d, 1H), 8.35 (s, 1H), 7.65 (b, 1H), 7.600 (s, 1H), 7.0 (s, 1H), 4.4 (m, 1H), 4.0
(m, 1H), 3.8 (m, 1H), 3.6 (s, 3H), 2.1 (m, 1H), 2.2 (m, 1H), 1.95 (m7 2H), 0.75 (t, 3H); LC/MS
(M+H)+:m/z = 330.

Step 1: (lE)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]meti^l-7H-pyrrolo[2,3Hl]pyrimidin-4-yl)-IH-pyrazol-
1-yljpentanal oxime
To a solution of 3-[4-(7-[2-(trimethylsilyl)emoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
lH-pyrazol-l-yl]pentanal (60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05
mol) was added hydroxylamine hydrochloride (16 mg, 0.00022 mol) and potassium bicarbonate (22
mg, 0.00022 mol). The reaction was stirred at room temperature for 2h, water was added and the
product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium
chloride, dried over magnesium sulfate, filtered and concentrated to give (lE)-3-[4-(7-[2-(trimethyl-
silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanal oxime as a semisolid
residue (50 mg, 80%). LC/MS (M+H)+: m/z = 415.
Step 2:
Using a procedure analogous to Example 61 for the removal of the SEM protecting the title
compound was isolated as an amorphous white solid. 1H NMR (400 MHz, DMSO): £ 12.0 (b, 1H),
8.6 (m, 2H), 8.2 (m, 1H), 7.5 (d, 1H), 7.1 and 6.5 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.6-2.8 (m, 2H),
1.8 (m, 2H), 0.65 (t, 3H); LC/MS (M+H)+: m/z = 285.

Example 501(a): (lE)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanaI O-
metbyloxime,
and
Example 502(a): (lZ)-3-[4-(7H-Pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]pentanal O-
methyloxime

Step 1: (lE)-3-[4-(7-[2-(Tnmethylsilyl)ethoxy]methyl-7H-pynolo[2,3]pyrimidin-4-yl)-lH-pyrazol-
l-yllpentanal O-methyloxime
and
(1Z)-3-f4-(7-f2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolof2J-dJpyrimidin-4-yl)-1H-pyrazol-l-
yljpentanal O-methyloxime
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyirolo[2,3-d]pyrimidin-4-yI)-
lH-pyrazol-l-yl]pentanal (70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added
methoxylamine hydrochloride (19 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022
mol). The reaction was stirred at room temperature for 2h, water was added and the product was
extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride,
dried over magnesium sulfate, was filtered and was concentrated to give 3-[4-(7-[2-(trimethylsilyl)-
ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljpentanal O-methyloxime as a
mixture of isomers (70 mg, 90%) crude product. LC/MS (M+H)+: m/z = 429.
Step 2:
Using a procedure analogous to Example 61 for the removal of the SEM protecting the title
compound was isolated as an amorphous white solid (4 mg, 25 %). Isomer 1, !H NMR (400 MHz,
DMSO): 8. 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s, 1H), 7.3 (t, 1H), 7.0 (s, 1H), 4.6(m, 1H), 3.3 (s, 3H), 2.8
(m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/S (M+H)+: m/z = 299.1somer 2 (3 mg, 22%), *H NMR (400
MHz, DMSO): 5 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s, 1H), 7.0 (s, 1H), 6.7 (t, 1H), 4.5(m, 1H), 3.3 (s, 3H),
2.8-3.0 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/MS (M+H)+: m/z = 299.
Example 503: 4-[l-(4,4-Dibromo-l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d)-
pyrimidine trifluoroacetate

Step 1: 4-[l-(4,4-Dibromo-l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-
7H-pyrrolo[2,3-dJpyrimidine
To a solution of 3-[4-(7-[2-(trimethylsilyl)elhoxy]methyl-7H-pynx)lo[2,3-d]pyriniidin-4-yl)-
lH-pyrazol-l-yl]pentanal (300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0 °C,
triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg, 0.002 mol) were added.
The reaction was stirred at 0 °C for 10 min, water was added and extracted with ethyl acetate. The
combined organic extracts were washed with saturated sodium chloride, dried over magnesium
sulfate, filtered and concentrated. The crude product was purified by prep LC-MS (ACN, water,
NHUOH) to give 4-tl-(4,4-dibromo-l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)-
ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as an amorphous solid (50 mg, 10%).1H NMR (400
MHz, CDC13): 5 . 8.9 (s, 2H), 8.4 (s, 1H), 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H), 6.4 (m,
1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m, 1H), 2.0 (m, 1H), 1.0 (m, 5H),
LC/MS (M+H)+: m/z = 556
Step 2:
Using a procedure analogous to Example 61 for the removal of the SEM protecting the title
compound was isolated as an amorphous white solid (8 mg, 40 %). 'H NMR (400 MHz, DMSO):
8. 8.8 (s, 2H), 8.4 (s, 1H), 7.7 (b, 1H), 7.2 (b, 1H), 6.5 (t, 1H), 4.4 (m, 1H), 2.6 (m, 2H), 1.8 (m, 2H), .
0.8 (t, 3H); LC/MS (M+H)+: m/z =: 426.
Example 506: 4-[l-(l-EthyIbut-3-yn-l-yl)-lH-pyrazol-4-ylI-7H-pyrrolo[2,3-d]pyrimidinc
trifluoroacetate.

Step 1:4-[l-(l-Ethylbut-3-yn-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidine

A solution of 4-[l-(4,4-dibromo-l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)-
ethoxy]methyl-7H-pyirolo[233-d]pyrimidine (20 mg, 0.00004 mol) (from Example 503 Step 1) in
THF (1 mL, 0.01 mol) at -78 °C was treated with 2.5 M n-butyllithium in hexane (0.032 mL). The
mixture was stirred at -78 °C for lh and then at room temperature for lh. The reaction was quenched
with water (1 mL, 0.06 mol) and IN HC1. The reaction was partitioned between water and ethyl
acetate. The organic extract was washed with saturated sodium chloride, dried over magnesium
sulfate, filtered and concentrated to give 4-[l-(l-ethylbut-3-yn-l-yl)-lH-pyrazol-4-yl]-7-[2-(tri-
methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a semisolid (12 mg, 80%). LC/MS
(M+H)+:m/z = 396.
Step 2:
Using a procedure analogous to Example 61 for the removal of the SEM protecting the title
compound was isolated as an amorphous white solid (4 mg, 30 %). 1H NMR (400 MHz, DMSO): £
12.2 (b, 1H), 8.8 (s, 2H), 8.4 (s, 1H), 7.6 (s, 1H), 7.1 (s, 1H), 4.4 (m, 1H), 2.8 (m, 3H), 1.9 (m, 2H),
0.8(t,3H);LC/MS(M+H)+:m/z= 266.
Example 516: (R)-3-[3-(Ethylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]propanenitrile,
and
(S)-3-[3-(EthylsuIfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-

Step 1: l-Bromo-3-(ethylthio)benzene
Iodoethane (0.46 mL, 0.0058 mol) was added to a suspension of 3-bromothiophenol
(0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) and potassium carbonate (2.0 g, 0.014 mol). The
reaction was stirred for 2 h at rt, was diluted with ethyl acetate and filtered to remove the solids. The
reaction was concentrated in vacuo to give 1 -bromo-3-(ethylthio)benzene as a colorless oil 1.0 gm,
100%
Step 2: l-Bromo-3-(ethylsulfonyl)benzene

The MCPBA (2.37 g, 10.6 mmol) was added to a solution of l-bromo-3-(ethylthio)benzene
(1.00 g, 4.80 mmol) in DCM (10 ml, 156 mmol) cooled to 0 °C. The reaction was stirred for 1 h and
then was dilated with water and extracted with ethyl acetate three times. The combined organic layers
were dried with magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude residue
was purified by flash column chromatography with a hexane: ethyl acetate gradient to give 1 -bromo-
3-(ethylsulfonyl)benzene as a colorless oil 1.1 gm 92%, 'H NMR (300 MHz, CDC13): £8.09(m, 1H),
7.85(d,lH), 7.78(d, 1H) 7.45(t,lH), 3.14(q, 2H), 1.25(t, 3H).
Step 3: (2E&Z)-3-[3-(Ethylsulfonyl)phenyl]acrylonitrile
l-Bromo-3-(ethylsulfonyl)benzene (1.3 g, 0.0052 mol) was dissolved in the DMF (15.0 mL,
0.194 mol) and 2-propenenitrile (0.68 mL, 0.010 mol), TEA (1.4 mL, 0.010 mol) and
triphenylphosphine (0.23 g, 0.00089 mol) were added. The resulting solution was degassed with
nitrogen, and palladium acetate (0.07 g, 0.0003 mol) was added. Again the reaction was degassed
with nitrogen and then heated to 110 °C in a sealed tube for 8 hrs. The reaction was complete by
HPLC, and was then allowed to cool to rt and then partitioned between ethyl acetate and water. The
organic layer was washed with brine, dried over magnesium sulfate and concentrated. The product
was purified by FCC on silica gel eluting with a hexane; ethyl acetate gradient to give (2E&Z)-3-[3-
(ethylsulfonyl)phenyl]acrylonitrile as an amber oil (1.1 gm, 92%) LC/MS (M+H)+: m/z = 222.
Step 4: 3-[3-(Ethylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrinudin-4-yl)-lH-pyrazol-l-yl]propanenitrile
The (2E&Z)-3-[3-(ethylsulfonyl)ph6nyl]acrylonitrile (1.0 g, 0.0045 mol) was combined with
4-(lH-pyrazol-4-yl)-7-[2-(trimethylsiIyI)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 0.0041
mol) and DBU (0.61 mL, 0.0041 mol) in ACN (10.0 mL, 0.191 mol) under nitrogen at rt. The
reaction was stirred at rt for 24 h. This was partitioned between ethyl acetate and water, and 0.1N
HC1 was added to adjust the pH to 7. The combined organic extracts were washed with brine, dried
over magnesium sulfate and concentrated to give a crude oil. The product was purified by FCC on
silica gel eluting with a hexane: ethyl acetate gradient to give 3-[3-(ethylsulfonyl)phenyl]-3-[4-(7-[2-
(trimethylsilyl)emoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yljpropanenitrile as an
oil (1.5 gm, 68%). LC/MS (M+H)+: m/z = 537. The oil was a racimate, which was separated by chiral
column chromatography (Chiracel OD-H, eluting with ethanol: methanol: hexane 30:30:40, Rt 13,2
and 17.1 minutes) to give the two enantiomers, each as a glass (0.51 gm) LC/MS (M+H)+: m/z = 537,
'H NMR (300 MHz, CDC13): 5 8.89(s, 1H), 8.45(s, 1H), 8.35(s,lH), 8.09(s, lh), 8.05(d, 1H), 7.75(d,
1H), 7.71(t, 1H), 7.45(d, 1H), 6.83(d, 1H), 5.85(t, 1H), 5.75(s, 2H), 3.78-3.42(m, 4H), 3.18(m, 2H),
1.35(t, 3H), O.97(t, 2H), 0.05(s, 9H).

Step 5:
Using a procedure analogous to Example 61 for the removal of the SEM protecting group the
title compounds were prepared to give isomer #1 as an amorphous white solid (300 mg, 80 %). H
NMR (400 MHz, DMSO): S 9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1 (s,
1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)+: m/z = 407.
Using a procedure analogous to Example 61 for the removal of the SEM protecting group the
title compounds were prepared to give isomer #2 as an amorphous white solid (300 mg, 80 %).
JH NMP (400 MHz, DMSO): 8. 9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1
(s, 1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)+: m/z = 407.

Step 1: 4-[l-(l-Ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(triTnethylsilyl)ethoxy]methyl-7H-pyrrolo-
[2,3-dJpyrimidine
To an ice cooled solution of methyl triphenylphosphonium bromide (100 mg, 0.0004 mol) in
THF (2 mL, 0.02 mol) was added 0.5 M potassium bis(trimethylsilyl)amide in toluene (0.8 mL). The
mixture was stirred for lh at 0 °C ice bath, and was then cooled to -78 °C and treated with 3-[4-(7-[2-
(trimethylsilyI)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]pentanal (80 mg,
0.0002 mol) (from Example 498). The reaction was stirred at -78 °C and gradually was warmed to
room temperature overnight. The reaction was partitioned between water and ethyl acetate. The
organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and
concentrated to give 4-[l-(l-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-
7H-pyrrolo[2,3-d]pyrimidine 150 mg as a crude product. LC/MS = 398 (M+l).
Step 2: 4-[l-(l-Ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine
Using a procedure analogous to Example 61 for the removal of the SEM protecting group the
title compound was isolated as an amorphous white solid (25 mg, 1%). 'H NMR (400 MHz, DMSO):
5. 8.6 (s, 2H), 8.2 (s, 1H), 7.4 (s, 1H), 6.9 (s, 1H), 5.8 (m, 1H), 5.0 (dd, 2H), 4.2 (m, 1H), 2.4-2.6 (m,
2H), 1.7-1.9 (m, 2H), 0.6 (t, 3H); LC/MS: 268 (M+l).

Step 1. 4-Chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine
A mixture of 4-chloropyrrolo[233-d]pyrimidine (2.00 g, 0.0130 mol) and ethyl orthoformate
(25 mL, 0.15 mol) was heated to reflux for 2 hours. The solvent was evaporated, and the residue was
purified by flash column chromatography (eluting with ethyl acetate/hexanes) to yield the desired
product (1.13 g, 34%).
1H NMR (400 MHz, CDC13): 5 8.63 (s, 1H), 7.58 (d, 1H), 6.71 (s, 1H), 6.65 (d, 1H), 3.77-3.67 (m,
2H), 3.58-3.49 (m, 2H), 123 (t, 3H), 1.23 (t, 3H).
Step 2. 7-(Diethoxymethyl)-4-(lH-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
To a degassed solution of 4-chloro-7-(diethoxvmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.13 g,
0.00442 mol) and l-(triisopropylsilyl)-3-boronic acid (1.00 g, 0.00374 mol) and sodium carbonate
(0.396 g, 0.00374 mol) in 1,2-dimethoxyethane (15 mL) and water (3 mL) was added
tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.00019 mol). This mixture was stirred at ambient
temperature for 2 hours, and then was heated to reflux for 4 hours. The mixture was then cooled,
concentrated, and purified by flash column chromatography (eluting with ethyl acetate/hexanes) to
afford a residue as an oil. ACN was added to the residue, and the product which precipitated was
filtered off and washed with a small quantity of ACN (165 mg, 13%).
'H NMR (400 MHz, Dg-dmso): § 11.44 (or s, 1H), 8.66 (s, 1H), 7.80-7.78 (m, 1H), 7.58 (d, 1H), 7.03
(d, 1H), 6.94 (dd, 1H), 6.90 (dd, 1H), 6.75 (s, 1H), 3.74-3.65 (m, 2H), 3.59-3.50 (m, 2H), 1.15 (t, 6H);
MS(ES): M+H = 287.
Step 3.
To a solution of 7-(diethoxvmethyl)-4-(lH-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.125
g, 0.436 mmol) and 4,4,4-trifluorobut-2-enenitrile (0.0476 mL, 0.480 mmol) in ACN (1 mL) was
added DBU (0.0653 mL, 0.436 mmol). TFA (0.5 mL) was added and the mixture was stirred for 1
hour. The TFA and solvent was removed in vacuo. The residue was purified by preparative-
HPLC/MS (C-18 eluting with a gradient of H2O/ACN containing 0.15% NH4OH) to afford the

product (102 mg, 76%). Where desired, the enantiomers were separated in substantially pure form by
chiral HPLC (AD-H, 20% EtOH/Hexane).
1H NMR (300 MHz, D6-dmso): 8 12.05 (br s, 1H), 8.65 (s, 1H), 8.04 (s, 1H), 7.56 (dd, 1H), 7.21 (t,
1H), 7.02 (dd, 1H), 6.93 (dd, 1H), 5.89-5.74 (m, 1H), 3.95 (dd, 1H), 3.66 (dd, 1H); MS(ES): M+H =
306.
The analog in Table 12 was prepared in racemic form according to the same procedure, using
a different conjugate acceptor and with the exception that in the conjugate addition in Step 3, the
reaction was carried out at 40 °C for 3 days.

Step 1: 4-[(3-Bromophenyl)sulfonyl]morpholine
Morpholine (0.19 mL, 0.0022 mol) in 1.0 ml of THF was added dropwise to a solution of 3-
bromobenzenesulfonyl chloride (0.3 mL, 0.002 mol) and TEA (0.30 mL, 0.0022 mol) in dry 4.0 mL
of THF cooled in an ice bath. The reaction mixture was stirred overnight at room temperature and was
then partitioned between 0.05N HC1 and ethyl acetate. The organic layer was washed with water (2X),
and brine (IX), and was then dried over anhydrous magnesium sulfate, filtered and then was
concentrated in vacuo to give 4-[(3-bromophenyl)sulfonyl]morpholine as a white crystalline product
(470mg,78%). LCMS (M+H)+: m/z= 306,308.
Step 2: (2E&Z)-3-[3-(Morpholin-4-ylsulfonyl)phenyl]acrylonitrile

The 4-[(3-bromophenyl)sulfonyl]morpholine (0.250 g, 0.000816 mol) was dissolved in dry
DMF (2.5 mL, 0.032 mol) and the mixture was degassed using a stream of nitrogen. To this mixture
' was added TEA (0.23 mL, 0.0016 mol), 2-propenenitrile (0.11 mL, 0.0016 mol), palladium acetate
(0.011 g, 0.000049 mol), and triphenylphosphine (0.0364 g, 0.000139 mol) and again the mixture was
degassed with nitrogen. The reaction mixture in a sealed tube was heated at 110 °C for 16 hours. The
reaction mixture, after cooling to room temperature, was partitioned between 0.05N HC1 and ethyl
acetate. The organic layer was washed with water (2X), and brine (IX), dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacua, to give (2E&Z)-3-[3-(morpholin-4-yl-
sulfonyl)phenyl]acrylonitrile as an oil (0.240gm, 85%) which was a mixture of cis and trans isomers.
LCMS (M+H)+: m/z - 279.
Step 3: 3-[3-(Morpholin-4-ylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyI-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yljpropanenitrile
To a mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (0.100 g, 0.000317 mol) and (2E&Z)-3-[3-(morpholin-4-ylsulfonyl)phenyl]acrylonitrile
(0.097 g, 0.00035 mol) in dry ACN (2.0 mL, 0.038 mol) was added DBU (0.095 mL, 0.00063 mol),
and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then
diluted with water and extracted with ethyl acetate. The combined organic phase was washed with
water (2X), and brine (IX), dried over magnesium sulfate, filtered and then concentrated in vacuo to
give the crude product. The crude product was purified by silica gel flash column chromatography
using ethyl acetate-hexanes (6:4) as an eluent to give 3-[3-(morpholin-4-ylsulfonyl)phenyl]-3-[4-(7-
[2-(trimethylsilyl)ethoxy]memyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile as
a viscous oil (62 mg, 32.94%). LCMS (M+H)+: m/z = 594
Step 4:
Using a procedure analogous to Example 61 for the removal of the SEM protecting the title
compound was isolated as an amorphous white solid (30 mg, 63.84%. LCMS (M+H)+: m/z = 464. 1H
NMR (400 MHz, DMSO-d6): 8 8.88 (s), 8.62 (s), 8.1(s), 7.78(m), 7.70(m), 7.58(m), 6.95(m),
6.20(m), 3.84(m), 3.70(m),3.45(m), 2.78(m).
Example 679: cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexyl-
acetonitrile

Step 1: 4-(Hydroxymethyl)cyclohexanol.
Ethyl 4-oxocyclohexanecarboxylate (2.0 g, 0.012 mol) was dissolved in ether (20.0 mL) and
was then cooled at 0 °C Into the mixture was added 1 M lithium tetrahydroaluminate in ether (20
mL) and the resulting mixture was stirred at 0 °C for 2 hours. The reaction was quenched with water
(2 mL) and 1 N NaOH (2 mL) and ether was added (100 mL). The precipitated solids were filtered off
and the residue was used in the next reaction. 1H NMR(CDC13):6 4.02 and 3.75 (m, 1H), 3.45-3.61
(m, 2H), 2.02 (m, 2H), 1.84 (m, 1H), 1.52-1.80 (m, 2H), 1.44 (m, 1H), 1,32 (m, 2H), 1.03 (m, 1H).
Step 2: 4-[(Trityloxy)methylJcyclohexanol.
4-(Hdroxymethyl)cyclohexanol (2.0 g, 0.015 mol) was dissolved in pyridine (15.0 mL) and
the mixture was cooled to 0 °C. To the reaction was added triphenylmethyl chloride (4.7 g, 0.017
mol) and the resulting mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. The reaction
was then concentrated using a rotory evaporator, and the concentrate was extracted with ethyl acetate.
The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated
in vacuo. The reaction was chromatographed on silica gel using 30% EtOAc/hexanes to give the cis
isomer (0.74 g) 1H NMR(CDC13):5 7.52 (m, 6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (m, 2H), 1.21-1.68
(m, 9H); and the trans isomer (2.72 g) 'H NMR(CDC13):8 7.44 (m, 6H), 7.20-7.31 (m, 9H), 3.54 (m,
1H), 2.88 (m, 2H), 1. 98 (m, 2H), 1.88 (m, 2H), 1.60 (m, 1H), 0.99-1.37 (m, 4H).
Step 3: trans-4-[(Trityloxy)methyl]cyclohexyl methanesulfonate.
trans-4-[(Trityloxy)methyl]cyclohexanol (2.72 g, 0.00730 mol) was dissolved in chloroform
(30.0 mL) and the mixture was cooled at 0 °C To this mixture was added TEA (1.4 mL, 0.010 mol)
and methanesulfonyl chloride (0.68 mL, 0.0088 mol) and the resulting mixture was stirred at
0 °C for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were
washed with water, saturated NaCl, dried (MgSO4) and the concentrated in vacuo. 'H NMR (CDC13):5
7.43 (m, 6H), 7.20-7.31 (m, 9H), 4.57 (m, 1H), 3.00 (m, 3H), 2.90 (m, 2H), 2.16 (m, 2H), 1.93 (m,
2H), 1.09-1.60 (m,5H).

Step 4: 7-[2-(Trimethylsilyl)ethoxy)methyl-4-(l-cis-4-[(trityloxy)methyl]cyclohexyl-lH^
7H-pyrrolo[2,3-d]pyrimidine.
4 0.0048 mol) was mixed with sodium hydride (0.34 g, 0.0086 mol) and trans-4-
[(trityloxy)methyl]cyclohexyl metbanesulfonate (3.00 g, 0.00666 mol) and the mixture was cooled to
-78 °C To this mixture was added DMF (8.3 mL) and the mixture was allowed to warm to 25 °C
and was stirred for 20 minutes. The wanned mixture was stirred at 55 °C for 48 hours. The reaction
was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl,
dried (MgSO4) and then concentrated in vacuo. The concentrate was chromatographed on silica gel
using 40% EtOAc/hexanes to give the product. LC/MS (M+H)+: 670, 1H NMR(CDC13):5 8.89 (s, 1H),
8.27 (s, 1H), 8.24 (s, 1H), 6.84-7.51 (m, 10H), 6.87 (d, 1H), 5.73 (s, 2H), 4.39 (m, 1H), 3.60 (m, 2H),
3.12 (m, 2H), 1.76-2.11 (m, 9H), 0.96 (m, 2H), 0.00 (s, 9H).
Step 5: cis-4-[4~(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2J-dJpynmidin-4-yl)-lH-pyrazol-l-
yljcyclohexylmethanol.
7-[2-(Trimethylsilyl)ethoxy]methyl-4-(l-cis-4-[(trityloxy)methyl]cyclohexyl-lH-pyrazoI-4-
yl)-7H-pyrrolo[2,3-d]pyrimidine (0.3 g, 0.0004 mol) was dissolved in methanol (7.0 mL) and THF
(2.0 mL, 0.025 mol) and 4.0 M HC1 in 1,4-dioxane (0.5 mL) was added. The reaction was then stirred
at 25 °C for 2 hours TLC analysis showed no starting material present and LCMS analysis showed
the presence of the product. The reaction was added to a saturated NaHCO3 solution and was
extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried
(MgSCXt) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc
as eluent to give the product. LC/MS (M+H)+: 428
1H NMR (CDC13):5 8.89 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H), 5.73 (d, 2H),
4.41 (m, 1H), 3.51-3.71 (m, 4H), 2.31 (m, 2H), 2.08 (m, 3H), 1.70-1.93 (m, 4H), 0.98 (m, 2H), 0.00
(s, 9H).
Step 6: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3^]pyrimidin-4-yl)-lH-pyrazol-l-
yl]cyclohexylmethyl methanesulfonate.
cis-4-[4-(7-[2-(Trimemylsilyl)emoxy]methyl-7H-pyrTolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-
l-yl]cyclohexylmethanol was dissolved in chloroform (3.00 mL) and was cooled to
0 °C To the reaction was added TEA (0.10 mL, 0.00072 mol) and methanesulfonyl chloride
(0.05 mL, 0.0006 mol) and this mixture was stirred at 0 °C for 2 hours at which time LCMS analysis
showed mainly the product present in the mixture. The reaction was extracted with ethyl acetate and
the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in
vacuo. LC/MS (M+H)+: 506

Step 7: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]metkyl-7H-pyrrolo[2,3^Jpyrimidin-4-yl)-lH-pyrazol-l-
yl] cyclohexylacetonitrile.
cis-4-[4-(7-[-2-(TriethylsilyOethoxylmethyl-TH-pyrrolo[2,3,4]pyrimidin-4y1)-lH-pyrazol-
l-y]]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) and sodium cyanide (0.050 g, 0.0010
mol) and DMSO (1.0 mL) were mixed. The mixture was stirred at 60 °C for 24 hours, at which time
LCMS analysis showed most of the starting material had been consumed. The reaction was extracted
with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4)
and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent
to give the product. LCMS (M+H)+: 437, 1H NMR(CDC13):5 8.90 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H),
7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.43 (m, 1H), 3.60 (m, 2H), 2.45(d, 2H, J = 7.6 Hz), 2.37 (m,
2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Step 8: cis-4-[4-(7H-Pyrrolo[2,3-d]pyritnidin-4-yl)-lH-pyrazol-l-ylJcyclohexylacetonitrile.
cis-4-[4-(7-[2-(Trimethykilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrirnidin-4-yl)-lH-pyrazol-
l-yl]cyclohexylacetonitrile (0.080 g, 0.00018 mol) and TFA (0.50 mL, 0.0065 mol) were added to
DCM (3.00 mL, 0.0468 mol) and the mixture was stirred at 25 °C for 16 hours. The reaction was
concentrated by roto-evaporation and the concentrate was dissolved in raethanol (3.0 mL, 0.074 mol)
and ammonium hydroxide (0.5 mL, 0.01 mol) was added This reaction was stirred at 25 °C for 6
hours at which time LCMS analysis showed no starting material present. The reaction was
chromatographed on silica gel using 5% MeOH/EtOAc to give the product.
LCMS (M+H)+:307, 'H NMR(CD3OD):5 8.64 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96
(d, 1H), 4.42 (m, 1H), 2.61(d, 2H, J = 8.0 Hz), 2.27 (m, 2H), 1.70-2.15 (m, 7H).

Step J: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxyJ]methyl-7H-pyrrolo[2,3-d]pyrimidin4--yl)-lH-pyreaol-l-
yl]cyclohexylmethyl thiocyanate
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-
l-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) was dissolved in DMSO (1.00 mL)

with potassium thiocyanate (0.082 g, 0.00084 mol). The reactioa was heated at 68 °C for 4 days at
which time LCMS analysis showed ~4:1 product/starting material ratio. The reaction was extracted
with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4)
and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1
EtOAc/hexanes to give the product. LC/MS (M+H)+: 469, 1H NMR(CDC13):5 8.89 (s, 1H), 8.36 (s,
1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (m, 1H), 3.60 (m, 2H), 3.05 (m, 2H),
2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Step 2: cis-4-[4-(7H-PyrTolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl thiocyanate).
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrinnidin-4-yl)-lH-pyrazol-
l-yl]cyclohexylmethyl thiocyanate was dissolved in methanol (2.0 mL, 0.049 mol) and DCM (2.0
mL, 0.031 mol), and TFA (0.5 mL, 0.006 mol) was added. The resulting mixture was stirred at 25 °C
for 16 hours. TLC analysis showed no starting material present and LCMS analysis showed product.
The reaction was concentrated using a rotary evaporator and the concentrate was chromatographed on
silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+H)+:339, 1H NMR(CD3OD) 6 8.65
(s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.43 (m, 1H), 3.20 (d, 2H, J = 7.6 Hz),
2.24 (m, 2H), 1.80-2.17 (m, 7H).

Step 1: 5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrmiditdin -4-0-1H
pyrazol-l-yl]cyclohexylmeikyl)thio]-4H-l,2,4-triazol-3-amin
cis-4-[4-(7-t2-(Trimethylsilyl)ethoxy]methyl-7H-pynrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-
l-yl]cyclohexylmethyl methanesulfonate (124.56 mg, 0.00024 mol), and 5-amino-4H-l,2,4-triazole-
3-thiol (43.00 mg, 0.0003702 mol) were dissolved in DMF (1.20 mL) and potassium carbonate (0.122
g, 0.000887 mol) was added. The reaction was stirred at 50 °C for 18h, at which time LCMS showed
nearly complete reaction, and product present. The reaction was extracted with ethyl acetate and the

organic extracts were washed with water, saturated NaCl, dried (MgSO4,) and concentrated in vacuo.
The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product.
LC/MS (M+H)+: 526, 1H NMR(CDC13):8 8.90 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 6.87 (d,
1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41 (m, 1H), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H),
1.70-2.10 (m,7H), 0.98 (m,2H), 0.00 (s,9H).
Step 2.- 5-[(cis-4-[4-(7H-Pyrrolo[2,3^Jpyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohe^lmethyl)thioJ-4H^
1,2,4-triazol-3-amine
5-[(cis-[4-(742-(TrimethyIsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazoI-l-yl]cyclohexylmethyl)thio]-4H-l,2,4-triazoll-3-amine (9a) was dissolved in TFA (1 mL) and
was stirred for 2h. The solution was concentrated using a rotary evaporator to remove TFA. The
residue was dissolved in methanol (1 mL) and ammonium hydroxide (I mL) added. The solution was
stirred overnight. LCMS showed complete de-protection. The solution was concentrated using a
rotary evaporator. The product was isolated by prep LCMS using a 30mm x 100mm C18 column;
11%CH3CN-H2O (0.1%TFA), 1.5 min, to 33% at 6 min; 60 mL/min; detector set at m/z 396; retention
time, 5.5min (2 runs). The eluate was freeze dried. Yield 21 mg (di-TFA salt). LC/MS (M+H)+:396,
1HNMR (4,-DMSO) 8 12.9 (brs, 1H, NH); 8.9 (2 singlets, 2H); 8.5 (s, 1H); 7.9 (m, 1H); 7.3 (m, 1H);
4.4 (m, 1H, NCH); 3.1 (d, 2H); 2.2 (m, 2H); 1.9 (m, 3H); 1.7 (m, 2H); 1.6 (m, 2H). MS(ES) 396
(M+l).

Step J: N-5-((cis^-[4-(7-[2-(TrimethylsUyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidm-4-yl)-lH-
pyrazol-l-yl]cyclohexylmethyl)thio]-4H'l,2,4-triazol-3-ylpyrimidin-2-amxne
In a vial [A] 5-[(cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-
yl)-lH-pyrazol-l-yl]cyclohexyhnethyl)thio]-4H-l,2,4-triazol-3-amine (0.047 g, 0.000089 mol) was

heated with 2-chloropyrimidine (0.011 g, 0.000096 mol) in 1,4-dioxane (1.00 mL, 0.0128 mol) at
ISO °C for 40 minutes in a microwave reactor. LCMS analysis showed that no reaction had taken
place. To the reaction was added 2-chloropyrimidine (0.020 g, 0.00017 mol) with cesium carbonate
(0.033 g, 0.00010 mol) and copper(I) iodide (4.00 mg, 0.0000210 mol) and this mixture was heated at
115 °C for 3 hours, at which time LCMS analysis showed no starting material present and mainly
product was present. The reaction was chromatographed on silica gel using 2% MeOH/EtOAc to give
the product. LC/MS (M+l)+:604, 'NMR(CDCl3): 8.89 (s, 1H), 8.82 m, 2H), 8.43 (s, 1H), 8.30 (s, 1H),
7.44 (d, 1H), 7.23 (m, 1H), 7.03 (br s, 2H), 6.88 (d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 3.60 (m, 2H),
3.35 (d, 2H), 2.34 (m, 2H), 1.80-2.15 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).
Step 2: N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)thio]-
4H-1,2,4-triazol~3-ylpyrimidin-2-amine.
N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy3methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-
pyrazol-l-yl]cyclohexylmethyl)thio]-4H-l,2,4-triazol-3-ylpyrimidin-2-amine (0.024 g, 0.000040 mol)
was dissolved in DCM (4.00 mL), and TFA (0.50 mL, 0.0065 mol) was added. The reaction was
stirred at 25 °C for 16 hours and was concentrated in vacuo. The residue was dissolved in methanol
(3.00 mL) and concentrated ammonium hydroxide (0.50 mL) was added. This reaction was stirred at
25 °C for 2 hours at which time LCMS analysis showed mostly product. The reaction was
concentrated using a rotary evaporator and the concentrate was purified by prep LC to give the
product as the trifluoroacetate salt. LC/MS (M+H)+:474, 1H NMR(CD3OD) 8 8.87 (s, 1H), 8.85 (s,
1H), 8.81 (s, 1H), 8.79 (s, 1H), 8.45 (s, 1H), 7.85 (d, 1H), 7.34 (m, 2H), 4.43 (m, 1H), 3.20 (d, 2H, J =
7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H).

Step 1: 2-(l,4-Dioxaspiro[4.5]dec-8-yl)ethanol.
Ethyl l,4-dioxaspiro[4.5]dec-8-ylacetate (3.40 g, 0.0149 mol) prepared according to the
procedure of Itagaki, Noriaki; Kimura, Man; Sugahara, Tsutomu; Iwabuchi, Yoshiharu. (Organic
Letters 2005; 7(19); 4181-4183.) was dissolved in ether (30.00 mL) and the mixture was cooled to
0 °C. To the reaction was added 1.00 M lithium tetrahydroaluminate in ether (15.0 mL) and the
resulting mixture was stirred at 0 °C for 60 minutes and at 25 °C for 2 hours. The reaction was

cooled and water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL).
To the reaction was then added ether (100.00 mL) and the solid that precipitated was filtered off. The
filtrate was concentrated using a rotary evaporator to give the product. 1H NMR(CDCI3): 3.94 (s,
4H), 3.67 (t, 2H), 1.20-1.80 (m, 11H).
Step 2: 4-(2-Hydroxyethyl)cyclohexanone.
2-(l,4-Dioxaspiro[4.5]dec-8-yl)ethanol (2.70 g, 0.0145 mol) was dissolved in acetone (10.00
mL) and THF (10.00 mL) and 6.00 M HC1 (6.00 mL) was added. The reaction was stirred at 25 °C
for 16 hours, neutralized with NaHCO3 solution and was then extracted with ethyl acetate. The
organic extracts were washed with water, and with saturated NaCl, then dried (MgSO4) and
concentrated in vacua. The crude product was used in the next reaction without further purification.
1H NMR(CDC13): 3.75 { m, 2H), 2.36 (m, 4H), 1.20-2.13 (m, 7H).
Step 3: 4-(2-Hydroxyethyl)cyclohexanol.
4-(2-Hydroxyethyl)cyclohexanone (2.00 g, 0.0141 mol) was dissolved in ether (30.00 mL)
and was cooled at 0 °C. To the reaction was added 1.0 M lithium tetrahydroaluminate in ether (14.1
mL) and the resulting mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. To the
reaction was added THF (20.00 mL) and this mixture was cooled at 0 °C and then water (0.40 mL,
0.022 mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL). To the reaction was then
added ether (100.00 mL) and the resulting mixture was stirred for 10 minutes, then was filtered and
the filtrate was concentrated using a rotary evaporator to provide the crude product. The crude
product was used in the next reaction without further purification.
'H NMR(CDC13): 3.96 and 3.57 (m, 1H) minor and major CHOH (-1:5 ratio) 3.70(m, 2H), 0.94-2.02
(m, 11H).
Step 4: 4-[2-(Trityloxy)ethyl]cyclohexanol.
4-(2-Hydroxyethyl)cyclohexanol (crude from the previous reaction) (1.88 g, 0.0130 mol) was
dissolved in pyridine (20.00 mL) and was cooled at 0 °C. To the reaction was added triphenylmethyl
chloride (4.0 g, 0.014 mol) and this mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours.
The reaction was concentrated using a rotary evaporator and the concentrate was extracted with ethyl
acetate. The organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and
concentrated in vacuo. The concentrate was chrornatographed on silica gel (30%EtOAc/hexanes) to
give the trans isomer (1.98 g)
1H NMR(CDC13): 7.42-7.45 (m, 6H), 7.20-7.30 (m, 9H), 3.50 (m, 1H), 3.07 (m, 2H), 1.93 (m, 2H),
1.66 (m, 2H), 1.17-1.60 (m, 5H)5 0.89 (m, 2H).
Step 5: trans-4-[2-(Trityloxy)ethyl]cyclohexyl methanesulfonate.

trans-4-[2-(Trityloxy)ethyl]cyclohexanol (1.95 g, 0.00504 mol) was dissolved in chloroform
(40.00 mL) and the mixture was cooled to 0 °C. To the reaction was added TEA (0.98 mL, 0.0071
mol) and methanesulfonyl chloride (0.47 mL, 0.0060 mol) and this mixture was stirred at
0 °C for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were
washed with water, and saturated Nad, then dried (MgSO4) and concentrated in vacua.
'H NMR(CDC13): 7.41-7.45 (m, 6H), 7.20-7.32 (m, 9H), 4.55 (m, 1H), 3.07 (m, 2H), 2.10 (m, 2H),
1.70 (m, 2H), 1.20-1.60 (m, 5H), 0.95 (m, 2H).
Step 6; 7-[2-CTrimethylsilyt)ethoxyJmethyl-4-(l-cis-4-[2-(trityloxy)ethylJcyclohexyl-lH-pyrazol-4-yl)-
7H-pyrrolo[2,3-d]pyrimidine.
4-(lH-Pyrazol-4-yl)-7-[2-(triraethylsuyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrirnidine (1.0 g,
0.0032 mol) was mixed with sodium hydride (0.23 g, 0.0058 mol) and trans-4-[2-
(trityloxy)ethyl]cyclohexyl methanesulfonate (2.10 g, 0.00452 mol) and this mixture was cooled to
-78 °C. To the reaction was added DMF (6.00 mL) and this mixture was allowed to warm to 25 °C
and was then stirred for 20 minutes. The reaction was stirred at 55 °C for 48 hours at which time
LCMS analysis showed mostly product. The reaction was extracted with ethyl acetate and the organic
extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo.
The concentrate was chromatographed on silica gel using 40% EtOAc/hexanes to give the product.
LC/MS (M+H)+:684, 'H NMR(CDC13): 8.89 (s, 1H), 8.35 (br s, 1H), 8.30 (s, 1H), 7.50 (m, 6H), 7.44
(d, IH), 7.27-7.32 (m, 9H), 6.87 (d, 1H), 5.73 (s, 2H), 4.33 (m, 1H), 3.60 (m, 2H), 3.17 (t, 2H), 1.50-
2.25 (m, 11H). 0.98 (m, 2H), 0.00(s, 9H).
Step 7: 2-cis-4-[4-p-[2-(Trimethylsilyl)ethoxy]methyl-7H-pytrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-
l-yljcyclokexylethanol (7b).
7-[2-(Trimethylsilyl)ethoxy]methyl-4-(l-cis-4-[2-(trityloxy)ethyl]cyclohexyl-lH-pyrazol-4-
yl)-7H-pyrrolo[2,3-d]pyrimidine (1.45 g, 0.00212 mol) was dissolved in methanol (30.00 mL) and
THF (10.00 mL) and 4.0 M HC1 in 1,4-dioxane (2.00 mL) was added. The mixture was stirred at
25 °C for 2 hours, at which time, TLC analysis showed no starting material present and LCMS
analysis showed the presence of the product. The reaction was added into a saturated NaHCO3
solution, and was then extracted with ethyl acetate. The organic extracts were washed with water and
saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was
chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 442
Step 8: 2-cis-4-l4-(7-[2-(Trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-
l-yl]cyclohexylethyl methanesulfonate (8b).
2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]cyclohexylethanol (0.89 g, 0.0020 mol) was dissolved in DCM (12.00 mL, 0.1872 mol)

and was cooled at 0 °C To the reaction was added TEA (0.43 mL, 0.0031 mol) and methanesulfonyl
chloride (0.19 mL, 0.0024 mol) and this mixture was stirred at 0 °C for 2 hours at which time LCMS
analysis showed mainly product present. The reaction was extracted with ethyl acetate and the organic
extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo.
LCMS (M+H)+:520, 1H NMR(CDCl3): 8.90 (s, 1H), 8.38 (br s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.88
(d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 4.27 (t, 2H), 3.60 (m, 2H), 3.07 (s, 3H), 1.60-2.40 (m, 11H). 0.98
(m, 2H), 0.00(s, 9H)
Step 9: 3^is-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylpropanenitrile
trifluoroacetate (9b).
2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-yrrolo[2,3-]pyrimidin-4-yl)-lH-
pyrazol-l-yl]cyclohexylethyl methanesulfonate (0.075 g, 0.00014 mol) was dissolved in DMSO (1.50
mL) and sodium cyanide (0.035 g, 0.00072 mol) was added. The reaction was stirred at 40 °C for 16
hours at which time LCMS analysis showed no starting material present. The reaction was then
extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then
dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (3.00 mL) and TFA
(0.50 mL, 0.0065 mol) was added. This mixture was stirred at 25 °C for 16 hours at which time
LCMS analysis showed mostly the hydroxymethyl intermediate. The mixture was concentrated using
a rotary evaporator and the concentrate was dissolved in methanol (3.00 mL) and concentrated
ammonium hydroxide (0.50 mL) was added. The reaction was stirred at 25 °C for 3 hours at which
time LCMS analysis showed no starting material present. The reaction was then concentrated using a
rotary evaporator and the concentrate was purified by prep LC to give the product as the TFA salt
(47.8 mg). LC/MS (M+H)+:321, 1H NMR(CD3OD): 8.86 (s, 1H), 8.81(s, 1H), 8.44 (s, 1H), 7.84 (d,
1H), 7.31 (d, 1H), 4.48 (m, 1H), 2.51 (m, 2H), 2.28 (m, 2H), 2.00 (m, 2H), 1.80 (m, 5H), 1.67 (m,
2H).

2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriniiclin-4-yl)-lH-
pyrazol-l-yl]cyclohexylethyl methanesulfonate (0.060 g, 0.00012 mol) was dissolved in DMF (1.31
mL) with 5-amino-4H-l,2,3-triazole-3-thiol (0.020 g, 0.00017 mol) and potassium carbonate (0.024 g,
0.00017 mol). This mixture was heated at 40 °C for 18 hours at which time LCMS analysis showed
no starting material present. The reaction was diluted with EtOAc, filtered and was then concentrated
using a rotary evaporator. The residue was dissolved in DCM (3.60 mL) and TFA (0.60 mL, 0.0078
mol) was added. This mixture was stirred at 25 °C for 5 hours and was then concentrated using a
rotary evaporator. The residue was dissolved in methanol (3.60 mL) and concentrated ammonium
hydroxide (0.60 mL) was added and this mixture was stirred at 25 °C for 2 hours. The reaction was
concentrated using a rotary evaporator and the concentrate was purified by prep. LC to give the
product. LC/MS (M+H)+:410, 1H NMR(CD3OD): 8.85 (s, 1H), 8.80(s, 1H), 8.44 (s, 1H), 7.83 (d, 1H),
7.30 (d, 1H), 4.46 (m, 1H), 3.17 (m, 2H), 2.27 (m, 2H), 2.00 (m, 2H), 1.62-1.90 (m, 7H).

Step 1: 1,4-Dioxaspiro[4.5]decan-8-ol
l,4-Dioxa-spiro[4.5]decan-8-one (2.00 g, 0.0128 mol) was dissolved in ether (50 mL) and the
mixture was cooled to 0 °C. To the reaction was added 1 M lithium tetrahydroaluminate in ether (7.0
mL) and this mixture was stirred at 0 °C for 2 hours at which time TLC analysis showed no starting
material present. The reaction was then quenched with water and 1 N NaOH (0.5 mL of each) and
then filtered. The filtered solid was washed with ether and the combined ether filtrate was
concentrated using a rotary evaporator to give the product. NMR (CDC13): 3.94 (m, 4H), 3.81 (m,
1H), 1.79-1.92 (m, 4H), 1.54-1.70 (m, 4H).
Step 2: l,4-Dioxaspiro[4.5]dec-8-yl methanesulfonate.
l,4-Dioxaspiro[4.5]decan-8-ol (0.40 g, 0.0025 mol) was dissolved in chloroform (10.0 mL)
and the resulting mixture was cooled at 0 °C. To the mixture was added TEA (0.49 mL, 0.0035 mol)
and methanesulfonyl chloride (0.23 mL, 0.0030 mol) and this mixture was stirred at 0 °C for 2 hours.
The reaction was extracted with ethyl acetate and the organic extracts were washed with water, and
saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the
next reaction without further purification.

1H NMR(CDC13): 4.85 (m, 1H), 3.95 (m, 4H), 3.02 (s, 3H), 1.98-2.05 (m, 4H), 1.82-1.89 (m, 2H),
1.61-1.70 (m,2H).
Step3:4-[l-(lA-Dioxaspiro[4.S]dec^-yl)-lH-pyrazol-4-yl]-7-[2-(trirmihylsilyl)ethoxyl] methyl -7H
pyrrolo[2,3-d]pyrimidine.
A mixture of l,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (0.50 g, 0.0015 mol) with 4-(lH-
pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyirolo[2,3-d]pyrimidme (0.36 g, 0.0011 mol)
and sodium hydride (0.082 g, 0.0020 mol) was cooled at -78 °C and DMF (2.0 mL) was added. The
reaction was allowed to warm to 25 °C and was then stirred for 20 minutes and was then heated to
55 °C for 24 hours. The reaction was then extracted with ethyl acetate. The organic extracts were
washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The
concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS
(M+H)+:456, 1H NMR(CDC13): 8.89 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H),
5.73 (s, 2H), 4.38 (m, 1H), 4.06 (s, 4H), 3.60 (m, 2H), 2.22-2.31 (m, 4H), 2.00 (m, 2H), 1.86 (m, 2H),
0.98 (m, 2H), 0.00(s, 9H)
Step 4: 4-[4-(7-[2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]cyclohexanone
To 4-[l-(l,4-dioxaspiro[4.5]dec-8-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-
7H-pyrrolo[2,3-d]pyrimidine (2.13 g, 0.00467 mol), was added acetone (85 mL) followed by 12 M
HC1 in water (4.0 mL). The reaction was stirred at RT. After 1 h, LCMS analysis showed 66%
reaction. After 4 h, HPLC showed 80% reaction. After 20 h, HPLC showed no change (and no loss of
SEM). The reaction mixture was quenched into excess sat'd NaHCO3. The acetone was removed by
roto-evaporation. The resulting mixture of aqueous bicarbonate and a white solid was then extracted
with EtOAc. The combined organic extract was shaken with sat'd NaCl, dried over Na2SO4, then
concentrated to dryness to leave 2.0 g of a crude product. TLC (5% iPrOH-40% EtOAc-hexane):
product Rf 0.12 (ketal 0.22). The crude product was purified by automatic flash chromatography on
silica gel. Used a 40g column; flow 40 mL/min; [A= 2% iPrOH-hexane] [B= 6% iPrOH-50%
EtOAc/hexane]; A, 2 min; Gradient to B in 25 min, then B for 10 min. The eluent was concentrated .
using a rotary evaporator to give 1.3 g of a white solid. HPLC Method: Zorbax SB C18, 5 m, 15 cm,
35 °C, flow 1.2 ml/min, 10% CH3CN-H2O (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3
min; detector 268 nm; retention time starting material, 7.4 min; product, 6.9 min (UV max 220, 268,
300, 322 nm). 1H NMR (CDC13) 8 8.8 (s, 1H); 8.3 (m, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.8 (d, 1H); 5.7
(s, 2H); 4.7 (m, 1H, NCH); 3.6 (t, 2H); 2.3-2.5 (m, 8H); 0.9 (t, 2H); -0.1 (s, 9H). MS(ES) 412 (M+l).

Step 5: 4-[4-(7-[2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l~
yl]cyclohexylideneacetonitrile
To a solution of 1.0 M potassium terf-butoxide in THF (1.90 mL) at 0 oC was added a
solution of diethyl cyanomethylphosphonate (321 L, 0.00198 mol) in THF (4 mL) dropwise. The
reaction was held for 10 min, then it was added to a solution of 4-[4-(7-[2-(trimethylsilyl)-
ethoxy]methyl-7H-pyrrolo[2,3-d]pyrmidin-4-yl)-lH-pyrazol-l-yl]cycIohexanone (743 mg, 0.00180
mol) in THF (5 mL) stirring at 0 °C under a nitrogen atmosphere. The reaction was stirred 1.5 h at rt.
LCMS analysis showed clean conversion to the desired product. To the reaction mixture was then
added water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc.
The combined organic extract was washed with water, then sat'd NaCl, then dried over Na2SO4, and
concentrated to dryness to yield 0.76 g of a white crystalline solid (TLC (EtOAc) Rf 0.33). The
product was purified by automatic flash chromatography on silica gel. Used 40g column; flow 40
mL/min; [A= hexane] [B= EtOAc]; A, 2 min; Gradient to B in 20 min. Rotary evaporation yielded
0.70 g of a white crystalline solid (89% yield). 'H NMR (CDCfe) 8 8.9 (s, 1H); 8.3 (s, 2H); 7.4 (d,
1H); 7.3 (s, 1H); 6.9 (d, 1H); 5.7 (s, 2H); 5.3 (s, 1H, olefin); 4.5 (m, 1H, NCH); 3.6 (m, 2H); 3.2 (m,
1H); 2.7 (m, 1H); 2.5 (m, 4H); 2.1 (m, 2H); 1.0 (m, 2H); -0.1 (s, 9H). MS(ES) 435 (M+l).
Step 6: 4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylideneacetonitrile
A solution of TFA (0.5 mL, 0.006 mol) and 4-[4-(7-[2-(trimethylsilyI)ethoxy]methyI-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yljcyclohexylideneacetonitrile (22.7 mg, 0.0000522
mol), was stirred for 1.5h. The solution was then concentrated using a rotary evaporator to remove
TFA. LCMS analysis showed conversion to the hydroxymethyl intermediate, M+H 335. Methanol
was added; and the methanol mixture was concentrated again using a rotary evaporator. The resulting
residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL, 0.0064 mol) was
added. The resulting solution was stirred for 16 h. LCMS analysis showed complete de-protection.
The solution was then concentrated using a rotary evaporator. The product was isolated by prep
HPLC using a 30 mm x 100 mm C18 column; 18% CH3CN-H2O (0.1%TFA), lmin, to 35% at 6min;
60 mL/min; detector set at 254nm; retention time, 4.4min. The eluate was freeze dried, yield 7.6 mg
of a white solid (TFA salt; racemic; 34.6%). 'H NMR G/eJDMSO) 6 12.9 (br s, 1H, NH); 8.9 (s, 2H);
8.5 (s, 1H); 7.8 (m, 1H); 7.3 (m, 1H); 5.6 (s, 1H, olefin); 4.6 (m, 1H,NCH); 2.8 (m, 1H); 2.6 (m, 1H);
2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS(ES) 305 (M+l).
Example 686: cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI] cyclohexanecarbo-
nitrile trifluoroacetate

Step 1: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyt- 7H~pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl] cyclohexanecarbaldehyde oxime
A solution of sulfur trioxide-pyridine complex (53.4 mg, 0.000336 mol) in DMSO (0.3 mL,
0.004 mol) was added to a solution of cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethanol (57.4 mg, 0.000134 mol) and TEA (56.1 uL,
0.000403 mol) in DCM (0.3 mL, 0.004 mol) at -10 °C. The mixture was stirred vigorously at 10-20 °C
for one hour. LCMS analysis showed conversion to the aldehyde. The mixture was then poured into
ice-water, and extracted with DCM. The extracts were washed with 10 % citric acid, water, saturated
aqueous sodium bicarbonate, water, and brine, and then dried over sodium sulfate. Concentration gave
57 mg of a residue.
To the resulting residue was added hydroxylamine-HCl (50mg), 1 mL 20% K2CO3, and 3 mL
MeOH and this mixture was stirred at rt until LCMS showed conversion to the corresponding oxime,
M+H 441. The product was isolated by prep HPLCMS using a 30 mm x 10, 0 mm, Cl 8 column; 30%
CH3CN-H2O (0.1%TFA), 1 min, to 60% at 6 min; 60 mL/min; detector set at m/z 441; retention time,
6.0min. freeze-dried. yield 17.4 mg of a white solid.
Step 2: cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazot-J-yl]cyclohexanecarbonitrile
[A] cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyra2ol-l-yl]cyclohexanecarbaldehyde oxime (11.0 mg, 0.0000250 mol) was dissolved in pyridine
(0.25 mL, 0.0031 mol), and benzenesulfonyl chloride (10.0 L, 0.0000784 mol) was added and the
resulting mixture was stirred at rt. After stirring 15 h, LCMS analysis showed formation of the
product, M+H 423. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18
column; 45% CH3CN-H2O (0.1% NH4OH), lmin, to 75% at 6 min; 30 mL/min; detector set at m/z
423; retention time, 4.8 min. The eluent was concentrated using a rotary evaporator to give 8 mg of
the desired product
The product was dissolved in TFA (0.25 mL). stirred for 2h. The solution was concentrated
using a rotary evaporator to remove TFA. Methanol was added and the mixture was concentrated
again. LCMS showed clean conversion to the hydroxymethyl intermediate (M+H 323). The residue
was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL) was added. The solution was
stirred 0.5 h, at which time, LCMS showed complete de-protection to the desired product M+H 293.
The mixture was then concentrated by roto-evaporation, and the product was isolated by prep
HPLCMS using a 19 mm x 100 mm C18 column; 15% CH3CN-H2O (0.1% TFA), 1.5 min, to 30% at

6 min; 30 mL/min; detector set at m/z 293; retention time, 5.2 min. The eluate was freeze dried to
yield 5.5 mg of the product as a TFA salt. 1H NMR (d6DMSO) 5 12.82 (br s, 1H, NH); 8.87 (s, 1H);
8.85 (s, 1H); 8.48 (s, 1H); 7.82 (m, 1H); 7.24 (m, 1H); 4.40 (m, 1H, NCH); 3.22 (m, 1H); 2.05 (m,
6H); 1.79 (m, 2H). MS(ES) 293 (M+l).

Step /: 4-[l-(cis-4-[(2-Bromaphenyl)thio]methylcyclohexyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)-
ethoxy] methyl- 7H-pyrrolo[2,3-d]pyrimidine
This compound was prepared from (cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl methanesulfonate as in Example
686[A]. Yield 73%. The product was purified using the following HPLC method: Zorbax SB C18, 5
m, 15cm, 35 C, flow 1.2 mL/min, 10% CH3CN-H2O (0.05% TFA), to 100% CH3CN in 9.0 min; stop
time 12.3 min; detector 254 nm; retention time starting mesylate, 7.5 min; product, 9.9 min (UV max
215, 258, 300, & 326 nm). TLC: Rf 0.3 using 35% EtOAc/5% iPrOH/hexane. The product was
purified by automated silica gel flash chromatography using 30% EtOAc/5% iPrOH/hexane. 'H NMR
(CDC13) 8 8.84 (s, 1H); 8.31 (s, 1H); 8.26 (s, 1H); 7.55 (m, 1H); 7.39 (d, 1H); 7.27 (m, 2H); 7.03 (m,
1H); 6.82 (d, 1H); 5.67 (s, 2H); 4.34 (m, 1H, NCH); 3.55 (m, 2H); 2.98 (d, 2H); 2.28 (m, 2H); 2.02
(m, 3H); 1.83 (m, 4H); 0.92 (m, 2H); -0.06 (s, 9H). MS(ES) 598/600 1:1 (M+l).
Step 2: 2-[(cis-4-[4-(7-[2'(Tnmethylsilyl)ethoxyl]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]cyclohexylmeihyl)thio]benzonitrile
4-[l-(cis-4-[(2-Bromophenyl)thio]methylcyclohexyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)-
ethoxy3methyl-7H-pyrTolo[2,3-d]pyrimidine (62.7 mg, 0.000105 mol), zinc cyanide (123 mg, 0.00105
mol), and tetrakis(triphenylphosphine)palladium(0) (30.2 mg, 0.0000262 mol) were stirred in DMF (3
mL) and the solution was flushed with nitrogen. The solution was then heated to 100 °C for 25 min in
a microwave reactor. LCMS and HPLC analyses showed > 90% reaction. The product was isolated by
prep HPLCMS using a 30 mm x 100 mm C18 column; 52%CH3CN-H2O (0.1%TFA), 1.5 min, to 75%
at 6 min; 60 mL/min; detector set at 545 nm. The eluent was concentrated using a rotary evaporator to
give 37 mg of the 2-cyanophenylsulfide TFA salt. HPLC Method: Zorbax SB C18, 5 m, 15 cm, 35

C, flow 1.2 ml/min, 10% CH3CN-H2O (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3
min; detector 265 nm; retention time starting material, 9.9 min; product, 8.9 min. MS(ES) 545 (M+l).
Step 3: 2-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-I-yl]cyclohexylmethyl)sulflnyl]-
benzonitrile
A solution of 2-[(cis-4--[4-(7-[2-(trimeihylsilyl)etlioxy]methyI-7H-pyrrolo[2,3-d]pyrimidin-4-
yl)-lH-pyrazol-l-yl]cyclohexylmethyl)thio]benzonitrile (30.6 mg, 0.0000562 mol), in TFA (1 mL)
was stirred for 2 h. The solution was concentrated using a rotary evaporator to remove TFA. Methanol
was added, and the mixture was concentrated again. The resulting residue was dissolved in methanol
(1 mL) and ammonium hydroxide (1 mL) was added. The resulting solution was stirred overnight, at
which time HPLC showed complete deprotection. The product was isolated by prep HPLCMS using a
19 mm x 100 mm C18 column; 30% CH3CN-H2O (0.1% TFA), 1.5 min, to 59% at 6 min; 30 mlVmin;
detector set at m/z 415 nm; retention time, 4.7 min. The eluate was concentrated using a rotary
evaporator to give 36 mg of the sulfide TFA salt, a colorless glassy material. NMR (d6-DMSO) 8
12.82 (or s, 1H, NH); 8.84 (2 singlets, 2H); 8.45 (s, 1H); 7.8 (m, 2H); 7.64 (m, 2H); 7.34 (td, 1H);
7.24 (s, 1H); 4.39 (m, 1H, NCH); 3.23 (d, 2H); 2.19 (m, 2H); 1.89 (m, 3H); 1.72 (m, 4H). MS(ES)
415 (M+l). This material was then dissolved in CH2C12 and cooled to 0 °C. To the cooled mixture was
added MCPBA(12.9 mg, 0.0000562 mol), and the resulting mixture was stirred for 1 h. LCMS
showed conversion to the product, and no remaining sulfide. The reaction mixture was concentrated
by rotovap, and the product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column;
18% CH3CN-H2O (0.1% TFA), 1. 0 min, to 35% at 6 min; 30 mL/min; detector set at m/z 431 nm;
retention time, 5.6 min. The product was isolated from the eluent by freeze-drying. The yield was
27.6 mg of the TFA salt. The HPLC method was: Zorbax SB C18, 5 m, 15 cm, 35 °C, flow 1.2
mL/min, 10% CH3CN-H20 (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector
268 nm; retention time starting material, 5.6 min; sulfbxide, 4.8 min; sulfone, 5.2 min; MCPBA, 6.0
min. 1H NMR (CDC13) 8 12.1 (br s, 1H, NH); 9.0 (s, 1H); 8.9 (s, 1H); 8.3 (s, 1H); 8.1 (m, 1H); 7.9 (m,
1H); 7.8 (m, 1H); 7.6 (m, 2H); 7.0 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (dd, 1H); 2.9 (dd, 1H); 2.5 (m,
1H); 2.3 (m, 1H); 2.3-1.7 (m, 7H). MS(ES) 431 (M+l).

2-[(cis-4-t4-(7H-Pyrrolo[2,3-d3pyaimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)sulfinyl]-
benzonitrile (17.2 mg, 0.0000400 mol) (21 mg TFA salt), was dissolved in DCM (10 mL) and cooled
to 0 °C. To this mixture was added MCPBA (18 mg, 0.0000800 mol). The resulting mixture was
stirred for lh at 0 DC, and then for 16 h at rt. HPLC and LCMS showed 80 area% product, and 3
area% sulfoxide. The MCPBA was removed using a sat'd NaHCO3 wash, and the resulting washed
mixture was concentrated by roto-evaporation. The product was isolated by prep HPLCMS using a 19
mm x 100 mm C18 column; 23%CH3CN-H2O (0.1%TFA), 1.0 min, to 43% at 6 min; 30 mL/min;
detector set at m/z 447 nm; retention time, 5.1 min. The product was isolated from the eluent by
freeze-drying. The yield was 5 mg of the TFA salt. 'H NMR (dg-DMSO) 5 12.70 (br s, 1H, NH); 8.83
(s, 1H); 8.82 (s, 1H); 8.41 (s, 1H); 8.21 (dd, 1H); 8.16 (dd, 1H); 8.01 (td, 1H); 7.95 (td, 1H); 7.78 (s,
1H); 7.19 (s, 1H); 4.34 (m, 1H, NCH); 3.62 (d, 2H); 2.28 (m, 1H); 2.10 (m, 2H); 1.90 (m, 2H); 1.72
(m, 4H). MS(ES) 447 (M+l).

Step 1: 3-[4-(7-[2-(Tnmethyhilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-I-yl]-
cyclohexanone
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (309 mg, 0.980 mmol) in ACN (6 mL) was added 2-cyclohexen-l-one (190 L, 01.96
mmol), followed by DBU (40 L, 0.3 mmol). The resulting mixture was stirred for one hour at which
point LCMS indicated complete addition. The mixture was reduced in vacuo and the crude product
was purified by column chromatography to obtain the product (397 mg, 98%). 1H NMR (400 MHz,
CDC13): 5 8.84 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.45 (d, 1H), 6.79 (d, 1H), 5.67 (s, 2H), 4.61 (m,
1H), 3.55 (m, 2H), 3.05-2.90 (m, 2H), 2.45-2.30 (m, 4H), 2.05 (m, 1H), 1.90 (m, 1H), 0.92 (m, 2H),
-0.06 (s, 9H). MS (El) m/z = 412.2 (M+H).
Step 2: (2E,Z)-3-[4-(7-[2-(Trimethyhilyl)ethoxy]methyl-7H~pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]cyclohexylideneacetonitrile

To a solution of t-BuOK in THF (1.0 M, 0.255 mL, 0.255 nunol) at 0 °C was added a solution
of diethyl cyanomethylphosphonate (43 L, 0.27 mmol) in THF (0.6 mL) dropwise. The reaction was
held for 10 minutes, then a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexanone (100.0 mg, 0.2430 mmol) in THF (0.34 mL) was
added dropwise. After complete addition, the cooling bath was removed and the reaction was held at
ambient temperature for 16 hours, at which point LCMS indicated complete addition to yield the
desired product as a mixture of E and Z isomers (87.9 mg, 83%). 'H NMR (400 MHz, CDC13): 5 8.84
(s, 0.5H), 8.83 (s, 0.5 H), 8.27 (d, 1H), 8.25 (s, 1H), 7.40 (s, 0.5H), 7.39 (s, 0.5H), 6.81 (d, 0.5H), 6.79
(d, 0.5H), 5.67 (s, 2H), 5.28 (s, 0.5H), 5.24 (s, 0.5H), 4.4 (m, 1H), 3.55 (m, 2H), 3.1-2.8 (m, 2H), 2.5-
2.1 (m, 6H), 0.92 (m, 2H), -0.06 (s, 9H). MS (EX) m/z = 435.2 (M+H).
Step 3: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
cyclohexylaceton itrile
To (2E, Z)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-
pyrazol-l-yl]cyclohexylideneacetonitrile (42.0 mg, 0.0966 mmol) was added THF (0.5 mL). The
resulting solution was cooled to -78 °C, and then 1.0 M L-Selectride® in THF (120 uL, 0.12 mmol)
was added dropwise. The reaction was held at -78 °C for lh at which point LCMS indicated complete
reduction. The reaction was quenched at -78 °C by addition of saturated aqueous NH4CI and EtOAc,
and was then allowed to warm to ambient temperature. The phases were separated and the aqueous
phase was extracted with additional EtOAc. The combined organic phase was washed with water,
then saturated NaCl, and then was dried over MgSO4. The crude product was purified by column
chromatography to obtain the product (26.5 mg, 63%). 1H NMR (400 MHz, CDC13): S 8.84 (s, 1H),
8.32 (s, 1H), 8.25 (s, 1H), 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.53 (m, 1H), 3.52 (m, 2H), 2.6-1.4
(m, 11H), 0.92 (m, 2H), -0.06 (s, 9H). MS (El) m/z = 437.2 (M+H).
Step 4: 3-[4-(7H-Pyrrolo[2,3-dJpyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylacetonitrile
trifluoroacetate
To 3-[4-(7-[2-(triniethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -
yl]cyclohexylacetonitrile (30.1 mg, 0.0689 mmol) was added DCM (1.0 mL) and TFA (1.0 mL). The
resulting mixture was stirred for 1 hour at ambient temperature, at which point LCMS indicated
complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to the residue
was added methanol (1.0 mL) followed by ethylenediamine (37 L, 0.55 mmol), after which the
reaction was stirred for 5 hours, at which point LCMS indicated complete reaction. The solvent was
removed and the residue was purified by preparative LCMS to provide the product as a TFA salt (24
mg, 83%). 1H NMR (400 MHz, CD3OD): 8 8.91 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.31
(s, 1H), 4.69 (s, 1H), 2.58 (d, 2H), 2.5-1.5 (m, 9H). MS (El) m/z = 307.10 (M+H).

Step 1: trans-4-[4-(7-[2-(Trimethylsilyl)ethoxy]meikyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-J-ylJcyclohexanol
A solution of 4-[4-(7-[2^trimethylssilyl)e1thoxy]methyl-7H-pyrrolo[2,3^]pyriniidin-4-yl)-lH-
pyrazol-l-yl]cyclohexanone (662 mg, 1.61 mmol) in THF (5 mL) was cooled to 0 °C and lithium
tetrahydroaluminate (2M in THF, 0.804 mL, 1.61 mmol) was added slowly. The mixture was allowed
to warm slowly to ambient temperature until LCMS indicated complete reduction. The reaction was
cooled to 0 °C and quenched with dropwise addition of water (0.5 mL). DCM was added, and the
mixture was stirred for 1 hour at ambient temperature, after which the precipitated solids were
removed by filtration. The filtrate was reduced in vacuo to leave a white solid (0.63g, 99%). HPLC
of the solid showed an approximately 4:1 ratio of trans to cis product. Tic (6:3:1
EtOAc:hexanes:isopropanol) gave an Rf of 0.25 for the cis product , and 0.18 for the trans product.
The product was purified by flash chromatography on silica gel to recover 230 mg of the pure trans
alcohol and 25 mg pure of the cis alcohol, and 350 mg of mixed isomers.
1H NMR (400 MHz, CDC13): 5 8.83 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H)5 7.39 (d, 1H), 6.81 (d, 1H),
5.67 (s, 2H), 4.24 (m, 1H), 3.79 (m, 1H), 3.54 (m, 2H), 2.28 (m, 2H), 2.17 (m, 2H), 1.94 (m, 2H), 1.53
(m, 2H), 0.92 (m, 2H), -0.06 (s, 9H). MS (El) m/z = 414 (M+H).
Step 2: trans-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol-
j-yljcyclohexyl methanesulfonate
To trans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]cyclohexanol (154 mg, 0.372 mmol) was added DCM (1.0 mL) and TEA (73 L, 0.52
mmol). The resulting solution was then cooled to 0 °C and methanesulfonyl chloride (34 L, 0.45
mmol) was added. The reaction was held for 2 hours, at which point tic and LCMS indicated complete
reaction. The reaction was partitioned between water and DCM, the phases were separated and the
aqueous phase was extracted with additional solvent. The combined organic phase was washed with
water, then saturated NaCl, then was dried over MgSO4 and reduced in vacuo to give the crude

product which was used without further purification (173 mg, 95%). 1H NMR (400 MHz, CDC13): 8
8.83 (s, 1H), 8.24 (s, 2H), 8.24 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, 1H), 4.27 (m,
1H), 3.54 (m, 2H), 3.06 (s, 3H), 2.36 (m, 4H), 2.03 (m, 2H), 1.82 (m, 2H), 1.53 (m, 2H), 0.92 (m,
2H), -0.06 (s, 9H). MS (El) m/z = 492.1 (M+H).
Step 3: 5-({cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cycloh^
triazol-3-amine bis(trifluoroacetate)
To a solution of trans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriniidin-
4-y])-lH-pyrazol-l-yl]cyclohexyl methanesulfonate (42 mg, 0.085 mmol) in DMF (800 uL) was
added 3-amino-lH-l,2,4-triazole-5-thiol (30 mg, 0.26 mmol) and K2CO3 (36 mg, 0.26 mmol). The
reaction was sealed and held at 100 °C for 2 hours at which point LCMS indicated conversion to
desired product. The reaction was diluted with water and extracted successively with ether, ethyl
acetate, and 3:1 chloroform:isopropyl alcohol. The combined organic phase was washed with water,
then saturated NaCl, dried over MgSO4 and reduced in vacua, and the crude product was purified by
column chromatography to give 5-({cis-4-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexyl}thio)-lH-l,2,4-triazol-3-amine (27.3 mg, 63%). To
the product was added DCM (0.5 mL) and TFA (0.5 mL), and the reaction was stirred for 1 hour at
ambient temperature at which point LCMS indicated complete cleavage to the N-hydroxymethyl
intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by
NH4OH (0.3 mL), the reaction was stirred for 16 hours at which point LCMS indicated complete
deprotection. The solvent was removed and the residue was purified by preparative LCMS to provide
the product as a bis-TFA salt (15.1 mg, 29%). 1HNMR (400 MHz, CD3OD): 8 8.77 (s, 1H), 8.72 (s,
1H), 8.37 (s, 1H), 7.74 (d, 1H), 7.21 (d, 1H), 4.40 (m, 1H), 3.97 (m, 1H), 2.25(m, 2H), 2.04 (m, 6H).
MS (ET)tm/z= 382.2 (M+H).

Stepl.N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxyJmethyl-7H-pynolo[2,3^Jpyrimidin-4-yl)-lH-
pyrazol-l-yl]cyclohexylmethyl)thio]-4H-l,2,4-triazol-3-ylmethanesulfonamide
5-[(cis-4-[4-(7-[2-(Trim6thylsilyl)ethoxy]mcthy]-7H-pyrrolo[2,3-dl]pyrimidm-4-yl)-lH-
pyrazol-l-yl]cyclohexylmethyl)thio]-4H-l,2,4-triazol-3-amine (30.00 mg, 5.706E-5 mol) was
dissolved in DCM (2.00 mL, 0.0312 mol) with TEA (0.024 mL, 0.00017 mol) and was cooled at 0 °C.
To the reaction was added methanesuifonyl chloride (0.0066 mL, 0.000086 mol) and the resulting
mixture was stirred at 0 °C for 60 minutes, at which time LCMS analysis showed mostly product.
The reaction was chromatographed on silica gel using EtOAc as ehient to give the product. LC/MS
(M+l)+:604
Step2.N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)thio]
4H-l,2,4-triazol-3-ylmethanesulfonamide
Into a 1-neck round-bottom flask [A] N-5-[(cis-4-[4-(7-[2-(trimethylsilyI)ethoxy]methyl-7H-
pyrroloP.S-dlpyrimidin^-y^-lH-pyrazol-l-ylJcyclohexylmethyOthiol^H-l^^triazol-S-ylmethane-
ulfonamide (0.025 g, 0.000041 mol) was dissolved in DCM (3.00 mL, 0.0468 mol) and TFA (mL,
0.006 mol) was added. The reaction was stirred at 25 °C for 16 hours at which time LCMS analysis
showed no starting material present. The reaction was concentrated using a rotary evaporator and was
dissolved in methanol (2.00 mL, 0.0494 mol) and 16 M ammonia in water (0.2 mL) was added. The
reaction was stirred at 25 °C for 3 hours at which time LCMS analysis showed no starting material
present. The reaction was concentrated using a rotary evaporator and was purified by prep LC to give
the product as the trifluoroacetate salt. LC/MS (M+l)+:474, 1HNMR(CD3OD): 8.87 (s, 1H), 8.82 (s,
1H), 8.45 (s, 1H), 7.85 (d, 1H), 7.33 (d, 1H), 4.48 (m, 1H), 3.36 (s, 3H), 3.23 (d, 2H), 2.30 (m, 2H),
2.04 (m, 3H), 1.85 (m, 4H).

1H-1,2,4-Triazole (91.0 mg, 0.00132 mol), DBU (174 L, 0.00070 mol), [A] 4-[4-(7-[2-
(1ximethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylidene-
acetonitrile (86.4 mg, 0.000199 mol), and ACN (2.0 mL) were stirred at rt. After 4d, LCMS showed
about 58 area% product (two peaks, M+H 504, ratio 1:1). The DBU in the reaction was neutralized
with TFA. The product was isolated by prep HPLC using a 30 mm x 100 mm C18 column; 32%

CH3CN-H2O (0.1%TFA), 1 min, to 47% at 6 min; 60 mL/min; detector set at 254 nm; retention time,
5.1 (A) & 5.4 (B) min. The eluent was concentrated using a rotary evaporator to give 22 mg of (A) &
36 mg of (B).
Deprotection: The products were dissolved separately in TFA (0.5 mL) and stirred for lh.
LCMS showed conversion to the hydroxymethyl derivative (M+H 404). The solutions were
concentrated using a rotary evaporator to remove TFA. Methanol was added, and the resulting
mixtures were concentrated again. The resulting residue was dissolved in methanol (1 mL), and
ammonium hydroxide (0.25 mL) added. The solution was stirred 0.5h. LCMS showed complete de-
protection (M+H 374) and the mixture was then concentrated by roto-evaporation. Each isomer was
isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH3CN-H2O (0.1% TFA), 1.5
min, to 32% at 6 min; 30 mL/min; detector set at m/z 374; retention time, 4.5 min (A) & 4.7 min (B) .
The eluates were freeze dried. Yield 13 mg isomer A and 24 mg isomer B (TFA salts, white solids).
NMR analysis (including NOE & COSY) was consistent with expectation for the structures, with
A=cis, and B=trans. NMR (d6DMSO) 5 cis: 12.94 (br s, 1H, NH); 8.95 (s, 1H); 8.87 (s, 1H); 8.81 (s,
1H); 8.42 (s, 1H); 8.14 (s, 1H); 7.85 (m, 1H); 7.22 (m, 1H); 4.48 (m, 1H, NCH); 3.12 (s, 2H); 2.84
(m, 2H); 2.07 (m, 4H); 1.69 (m, 2H). MS(ES) 374 (M+l). trans: 12.85 (br s, 1H, NH); 8.94 (s, 1H);
8.89 (s, 1H); 8.84 (s, 1H); 8.47 (s, 1H); 8.11 (s, 1H); 7.84 (m, 1H); 7.26 (m, 1H); 4.50 (m, 1H, NCH);
3.48 (s, 2H); 2.42-2.10 (m, 8H). MS(ES) 374 (M+l).

1 M Diisoburylalumimim hydride in hexane (0.31 mL) was added dropwise to a solution of
methyl 3-3-cyanophenyl-2-[4--(7-[2-(trimethylsily)ethoxylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-
yl)-lH-pyrazol-l-yl]propanoate (100 mg, 0.0002 mol) (prepared by using a procedure analogous to
Example 712, Step 1) in DCM (3 mL, 0.05 mol) and the mixture was cooled to -78 °C. The reaction
mixture was stirred at -78 CC for 4 h and was afterward quenched with cold methanol (3 mL, 0.07
mol). The reaction was allowed to warm to 0 °C and potassium carbonate (60 mg, 0.0004 mol) and
Bestmann-Ohira reagent (1.5 eq, 57 mg) (E. Quesada et at, Tetrahedron, 62 (2006) 6673-6680) were
added. The reaction was stirred at room temperature overnight, and then partitioned between ethyl
acetate and water. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and
concentrated to give the crude product. The crude product was purified using silica gel
(EtOAC/Hexane 1:3 to 1:1) to give the desired product, 3-{l-[4-(7-{[2-(trimethylsilyl)ethoxy]-
memyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]but-3-yn-l-yl}beiizonitrile (40 mg of
mixture), m/z = 469 (M+l).
Step 2: 3-l-[4-(7H-Pyrrolo[2,3d]pyrirrudin-4-yl)-lH-pyrazol-l-ylJbut-3-yn-l-ylbenzonitrile
trifluoroacetate
Using a procedure analogous to Example 712, Step 4, the title compound was prepared (4.5
mg, 46%) as an amorphous white solid. 1HNMR (500 MHz, DMSO): 8. 12.5 (b, 1H), 9 (s, 1H), 8.8
(s, 1H), 8.4 (s, 1H), 8 (s, 1H), 7.8 (m 2H), 7.7 (s, 1H), 7.6 (m, 1H), 7 (m, 1H), 5.9 (m, 1H), 3.4 (dd,
1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z = 339 (M+l).

Using the procedure of Example 705, the title compound was prepared as a secondary product
(4.5 mg, 46%) as an amorphous white solid. *H NMR (400 MHz, CDC13): £ 10 (s, 1H), 9 (s, IH), 8.8
(s, 1H), 8.4 (s, 1H), 8 (s, 1H), 7.9 (m 1H), 7.8 (m, 1H), 7.7 s, 1H), 7.6 (m, 1H), 7.1 (s, 1H), 5.9 (m,
1H), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z = 342.

A solution of methyl (2E)-3-phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol)
was slowly added to a solution of 4-(lH-pyrazol-4-yl)-7-t2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrirnidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 L, 0.003 mol).
The reaction was stirred at room temperature over the weekend. The reaction was partitioned between
water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4,
filtered and concentrated to give an oil. The product was purified by FCC on silica gel using
EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanoate (500 mg, 70%) as a semisolid residue.
1H NMR (400 MHz, CDC13): 8. 8.9 (s, 1H), 8.4 (s, 2H), 7.4 (m, 5H), 6.8 (d, 1H), 6 (m, 1H), 5.7 (s,
2H), 3.7-3.8 (m, 3H), 3.6 (m, 2H), 2.2 (m, 1H), 1.4 (m, 2H), 1.1 (m, 2H), 0.02 (s, 9H), m/z = 478
(M+l).

Diisobutylaluminum hydride in hexane (1 M, 0.69 mL) was added to a solution of methyl 3-
phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI]-
propanoate (150 mg, 0.00031 mol) in DCM (3 mL, 0.05 mol) and the mixture was cooled to -78 oC
under a nitrogen atmosphere. The reaction was stirred for 1 h at -78 oC and was allowed to warm to
room temperature for 4 hrs. The reaction was quenched with methanol (100 L), and saturated
ammonium chloride (100 L), and then taken up in ethyl acetate dried over MgSO4 and filtered. The
filtrate was concentrated to give 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propan-l-ol (130 mg, 92%) as an oil. m/z = 450 (M+l).
Step 3: 4-[l-(3-Methoxy-l-phenylpropyl)-lH-pyrazol-4-yl]- 7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-djpyrimidine

Sodium hydride (9.6 mg, 0.00040 mol) was added to a solution of 3-phenyl-3-[4-(7-{2-(tri-
methylsilyl)ethoxy]memyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propan-l-ol (120 mg,
0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0 °C. The reaction was stirred
for 20 min and methyl iodide (22 L, 0.00035 mol) was added. The reaction was allowed to warm to
room temperatures and stirred overnight. The reaction was partitioned between water and EtOAc. The
organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give 4-

[l-(3-methoxy-l-phenylpropyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyi-7H-pyrrolo[2,3-
d]pyrimidine (100 mg, 88%) as a semisolid. m/z = 464 (M+l).
Step 4: 4-[l-(3-Methoxy-l-pkenylpropyl)-lH-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine
trifluoroacetate
Trifluoroacetic Acid (2 mL, 0.02 mol) was added to a mixture of 4-[l-(3-methoxy-l-
phenylpropyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (80
mg, 0.0002 mol) in DCM (3 mL, 0.05 mol) at room temperature. The starting material was consumed
after stirring for 2hrs and the reaction solution was concentrated to remove the TFA. The crude
reaction was diluted with methanol (3 mL, 0.07 mol) and was treated with ethylenediamine (0.3 mL,
0.004 mol) at room temperature. The reaction mixture was stirred for 18 hs and was concentrated and
purified using HPLC on a C-1 8 column eluting with an ACN: water gradient containing 0.2% TFA, to
give the title compound (43 mg, 60%) as a white amorphous solid. 1H NMR (400 MHz, CDC13): §8.9
(s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.8 (s, 1H), 7.4 (m, 1H), 7.3 (m, 5H), 7.2 (h, 1H), 5.7 (m, 1H), 3.3 (m,
1H), 3.2 (s, 3H), 2.7 (m, 1H), 2.4 (m, IH). m/z = 334 (M+l).

A mixture of [4-l-[l-(3-bromophenyl)but-3-en-l-yl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-d]-
pyrimidine (20 nag, 0.00005 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (60 mg, 0.0005 mol)
was degassed with a nitrogen stream. The mixture was then treated with tetrakis(triphenyl-
phosphine)palladium(O) (40 mg, 0.00003 mol), again degassed with nitrogen, and was then heated in
a microwave reactor to 170 °C for 15 min. The reaction was allowed to cool, was filtered and purified
by HPLC on a C-l 8 column eluting with an ACN/water/TFA gradient to give the title compound (10
mg, 40%) as a white amorphous solid.
1H NMR (400 MHz, DMSO): 8 8.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.9 (s, 1H), 7.8 (m, 3H), 7.6 (m,
1H), 7.1 (b, 1H), 5.6-5.8 (m, 2H), 5.1 (d, 1H), 5 (d, 1H), 3.3 (m, 1H), 3 (m, 1H). m/z = 341 (M+l).
Example 716: 4-l-[l-(3-Bromophenyl)but-3-en-l-ylJ-lH-pyrazoI-4-yI-7H-pyrrolo [2,3-dl-
pyrimidine

Diisobutylaluminum hydride in hexane (1 M, 4 mL) was added to a -78 °C solution of ethyl
3-(3-bromophenyl)0-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pynx)lo[2)3-d]pyrmidin-4-yl)-lH-
pyrazol-l-yl]propanoate (600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirring, for 4 h, the
reaction was quenched with cold methanol (300 L), and then saturated ammonium chloride (500 L)
was added and the resulting solution was stirred for 1 h. The reaction was partitioned between water
and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated.
The product was purified by flash chromatography on silica gel eluting with hexane: EtOAc, (2:1 to
1:2), to give 3-(3-bromophenyl)-3-[4-(7-[2-(triniethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (400 mg, 70%) as an oil.. 1H NMR (400 MHz, CDCI3): 5
9.9 (s, 1H), 8.9 (s, 1H), 8.4 (s, 2H), 7.6 (d, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.4 (m, 2H), 6.8 (d, 1H),
6.1 (m, 1H), 5.7 (s, 2H), 4 (m, 1H), 3.6 (m, 2H), 3.3 (dd, 1H), 1.0 (m, 2H), 0.01(s, 9H). m/z - 526,
528 (M+l),
Step 2: 4-l-[l-(3-Bronwphenyl)but-3-en-l-ylj-lH~pyrazol^-yl-7-[2-(trimethylsilyl)ethoxy]methyl-
7H-pyrrolo[2,3-d]pyrimidine

Potassium tert-butoxide in THF (!M, 200 L) was added to a solution of methyltriphenyl-
phosphonium iodide (80 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) at 0 °C. The reaction was stirred
at room temperature for 1h and then cooled to -78 °C. The 3-(3-bromophenyl)-3-[4-(7-[2-(triniethyl-
silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (90 mg, 0.0002 mol)
in THF (2 mL, 0.02 mol) was added dropwise. The reaction was allowed to warm to room
temperature gradually. The reaction was partitioned between water and EtOAc. The organic layer
was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The
product was purified by FCC on silica gel eluting with EtOAc:Hexane, (1:1) to give 4-l-[l-(3-
bromophenyl)but-3-en-l-yl]-lH-pyrazo-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidine (35 mg, 40%) as an oil. m/z = 524, 526 (M+l).
Step 3: 4-l-[l-(3-Bromophenyl)but-3-en-l-yl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-dJpyrimidine
Using a procedure analogous to Example 712, Step 4, but using 4-l-[l-(3-bromophenyl)but-
3-en-l -yl]-l H-pyrazo1-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine the title
compound was prepared (10 mg, 30%) as a white amorphous solid, 1H NMR (400 MHz, DMSO):&
8.9(s,lH), 8.8(s,lH), 8.4(s,lH), 7.8(s,lH), 7.7(s,lH), 7.5 (m,2H), 7.3(m,lH), 7.1(s,lH), 5.7(m,2H),
5.2(d,lH), 5.0(d,lH), 3.2(m,lH), 3.0(m,lH). m/z = 394, 396 (M+l).

To a solution of 3-(3-bromophenyl)-3-t4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (0.05 g, 0.00009 mol) in N,N-dimethylacetamide (2 mL,
0.02 mol) was added triphenylphosphine (0.1 g, 0.0006 mol), dibromodifluoromethane (50 L, 0.0006
mol) and 0.76 M zinc in THF (0.7 mL). The reaction was stirred at room temperature for 18 hs. The
reaction was partitioned between water and EtOAc. The organic layer was washed with saturated
NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC
on silica gel eluting with EtOAc, Hexane (1:2) to give 4-{l-[l-(3-bromophenyl)-4,4-difluorobut-3-en-
l-yl]-lH-pyrazoM-yl}-7-{[2^trimethylsUyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (20 mg,
40%) as a clear oil. m/z = 560, 562 (M+l).

Using a procedure analogous to Example 712, Step 4, but using 4-{l -[l-(3-bromophenyl)-4,4-
difluorobut-3-en-l -yl]-l H-pyrazol-4-yl} -7- {[2-(trimethylsilyl)ethoxy]methyl} -7H-pyrroIo[2,3-
d]pyrimidme, the compound 4-l-[l-(3-bromophenyl)-4,4-difluorobut-3-en-l-yl]-lH-pyrazol-4-yl-7H-
pyrrolo[2,3-d]pyrimidine was prepared (30 mg, 99%) as an oil. m/z = 430,432 (M+l).
Step 3: 3-4A-Difluoro-l-[4-(7H-pyrrolo[2,3-d]pyrimidm-4-yl)-lH-pyrazol-l-yl]but-3-en-l-yl-
benzonitrile

A mixture of 4-l-[l-(3-bromophenyl)-4,4-difluorobut-3-en-l-yl]-lH-pyrazol-4-yl-7H-
pyrrolo[2,3-djpyrirnidine (30 mg, 0.00007 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (80 mg,
0.0007 mol) was degassed with nitrogen. The mixture was then treated with tetrakis(triphenyl-
phosphine)palladium(O) (50 mg, 0.00004 mol) and was degassed with nitrogen, and then was heated
in microwave at 170 °C for 15 min. The reaction was then allowed to cool, filtered and purified by
HPLC on a C-18 column eluting with an ACN/water/TFA gradient to give the title compound (10 mg,
30%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): £8.9 (s, 1H), 8.7 (s, 1H), 8.4 (s, 1H),
7.9 (s, 1H), 7.7 -7.8 (m, 3H), 7.5 (m, 1H), 7.1 (m, 1H), 5.7 (m, 1H), 4.3-4.4 (m, 1H), 3.1 (m, 1H), 2.9
(m, 1H). m/z = 377 (M+l).
The following compounds in Table 14 were prepared as indicated in the column labeled
"Prep. Ex. No." and the details of certain exemplary synthetic procedures are provided following

* Step 1 of example 731 was modified as follows: The Ph3P and CF2Br2 were combined in
DMAC at 0 °C and then allowed to warm to room temperature until the ylid formation was complete
as determined by LCMS. The solution of the ylid was then re-cooled to 0 °C and the aldehyde and
zinc were added to the ylid solution and the reaction was slowly warmed to room temperature.
Example 727: 4-[l-(l-Cyclopentylbat-3-eii-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2r3-dJpyriniidine
trifluoroacetate salt

Step 1: (2h)-3~L,yclopentylacrylic acid
t
To a solution of malonic acid (1.06 g, 10.2 mol) in pyridine (1.25 mL) was added pipendine
(0.15 mL) and cyclopentanecarbaldehyde (1.00 g, 10.2 mmol). The mixture was heated to 40 °C for 2
hours, followed by stirring at room temperature for 16 hours. The mixture was then cooled in an ice
bath and 2N HC1 was added to acidify. The product was extracted with ether. The ether extract was
washed with aq. HC1 and brine, dried over sodium sulfate, filtered, and the solvent was removed in
vacuo to afford the product (1.30 g, 77%), which was used without further purification.
'H NMR (300 MHz, CDC13): 57.06 (dd, 1H), 5.80 (dd, 1H), 2.70-2.54 (m, 1H), 1.93-1.32 (m, 8H);
MS(ES):141(M+H).

Step 2. Methyl (2E)-3-cyclopentylacrylate
To a solution of (2E)-3-cyclopentylacrylic acid (1.3 g, 9.3 mmol) in DCM (65 mL) at 0 °C
was added oxalyl chloride (3.1 mL, 37 mmol), dropwise. The resulting solution was stirred at 0 °C for
40 minutes, then at room temperature for 2 hours. The volatiles were evaporated to afford (2E)-3-
cyclopentylacryloyl chloride as a colorless liquid. A portion of this (2E)-3-cyclopentylacryloyl
chloride (0.75 g, 4.7 mol) was dissolved in methanol (10 mL) and the resulting solution was stirred
for 2 hours. The solvent was evaporated to afford the product (700 mg, 96%).
1H NMR (300 MHz, CDC13): 86.94 (dd, 1H), 5.79 (dd, 1H), 3.71 (s, 3H), 2.66-2.50 (m, 1H), 1.92-
1.27 (m,8H).
Step 3. Methyl 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-
yl)-IH-pyrazol-l-yl]propanoate
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidine (2.9 g, 9.2 mmol) and methyl (2E)-3-cyclopentylacrylate (1.70 g, 11.0 mmol) in ACN
(100 mL), was added DBU (2.7 mL, 18 mmol). The resulting mixture was stirred for 96 hours. The
ACN was removed in vacuo, and the resulting residue was dissolved in ethyl acetate. This solution
was washed with 1.0 N HC1, followed by brine, and then dried over sodium sulfate, and the solvent
removed in vacuo. Flash column chromatography (eluting with a gradient from 0-70% ethyl acetate in
hexanes) afforded the product (2.73 g, 63%).
'H NMR (300 MHz, CDC13): & 8.84 (s, 1H), 8.28 (s, 2H), 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H),
4.46 (dt, 1H), 3.60 (s, 3H), 3.54 (t, 2H), 3.18 (dd, 1H), 2.89 (dd, 1H), 2.59-2.42 (m, 1H), 1.95-1.80
(m, 1H), 1.75-1.10 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):470(M+H).
Step 4. 3-Cyclopentyl-3-[4-(7-f2-(trimethylsilyl)etho^Jmethyl-7H-pyrrolo[2,3-dJpyrimidin-4-yl)-JH-
pyrazol-l-yljpropanal
To a solution of methyl 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanoate (0.501 g, 1.07 mmol) in THF (5.0 mL) at -78 °C
was added 1.00 M diisobutylaluminum hydride in DCM (2.35 mL) dropwise. The reaction was
stirred with gradual warming to -10 °C over the course of 2 hours. At this temperature, a further
portion of 1.0 M diisobutylaluminum hydride in DCM (1.50 mL) was added. When the reaction was
determined to be complete by LCMS, a saturated solution of K/Na tartrate was added, followed by
ether. The resulting mixture was stirred for two hours at room temperature. The organic layer was
separated and washed with water, and brine, then dried over sodium sulfate and the solvent was
removed in vacuo to give a viscous oil, which was used without further purification.
MS(ES):442(M+H).

To a solution of oxalyl chloride (0.108 mL, 1.28 mmol) in DCM (10.0 mL) at -78 °C was
added DMSO (151 L. 2.13 mmol). After stirring for 5 minutes, 3-cyclopentyl-3-[4-(7-[2-
(trimethylsilyl)ethoxy]methyl-7H-pyirolo[2J3-d]pyriimdin-4-yl)-lH-pyrazol-l-yl]propan-l-ol (471
mg, 1.07 mmol) in DCM (3.00 mL) was added. The mixture was stirred for 30 minutes at -78 °C.
TEA (594 L, 4.26 mmol) was then added. The resulting mixture was then allowed to warm to room
temperature over the course of 30 minutes. Water was added, and the layers were separated. The
organic layer was washed successively with 0.1 N HC1, water, saturated sodium bicarbonate solution,
and brine, and was then dried over sodium sulfate and the solvent was removed in vacuo. Flash
column chromatography (eluting with a gradient of 0-60% ethyl acetate in hexanes) afforded the
product (384 mg, 82%).
1H NMR (300 MHz, CDC13): 5 9.73 (s, 1H), 8.87 (s, 1H), 8.71 (br s, 1H), 8.30 (s, 1H), 7.47 (br s,
1H), 6.88 (br s, IH), 5.69 (s, 2H), 4.66-4.49 (m, 1H), 3.54 (t, 2H), 3.40 (ddd, 1H), 2.95 (ddd, 1H),
2.55-2.44 (m, 1H), 2.01-1.21 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):440(M+H).
Step j. 4-[1-(l-Cyclopentylbut-3-en-l-yl)-lH-pyrazol^~ylJ~7-[2-(lrirnethyhilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidine
To a solution of 1.0 M potassium ter/-butoxide in THF (0.207 mL) in THF (2.0 mL) at 0 °C
was added triphenylmethylphosphonium bromide (77.8 mg, 0.218 mmol). The resulting mixture was
warmed to room temperature and allowed to stir for 30 minutes. A solution of 3-cyclopentyl-3-[4-(7-
[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]propanal (0.100
g, 0.228 mmol) in THF (2.0 mL) was added. After 30 minutes, the mixture was quenched by the
addition of saturated ammonium chloride solution and the product was then extracted with ether. The
ether extract was dried over sodium sulfate and the solvent was removed in vacuo. Flash column
chromatography (eluting with a gradient of 0-40% ethyl acetate in hexanes) afforded the product (40
mg, 44%).
'H NMR (400 MHz, CDCl3): 8 8.84 (s, IH), 8.26 (s, IH), 8.19 (br s, IH), 7.40 (s, IH), 6.83 (br s, IH),
5.67 (s, 2H), 5.60 (ddt, IH), 5.01 (dq, 1H), 4.97-4,93 (m, IH), 3.99 (dt, IH), 3.54 (t, 2H), 2.79-2.60
(m, 2H), 2.60-2.40 (m, IH), 1.99-1.89 (m, IH), 1.75-1.41 (m, 5H), 1.37-1.12 (m, 2H), 0.92 (t, 2H), -
0.06 (s, 9H); MS(ES):438(M+H).
Step 6. 4-[l-(l-Cyelopentylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-dJpyrimidine
trifluoroacetate salt
4-[l-(l-Cyclopentylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrimidine (13 mg, 0.030 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) was
added. The resulting solution was stirred at room temperature for 3 hours. The solvent was removed
in vacuo. The residue was dissolved in THF (2 mL), and 6 N NaOH (1 mL) was added. The mixture

was stirred at room temperature for 1 hour, and then was partitioned between water and ethyl acetate.
The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification
via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA)
afforded the product (10 nag, 80%).
1H NMR (400 MHz, ds-DMSO): £12.73 (s, 1H), 8.88 (s, 2H), 8.43 (s, 1H), 7.79 (t, 1H), 7.19 (dd, 1H),
5.60 (ddt, 1H), 5.00-4.93 (m, 1H), 4.91-4.87 (m, 1H), 4.23 (dt, 1H), 2.76-2.59 (m, 2H), 2.47-2.34 (m,
1H), 1.92-1.82 (m, 1H), 1.68-1.22 (m, 6H), 1.21-1.09 (m, 1H); MS(ES):308(M+H).

Step I. 4-[l-(l-Cyclopentyl-2-cyclopropylethyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-
7H-pyrrolo[2,3-d]pyrimidine trijluoroacetate salt
A solution of 4-[l-(l-cyclopentylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)-
ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared in Example 727, Step 5) (54.0 mg, 0.123
mmol) in DCM (1 mL) was added to a freshly prepared ethereal solution of excess CH2N2 held at
0 °C. Palladium acetate (10.0 mg, 0.044 mol) was added. After standing for 2 hours, the excess
CH2N2 was quenched by the addition of acetic acid. The solution was then diluted with further DCM,
washed successively with saturated sodium bicarbonate solution, water, and brine, and dried over
sodium sulfate, and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18
eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (13 mg, 18%).
'H NMR (300 MHz, CDC13): £ 9.05 (s, 1H), 8.81 (d, 1H), 8.35 (s, 1H), 7.59 (t, 1H), 7.03 (t, 1H), 5.76
(s, 2H), 4.10 (t, 1H), 3.59 (t, 2H), 2.57-2.36 (m, 1H), 2.15-2.00 (m, 1H), 2.00-1.83 (m, 1H), 1.79-1.40
(m, 6H), 1.37-1.09 (m, 2H), 0.97 (t, 2H), 0.55-0.26 (m, 3H), 0.07- "0.15 (m, 11H);
MS(ES):452(M+H).
Step 2. 4-[l-(lCyclopentyl-2-cyclopropylethyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrirnidinfi
trijluoroacetate salt
4-[l-(l-Cyclopentyl-2-cyclopropylethyl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]-
methyl-7H-pyrrolo[2,3-d3pyrimidine.trifluoroacetatc salt (13 mg, 0.023 mol) was stilted at room
temperature in a solution of DCM (2 mL) containing TFA (1.5 mL) for two hours. The solvent was

removed in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was
added. After stirring for one hour, the mixture was partitioned between water and ethyl acetate. The
organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification, via
preparative-HPLC/MS (Cl 8 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded
the product (9 mg, 90%).
1H NMR (400 MHz, dg-DMSO): § 12.75 (s, 1H), 8.90 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.81 (s, 1H),
7.22 (s, 1H), 4.19 (dt, 1H), 2.43-2.29 (m, 1H), 2.03-1.92 (m, 1H), 1.88-1.76 (m, 1H), 1.68-1.37 (m,
5H), 1.35-1.08 (m, 3H), 0.43-0.26 (m, 2H), 0.24-0.13 (m, 1H), 0.07- 0.03 (m, 1H), 0.14- "0.24 (m,
1H); MS(ES):322(M+H).

Step 1. 4-[l-(l-Cyclopentylbut-3-yn-l-yl)-lH-pyrazol1-4yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-
pyrrolo[2,3-d]pyrlmidine
To a mixture of potassium carbonate (38.4 mg, 0.278 mmol) in methanol (2.0 mL) at 0 °C
was added a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (prepared as in Example 727, step 4) (61.0 mg, 0.139
mmol) in methanol (1.0 mL), followed by a solution of dimethyl (l-diazo-2-oxopropyl)phosphonate
(40.0 mg, 0.208 mmol) in methanol (1.0 mL). The mixture was slowly warmed to ambient
temperature and stirred for 16 hours. The mixture was then diluted with water and extracted with ethyl
acetate. The combined extracts were washed with water, saturated ammonium chloride, and then dried
over sodium sulfate and the solvent was removed in vacuo to afford the product, which was used
without further purification (52 mg, 86%).
H NMR (300 MHz, CDC13): 5 8.85 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.41 (d, 1H), 6.84 (d, 1H),
5.67 (s, 2H), 4.14 (ddd, 1H), 3.53 (t, 2H), 2.90 (ddd, 1H), 2.79 (ddd, 1H), 2.66-2.49 (m, 1H), 1.98 (t,
1H), 2.00-1.88 (m, 1H), 1.78-1.44 (m, 5H), 1.39-1.11 (m, 2H), 0.92 (t, 2H), -0.06 (s, 9H);
MS(ES):436(M+H).

Step 2. 4-[l-(l-Cyclopenfylbut-3-yn-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrirnidine
trifluoroacetate salt
A solution of 4-[l-(l-cyclopentylbut-3-yn-l-yl)-lH-pyrazol-4-yl3-7-[2-(trimethylsilyl)-
ethoxy]methyl-7H-pyrrolo{2,3-d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL)
was stirred for 2 hours. The solvents were removed in vacuo. The resulting residue was dissolved in
THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned
between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was
removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and
ACN containing 0.1% TFA) afforded product (30 mg, 60%).
1H NMR (300 MHz, d6-DMSO): § 12.72 (s, 1H), 8.91 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.80 (s, 1H),
7.19 (s, 1H), 4.34 (dt, 1H), 2.97-2.69 (m, 3H), 2.50-2.32 (m, 1H), 1.93-1.77 (m, 1H), 1.70-1.09 (m,
7H); MS(ES):306(M+H).

4-[l-(1 -Cyclopentylbut-3-yn-l -yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate
salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a
catalytic amount of 5% Pd-C was added. The mixture was stirred under 1 atmosphere of hydrogen via
an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS
(C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg
69%).
1H NMR (400 MHz, d6-DMSO): § 12.73 (s, 1H), 8.86 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.79 (t, 1H),
7.20 (d, 1H), 4.11 (dt, 1H), 2.43-2.26 (m, 1H), 2.02-1.70 (m, 3H), 1.68-1.35 (m, 4H), 1.33-0.89 (m,
5H), 0.83 (t, 3H); MS(ES):310(M+H).
Example 732: 4-[l-(l-Cyclopentyl-4,4-difluorobut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-
d]pyrimidine trifluoroacetate salt

Step 1. 4-[l-(l-Cyclopentyl-4,4-difluorobut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(trirnethylsilyl)ethoxy]-
methyl- 7H-pyrrolo[2,3-dJpyrimidine
To a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]propanal (prepared as in Example 727, Step 4) (181 mg, 0.41 mmol)
in N.N-dimethylacetamide (3.6 mL) was added triphenylphosphine (294 mg, 1.12 mmol) followed by
dibromodifluoromethane (235 mg, 1.12 mmol). Rieke® Zinc (1.8 mL of a suspension of 2.5 g in 50
ml THF) was then added in one portion. The resulting mixture was stirred at room temperature for 4.5
hours. The mixture was filtered through diatomaceous earth. The filtrate was partitioned between
ether and water. The ether layer was washed with water, and brine, then dried over sodium sulfate,
and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0-
30% ethyl acetate in hexanes) afforded product (104 mg, 53%).
1H NMR (400 MHz, CDC13): £ 8.91 (s, 1H), 8.51 (br s, 1H), 8.34 (s, 1H), 7.51 (d, 1H), 6.93 (d, 1H),
5.74 (s, 2H), 4.05 (ddd, 1H), 4.04-3.96 (m, 1H), 3.60 (t, 2H), 2.78-2.62 (m, 2H), 2.58-2.45 (m, 1H),
2.07-0.87 (m, 10H), 0.00 (s, 9H); MS(ES):474(M+H).
Step 2. 4-[l-(l-Cyclopentyl-4,4-difluorobut-3-en-l-yl)~lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin.e
trifluoroacetate salt
A solution of 4-[l-(l-cyclopentyl-4,4-difluorobut-3-en-l-yl)-lH-pyrazol-4-yl]-7-[2-(tri-
methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (41 mg, 0.086 mmol) in DCM (3 mL) and
TFA (1.5 mL) was stirred for two hours at room temperature. The solution was then concentrated in
vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After
stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was
dried over sodium sulfate and the solvent was removed in vacuo. Purification via' preparative-
HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the desired
product (39 mg, 98%).
'H NMR (400 MHz, ds-DMSO): 8 12.72 (s, 1H), 8.84 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.80 (t, 1H),
7.18 (d, 1H), 4.32 (ddt 1H), 4.20 (dt, 1H), 2.72-2.37 (m, 3H), 1.95-1.81 (m, 1H), 1.69-1.06 (m, 7H);
MS(ES):344(M+H).

Where conjugate acceptors, such as were used in Example 737, Step 3 were not commercially
available, such compounds were generated according to the procedure provided below for ethyl (2E)-
3-(tetrahydrofuran-3-yl)acrylate (toward the preparation of Example 733).
Preparation of ethyl (2E)-3-(tetrahydrofuran-3-yl)acrylate:

To a solution of Dess-Martin periodinane (3.37 g, 7.95 mmol) in DCM (20 mL) was added
tetrahydrofuran-3-ylmethanol (0.701 mL, 7.23 mmol). The reaction was stirred at ambient
temperature for 2 hours, and the solvent was then removed in vacuo. Flash column chromatography
(using DCM as eluent) afforded the product as a clear oil, which was used without further
purification.
1H NMR (400 MHz, CDC13): & 9.65 (d, 1H), 4.12-4.07 (m, 1H), 3.92-3.85 (m, 2H), 3.80-3.73 (m,
1H), 3.10-3.02 (m, 1H), 2.26-2.10 (m, 2H).
Step B: Ethyl (2E)-3-(tetrahydrofuran-3-yl)acrylate
To a 0 °C mixture of sodium hydride (60% in mineral oil) (382 mg, 9.40 mmol) in DMF (15.0
mL) (THF may also be used) was added triethyl phosphonoacetate (1.72 mL, 8.68 mmol) dropwise.
The resulting mixture was warmed to room temperature and stirred for 30 minutes, then was re-cooled
to 0 °C, at which time a solution of tetrahydrofuran-3-carbaldehyde (724 mg, 7.23 mmol) in DMF
(4.0 mL) was added dropwise. The resulting mixture was stirred at this temperature for 1.5 hours, at
which time the mixture was diluted with water and the product was extracted with ether. The
combined extracts were washed with water and brine, dried over sodium sulfate and the solvent
removed in vacuo. Flash column chromatography (eluting with a gradient from 0-40% ethyl acetate in
hexanes) afforded the product (640 mg, 52%).
'H NMR (400 MHz, CDC13): 5. 6.87 (dd, 1H), 5.86 (dd, 1H), 3.96-3.88 (m, 2H), 3.81 (dd, 1H), 3.53
(dd, 1H), 3.04-2.93 (m, 1H), 2.20-2.10 (m, 1H), 2.03 (s, 3H), 1.79 (dq, 1H).
Example 736: 4-Il-(l-Cyclopentyl-4,4-difluorobutyl)-lH-pyrazol-4-yl]-7H-pyrroloI2,3-d]-
pyrimidine trifluoroacetare salt

4-[ 1 -(1 -Cyclopentyl-4,4-difluorobut-3 -en-l-yl)-l H-pvrazol-4-yl]-7H-pyrrolo[2,3 -d]-
pyrimidine trifluoroacetate salt (prepared as in Example 731) (20.0 mg, 0.041 mmol) was dissolved in
methanol (3 mL), and a catalytic amount of 5% Pd on C was added. The mixture was stirred at room
5 temperature for 2 hours, under an atmosphere of hydrogen provided by an affixed balloon. The
mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and
ACN containing 0.1% TFA) to afford product (4 mg, 21%).
1H NMR (400 MHz, de-DMSO): 8 12.74 (s, 1H), 8.88 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.80 (t, 1H),
7.20 (dd, 1H), 6.05 (tt, 1H), 4.17 (dt, 1H), 2.47-2.34 (m, 1H), 2.14-1.08 (m, 12H);
MS(ES):346(M+H).
Example 737: 3-(l-Methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]propanenitrile trifluoroacetate salt

To a solution of cyclopentanecarbaldehyde (1.00 mL, 9.36 mmol) in DCM (47 mL) at 0 °C
was added solid potassium terf-butoxide (1.44 g, 12.2 mmol) in one portion followed by methyl
iodide (1.7 mL, 28 mmol) in one portion. After 30 minutes at 0 °C, the reaction mixture was allowed
to warm to room temperature and stirred at that temperature for 16 hours. The mixture was poured
into brine, and the layers were separated. The organic layer was dried over sodium sulfate, decanted
and concentrated, and used without further purification in Step 2.
Step 2: (2Z)- and (2E)-3-(l-Methylcyclopentyl)acrylonitrile

To a solution of 1.0 M potassium terf-butoxide in THF (9.36 mL) at 0 °C was added a
solution of diethyl cyanomethylphosphonate (1.59 mL, 9.81 mmol) in THF (10 mL) dropwise. The
cooling bath was removed and the reaction was wanned to room temperature followed by re-cooling
to 0 °C, at which time a solution of 1-methylcyclopentanecarbaldehyde (1.0 g, generated in Step 1) in
THF (2 mL) was added dropwise. The bath was removed and the reaction was stirred at ambient
temperature for 3 hours. To the mixture was added water and ethyl ether. The aqueous layer was
further extracted with ethyl ether. The combined extracts were washed with brine, dried over sodium
sulfate, filtered and adsorbed onto silica gel in vacuo. Flash column chromatography (eluting with a
gradient from 0-10% ethyl acetate in hexanes) afforded product as a mixture with hexanes, which
product was used without further purification in Step 3.
Step 3: 3-(l-Methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile trifluoroacetate salt
To a mixture of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidine (0.134 g, 0.426 mmol) in ACN (3 mL) was added a mixture of (2Z)- and (2E)-3-(l-
methylcyclopentyl)acrylonitrile (0.12 g, 0.9 mmol) followed by DBU (0.13 mL, 0.90 mmol). The
reaction was heated to 60 °C for 6 h. The ACN was removed in vacuo. Ethyl acetate was added,
followed by 0.1 N HC1. The aqueous layer was extracted with three portions of ethyl acetate. The
combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the solvent
was evaporated. The crude material was deprotected by stirring with TFA (2 mL) in DCM (8 mL) for
2 hours. The solvent and TFA were removed in vacuo. THF (8 mL) was used to dissolve the residue,
and 6.0 M sodium hydroxide in water (8 mL) was added. The reaction was stirred in this basic
mixture for 2 hours. Ethyl acetate was used to extract the product. The combined extracts were dried
(Na2SO4) and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting
with a gradient of H2O and ACN containing 0.1% TFA) afforded product (44 mg, 24%).
1HNMR (400 MHz, d6-DMSO): 6 12.71 (s, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.51 (s, 1H), 7.81 (s, 1H),
7.18 (s, 1H), 4.72 (dd, 1H), 3.47 (dd, 1H), 3.21 (dd, 1H), 1.74-1.51 (m, 6H), 1.44-1.32 (m, 1H), 1.09-
1.00 (m, 1H), 0.97 (s, 3H); MS(ES):321(M+H).
Example 739: l-2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]ethylcycIo-
propanecarbonitrile trifluoroacetate salt

Stepl: l-(Hydroxymethyl)cyclopropanecarbomtrue
Ethyl 1-cyanocyclopropanecarboxylate (801 mg, 5.76 mmol) in THF (12.0 mL) was treated
with lithium tetrahydroborate (251 mg, 11.5 mmol). The solution was heated to reflux for 1.5 hours.
Upon cooling to room temperature, the reaction was quenched with water, and extracted with ethyl
acetate. The combined extracts were dried over MgSO4, filtered and concentrated to afford a clear oil,
which was used without further purification in the following step (482 mg, 86%).
1H MMR (400 MHz, CDCl3): 5 3.61 (s, 2H), 1.27 (dd, 2H), 0.98 (dd, 2H).
Step2: 1-Formylcyclopropanecarbonitrile
Dess-Martin periodinane (1.11 g, 2.62 mmol) was dissolved in DCM (12 mL) and 1-
(hydroxymethyl)cyclopropanecarbonitrile (231 mg, 2.38 mmol) was added. The reaction was stirred
at ambient temperature for one hour. The mixture was then purified by flash column chromatography
(eluting with a gradient from 0-80% ethyl acetate in hexanes) to afford the product (106 mg, 46%).
1H NMR (400 MHz, CDC13): & 9.35 (s, 1H), 1.79-1.74 (m, 4H).
Step 3: l-[(E)-2-Cyanovinyl]cyclopropanecarbonitrile
To a solution of 1.0 M potassium tert-butoxide in THF (1.12 mL) at 0 °C was added slowly
dropwise a solution of diethyl cyanomethylphosphonate (210 mg, 1.2 mmol) in THF (2 mL). The cold
bath was removed and the reaction was warmed to ambient temperature. The solution was then re-
cooled to 0 °C and a solution of 1-formylcyclopropanecarbonitrile (101 mg, 1.06 mmol) in THF (1.0
mL) was added dropwise. The cold bath was removed and the reaction was stirred for 3 hours at
ambient temperature. The mixture was then diluted with ether and water, the ether solution was
separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed in
vacua. Flash column chromatography (eluting with a gradient from 0-60% ethyl ether in hexanes)
afforded the product (24 mg, 19%).
'H NMR (400 MHz, CDC13): £ 5.94 (d, 1H), 5.82 (d, 1H), 1.80 (dd, 2H), 1.39 (dd, 2H).
Step 4: l-2-Cyano-l-[4-(7-[2-(trimethyIsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin~4-yl)-lH-
pyrazol-l-yl]ethylcyclopropanecarbonitrile

To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (61.4 mg, 0.0195 mmol) and l-[(E)-2-cyanovinyl]cyclopropanecarbonitrile (23 mg, 0.19
mmol) in ACN (2 mL) was added DBU (58 uL, 0.39 mmol) and the resulting mixture was stirred for
16 hours. The ACN was evaporated, and the residue was dissolved in ethyl acetate. This solution was
washed with 1.0 N HC1, water, and brine, and dried over sodium sulfate, and the solvent removed in
vacuo. Flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes)
afforded the product (49 mg, 58%).
1H NMR (400 MHz, CDC13): § 8.85 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H),
5.68 (s, 2H), 3.54 (dd, 1H), 3.51 (dd, 1H), 3.36 (dd, 1H), 1.62 (ddd, 1H), 1.45 (ddd, 1H), 1.34 (ddd,
1H), 1.25 (ddd, 1H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):434(M+H).
Step 5: l-2-Cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylcyclopropane-
carbonitrUe trifluoroacetate salt
l-2-yano-l-[4-(7-[2-(1rimethylsilyl)emoxy]methyl-7H-pyrrzolo[23-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]ethylcyclopropanecarbonitrile (48 mg, 0.11 mmol) was stirred in a mixture of DCM (3
mL) and TFA (2 mL) for 3 hours. The solvents were removed in vacuo and the residue was re-
dissolved in THF (3 mL). 6N NaOH (2 mL) was added and the resulting mixture was stirred at
ambient temperature for 3 hours. The crude reaction mixture was partitioned between ethyl acetate
and water. The layers were separated and the organic layer was dried over sodium sulfate and the
solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of
H2O and ACN containing 0.1 % TFA) afforded product (20 mg, 43%).
1H NMR (400 MHz, d6-DMSO): £12.74 (s, 1H)S 8.99 (s, 1H), 8.88 (s, 1H), 8.60 (s, 1H), 7.83 (t, 1H),
7.17 (dd, 1H), 4.55 (dd, 1H), 3.66 (dd, 1H), 3.54 (dd, 1H), 1.55-1.30 (m, 4H); MS(ES):304(M+H).

Step 1: Methyl 1 -cyanocyclopentanecarboxylate
To a solution of acetic acid, cyano-, methyl ester (2.66 mL, 30.3 mmol) and 1,4-
dibromobutane, (3.62 mL, 30.3 mmol) in acetone (50 mL) was added potassium carbonate (8.37 g,

60.6 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction was filtered
through diatomaceous earth and concentrated.. The resulting residue was partitioned between ether
and saturated NH4C1 solution, and the aqueous layer was extracted with two further portions of ether.
The combined ethereal extracts were washed with brine, and dried over sodium sulfate, then filtered
and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from
0-30% ethyl acetate in hexanes) afforded the product (2.92 g, 63%).
'H NMR (300 MHz, CDC13): £3.82 (s, 3H), 2.30-2.21 (m, 4H), 1.93-1.82 (m, 4H).
Step 2: Methyl l-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate
To a solution of methyl 1-cyanocyclopentanecarboxylate (1.26 g, 8.22 mmol) in methanol
(100 mL) was added cobalt dichloride (2.1 g, 16.0 mmol). The purple mixture was cooled in an ice-
water bath. Sodium tetrahydroborate (3.11 g, 82.2 mmol) was added portionwise with caution
(exothermic) to provide a black mixture. Upon complete addition, cooling was discontinued and the
reaction was .stirred for 40 minutes under nitrogen and the reaction was quenched by the careful
addition of IN HCI (700 ml). The methanol was removed in vacuo, and the solution was then made
alkaline (pH ~ 9) by the addition of concentrated NH4OH(aq). The mixture was extracted with DCM
(6 times), and the combined DCM extracts were dried over sodium sulfate and concentrated to afford
the crude product as a light yellow oil. To this crude amine in DCM (50 ml) was added di-tert-
butyldicarbonate (1.31 g, 6.01 mmol) and the reaction was stirred at 25 °C for 30 minutes. The
reaction was diluted with water and extracted with ethyl acetate three times. The combined extracts
were dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude residue was
purified by flash column chromatography to yield the desired product (1.5 g, 71%).
'H NMR (300 MHz, CDC13): £ 5.03 (s, 1H), 3.69 (s, 3H), 3.26 (d, 2H), 2.02-1.33 (m, 17H).
Step 3: tert-Butyl [l-(hydroxymethyl)cyclopentyl]methylcarbamate
To a solution of methyl l-[(fer/-butoxycarbonyl)ammo]methylcyclopentanecarboxylate (1.50
g, 5.83 mmol) in THF (25.0 mL) at -78 °C was added dropwise 1.0 M diisobutylaluminum hydride in
DCM (17.5 mL). The reaction was stirred for 2 hours with slow wanning to -10 °C. A saturated
solution of K/Na tartrate was added, followed by ether. This mixture was stirred for 30 minutes at
ambient temperature and the organic layer was separated and washed with water, and brine. The
organic layer was then dried over sodium sulfate, and the solvent was removed in vacuo to afford the
product (1.03 g, 77%). 'H NMR (300 MHz, CDC13): § 4.90 (br s, 1H), 3.27 (s, 2H), 3.06 (d, 2H), 1.5-
1.17 (m, 8H), 1.44 (s, 9H).
Step 4: tert-Butyl [(l-formylcyclopentyl)methyl]carbamate

To a solution of oxalyl chloride (456 L, 5.38 mmol) in DCM (30.0 mL) at -78 °C was added
DMSO (637 L, 8.97 mmol) and the resulting mixture was stirred for 5 minutes. tert-Butyl [1-
(hydroxymethyl)cyclopentyl]methylcarbamate (1.03 g, 4.48 mmol) in DCM (10.0 mL) was added and
the resulting mixture was stirred for 30 minutes at -78 °C. TEA (2.50 mL, 17.9 mmol) was added and
the resulting mixture was allowed to warm to ambient temperature over 30 minutes. Water was added.
The organic phase was washed sequentially with 0.1 N HC1, water, saturated sodium bicarbonate
solution, and brine, and then dried over sodium sulfate and the solvent was removed in vacua to
afford the product (957 mg, 94%). ]H NMR (300 MHz, CDC13): 5 9.39 (s, 1H), 4.94 (br s, 1H), 3.25
(d, 2H), 1.89-1.46 (m, 8H), 1.41 (s, 9H).
Step 5: tert-Butyl (l-[(E)-2-eyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (l-[(Z)-2-cyano-
vinyl]cyclopentylmethyl)carbamate
To a solution of 1.0 M potassium tert-butoxide in THF (4.4 mL) at 0 °C was added a solution
of diethyl cyanomethylphosphonate (820 mg, 4.6 mmol) in THF (6.0 mL) dropwise. The cold bath
was removed and the reaction was warmed to ambient temperature. The mixture was then re-cooled to
0 °C and a solution of tert-butyl [(l-formylcyclopentyl)methyl]carbamate (952 mg, 4.19 mmol) in
THF (4.0 mL) was added dropwise. The reaction was allowed to warm to ambient temperature and
the wanned mixture was stir for 16 hours. The reaction mixture was then diluted with ether and water.
The organic layer was separated and washed sequentially with water and brine, then dried over
sodium sulfate, then filtered, and the solvent was removed in vacuo to afford the product (1.05 g,
99%) as a mixture of (E) and (Z) isomers.
1H NMR (300 MHz, CDC13): 8 6.71 (d, 1H, E), 6A6 (d, 1H, Z), 5.36 (d, 1H, Z), 5.36 (d, 1H, £), 4.70
(br s, 1H, 2), 4.51 (br s, 1H, E), 3.25 (d, 2H, Z), 3.18 (d, 2H, £), 1.88-1.48 (m, 8H (E) and 8H (Z»,
1.43 (s, 9H (E) and 9H (£)); MS(ES):151(M+H-Boc).
Step 6: tert-Butyl [(l-2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]rnethyl-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)-JH-pyrazol-l-yl]ethylcyclopentyl)methyl]carbamate
To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidine (355 mg, 1.12 mmol) and tert-butyl (l-[(E)-2-cyanovinyl]cyclopentylmethyl)carbamate
and tert-butyl (l-[(Z)-2-cyanovinyl]cyclopentylmethyl)carbamate as a mixture of isomers (329 mg,
1.31 mmol) in ACN (10 mL) was added DBU (0.168 mL, 1.12 mmol). The resulting mixture was
stirred at ambient temperature for 3 hours followed by heating to 60 GC for 2.5 hours. The ACN was
removed in vacuo and the resulting residue was purified by flash column chromatography (eluting
with 0-55% ethyl acetate in hexanes) to afford the product (350 mg, 55%).

1H NMR (300 MHz, CDClj): £ 8.85 (s, 1H), 8.37 (br s, 1H), 8.34 (s, 1H), 7.41 (d, 1H), 6.82 (d, 1H),
5.68 (s, 2H), 5.37 (br s, 1H), 4.52 (dd, 1H), 3.54 (t, 2H), 3.40 (dd, 1H), 3.23 (dd, IH), 3.08 (d, 1H),
2.90 (dd, 1H), 1.84-1.47 (m, 8H), 1.45 (s, 9H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):566(M+H).
Siep 7: N-[(l-2-Cyano-l-[4-(7H-pyrralo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylcyclopentyl)-
methyljbenzamide
A solution of tert-bxxtyl [(l-2-cyano-l-[4-(7-t2-(trimethylsilyl)ethoxy]methyl-7H-pyrroIo[2,3-
d]pyrimidin-4-yl)-lH-pyrazo]-l-yl]ethylcyclopentyl)memyl]carbamate (175 mg, 0.309 mmol) in
DCM (5 mL) and TFA (5 mL) was stirred for 3 hours and the solvents were then removed in vacuo.
The resulting residue was stirred in a mixture of THF (3 mL) and 6N NaOH (3 mL) for 3 hours. The
THF was removed in vacuo, and water (10 mL) was added. The mixture was extracted with several
portions of DCM containing 15% isopropanol. The combined extracts were dried over sodium sulfate
and the solvents were removed in vacuo to afford the product, which was used without further
purification. MS(ES):336(M+H).
To a solution of 3-[l-(aminomethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-l-yl]propanenitrile (31 mg, 0.060 mmol) and benzoyl chloride (7.0 L, 0.060 mol) in DCM
(1.0 mL), was added TEA (17 L, 0.12 mmol). After 15 minutes, the solvent was removed in vacuo
and the mixture was purified via preparative-HPLC/MS (C18 eluting first with a gradient of H2O and
ACN containing 0.1% TFA, followed by chromatographic purification, eluting with a gradient of H2O
and ACN containing 0.15% NH4OH) to afford the product (7 mg, 27%).
'H NMR (400 MHz, d6-DMSO): £12.12 (s, 1H), 8.95 (s, IH), 8.68 (s, IH), 8.55 (s, 1H), 8.41 (s, IH),
7.92-7.87 (m, 2H), 7.60 (d, IH), 7.59-7.48 (m, 3H), 7.02 (d, IH), 4.83 (dd, 1H), 3.52-3.45 (m, 2H),
3.42 (dd, IH), 3.27 (dd, 1H), 2.06-1.95 (m, IH), 1.68-1.12 (m, 7H); MS(ES):440(M+H).

Step 1: l-(Hydroxymethyl)cyclopentanecarbonitrile
A mixture of methyl 1-eyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500
mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The

resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours.
The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The
combined organic extracts were dried over Na2SO4, then filtered and the solvent was removed in
vacua to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDC13): 53.62 (s, 2H), 2.39-1.60
(m, 8H).
Step 2: l-[(Benzyloxy)methyl]cyclopentanecarbonitrile
To a solution of l-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4
mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting
mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol).
The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60%
dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added
and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture,
followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were
combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting
residue was added water. The product was isolated by extraction with diethyl ether. The ethereal
extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column
chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330
mg, 64%).
1H NMR (300 MHz, CDC13): £7.40-7.27 (m, 5H), 4.62 (s, 2H), 3.44 (s, 2H), 2.18-2.03 (m, 2H), 1.90-
1.62 (m,6H).
Step 3: l-[(Benzyloxy)methyl]cyclopentanecarbaldehyde
To a mixture containing l-[(benzyloxy)methyl]cyclopentanecarbonitrile (0.16 g, 0.75 mmol)
in toluene (5 mL) at 0 °C was added 1.0 M diisobutylaluminum hydride in hexanes (0.8 mL). The
reaction was stirred at 0 °C for 1.5 hours, during which time the starting nitrile was consumed. The
reaction was cooled to -78 °C and quenched by the addition of methanol. The mixture was warmed to
ambient temperature and 3 N HC1 was added. Following stirring for 45 minutes, solid NaCl was
added, and the mixture was extracted with three portions of ethyl acetate. The combined extracts were
dried (Na2SO4), and filtered, and the solvent was removed in vacuo. Flash column chromatography of
the resulting residue (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded the
product (20 mg, 12%).
1H NMR (300 MHz, CDC13): 6 9.60 (s, 1H), 7.38-7.26 (m, 5H), 4.52 (s, 2H), 3.54 (s, 2H), 2.00-1.89
(m, 2H), 1.66-1.46 (m, 6H).
Step 4: (2E)- and (2Z)-3-I-[(Benzyloxy)methyl]cyclopentylacrylonitriIe

To a stirred solution of diethyl cyanomethylphosphonate (18 L, 0.11 mmol) in THF (1 mL)
was added 1.0 M potassium tert-butoxide in THF (0.10 mL). The resulting mixture was stirred 30
minutes, after which a solution of l-[(benzyloxy)methyl]cyolopentanecarbaldehyde (0.020 g, 0.092
mmol) in THF (1 mL) was added. The resulting mixture was stirred for 16 hours. Water was then
added to the reaction and the resulting mixture was extracted with three portions of ethyl ether. The
combined extracts were washed with brine, then dried over sodium sulfate, decanted from the sodium
sulfate, and the solvent was removed in vacuo to afford the product, which was used without further
purification in the subsequent conjugate addition step.
1H NMR (400 MHz, CDCl3): § 7.37-7.27 (m, 5H), 6.80 (d, 1H (E)), 6.59 (d, 1H (Z)), 5.34 (d, 1H (E)),
5.33 (d, 1H (Z)), 4.53 (s, 2H (Z)), 4.50 (s, 2H (E)), 3-45 (s, 2H (Z)), 3.31 (s, 2H (E)), 1.80-1.55 (m,
8H); MS(ES>=242(M+H).
Step 5: 3-l-[(Benzyloxy)methylJcyclopentyl-3-[4-(7H-pyrrolo[2,3-dJpyrimidin-4-yl)-lH-pyrazal-l-
yljpropanenitrile trifluoroacetate salt
To a mixture of (2E)- and (2Z)-3-l-[(benzy]oxy)methyl]cyclopentylacrylonitrile (generated in
Step 4) and 4-(lH-pyrazo1-4-yl)-7-[2-(trimemylsilyl)emoxy]meth.yl-7H-pynx3lo[2,3-d]pyrirnidine
(0.037 g, 0.12 mmol) in ACN (1.5 mL) was added DBU (18 fiL, 0.12 mmol). The resulting mixture
was stirred at ambient temperature for 3 hours, and then was heated to 60 °C for 28 hours. The
reaction mixture was diluted with diethyl ether and 0.1 N HC1. The layers were separated and the
aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried
over sodium sulfate, decanted, and the solvent was removed in vacuo. The resulting residue was
dissolved in DCM (3 mL) and TFA (0.75 mL), and this solution was stirred for 3 hours. The solvents
were removed in vacuo, and the resulting residue was dissolved in THF (5 mL) and 6.0 M sodium
hydroxide in water (3 mL) and stirred for 2 hours. The reaction mixture was extracted with three
portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate,
decanted, and the solvent was removed in vacuo. The crude mixture was purified by preparative-
HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) and lyophilized to
afford the desired product (10 mg, 20% over the two steps).
'H NMR (400 MHz, de-DMSO): $12.71 (br s, 1H), 8.99 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 7.80 (s,
1H), 7.38-7.23 (m, 5H), 7.19-7.16 (m, 1H), 4.92 (dd, 1H), 4.50 (d, 1H), 4.44 (d, 1H), 3.49 (dd, 1H),
3.35 (d, 1H), 3.23 (dd, 1H), 3.05 (d, 1H), 1.92-1.82 (m, 1H), 1.66-1.27 (m, 7H); MS(ES):427(M+H).
Example 742: 3-[l-(MethyIsuIfonyl)pyrroIidin-3-yl]-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-lH-
pyrazol-l-yl]propanenitrile trifluoroacetate salt

Step 1: Benzyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate
To a solution of l-[(benzyloxy)carbonyl]pyrrolidine-3-carboxylic acid (1.0 g, 4.0 mmol) in
THF (37 mL) at 0 °C was added dropwise a solution of 1.0 M borane in THF (16.4 mL). The reaction
was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to
0 °C and 10% HC1 (50 mL) was added. After the addition, the mixture was extracted with DCM, and
the extract was washed sequentially with saturated NaHCQ3 solution and brine, then dried over
sodium sulfate, filtered and the solvent was removed in vacuo. The product was used without further
purification in the subsequent oxidation step.
'H NMR (300 MHz, CDC13): £ 7.39-7.26 (m, 5H), 5.11 (s, 2H), 3.61-3.31 (m, 5H), 3.18 (dt, 1H),
2.75 (br s, 0.45H), 2.59 (br s, 0.45H), 2.49-2.31 (m, 1H), 2.19 (br s, 0.1H), 2.05-1.89 (m, 1H), 1.77-
1.58 (m, 1H); MS(ES):236(M+H).
Step 2: Benzyl 3-formylpyrrolidine-l-carboxylate
DMSO (597 L,, 8.42 mmol) was added to a solution of oxalyl chloride (427 L, 5.05 mmol)
in DCM (25 mL) at -78 °C. After 5 minutes, benzyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate
(generated in Step 1) was added. The reaction was continued for 30 minutes at -78 °C. TEA (2.3 mL,
17 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over
the course of 30 minutes. Water was then added. The layers were separated and the organic phase
was washed sequentially with 0.1 N HC1, water, saturated NaHCO3, and brine. The organic phase was
then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (0.82 g,
88% over two steps).
!H NMR (300 MHz, CDC13): 0 9.68 (d, 1H), 7.38-7.28 (m, 5H), 5.13 (s, 2H), 3.79 (dd, 1H), 3.65-3.35
(m, 3H), 3.11-2.99 (m, 1H), 2.32-2.04 (m, 2H).
Step 3: Benzyl 3-[(E)-2-cyanovinyl]pyrrolidine-l-carboxylate and benzyl 3-[(Z)-2-cyanovinyl]-
pyrrolidine-1 -carboxylate

To a solution of 1.0 M potassium tert-butoxide in THF (4.40 mL) at 0 °C was added a
solution of diethyl cyanomethylphosphonate (820 mg, 4.6 mmol) in THF (6.0 mL) dropwise. The cold
bath was removed and the reaction was wanned to room temperature and stirred for 15 minutes. The
mixture was cooled to 0 °C and a solution of benzyl 3-formylpyrrolidine-l-carboxylate (0.82 g, 2.3
mmol) in THF (4.00 mL) was added dropwise. Cooling was discontinued and the reaction stirred for
16 hours at ambient temperature. The mixture was diluted with ether and water, the layers were
separated and the organic layer was washed with water, followed by brine, and then dried aver
sodium sulfate, filtered and the solvent was removed in vacuo. The resulting residue was purified by
flash column chromatography (eluting with a gradient from 0-35% ethyl acetate in hexanes) to afford
the product as a mixture of E and Z isomers (246 mg, 42%).
'H NMR (300 MHz, CDC13): 8 7.41-7.27 (m, 5H), 6.70-6.58 (m, 0.3H (E)), 6.38 (dt, 0.7H (2)), 5.50-
5.30 (m, 1H), 5.14 (s, 2H), 3.79-3.11 (m, 5H), 2.27-2.06 (m, 1H), 1.90-1.70 (m, 1H);
MS(ES):279(M+Na).
Step 4: Benzyl 3-2-cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
1H-pyrazol-1-ylJethylpyrrolidine-l-carboxylate
To a mixture of benzyl 3-[(E)-2-cyanovinyl]pyrroh'dine-l-carboxylate and benzyl 3-[(Z)-2-
cyanovinyllpyrrolidine-1-carboxylate (241 mg, 0.940 mmol) and DBU (234 L, 1.57 mmol) in ACN
(13 mL) was added 4-(lH-pyrazol-4-yl)-7-[2-(trimethy]silyl)ethoxy]methyl-7H-pyrrolo[2,3-
d]pyrimidine (250 mg, 0.78 mmol). The mixture was stirred at ambient temperature for 3 hours. The
solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, and the organic
layer was washed sequentially with IN HC1, water, saturated NaHCO3, and brine. The washed
solution was dried over sodium sulfate and the solvent was removed in vacuo. Purification via flash
column chromatography (eluting with a gradient of 0-100% [5% MeOH/DCM] in hexanes) afforded
the produce as a mixture of diastereomers (400 mg, 89%).
1H NMR (400 MHz, CDC13 a mixture of diastereomers):§ 8.85 (s, 1H), 8.35-8.28 (m, 2H), 7.42-7.25
(m, 6H), 6.80-6.76 (m, 1H), 5.69-5.66 (m, 2H), 5,15-5.04 (m, 2H), 4.46-4.32 (m, 1H), 3.84-3.84 (m,
6H), 3.54 (t, 2H), 2.26-2.13 (m, 1H), 1.84-1.54 (m, 2H), 0.95-0.89 (m, 2H), -0.06 (s, 9H);
MS(ES):572(M+H).
Step 5. 3-Pyrrolidin-3yl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
lH-pyrazol-l-yl]propanenitrile
Benzyl 3-2-cyano-l-[4-(7-[2-(trimethyIsiIyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidm-4-
yl)-lH-pyrazol-l-yl]ethylpyrrolidine-l-carboxylate (161 mg, 0.282 mmol) was dissolved in methanol
(5 mL), and a catalytic amount of 5% Pd-C was added. The suspension was stirred at ambient
temperature for 1 hour under an atmosphere of hydrogen provided by a balloon. A catalytic amount of

10% Pd-C was then added, and the reaction stirred for 2 hours under an atmosphere of hydrogen
provided by a balloon. The mixture was then filtered, and purified via preparative-HPLC/MS (C18
eluting with a gradient of H2O and ACN containing G. 15% NH4OH) to afford the product as a mixture
of diastereomers (57 mg, 46%).
1H NMR (400 MHz, CDC13, a mixture of diastereomers): 5 8.84 (s, 1H), 8.34-8.32 (m, 2H), 7-40 (d,
1H), 6.81-6.78 (m, 1H), 5.67 (s, 2H), 4.38 (dt, 1H), 3.54 (t, 2H), 3.30-1.38 (m, 9H), 0.92 (t, 2H), -0.06
(s, 9H); MS(ES):438(M+H).
Step 6: 3-[l-(Methylsulfonyl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2J-d]pyrimidin-4-yl)-1H- pyrazol-1
yl]propanenitrile trifluoroacetate salt
To a solution of 3-pyrrolidin-3-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-
d]pyrimidinyl)lH-pyrazol-l-yl]propanenitrile (25 mg, 0.057 mmol) and TEA (10 L, 0.074 mmol) in
DCM (1.0 mL) at 0 °C was added methanesulfonyl chloride (6 L, 0.074 mmol). The reaction was
allowed to reach ambient temperature and stir for 16 hours. Half of the solvent was removed in vacuo
and TFA (1 mL) was added to the vial. After stirring for 1 hour at room temperature, the solvents
were removed in vacuo and the resulting residue reconstituted in THF (0.5 mL). To this was added
6 N NaOH (1 mL) and this solution was stirred for 2 hours. The reaction mixture was extracted with
five portions of ethyl acetate. The combined extracts were dried (Na2SO4), decanted and concentrated.
Preparative-HPLC/MS (Cl 8 eluting with a gradient of H2O and ACN containing 0.1% TFA) was used
to afford the product (16 mg, 57%).
'H NMR (400 MHz, ds-DMSO, a mixture of diastereomers): 8 12.69 (s, 1H), 8.98 (s, 0.5H), 8.95 (s,
0.5H), 8.84 (s, 1H), 8.53-8.51 (m, 1H), ,7.80-7.77 (m, 1H), 7.16-7.13 (m, 1H), 4.86-4.75 (m, 1H),
3.55-3.48 (m, 1H), 3.42-3.08 (m, 4H), 2.99-2.91 (m, 1H), 2.90 (s, 1.5H), 2.85 (s, 1.5H), 2.16-2.07 (m,
1H), 1.82-1.70 (m, 1H), 1.64-1.48 (m, 1H); MS(ES):386(M+H).

Step I: tert-Butyl 4-(cyanomethylene)piperidine-l-carboxylate
To a solution of 1.0 M potassium ter/-butoxide in THF (10.1 mL) at 0 °C was added a
solution of diethyl cyanomethylphosphonate (1.66 mL, 0.0102 mol) in THF (20 mL) dropwise. The
reaction was held for 10 min, then added to a solution of ferf-butyl 4-oxo-l-piperidinecarboxylate

(2.00 g, 0.0100 mol) in THF (30 mL) stirring at 0 °C under an atmosphere of nitrogen. After
complete addition, the cold bath was removed and the reaction was allowed to stir 1.0 h at 20 °C.
LGMS analysis showed the desired product and no remaining starting material. HPLC showed the
product UVmax at 200 & 230 nm. Water and EtOAc were added to the reaction mixture. The phases
were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was
washed with water, then saturated NaCl, then dried over Na2SO4, and concentrated to drysoess to
provide 2.5 g of the product as a yellow oil. TLC (25% EtOAc/hexane) Rf 0.22. The product was
purified by automatic flash chromatography on silica gel. Used a 40g column; flow 40 mL/min; [A=
hexane] [B= EtOAc]. A, 4 min; Gradient to 20% B in 30 min. Collected 44 mL fractions. The
product eluted in 21-27 min. The fractions were contrated to yield 0.67 g of a white solid. lH NMR
(CDC13) 8 5.19 (s, 1H); 3.51 (m, 4H); 2.56 (t, 2H); 2.33 (t, 2H); 1.50 (s, 9H). MS(ES) 245 (M+Na,
weak; base peak M+H-56 = 167).
Step 2: tert-Butyl 4-(cyanomethyl)-4-[4-(7-[2-(tHmethylsilyl)ethoxy]methyl'7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]piperidine-l-carboxylate
4 g, 2.66 mmol) was slurried in a mixture of ACN (20 mL) and DBU (398 \iL, 2.66 mmol), and tert-
butyl 4-(cyanomethylene)piperidine-l-carboxylate (0.651 g, 2.93 mmol) was added. The pyrazole did
not dissolve at 20° C, but a solution was formed when the mixture was heated to 40 °C for l h. LCMS
and HPLC analyses showed about 20% conversion to product. The mixture was stirred at 40-45 °C
overnight. HPLC showed 60 area% product. The ACN was removed by retory evaporator at 20 °C. To
the resulting residue was added saturated NaHCO3 and EtOAc. The organic layer was shaken with
more aqueous saturated NaHCO3, then dried (Na2SO4) and rotovaped to give 1.6g of a brown oil
residue. TLC (60% EtOAc/hexane): product Rf = 0.25. The product was purified by automatic flash
chromatography on silica gel, using a 40g column, at a flow of 40 mL/min; [A= hexane] [B= EtOAc].
A, 3min; Gradient to 100% B in 50 min. Collected 44 mL fractions. The product eluted in 24-29 min;
the pyrazole in 39-46 min; and the olefin in 13-15 min. Solvent was removed in vacuo for the
appropriate fractions to give 0.27 g olefin; 0.30 g pyrazole; and a yield of 0.67 g of the product, all of
which were isolated as white solids. 1H NMR (CDC13) 8 8.84 (s, 1H); 8.42 (s, 1H); 8.33 (s, 1H); 7,40
(d, 1H); 6.79 (d, 1H); 5.67 (s, 2H); 3.94 (m, 2H); 3.54 (m, 2H); 3.07 (m, 2H); 2.90 (s, 2H); 2.72 (m,
2H); 2.08 (m, 2H); 1.45 (s, 9H); 0.91 (m, 2H); -0.06 (s, 9H). MS(ES) 538 (M+H).
Step 3: 4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]piperidin-4-ylacetonitrile
tert-Butyl 4-(cyanomethyl)-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]piperidine-l-carboxylate (0.670 g, 1.24 mmol) was dissolved in TFA
(5.0 mL, 65 mmol) and was stirred for 1.3 h. LCMS showed conversion to the hydroxymethyl
intermediate, M+H 338. The solution was concentrated to remove the TFA. Methanol was added to

the resulting residue, and the resulting mixture was concentrated. The resulting residue was dissolved
in methanol (10 mL) and 15.0 M ammonium hydroxide in water (1.66 mL) was added. The resulting
solution was stirred for 2 h. LCMS and HPLC analyses showed complete deprotection. The mixture
was concentrated. Toluene was added to the resulting residue and the resulting mixture was
concentrated to provide a white semisolid. Most of this intermediate product was used for the next
step. The rest was purified by prep HPLC using a 30 mm x 100 mm C18 column; 8% ACN-H2O
(0.1% NH4OH), l.Omin, to 27% at 6min; 60 mL/min; detector set at m/z 308; retention time, 5.4 min.
Tubes containing pure product were combined and freeze dried to give 13.6 mg of the product.
1H NMR (ds-DMSO) 8 12.07 (s, 1H); 8.68 (s, 1H); 8.62 (s, 1H); 8.36 (s, 1H); 7.54 (d, 1H);
7.00 (d, 1H); 3.16 (s, 2H); 2.87 (m, 2H); 2.55 (m, 4H); 1.94 (m, 2H). MS(ES) 308 (M+H).
Step 4: Methyl N-cyano-4-(cyanomethyl)~4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
piperidine-1-carbimidothioate
4-[4-(7H-Pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]piperidln-4-ylacetomtrile (361 mg,
1.17 mmol) and iV-cyano-S',S-dimethyldithioimido carbonate (344 mg, 2.35 mmol) were dissolved in
isopropyl alcohol (2.5 mL) and DMSO (2.5 mL) at 20 °C. After 16 h reaction time, LCMS analysis
showed the presence of some product, M+H 406; of the reagent, M+H 147; and of the piperidine,
M+H 308. HPLC analysis showed about 2% reaction. The HPLC method was: Zorbax SB C18, 5m,
15 cm, 35 °C, flow 1.2 mL/min, 5% ACN-H2O (0.05% TFA), 1.5 min, to 100% ACN in 15.0 min;
detector set at 324, 225, and 265 nm. The retention time of the starting material was 4.9 min (UV
max 224, 262,292, & 325 nm); of the product, 6.5 min (UV max 226,262,290, & 324nm); and of the
reagent, 7.7min (UV max 265nm). To the product was added TEA (327 L, 2.35 mmol), and the
resulting mixture was stirred at RT. After stirring for 3 h, HPLC and LCMS analyses showed 60%
reaction. The product and the unreacted piperidine were isolated by prep HPLC using a 30 mm x 100
mm C18 column; 5%ACN-H2O (0.1%TFA), l.Omin, to 35% at 6min; 60 mL/min; detector set at 326
nm. The retention time for the product was 5.9 min; and for the starting piperidine was 3.5-4.3 min.
The product was freeze dried to yield 301 mg of a white solid TFA salt. 1H NMR (d6-DMSO) 6 12.85
(s, 1H); 9.01 (s, 1H); 8.90 (s, 1H); 8.59 (s, 1H); 7.85 (m, 1H); 7.30 (m, 1H); 4.23 (m, 2H); 3.35 (m,
2H); 3.30 (s, 2H); 2.78 (m, 2H); 2.68 (s, 3H); 2.16 (m, 2H). MS(ES) 406 (M+H).
Step 5: N'-Cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]piperi-
dine-1-carboximidamide
Methyl N-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pvrazol-l-yl]-
piperidine-1-carbimidothioate (41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M
ammonia in isopropyl alcohol (4.00 mL). The resulting mixture was heated to 100 °C for 1 h in a
microwave reactor. Analysis by HPLC and LCMS showed 60% reaction to give the expected M+H

375 (50 area%). To this mixture was added 2 mL of 7 N NH3/MeOH. The resulting mixture was
heated at 120 °C for one hour. HPLC and LCMS analyses showed no remaining starting material.
The reaction mixture was concentrated on a rotory evaporator. The product was isolated by prep
HPLCMS using a 30 mm x 100 mm C18 column, eluting with a solvent gradient; 10% ACN-H2O
(0.1%TFA), 1.5min, to 30% at 6min; 60mL/min; detector set at m/z 375; retention time, 4.7 rain. The
eluate was freeze-dried to yield 11.7 mg of the product TFA salt as a white solid. 1H NMR (dr
DMSO) δ 12.69 (s, 1H, NH); 8.92 (s, 1H); 8.81 (s, 1H); 8.51 (s, 1H); 7.75 (m, 1H); 7.22 (m, 1H); 7.18
(s, 2H, NH2); 3.84 (m, 2H); 3.23 (s, 2H); 2.99 (m, 2H); 2.60 (m, 2H); 1.97 (m, 2H). MS(ES) 375
(M+H).

To a -70 °C solution of (3R)-4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93,
Stepl) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL).
The resulting mixture was stirred for 3h and allowed to warm during this time interval from -70 to
-25 °C, after which the reaction was cooled back at -70 °C. Methanol (1.5 mL, 0.037 mol) was added,
followed by 2.0 M HC1 in water (15 mL). Insoluble material was then filtered from the reaction
mixture. The organic filtrate was washed sequentially with: 2.0 M HC1 in water, water and saturated

aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using
a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product
was chromatographed with 0-80% ethyl acetate/hexanes to give the purified product (0.9 g) as a pale
orange oil (47% yield).
'H NMR (400 MHz, CDC13): 6 9.85 (IH, s); 8.95 (1H, s); 8.5 (1H, s); 8.4 (1H, s); 7.5 (1H, d); 6.85
(1H, d); 5.75 (2H, s); 5.5 (1H, m); 4.0 (1H, dd); 3.6 (2H, t); 3.3 (IH, dd); 1.99 (2H, t); 0.0 (9H, s). MS
(M+H): 440.
Step2: 4-J-f2,2,2-Trifltwro-I-(lH-imidazol-2-ylmethylJethylJ-IH-pyrcaol-4-yl-7-f2-Ctrimethylsily0-
ethoxy] methyl- 7H-pyrrolo[2,3-dJpyrimidine

A solution of 4,4,4-trifluoro-3-[4-(7-t2-(trimethyIsilyl)ethoxy3raethyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-lH-pyrazol-l-yl]butanal (0.138 g, 0.000314 mol), 7.0 M ammonia in methanol (1
mL), ethanedial (0.5 mL, 0.004 mol) and acetic acid (20 L, 0.0004 mol) in methanol (2 mL, 0.05
mol) was microwaved on 100 watts, at 80 °C for 60 minutes. Following the microwave reaction, elhyl
acetate/water was added. The organic phase was separated and washed with saturated NaHCO3 and
saturated NaCl. The washed organic phase was dried and concentrated (rotory evaporator) to give 196
mg of the crude product as an orange glass. The crude product was purified by chromatography with
0-100% ethyl acetate/hexanes to give 57 mg of purified product as an off-white solid (38% yield).
1H NMR (400 MHz, CDC13): δ 8.91 (1H, s); 8.4 (IH, s); 8.2 (IH, s); 7.5 (1H, d); 7.0 (2H, s); 6.83
(IH, d); 5.75 (2H, s); 5.62 (IH, m); 4.15 (IH, dd); 3.8 (IH, dd); 3.6 (2H, t); 1.99 (2H, t); 0.0 (9H, s).
MS (M+H): 478.
Step3: 4-l-[2,2,2-Triftuoro-l-(lH-imidazol-2-ylmethyl)ethyl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-dJ-
pyrimidine
A solution of 4-l-[2,2,2-trifluoro-l-(lH-imidazol-2-ylmethyl)ethyl]-lH-pyrazol-4-yl-7-[2-
(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.055 g, 0.12 mmol) in 1,2-dichloro-
ethane (1 mL, 10 mmol) and TFA (0.5 mL, 6 mmol) was stirred overnight. The reaction was
concentrated to provide an orange oil. The oil was stirred in methanol (1 mL, 20 mmol) and 8.0 M

ammonium hydroxide in water (1 mL) for 4h. This mixture was then concentrated to provide a crude
product as an orange glass/solid. The crude product was purified by Prep HPLC (pHIO) to give 28
mg of purified product as a colorless glass, which was triturated with 2-methoxy-2-methylpropane (1
mL, 8 mmol), and then filtered and washed to provide 15 mg of the product as a white solid (38%
yield) which then was dried rt-50 °C for 3h.
'H NMR (400 MHz, DMSO): 6 12.13 (1H, s); 11.89 (1H, s); 8.65 (1H, s); 8.37 (1H, s); 7.6 (1H, d);
6.95 (1H, d); 6.92 (1H, d); 5.91 (1H, m); 3.78 (1H, dd); 3.47 (H, dd). MS (M+H): 348.
Example 745: 4-(l-(lR)-2,2,2-Trilluoro-l-[(4-methyl-l,3-thiazol-2-yl)methyl]ethyl-lH-pyrazol-
4-yl)-7H-pyrrolo[2,3-d]pyriinidine

A suspension of phosphorus pentasulfide (0.46 g, 1.0 mmol) in ethanol (0.5 mL, 8 mmol) was
stirred for Ih. (3RH,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3^]pyrimidin-4-yl)-lH-pyra2ol-l-yl]butane-
nitrile (0.15 g, 0.50 mmol) (see, Example 93) was added and the resulting mixture was heated at
80 °C in a sealed vial for 0.5h, during which reaction the mixture became a yellow solution. The
reaction was heated overnight. The reaction was then cooled to rt. Water (1 g, 60 mmol) and ethyl
acetate were added to the mixture. The organic phase was separated and washed with saturated
NaHCO3 and saturated aqueous NaCl. The washed organic phase was then dried and concentrated to
give 387 mg of a crude product as a white glass/oil. The crude product was chromatographed with 0-
10% MeOH/DCM, 0-1 %NH4OH to give 0.13 g of the purified product as a white solid (76% yield).

1H NMR (400 MHz, CDCI3): δ 8.7 (1H, s); 8.5 (1H, s); 8.3 (1H, s); 7.4 (1H, d); 7.0 6.75 (1H, d); 5.82
(1H, m); 3.75 (1H, dd); 3.2 (1H, dd). MS (M+H): 341.
A suspension of (3R)-4,4,4-trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-
yl]butanethioamide (0.038 g, 0.00011 mol), chloroacetone (15 L, 0.00019 mol) in ethanol (1 mL,
0.02 mol) and 1,2-dichloroethane (1 mL, 0.01 mol) was heated to reflux overnight. Following this, the
reaction mixture was filtered to remove insoluble material. The filtrate was dissolved in MeOH (1
mL) and DMF (1 mL) and purified by prep HPLC at pH10 to provide 6 mg of the purified product as
a colorless glass/oil, which was then triturated with MTBE/hexanes and was dried at 40 °C overnight
to give 5.2 mg of the purified product as an off-white solid (13% yield).
1H NMR (400 MHz, CDC13): δ 10.11 (1H, s); 8.88 (1H, s); 8.42 (1H, s); 8.38 (1H, s); 7.45 (1H, d);
6.79 (1H, s); 6.65 (1H, d); 5.41 (1H, m); 4.15 (1H, dd); 3.75 (H, dd); 2.18 (3H, s). MS (M+H): 379.
Example A: In vitro JAK Kinase Assay
Compounds herein were tested for inhibitory activity of JAK targets according to the
following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The
catalytic domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with
an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic
activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated
peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence
(HTRF). IC30s of compounds were measured for each kinase in the reactions that contain the enzyme,
ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1
g/mL (0.01%) BSA. The ATP concentration in the reactions was 90 M for Jakl, 30 M for Jak2
and 3 M for Jak3. Reactions were carried out at room temperature for 1 hr and then stopped with 20
(L 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA).
Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured
on a Fusion plate reader (Perkin Elmer, Boston, MA). Compounds having an ICS0 of 10 uM or less for
any of the above-mentioned JAK targets were considered active.
Example B: Cellular Assays
One or more compounds herein were tested for inhibitory activity of JAK targets according to
at least one of the following cellular assays.
Cancer cell lines dependent on cytokines and hence JAK/STAT signal transduction, for
growth, were plated at 6000 cells per well (96 well plate format) in RPMI 1640, 10% FBS, and 1
nG/mL of appropriate cytokine. Compounds were added to the cells in DMSO/media (final
concentration 0.2% DMSO) and incubated for 72 hours at 37 °C, 5% CO2- The effect of compound
on cell viability was assessed using the CellTiter-Glo Luminescent Cell Viability Assay (Promega)

followed by TopCount (Perkin Elmer, Boston, MA) quantitation. Potential off-target effects of
compounds were measured in parallel using a non-JAK driven cell line with the same assay readout.
Compounds having an IC50 of 10 uM or less with selectivity for JAK driven proliferation were
considered active. All experiments were performed in duplicate.
The above cell lines can also be used to examine the effects of compounds on
phosphorylation of JAK kinases or potential downstream substrates such as STAT proteins, Akt,
Shp2, or Erk. These experiments can be performed following an overnight cytokine starvation,
followed by a brief preincubation with compound (2 hours or less) and cytokine stimulation of
approximately 1 hour or less. Proteins are then extracted from cells and analyzed by techniques
familiar to those schooled in the art including Western blotting or ELISAs using antibodies that can
differentiate between phosphorylated and total protein. These experiments can utilize normal or
cancer cells to investigate the activity of compounds on tumor cell survival biology or on mediators of
inflammatory disease. For example, with regards to the latter, cytokines such as IL-6, IL-12, JL-23,
or IFN can be used to stimulate JAK activation resulting in phosphorylation of STAT protein(s) and
potentially in transcriptional profiles (assessed by array or qPCR technology) or production and/or
secretion of proteins, such as IL-17. The ability of compounds to inhibit these cytokine mediated
effects can be measured using techniques common to those schooled in the art.
Compounds herein can also be tested in cellular models designed to evaluate their potency
and activity against mutant JAKs, for example, the JAK2V617F mutation found in myeloid
proliferative disorders. These experiments often utilize cytokine dependent cells of hematological
lineage (e.g. BaF/3) into which the wild-type or mutant JAK kinases are ectopically expressed (James,
C, et al. Nature 434:1144-1148; Staerk, J., et al. JBC 280:41893-41899). Endpoints include the
effects of compounds on cell survival, proliferation, and phosphorylated JAK, STAT, Akt, or Erk
proteins.
Certain compounds herein have been or can be evaluated for their activity inhibiting T-cell
proliferation. Such as assay can be considered a second cytokine (i.e. JAK) driven proliferation assay
and also a simplistic assay of immune suppression or inhibition of immune activation. The following
is a brief outline of how such experiments can be performed. Peripheral blood mononuclear cells
(PBMCs) are prepared from human whole blood samples using Ficoll Hypaque separation method
and T-cells (traction 2000) can be obtained from PBMCs by elutriation. Freshly isolated human T-
cells can be maintained in culture medium (RPMI 1640 supplemented withl0% fetal bovine serum,
100 U/ml penicillin, 100 fig/ml streptomycin) at a density of 2 x 10s cells/ml at 37 "C for up to 2 days.
For IL-2 stimulated cell proliferation analysis, T-cells are first treated with Phytohemagglutinin
(PHA) at a final concentration of 10 ug/mL for 72h. After washing once with PBS, 6000 cells/well are
plated in 96-well plates and treated with compounds at different concentrations in the culture medium
in the presence of 100 U/mL human EL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel). The plates

are incubated at 37 °C for 72h and the proliferation index is assessed using CellTiter-Glo Luminescent
reagents following the manufactory suggested protocol (Promega; Madison, WT).
Example C: In vivo anti-tumor efficacy
Compounds herein can be evaluated in human tumor xenograft models in immune
compromised mice. For example, a tumorigenic variant of the INA-6 plasmacytoma cell line can be
used to inoculate SCBD mice subcutaneously (Burger, R., et al. Hematol J. 2:42-53, 2001). Tumor
bearing animals can then be randomized into drug or vehicle treatment groups and different doses of
compounds can be administered by any number of the usual routes including oral, i.p., or continuous
infusion using implantable pumps. Tumor growth is followed over time using calipers. Further,
tumor samples can be harvested at any time after the initiation of treatment for analysis as described
above (Example B) to evaluate compound effects on JAK activity and downstream signaling
pathways. In addition, selectivity of the compound(s) can be assessed using xenograft tumor models
that are driven by other know kinases (e.g. Bcr-Abl) such as the K562 tumor model.
Example D: Murine Skin Contact Delayed Hypersensitivity Response Test
Compounds herein can also be tested for their efficacies (of inhibiting JAK targets) in the T-
cell driven murine delayed hypersensitivity test model. The murine skin contact delayed-type
hypersensitivity (DTH) response is considered to be a valid model of clinical contact dermatitis, and
other T-lymphocyte mediated immune disorders of the skin, such as psoriasis (Immunol Today. 1998
Jan;19(l):37-44). Murine DTH shares multiple characteristics with psoriasis, including the immune
infiltrate, the accompanying increase in inflammatory cytokines, and keratinocyte hyperproliferation.
Furthermore, many classes of agents that are efficacious in treating psoriasis in the clinic are also
effective inhibitors of the DTH response in mice (Agents Actions. 1993 Jan;38(l-2):116-21).
On Day 0 and 1, Balb/c mice are sensitized with a topical application, to their shaved
abdomen with the antigen 2,4,dinitro-fluorobenzene (DNFB). On day 5, ears are measured for
thickness using an engineer's micrometer. This measurement is recorded and used as a baseline. Both
of the animals' ears are then challenged by a topical application of DNFB in a total of 20 L (10 L
on the internal pinna and 10 L on the external pinna) at a concentration of 0.2%. Twenty-four to
seventy-two hours after the challenge, ears are measured again. Treatment with the test compounds
was given throughout the sensitization and challenge phases (day -1 to day 7) or prior to and
throughout the challenge phase (usually afternoon of day 4 to day 7). Treatment of the test
compounds (in different concentration) was administered either systemically or topically (topical
application of the treatment to the ears). Efficacies of the test compounds are indicated by a reduction
in ear swelling comparing to the situation without the treatment. Compounds causing a reduction of
20% or more were considered efficacious. In some experiments, the mice are challenged but not
sensitized (negative control).

The inhibitive effect (inhibiting activation of the JAK-STAT pathways) of the test compounds
can be confirmed by immunohistochemical analysis. Activation of the JAK-STAT pathway(s) results
in the formation and translocation of functional transcription factors. Further, the influx of immune
cells and the increased proliferation of keratinocytes should also provide unique expression profile
changes in the ear that can be investigated and quantified. Formalin fixed and paraffin embedded ear
sections (harvested after the challenge phase in the DTH model) are subjected to
immunohistochemical analysis using an antibody that specifically interacts with phosphorylated
STAT3 (clone 58E12, Cell Signaling Technologies). The mouse ears are treated with test
compounds, vehicle, or dexamethasone (a clinically efficacious treatment for psoriasis), or without
any treatment, in the DTH model for comparisons. Test compounds and the dexamethasone can
produce similar transcriptional changes both qualitatively and quantitatively, and both the test
compounds and dexamethasone can reduce the number of infiltrating cells. Both systemically and
topical administration of the test compounds can produce inhibitive effects, i.e., reduction in the
number of infiltrating cells and inhibition of the transcriptional changes.
Example £: In vivo anti-inflammatory activity
Compounds herein can be or have been evaluated in rodent or non-rodent models designed to
replicate a single or complex inflammation response. For instance, rodent models of arthritis can be
used to evaluate the therapeutic potential of compounds dosed preventatively or therapeutically.
These models include but are not limited to mouse or rat collagen-induced arthritis, rat adjuvant-
induced arthritis, and collagen antibody-induced arthritis. Autoimmune diseases including, but not
limited to, multiple sclerosis, type I-diabetes mellitus, uveoretinitis, thyroditis, myasthenia gravis,
immunoglobulin nephropathies, myocarditis, airway sensitization (asthma), lupus, or colitis may also
be used to evaluate the therapeutic potential of compounds herein. These models are well established
in the research community and are familiar to those schooled in the art (Current Protocols in
Immunology, Vol 3., Coligan, J.E. et al, Wiley Press.; Methods in Molecular Biology: Vol. 225,
Inflammation Protocols., Winyard, P.G. and Willoughby, D.A., Humana Press, 2003.).
Various modifications of the invention, in addition to those described herein, will be apparent
to those skilled in the art from the foregoing description. Such modifications are also intended to fall
within the scope of the appended claims. Each reference cited in the present application is
incorporated herein by reference in its entirety.

including pharmaceutically acceptable salt forms or prodrugs thereof, wherein:
A1 and A2 are independently selected from C and N;
T, U, and V are independently selected from O, S, N, CRS, and NR6;
wherein the 5-membered ring formed by A1, A2, U, T, and V is aromatic;
X is N or CR4;
Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11Ri2)p-(C3.locycloalkylene)-
(CR11R12)p , (CR11R12)p-(arylene)-(CR11R12)q, (CR11R12)p-(C1-10 oheterocycloalkylene)-(CR11R12)q,
(CR11R12)p-(Cheteroarylene)-((CR11R12)p, (CR11R12)pO(CR11R12)p|, (CR11R12)p-s(CR11R12)p
(CR11'R12)p (CR11R12)p, (CR11R12)pC(CR11R12)p, (CR11R12)pC(O)O(CR11R12)p,
(CR11R12)p(CR11R12)q, (CR11R12)pOC(O)NRc(CR11R12)p> (CR11R12)qNRc(CR11R12)q,
(CR11R12)pNRcC(O)NRd(CR11R12)q, (CR11R12)qS(OXCR11R12),, (CR11R12)pS(O)NRc(CR11R12)q
(CR11R12)pS(CR11R12)q or (CR11R12)pS(O)2NRc(CR11R12)q) wherein said C1-8 alkylene, C2-8
alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is
optionally substituted with 1,2, or 3 substituents independently selected from -D1-D2-D3-D4;
Z is H, halo, C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4
hydroxyalkyl, C1-4 cyanoalkyl, =C-R', =N-R!, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd,
C(O)ORa, OC(O)Rb, OC(O)NRcRd, NReRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa,
C(=NR1)NR°Rd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb,
C(=NO(C1-6alkyl)Rb, and S(O)2NRcRl1, wherein said C2-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1,2, 3,4,5, or 6 substituents independently selected from halo,C1-4alkyl,
C2-4alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-6 cyanoalkyl, Cy1, CN,
NO2, OR', SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb,
NR'C(O)NRcHd, NRCC(O)OR°, C(=NR1)NRcRd, NR°C(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, C(=NOKDRb, C(=NO(C1-6 alkyl))Rb, and S(O)2NRcRd;
wherein when Z is H, n is 1
or the -(Y)n-Z moiety is taken together with i) A2 to which the moiety is attached, ii) R5 or R6
of either T or V, and iii) the C or N atom to which the Rs or R6 of either T or V is attached to form a

4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring
formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring is optionally substituted by 1, 2, 3,4, or 5 substituents independently selected
from-(W)ra-Q;
W is C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, O, S, C(O), C(O)NRC', C(O)O, OC(O)
OC(O)NRC", NRC, NRc'C(O)NRd', S(O), S(O)NRC, S(O)2, or S(O)2NRC;
Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halosulfanyl, aryl
cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8
haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1,2,3 or 4
substituents independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,
halosulfanyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, Cy2, CN, NO2) ORa, SRa, C(O)Rb, C(O)NRcRd,
C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRc'Rd,NRcC(O)Rb, NRcC(O)NRcRd, NRC'C(O)ORa,
S(O)Rb S(O)NRe'Rd, S(O)2Rb, NRe S(O)2Rb', and SC(O)2NRaRd;
Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl, each, optionally substituted by 1,2, 3,4 or 5 substituents independently selected
from halo,C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl,C1-4 hydroxyalkyl,C1-4
cyanoalkyl, CN, NO2) OR9, SRa, C(O)Rb, C(O)NRcRd, C(O)ORB, OC(O)Rb", OC(O)NRcRd,
NRcRd, NRcC(O)Rb,NRcC(O)ORa,NR°S(O)Rb,NRcS(O)2Rb, S(O)Rb, S(O)NRCRd,
S(O)2Rb, and S(O)2NRcRd;
R1, R2, R3, and R4 are independently selected from H, halo,C1-4 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7,
SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8, NReC(O)OR7,
S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and SC(O)2NR9R10;
Rs is H, halo, G1-4 alkyl,C1-4alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl, CN, NO2,
OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8,
NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)2NR9R10;
R6 is H, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, OR7, C(O)R8, C(O)NR9R10,
C(O)OR7, S(O)R8, S(O)NR9R10, SC(O)2R8, or SCO)2NR9R10;
R7 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R8 is H, C1-4 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R9 and R10 are independently selected from H, C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, C1-4alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
or R9 and R10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group;

R11 and R12 are independently selected from H and -E1-E2-E3-E4;
D1 and E1 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein
each of the C1-6alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1,2 or 3 substitoents independently selected from
halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy,
amino, C1-6 alkylamino, and C2-8 dialkylamino;
D2 and E2 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, (C1-6 alkylene)r-O-( C1-6 alkylene)s, (C1-6 alkylene)r-S-(C1-4 alkylene)s, (C1-6
alkylene)r-NRe-(C1-6 alkylene)s, (C1-6 alkylene),-CO(C1-6 alkylene)B, (C1-6alkylene)r-COO-(C1-6
alkylene)s (C1-6 alkylene)r-CONRe-(C1-6 alkylene),, (C1-6 alkylene)-SO-C1-6 alkylene),, (C1-6
alkylene)r-SO2-(C1-6 alkylene)s, (C1-6 alkylene)r-SONRe-(C1-4 alkylene)s, and (d1-6 alkylene)r-
NReCONRf-(C1-6 alkylenes, wherein each of the C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene is
optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN,
OH, C1-4alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6alkoxy, C1-6 haloalkoxy, amino, C1-6alkylamino,
and C2-8 dialkylamino;
D3 and E3 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein
each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from
halo, CN,NO2, N3, SCN, OH, C1-4alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6alkoxy, C1-6 haloalkoxy,
amino, C1-6 alkylamino, and C2-8 dialkylamino;
D4 and E4 are independently selected from H, halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb,
C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRC(O)NRcRd, NRcC(O)ORa,
C(=NR1)NReRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb,
C(=NO(CM alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl,
C2-4 alkenyl, C1-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN,
NO2, OR", SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NR.cRd, NRcRd, NRcC(O)Rb,
NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NR°C(=NR1)NRcRd, S(O)Rb, S(O)NReRd, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-4alkyl))Rb, and S(O)NRcRd;
Ra is H, Cy1, -(C1-6 alkyO-Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein
said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, halosulfanyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

Rb is H, Cy1 -(C1-6 alkyO-Cy1, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein
said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1,2, or 3
substituents independently selected from OH, GN, amino, halo, C1-4alkyl, C1-6 haloalkyl, C1-6
haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Ra and Ra are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected
from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rb' and Rb are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl,
C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc and Rd are independently selected from H, Cy1, -(C1-6 alkyl)-Cy1, C1-10 alkyl, C1-6
haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6
alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, -(C1-6
alkyl)-Cy1, OH, CN, amino, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 haloalkyl,and halosulfanyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently
selected from Cy1, -(C1-6 alkyl)-Cy1, OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6haloalkyl,
and halosulfanyl;
Rc" and Rd are independently selected from H, C1-10 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C1-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc' and Rd' together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

Rc" and Rd" are independently selected from H, C1-10 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aiylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocyclpalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C|.(alkyl, C1-6 haloalkyl, halosulfanyl, C1-6 haloalkyl, aryl, arylalkyi, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc" and Rd" together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R1 is H, CN, NO2, or C1-6 alkyl;
R1 and Rf are independently selected from H and C1-4 alkyl;
R1 is H,CN,or NO2;
m is 0 or 1 ;
n is O or 1;
p is O, 1,2,3,4, 5, or 6;
q is 0,1, 2, 3,4, 5 or 6;
risOor 1; and
s is O or 1;
wherein when X is N, n is 1, and the moiety formed by A1, A2, U, T, V, and -(y)n-Z has the formula:

then Y is other than (CR11R12)qC(O)NRc(CR' 'R12)q.
2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is N.
3. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is CR4.
4. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A1 is C.
5. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A1 is N.

6. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A2 is C.
7. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A2 is N.
8. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein at least one
of A1, A2, U, T, and V is N.
9. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the 5-
membered ring formed by A1, A2, U, T, and V is selected from:

wherein:
a designates the site of attachment of moiety-(Y)n-Z;
b designates the site of attachment to the core moiety:

c and c' designate the two sites of attachment of the fused 4- to 20-membered aryl, cycloalkyl,
heteroaryl, or heterocycloalkyl ring.

10. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein n is 0.
11. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1.
12. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1 and Y
is C1-8 alkylene, C2-8 alkenylene, (CR11R12)p C(O)(CR11R12)q, (CR11'R12)p C(O)NRcCR11R12)q,,
(CR11R12)pC(O)O(CR11R12)q, (CR11R12)qOC(O)(CR11R12)p > wherein saidC1-4alkylene or C2-8
alkenylene, is optionally substituted with 1,2, or 3 halo, OH, CN, amino, C1-4 alkylamino, or C2-8
dialkylamino.
13. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1 and Y
is C1-8 alkylene, (CR11R12)pC(O)(CR11R12)q, (CR11R12)pC(O)NRc(CR11R12)p ,
(CR11R12)qC(O)O(CR11R12)q> wherein said C1-10, alkylene is optionally substituted with 1,2, or 3 halo,
OH, CN, amino, C1-4 alkylamino, or C2-8 dialkylamino.
14. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1 and Y
is C1-8 alkylene optionally substituted with 1, 2, or 3 halo, OH, CN, amino,C1-4alkylamino, or C2-8
dialkylamino.
15. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1 and Y
is (CR11R12)qC(O)(CR11R12)q (CR11R12)qC(O)NRc(CR11R12)q, or (CRllRI2)pC(O)O(CR11R12)q.
16. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 0.
17. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 1.
18. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 2.
19. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein q is 0.
20. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein q is 1.
21. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein q is 2.
22. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein one of p and
q is 0 and the other of p and q is 1,2, or 3.

23. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6
substituents selected from halo,C1-4alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4
hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR', SRa, C(O)Rb, C(O)NRCR OC(O)NRcRa, NR0Rd NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd,
NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
24. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is aryl or
heteroaryl, each optionally substituted with 1, 2,3, 4, 5, or 6 substituents selected from halo, C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-6 hydroxyalkyl, C1-4 cyanoalkyl, Cy1,
CN, NO2, OR", SRa, C(O)Rb, C(O)NReRd, C(O)ORa, OC(O)Rb, OC(O)NRGRdl NRcRd, NRcC(O)Rb,
NRcC(O)NRcRd, NRcC(O)ORa, C(=NR!)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, and S(O)2NRcRd.
25. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is phenyl
or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3,4, 5, or 6 substituents
selected from halo,C1-4alkyl, C1-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4
hydroxyalkyl, C1-4 cyanoalkyl, Cy', CN, NO2, OR', SRa, C(O)Rb, C(O)NRcRd, C(O)OR8, OC(O)Rb,
OC(O)NRcRd, NRcRd, NRcC(O)Rb, NReC(O)NReRd, NRcC(O)ORa, C(=MRl)NRcRd,
NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcSCO)2Rb1, and S(O)2NRcRd.
26. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is phenyl
optionally substituted with 1,2, 3, 4, 5, or 6 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl,
C2-4 alkynyl,C1-4haloalkyl, halosulfanyl, d1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, OR", SRa,
C(O)Rb, C(O)NRcRd, C(O)ORa, 0C(O)Rb, OC(O)NRcRd, NR'R", NRcC(O)Rb, NRcC(O)NRcRd,
NRCC(O)OR8, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and
S(O)2NRcRd.
27. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is
cycloalkyl or heterocycloalkyl, each optionally substituted with 1,2, 3, 4, 5, or 6 substituents selected
from halo, C1-4 alkyl, C2-4 alkenyl,C1-4alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl,C1-4
cyanoalkyl. Cy1, CN, NO2 OR", SRa, C(O)Rb, C(O)NRcRd, C(O)OR\ OC(O)Rb, OC(O)NRcRd,
NRcRd, NReC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb,
S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.

28. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z is Cx.s
alkyl, C2-8 alkenyl, or C2-8 alkynyl, each optionally substituted with 1,2, 3, 4, 5, or 6 substituents
selected from halo, C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, halosulfanyl, C1-6
hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, SR", C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)R6,
OC(O)NB.cRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd,
NRcC(=NR1)NRcRd, S(O)Rb, S(O)NReRa, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd.
29. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z isC1-8
alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally
substituted with 1, 2,3,4,5, or 6 substituents selected from halo, C1-4 alkyl,C1-4 haloalkyl,
halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, ORa, C(O)NRcR6, C(O)ORa, NRcRd,
NRcC(O)Rb, and S(O)2Rb.
30. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z is C1-8
alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally
substituted with 1,2, or 3 substituents selected from halo,C1-4alkyl,C1-4haloalkyl, halosulfanyl, C1-4
hydroxyalkyl, C1-6 cyanoalkyl, Cy1, CN, NO2, ORa, C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, and
S(O)2Rb.
31. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z is
substituted with at least one substituent comprising at least one CN group.
32. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein Z is C1-8
alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with
at least one CN or C1-4 cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents
selected from halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl,C1-4
hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NReRd, C(O)OR", OC(O)Rb,
OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, and S(O)2NRcRd.
33. The compound of claim 1, or phannaceutically acceptable salt thereof, wherein the -(Y)n-Z
moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and
iii) the C or N atom to which said R3 or R6 of either T or V is attached to form a 4- to 20-membered
aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2,.
U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is
optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from -(W)ra-Q.

34. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the -(Y)n-Z
moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and
Hi) the C or N atom to which said Rs or R6 of either T or V is attached to form a 4- to 8-membered
aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2,
U, T, and V, wherein said 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is
optionally substituted by 1, 2, 3,4, or 5 substituents independently selected from -(W)m-Q-
35. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the -(YV-Z
moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and
iii) the C or N atom to which said Rs or R6 of either T or V is attached to form a 6-membered aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A1, A2, U, T,
and V, wherein said 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally
substituted by 1,2, or 3 substituents independently selected from halo, CN, NO2, C1-8 alkyl, C2-8
alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl
wherein said C1-8 alkyl, C2-6 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl is optionally substituted by 1, 2 or 3 CN.
36. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1, R2, RJ,
and R4 are independently selected from H, halo, and C1-4 alkyl.
37. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1, R2, R3,
and R4 are each H.
38. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1 is H, halo,
orC1-4alkyl.
39. The compound of claim 1, or phaxmaceutically acceptable salt thereof, wherein R5 is H, halo,
C1-4 alkyl,C1-4 haloalkyl, halosulfanyl, CN, or NR9R10.
40. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R5 is H.
41. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R6 is H or
C1-4alkyl.
42. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R6 is H.
43. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula II:

The compound of claim 1 selected from:
3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]benzonitrile;
3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]aciylonitrile;
3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yI)-lH-pyrazol-4-yl]propanenitrile;
4-(4-phenyl-lH-imidazol-l-yl)-lH-pyrrolo[2,3-b]pyridine;
[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-piperidin-l-yl-methanone;
[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin'4-yl)-lH-pyrazol-4-ylmethyl]-phenyl-ainine;
3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yI]-cyclohexanol;
4-[l-(3-methoxy-l-methyl-propyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[l-(l-methyl-3-pyrazol-l-yl-propy])-lH-pyrazol-4-yl]-lH-pyrrolo[2J3-b]pyridine;

1 -(lH-pyrroIo[2,3-b]pyridin-4-yl)-lH-pyrazole-4-carboxylic acid ethyl ester;
4-(3-methyl-4-phenyl-pyrazol-l-yl)-lH-pyrroIo[2,3-b]pyridine;
4-(3-phenyl-pyrazol-l-yl)-lH-pyrrolo[2,3-b]pyridine;
4-(4-bromo-imidazol-l -yl)-1 H-pyrrolo[2,3-b]pyridine;
4-(4-bromo-3-methyl-pyra2ol-l-yl)-lH-pyrrolo[2,3-b]pyridine;
3-[3-methyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-ben2onitri]e;
4-[3-methyl-l -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-4-yl]-benzonitriIe;
4-[4-(3-f]uoro-phenyl)-3-methyl-pyrazol-l-yl]-lH-pyrrolo[233-b]pyridine;
4-[4-(3,5-bis-trifluoromethyl-phenyl)-3-methyl-pyrazol-l -yl]-l H-pyrrolo[2,3-b]pyridine;
4-[4-(3,5-difluoro-phenyl)-3-methyl-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine;
{3-[3-methyl-l -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-phenyl} -methanol;
4-(3-methyl-4-pyrimidin-5-yl-pyrazol-l -yl)-l H-pyrrolo[2J3-b]pyridine;
4-[3-methy1-4-(l-methyl-lH-indol-5-yl)-pyra2ol-l-yl]-lH-pyrrolo[253-b]pyridine;
4-(3-methy1-4-tiuophen-3-yl-pyrazol-l-yl)-lH-pyrrolo[2,3-b]pyridine;
N,N-imethy1-4-[3-methyl-l-(lH-pynx)lo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-benzene-
sulfonamide;
N-{4-[3-raethyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-phenyl}-acetainide;
3-tert-buty]-l-(lH-pyrro]o[2)3-b]pyridin-4-yl)-lH-pyrazole-4-carbonitrile;
4-bromo-1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazole-3-carbonitrile;
4-(3-cyano-phenyl)-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazole-3-carbonitrile;
3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-3-trifluoromethyl-lH-pyrazol-4-yl]-propan-l-ol;
3-[3-methy]-l -(1 H-pyrrolo[2,3-b]pyridm-4-yl)-l H-pyrazol-4-yl]-prop-2-en-l -ol;
2-[4-bromo-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yl]-isoindole-l,3-dione;
4-[4-(2,6-dimethyl-phenyl)-3-methyl-pyrazol-l -yl]-l H-pyrrolo[2,3-b]pyridine;
3-[3-anuno-l-(lH-pyrro]o[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-ben2onitrile;
3-[3-benzylamino-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-benzonitrile;
N-[4-(3-cyano-phenyl)-l-(lH-pyn'olo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yI]-acetamide;
3-[4-(lH-pyrro]o[2J3-b]pyridin-4-yl)-pyrazoH-yl]-propan-l-ol;
3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-l-yl]-butan-l-01:
4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-pyrazoH-yl]-pentanenitrile;
4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-l-yl]-pentanoic acid amide;
4-[l-(3-imidazol-l-yl-l-methyl-propyl)-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine;
4-cyclopentyl-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-l-yl]-butyronitrile;
4-cyclopentyl-4-[4-(lH-pyiTolo[2,3-b]pyridin-4-yl)-pyrazol-l-yl]-butyramide;
3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-l-yl]-propionitrile;
4-(2-tert-butyl-l-methyl-lH-imidazol-4-yl)-lH-pyrrolo[2,3-b]pyridine;
4-(2-phenyl-lH-imidazol-5-yl)-lH-pyrrolo[2,3-b]pyridine;

4-(2-benzyl-lH-imida2ol-5-yl)-lH-pyrrolo[2,3-b]pyridme;
4-[2-(l-phenylethyl)-lH-imidazol-5-yl]-lH-pyrrolo[2,3-b]pyridine;
4-(2-phenyM,3-thiazol-4-yl)-lH-pyrrolo[2,3-b]pyridine,-
N-methyl-N-propyl-4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l,3-tbia2ol-2-aniine;
N-phenyl-4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l,3-thiazol-2-amine;
N-methyl-N-phenyl-4-(lH-pyrroloP.S-b]pyridin-4-yl0-l,3-thiazo1-2-amine;
4-(2-phenyl-l,3-thiazol-5-yl)-lH-pyrrolo[2,3-b]pyridine;
ethyl 2-methyl-2-[4-(lH-pyirolot2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanoate;
2-methyl-2-[4-(lH-pyrrolo[2,3-b]pyridiii-4-yl)-lH-pyrazol-l-yl]propanoicacid;
2-methyl-2-[4-(l H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]propanamide;
ethyl 3-methyl-3-[4-(lH-pyiTolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanoate;
3-methyl-3-[4-(lH-pyiTolo[2,3-b]pyridin-4-yl)-lH-pytazol-l-yl]butan-l-ol;
4-methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-y]]pentanenitrile;
4-methyl-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]pentanamide;
3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile;
3-[4-(lH-pyrrolo[2,3-b]pyiidin-4-yi)-l H-pyrazol-1 -yl]propanenitrile;
3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]hexanenitrile;
3-cyclopentyl-3-[4-(lH-pyirolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3-cyclohexyl-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanenitrile;
3-cyclopentyl-3-[4-(7H-pyirolo2,3-d]pyrimidin-4-y1)-1H-pyrazol-l-y1)propanenitrile;
2-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidm-4-yl)-lH-pyrazol-l-yl]propanenitxile;
3-[4(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile;
5-methyl-3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]hexanenitriIe;
3-cyclohexyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
4-cyclopropyl-3-[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl3butanenitrile;
4-{ 1 -[1 -methylbutyl]-lH-pyrazoI-4-yl}-7H-pyrrolo[2,3-d]pyriinidine;
4-tnethyl-4-[4-(7H-pyrrolot2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl3pentanenitrile;
3-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclopropylpropanenitrile;
4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile;
3-raethyl-3-[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanenitrile;
3-ethyl-3-[4-^7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile;
l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclopropylacetonitrile;
4-l-[(pyrrolidin-2-ylmethyl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrirnidine;
4-(l-[l-(methylsulfonyl)pyrrolidin-2-yl]methyl-lH-pyrazol-4-72yl)-7H-pyrrolo[2,3-d]-
pyrimidine;
ethyl 2-methyl-2-[4-(7H-pyrrolo[2,3-ki]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanoate;

3-cycIopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]acrylonitrile;
3-cyclopentylidene-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3-methyl[5^7H-pyrrolo[2,3-d]pyrimidin-4-yl)~l,3-thiazol--2-yl]aminopropanenitrile;
3-[5-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]hexaneaitrile;
3-cyclopentyI-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]propanenitrile;
5-methyl-3-[5-(7H-pyiTolo[2,3-d]pyriinidin-4-yl)-l,3-thiazol-2-yI]hexanenitriIe;
3-pyridin-3-yl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l13-thia2ol-2-yl]propanenitrile;
3(5-bromopyridinO-yl)-3-[5-(7H-pyn-olo[2,3-d]pyrimidin-4-y])-l,3-thiazol-2-yl)propane-
nitrile;
5-2-cyano-l-[5-(7H-pyrrolo[23d]pyrimidin-4-yl)-l,3-thiazol-2-yl]ethyl)nicotinonitrile;
3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]butanenitrile;
2-[5-(7H-pyTrolo[2)3-d]pyrimidin-4-yl)-l,3-thia2ol-2-yl]pentanenitrile;
4-[5-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-l,3-thiazol-2-yl]heptanenitrile;
3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thia2ol-2-yl]pentanedinitrile;
3-cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-oxa2o]-2-yl]propanenitrile;
3-[5-(7H-pyrrolo[2,3-d]pyrimiditi-4-yl)-l>3-oxazol-2-yl]hexanenitrile;
5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyratiudin-4-yl)-lH-pyrazol-l-yl]pentanenitrile;
5-(methylsulfinyl)-3-[4-(7H-pyrrolo[2,3di]pyriraidin-4-yl)-lH-pyrazol-l-yl]-pentanenitrile;
5-(methylsulfonyl)-3-[4-(7H-pyn-olo[23d]pyriiniditi-4-yl)-lH-pyrazol-l-yl]-pentanenitrile;
4,4J4-trifluoro-3-[4^7H-pyn-olo[2,3d]pyrimidin-4-yl)-pyra2ol-2-yl]-butyronitrile;
5,5-dimethyl-3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-pyrazol-l-yl]-hexanenitrile;
4-[l-(2-methanesulfonyl-ethyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;
5,5,5-trifluoro-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-l-yl]-pentanenitrile;
3-(2-cyano-1 -[4-(7H-pyrrolo[2J3-d]pyrimidin-4-y!)-lH-pyrazol-1 -yl]ethyl)-cyclopentane-
carbonitrile;
343-(hydroxymethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4--yl)-lH-pyrazol-l-yl]-
propanenitrile;
l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-indazole;
2-(l H-pyrrolo[2,3-b]pyridin-4-yl)-2H-indazole;
3-[3-(l H-pyrrolo[2,3-b]pyridin-4-y])-1,2,4-oxadiazol-5-yl]benzonitrile;
4-(I-benzothien-2-yl)-lH-pyrrolo[2,3-b]pyridine;
4-fluoro-2-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yl]phenoI;
4-3-[3-(trifluoromethyl)phenyl]-lH-pyrazol-l-yl-lH-pyrrolo[2,3-b]pyridine;
3-[l-(lH-pyrrolo[2,3-b3pyridin-4-yl)-lH-pyrazol-3-yl]benzonitrile;
3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl3benzonitrile;
2-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]-l,3-benzoxazole;
cyclohexyl[ 1 -(1 H-pyrrolo[2,3 -b]pyridin-4-yl)-l H-pyrazol-4-yl]methanol;

4-[4-(l-phenylvinyl)-lH-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine;
4-(l -benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridme;
4-fl-(2-naphthylmethyl)-lH-pyrazol-4-yl]-lH-pyiTolo[2,3-b]pyridine;
4-(l -phenyl-1 H-pyrazol-4-yl)-l H-pyrrolo[2,3-bjpyridine;
3-[4-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]benzonitrile;
4-{l-[l-methylbutyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridiiie;
4-methyl-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazoI-I-yl]benzonitrile;
2-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazole;
5-nitro-2-(l H-pyrrolo[2,3-b]pyridin-4-y])-2H-indazole;
6-nitro-2-(lH-pyrrolo[2,3-b]pyridin-4-yl)-2H-indazole;
3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-imidazol-4-yl]benzonitrile;
4-[4-(3-methoxyphenyl)-lH-imidazol-l-yl]-lH-pyrrolo[2,3-b]pyridine;
4-(5-phenyl-2-thienyl)-lH-pyrrolo[2,3-b]pyridine;
4-[3-(4-fluorophenyl)-l H-pyrazol-1 -yl]-lH-pyrrolo[2,3-b]pyridine;
4-[3-(3-nitrophenyl)-lH-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[3-(4-cIilorophenyl)-lH-pyrazol-l-yl3-lH-pyrrolo[2,3-b]pyridine;
4-[3-(4-methoxyphanyl)-lH-pyrazol-l-yl]-lH-pyrrolo[253-b]pyridine;
4-[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-3-yl]benzonitrile;
3-[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-3-yl]aniline;
4-[3-(3-methoxyphenyl)-lH-pyrazol-l -yl]-l H-pyrrolo[2s3-b]pyridine;
{3-[l-(lH-pyrrolo[273-b]pyridin-4-yl)-lH-pyrazol-3-yl]phenoxy}acetonitrile;
2-cyano-N-{3-[l-{lH-pyiTOlo[2,3-b]pyridin-4-yl)-lH-pyrazol-3-yl]phenyl}acetamide;
3-cyano-N-{3-[l-(lH-pyrrolo[2s3-b]pyridin-4-yl)-lH-pyrazol-3-yl]phenyl}ben2amide;
4-[4-(4-nitrophenyl)-lH-pyrazol-l -yl]-l H-pyrrolo[2,3-b]pyridine;
4-[l -(1 H-pyirolo[2,3-b]pyridin-4-yl)-lH-pyTazol-4-yl]anilinie;
4-(4-phenyl-lH-pyrazol-l -yl)-lH-pyrrolo[2,3-b]pyridine;
4-(4-pyridin-3-yl-lH-pyrazoI-l-yl)-lH-pyniolo[2,3-b]pyridine;
2-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazo]-4-yl]benzonitrile;
{2-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]phenyl}acetonitrile;
4-[4-(3-nitrophenyl)-lH-pyrazol-l-yl]-IH-pyrrolo[2,3-b]pyridine;
3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]aniline;
{3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]phenyl}acetonitrile;
4-[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]benzonitrile;
3-[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazoI-4-yl]phenoI;
methyl 3-[l-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]benzoate;
{4-[l-(lH-pyrrolo[2J3-b]pyridin-4-yl)-lH-pyrazol-4-yl]phenyl}acetonitri]e;
2-cyano-N- {3-[l -(1 H-pyrroIo[2,3-b]pyridin-4-yl)-1 H-pyrazol-4-yl]phenyl} acetamide;

4-[l-(lH-pyrrolo[2I3-b]pyridin-4-yl)-lH-pyrazoM-yl]phenol;
5-[l-(lH-pyrro]ot2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]nicotinonitrile;
{4-[l-(lH-pyiroIo[2,3-b]pyridin-4-yl)-lH-pyrazol-4-yl]phenoxy}acetonitrile;
4-(4-cyclohex-1 -en-1 -yl-1 H-pyrazol-1 -yl)-l H-pyrrolo[2,3-b]pyridine;
4-[4-(4-methoxyphenyl)-lH-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine;
4-(4-pyrimidin-4-yl-1 H-pyrazol-1 -yl)-l H-pyrrolo[2,3-b]pyridine;
3-{hydroxy[l--(lH-pyrrolo[2)3-b]pyridin-4-yl)-IH-pyrazol-4-yl]methyl}ben2onitrile;
4-[4-(cyclohex-l-en-l-ylmethyl)-lH-pyrazol-l-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[ 1 -(3,5-dimethoxybenzyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine;
4- [ 1 -(1 -phenylethyl)-1 H-pyrazoI-4-yl]-l H-pyrrolo[2,3-b]pyridine;
4-[l-(cyclohexylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2J3-b]pyridine;
3-{[4-(lH-pyrro]o[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]methyl}benzonitrile;
2-{[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]methyl}benzonitrilei
4- {[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l -yl]methyl} benzonitrile;
l-phenyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]ethanone;
3,3-dimethyl-l-(-4lH-pyrrolo[2,3-blpyridin-4-yl)-1H-pyrazol-l-yl]butan-2-one,-
4-{l-[(5-methylisoxazol-3-yl)methyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
4-[ 1 -(tetrahydro-2H-pyran-2-ylmethyl)-l H-pyrazol-4-yl]-1 H-pyrrolo[2,3 -b]pyridine;
4-(l-cyclohex-2-en-l-yl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine;
4-[l-(l-ethylpropyI)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-(l-cyclohexyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine;
2-[4-(lH-pyrro]o[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]acetaniide;
4'- {[4-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]methyl} biphaiyl-2-carbonitrile;
4-[ 1 -(2-nitrobenzyl)-1 H-pyrazol-4-yl]-1 H-pyrrolo[2,3-b]pyridine;
4-{l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
4-[ 1 -(3-nitrobenzyl)-1 H-pyrazol-4-yl]-1 H-pyrrolo[2,3-b]pyridine;
4-[ 1 -(2-bromobenzyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine;
N-phenyl-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanamide;
4-{ 1 -[3-(trifluoromethoxy)benzyl]-lH-pyrazol-4-yl} -lH-pyrrolo[2,3-b]pyridine;
4-{l-[2-fluoro-5-(trifluoromethyl)benzyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
4-{l-[3-(trifluoromethyl)benzyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
4-[l-(pyridin-3-ylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-{l-[l-phenylbutyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
l-phenyl-2-[4-(lH-pyrrolot2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propan-l-one;
4-[l-(2,6-dichlorobenzyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[l-(2,6-dimcthylphenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine-
2-[4-(1H-ppyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-5-(trifluoroinetliyl)-bcnzonitrile;

4-[l-(4-bromo-3J5)6-trifluoropyridin-2-yl)-lH-pyra2ol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[ 1-(cyclopropylmethyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine;
4-[l-(2,5-dimethylphenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridJne;
4-[l-(2-methylphenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridiiie;
4-[ 1-(2-methoxyphenyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine;
3-{l-[4-(lH-pyrroIo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]ethyl}benzonitrile;
3-chloro-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile;
4-[l -(1 -cyclohexylethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-fluoro-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-y0-lH-pyrazol-l-yl]benzonitrile;
2-fluoro-4-[4-(l H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]benzonitrile;
3-fluoro-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]ben2onitrile;
4-(l-{l-[3-(trifluoromethyl)phenyl]ethyl}-lH-pyrazo]-4-y])-lH-pyrrolo[2,3-b]pyridine;
4-[ I -(3,5-dimethylphenyl)-l H-pyrazol-4-yl] -1 H-pyrrolo[2,3-b]pyridine;
4-[4-(l H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazol-1 -yl]benzonitrile;
{4-[4-{lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]phenyl}acetonitrile;
4-[l-(l-methylhexyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-(l-sec-butyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine;
4-[ 1 -(1 -phenylpropyl)-l H-pyrazol-4-yl] -lH-pyrrolo[2,3-b]pyridine;
4-(l-{l-[4-(methylsulfonyl)phenyl]ethyl}-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine;
4-{l-[l-(3-fluoro-4-methoxyphenyl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
4-(l-{l-[2-(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-yl)-lH-pyrrolo[2>3-b]pyridine;
4-(l-{l-[3,5-bis(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine;
4-{l-[4-(lH-pyrrolo[2,3-b]pyridin-4-yI)-lH-pyrazol-l-yl]ethyl}benzonitrile;
4- {1 -[4-nitro-2-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl} -1 H-pyrrolo[2,3-b]pyridine;
3-methyl-4-[4-(lH-pyiTolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile;
4-[l-(2-chlorophenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2s3-b]pyridine;
3-bromo-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yI]benzonitrile;
ethyl 4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzoate;
4-{l-[2-chloro-6-nitro-4-(trifluoromethyl)phenyl]-]H-pyrazol-4-yl}-lH-pyrrolo[2,3-b]-
pyridine;
4-( 1 - {1 -[4-(trifluoromethyl)phenyl]ethyl} -1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridine;
4-[l-(2,3-dihydro-lH-indea-l-yl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[l-(l,2,3,4-tetrahydronaphthalen-l-yl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b}pyridine;
4-(l-{l-[2-cWoro-5-(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-yl)-lH-pyrroIo[2,3-b]-
pyridine;
4-{l-[l-C214-dicbJoro-5-fluorophenyl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
4-[l-(l-cyclopentylethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2J3-b]pyridine;

4-[l-(l-methyl-3-phenylpropyl)-lH-pyra2ol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[l -(1 -cyclobutylethyl)-lH-pyrazol-4-yl]-lH-pyirolo[2,3-b]pyridine;
[2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-5-(trifluoromethy])phenyl]-
acetonitrile;
[5-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-2-(trifluoroinethyl)phenyl]-
acetonitrile;
4-{l-[pent-3-en-l-yl]-lH-pyrazol-4-yl}-lH-pyrroIo[2,3-b]pyridine;
2-[4-( lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l -yl]propanenitrile;
4- {1 -[4-phenylbut-3-en-l -yl]-lH-pyrazol-4-yl} -1 H-pyrrolo[2,3-b]pyridine;
6-[4-(lH-pyrroIo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]hexanenitrile;
ethyl 3-amino-2-{[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]methyl}-propanoate;
ethyl 2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanoate;
4-[ 1 -(1-propylbutyl)-1 H-pyrazol-4-yl]-1 H-pyrrolot2,3-b]pyridine;
4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]butanenitrile;
[3-chloro-2-[4-(lH-pyxrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-5-(trifluoromethyl)phenyl]-
acetonitrile;
5-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-2-(trifluoromethyl)-benzonitrile;
4-{l-[2-chloro-4-(trifluoromethyl)phenyl]-lH-pyra2ol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-2-(trifluoromethyl)-benzonitrile;
2-[4-(lH-pyrroIo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-ylJbenzonitrile;
3-chloro-2-[4-(lH-pynx)lo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile;
4-amino-5,6-difluoro-2-[4-(lH-pyrrolo[2,3-b3pyridin-4-yl)-lH-pyrazol-l-yl]isophthalonitrile;
1 - {[4-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazol-1 -yl]methyl} -cyclopropanecarbonitrile;
5-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]hexanenitrile;
2J2-dimethyl-6-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]hexanenitrile;
4-[ 1 -(1 -ethyl-2-methylpropyl)-l H-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridine;
5-bromo-2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yI)-lH-pyrazol-l-yl]benzonitrile;
3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-4-(trifluoromethyl)-benzonitrile;
2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-3-(trifluoromethyl)-benzonitrile;
3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-4-(trifluoromethyl)beiizamide;
3-[4-( 1 H-pyrrolo[2,3-b]pyridin-4-yl)-l H-pyrazol-1 -yl]eyclohexanone;
2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]cyclohexanol;
4-(l-{[l-(methylsulfonyl)piperidin-4-yl]methyl}-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]-
pyridine;
2-[4-(lH-pyrrolo[2J3-b]pyridin-4-yl)-lH-pyrazol-l-yl]cyclohexanecarbonitrile;
4-{l-[2-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;
4-[l-(2,6-dichlorophenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b3pyridine;

(4-{[4-(lH-pyirolo[2,3-b]pyridin-4-yl>lH-pyrazol-l-yl]raethyl}cyclohexyl)methanol;
4-[l-(tetrahydrofuran-2-ylmethy])-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[ 1-(1-cyclopentylpropyl)-1 H-pyrazol-4-yl]-lH-pyiTolo[2,3-b]pyridine;
4-[l-(tetrahydrofuran-3-ylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
2-chloro-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile;
3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-3-(lJ3-thiazo]-5-y])propanenitrile;
l-ben2yl-4-{[4-1H-pyrrolo[2J3-b]pyridin-4-yl)-lH-pyrazol-l-yl]methyl}pyrrolidin-2-one;
3-(l-methyl-lH-imidazol-5-yl)-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]-3-(3-thienyl)propanenitrile;
{l-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]cyclopentyl}acetonitrile;
4-chloro-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]benzonitrile;
4-[4-(lH-pyiTolo[2>3-b]pyridin-4-yl)-lH-pyrazol-l-yl]phthalonitrile;
S-methyW-[-4lH-pyrrolo[2,3-b]pyridin-4--y1)-1H-pyrazol-l-yl]benzaldehyde;
4-[l-(2-methyl-4-nitrophenyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]cyclopentanone;
4-[l-(3-furylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
4-[l-(2-furylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine;
3-{2-cyano-l-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]ethyl}benzonitrile;
{3-methy-4--[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]phcnyl}niethanol;
4-methyl-4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]pentan-2-onej
3-(l-benzofuran-2-yl)-3-[4-(lH-pyrro]o[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3-(3-furyI)-3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]piopanenitrile;
{3-methyM-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]phenyl}acetonitrile;
4-methy]-3-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l-yl]benzonitrile;
4-[ 1 -(1 -cyclopentylpropyl)-1 H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;
{1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]cyclopentyl}acetonitrile;
3 - {(2-cyano-1 -[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yljethyl} benzonitrile;
3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-3-(3-thienyl)propanenitrile;
4-chloro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]benzonitrile;
3-(3-furyl)-3-[4-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]propanenitrile;
3-[4-(7H-pyrro]o[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanedinitrile;
3-{l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclopentyl}-propanenitrile;
{1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]cyclohexyl} acetonitrile;
{3-methyl-4-[4-(7H-pyrrolo[2,3-d]pyritnidin-4-yl)-lH-pyra2ol-l-yl]phenyl}methanol;
3-pyridin-4-ylO-[4^7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazo]-l-yl]propanenitrile;
3-pyridin-3-ylO-[4-(7H-pyrrolot2,3-d]pyriniidin-4-yl)-lH-pyrazol-I-yl]propanenitrile;

S-^-(methylthio)phenyy-S--4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl]propane-
nitrile;
3-(3-methoxyphenyl)-3-[4-(7H-pyrrolo[2,3d]pyrmidin-4-yl] 21 H pyrazol -1- propanenitrile-
3-(4-methoxyphenyl)0-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH--pyrazoI-1-yI]propanenitrile;
{3-methyl-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]phenyl}acetonitriIe;
3-[4-(methylsulfiyl)phenyl]-3-[4^7H-pyirolo[2,3^]pyrii!iaidin-4-yl)-lH-pyrazol-l-y]]-
propanenitrile;
3-[4-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3 -[3 -(cyanomethoxy)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazo1-1 -yl] -
propanenitrile;
3-(6-chloropyridin-3-y])-3-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH~pyrazol-l-yl]-
propanenitrile;
5-{2^yano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}pyridine-2-
carbonitrile;
3-(3,5^imethylisoxazol^-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrinaidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[4-(7H-pyiTolo[2^-d]pyrimidin^-yl)-lH-pyrazol-l-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]-
propanenitrile;
3-(6-methoxypyridin-3-yl)-3-[4 nitrile;
3-pyridin-2-yl-3-[4-(7H-pyrro]o[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3^6-bromopyridin-2-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
6- {2-cyano-l -[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} pyridine-2-
carbonitrile;
4-[4-(7H-pyrrolo[2,3-d]pyriraidin-4-yl)-lH-pyrazol-l-yl]heptanedinitrile;
3^5-bromopyridin-3-yl)^-[4-(7H-pyrrolo[2,3Kl]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
4-[4-(7H-pyrroIo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-l-yl]heptanedinitrile;
5-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} nicotinonitrile;
3-(2-methoxypyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
3-[4-(cyanomethoxy)phenyl]-3-[4-(7H-pyiTolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[2-(cyanomethoxy)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l-yl]-
propanenitrile;

3-(3,5-dibromophenyl)-3-[4-(7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
5-{2-cyano-l -[4-(7H-pyinolo[2,3-d]pyrimidin-4-yl)--lH-pyrazol-1-yl]ethyl}isophthalonitrile;
3-[6-(dimethylamino)pyridin-2-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-(4-bromo-2-thienyl)-3-[4-(7H-pyrrolo[2,3-d]pyrmidin-4-yl)-lH-pyra2ol-l-yl]propane-
nitrile;
5- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} thiophene-3-
carbonitrile;
3-(5-bromo-2-fluorophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-(3-nitrophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3-(5-bromo-2-methoxyphenyl)0-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyrazol-]-yl]-
propanenitrile;
3-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-l H-pyrazol-1-yl]ethyl}-4-methoxybenzo-
nitrile;
3-(3-bromophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyroraidin-4-yl)-lH-pyra2ol-l-yl]propanenitrile,:
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]ethyl}-4-fluorobenzo-
nitrile;
3-[5-bromo-2-(cyanomethoxy)phenyl]-3-[4(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]propanenitrile;
3-(4-bromo-2-furyl)-3-[4-(7H-p3mrolo[2,3d]3yrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
4-(cyanomethoxy)-3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl3-
ethyl}benzonitrile;
3-(4-brdmopyridin-2-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
2-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}isonicotinonitrile;
5- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -3-furonitrile;
3-[2-bromo-5-(cyanomethoxy)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidiri-4-yl)-lH-pyrazo1-1-
yl]propanenitrile;
4-(cyanomethoxy)-2- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]-
ethyl} benzonitrile;
3-pyrimidin-5-ylO-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3-(2-bromopyridin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimLidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
4-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-y]]ethyl}p3aidine-2-carbo-
nitrile;

3-(5-methoxypyridin-3-yl)-3-t4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
3-(3-chlorophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyritnidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l-yl]-3-[3-(trifluoromethyl)phenyl]-
propanenitrile;
3-(3-phcnoxyphenyl)-3-[4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-3-[3-(trifluoromethoxy)-phenyl]-
propanenitrile;
methyl 3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrmidin-4-yl)-lH-pyrazol-l-yl]ethyl}benzoate;
3-{2-oyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4--yI)-lH-pyrazol-l-yl]ethyl}benzoic acid;
3-[3-(lH-pyrazoll-yl)phenyl]-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-(3-aminophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile;
N-(3- {2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)4H-pyrazol-l -yl]ethyl}phenyl)-
acetamide;
N-(3-{2-cyano-l-[4-(7H-pyn-olot2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-
methanesulfonamide;
4-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}thiophene-2-
carbonitrile;
5-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrinudin-4-yl)-lH-pyrazol-l-yl]ethyl}thiophene-2-
carbonitrile;
3-[3-(morpholin-4-ylcarbonyl)phenyl]-3-[4-(7H-pyirolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -
yl]propanenitrile;
N-(2-aminoethyl)-3-{2cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
ethyl} benzamide;
3-(5-formyl-3-thienyl)-3-[4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-methylbenz-
amide;
2-yano-N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl3ethyl}-
phenyl)acetamide;
N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-
nicotinamide;
N-(3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]ethyl}phenyl)-N'-
isopropylurea;
isopropyl (3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]ethyl}-
phenyl)carbamate;

3-(5-phenylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l-yl3propane-
nitrite;
3-(3,3'-bipyridin-5-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrmidin-4-yl)--lH-pyrazol-l-yHpropane-
nitrile;
3^5-pyrimidin-5-ylpyridin-3-yl)-3-[4-(7H-pyn:olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[5-91-methyl-lH-pyrazol-4-yl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-1 -yl]propanenitrile;
3-(5ehynylpyridin-3-yl)-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propane-
nitrile;
3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl]-
propanenitrile;
3-(2-bromo-1,3-thiazol-5-yl)-3 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-y 1)-1 H-pyrazol-1 -yl] -
propanenitrile;
ethyl 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanoate;
3-(5-morpholin-4--ylpyridin-3-yl)-3-[4-47H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-(l-methyl-lH-pyrazo-4--yl0-3-[4-(7H-pyreolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
4-{l-[l-phenyl-2-(lH-lJ2,4-triazol-l-yl)ethyl]-lH-pyrazol-4-yl}-7H-pyrrolo[2,3-d]-
pyrimidine;
4- {1 -[ 1 -phenyJ-2-(4H-l ,2,4-triazol-4-yl)ethyl]-l H-pyrazol-4-yl} -7H-pyrrolo[2,3-d]-
pyrimidine;
3-(3-pyridin-3-ylphenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[5-(pheny]sulfinyl)pyridinO-yl]0-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[5-(phenylsulfonyl)pyridinO-yl]-3-[4 propanenitrile;
3-[4-(7H-pyrrolo[2,3-d]pyrimidin'4-yl)-lH-pyrazol-l-yl]pentan-l-ol;
methyl 3--4H-pyrrolo]2,3-dlpyrimidin-4-yl-lH-pyrazol-l-yllpentyl carbonate;
(lE)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanaloxime;
(lE)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanalO-methyloxime;
(lZ)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanalO-methyloxime;
4-[l -(4,4-dibromo-l -ethylbut-3-en-l -yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;
3-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]0-[5-(l,3-thiazol-2-ylthio)pyridin-
3-yl]propanenitrile;

3-[5-(ethylthio)pyridin-3-yl]-3-[4^7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
4-[l-(l-ethylbut-3-yn-l -yl)-l H-pyrazol-4-yl]-7H-pyrrolot2,3-d]pyrimidine trifluoroacetate;
4-{l-[l-methyl-2-(lH-l>2,4-triazol-l-yl)ethyl]-lH-pyrazol-4-yl}-7H-pyrrolo[2,3-d]-
pyrimidine;
4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]pentan-2-one trifluoroacetate;
l-phenyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propan-l-one;
S-[5-(ethylsulfinyl)pyridin-3-yll]-3-(7H-pyrrolo[2,3-dlpyrimidin-4-y1)-lH-pyrazol-l-yl]-
propanenitrile;
3-[5-(ethylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[5-(cycloh6xylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
l-phenyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propan-l-ol;
l-phenyl-2-t4-(7H-pyrrolo[2,3-d]pyrimidin-4-y])-lH-pyrazol-l-yl]propan-l-ol;
3-[3-(ethylthio)phenyI]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[3-(ethylsulfiny])phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[3-(ethylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[5-(cyclohexylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3d]-pyrimidin-4-yl)-lH-pyrazol-
1 -yl]propanenitrile;
3-[5-(cyclohexylsulfinyl)pyridinO-yl]-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]propanenitrile;
4-[ 1 -(1 -methyl-2-phenylethyl)-1 H-pyrazol-4-yl]-7H-pyrrolot2,3-d]pyriniidine;
4- {1 -[ 1 -methyl-2-(3-thienyl)ethyl]-l H-pyrazol-4-yl} -7H-pyrrolo[2,3-d]pyrimidine;
3-{l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}benzonitrile;
4-{ 1 -[2-(l H-imidazol-1 -yl)-l -methylethyl]-lH-pyrazol-4-yl}-7H-pyrrolot2,3-d]pyrimidine;
4-{l-[l-methyl-2-(3-methyl-l,2,4-oxadiazol-5-yl)ethyI]-lH-pyrazol-4-yl}-7H-pyrrolot2J3-d]-
pyrimidine;
3-[3-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-(3-pyridin-4-ylphenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl3propane-
nitrile;
4-[l-(I-ethylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyriinidine;
4-[l--(l,3-dimethylbut-3-en-l-yl)-lH-pyra2ol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;

3-[5-(isopropylthio)pyridin-3-yl]-3-l|4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[5-(isopropylsulfinyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyra2ol-l- -
yl]propanenitrile;
3-[5-(isopropylsulfonyl)pyridin-3-yl3^-3-[4 yljpropanenitrile;
3-[4-(7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-3-[5-(trifluoromethyl)pyridin-3-yl]-
propanenitrile;
3-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-pyra2ol-l-yl]-3-[5-(trifluoromethyl)pyridin-3-yl]-
propanenitrile;
2-[4-(7H-pyrrolo[2)3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-N-[3-(trifluoromethyl)phenyl]-
propanamide;
N-2-naphthyl-2-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanamide;
N-l-naphthyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-y]]propaiiamide;
N-(3-(yanophenyl)-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanamide;
N-benzyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanamide;
N-phenyl-2-[4-(7H-pyrrolo[2,3-d]-]-yrirnidin-4-yl)-lH-pyrazol-l-yl]-]butanamide;
N-(4-phenoxyphenyl)-2-[4-(7H-pyrrolo[2,3-d]pyriraidin-4-yl)-lH-pyrazol-l-yl]butanamide;
N-2-naphthyl-2- [4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl) -1 H-pyrazol-1 -yl]butanamide;
N-(3-cyanophenyl)-2-[4(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]butanamide;
N-bipheny-4-yl-2-[4-(7H-pynx)lo[2,3-d3pyrimidin-4-yl)-lH-pyrazol-I-yl]butanamide;
N-(biphenyl-4-ylrnethyl)-2-[4-(7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
butanamide;
N-(biphenyl-3-ylmethyl)-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI]-
butanamide;
N-(4-cyanophenyl)-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]butanamide;
N-l-naphthyl-(4H-pyrrolo]2,3]pyrimidin-4--yl]-lH-pyrazol-l-yl]butanamide;
5-{2-cyano-l-[4-(7H-pyrrolo[213-d]pyrimidin-4-y0-lH-pyrazol-l-yl]ethyl}-N-phenylnicotin-
amide;
N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-3-
(trifluoromethyl)benzamide;
N-(3-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyI}phenyl)-3-(trifluoro-
methyl)benzamide;
3-[3-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]-
propanenitrile;
3-[3-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;

N(-3-{[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}phenyl)benzene-
sulfonamide;
3- {[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]methyl} -N-[3-(trifluoromethyl)-
phenyl]benzamide;
3-{2-cyano-l -[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-l H-pyrazol-1-yl]ethyl} -N,N-dimethyl-
benzenesulfonamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N,N-dimethyl-
benzenesulfonamide;
N-benzyl-3- {2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yl]ethyl} -
benzenesulfonamide;
N-benzyl-3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethy]}-
benzamide;
3-{2-cyano-l-[4-(7H-pyrTolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-phenyl-
benzamide;
3-{2-cyano-l-[4-(7H-pyixolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-[3-(trifluoro-
methyl)phenyl]benzamide;
N-(3-cyanophenyl)-3-{[4-(7H-pyrrolo[2,3^]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}-
benzamide;
N-benzyl-3-{[4-(7H-pyrrolo-i[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl} benzamide;
N-l-naphthyl-3-{[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazo]-l-yl]methyl}benzamide;
N-2-naphthyl-3-{[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}benzamide;
N-(3-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}phenyl)-2-naphthaniide;
N-(3-{[4-(7H-pyiTolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]methyl}phenyl)-l-naphthamide;
2-phenyl-N-(3-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}phenyl)-
acetamide;
3-chloro-N-(3-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyTazol-l-yl]inethyl}phenyl)-
benzamide;
N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-2-
naphthamide;
N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-l-
naphthamide;
N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-ethyl}phenyl)-2-
phenylacetamide;
3-cyano-N-(3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-
phenyl)benzamide;
N-(3- {2-cyano-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} phenyl)-
benzamide;

N-(3-{2-yano-l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyO-4-
(trifluoromethyl)benzamide;
N-(3-{2-cyano-l-[4-(7H-pyn:olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-Nl-
phenylurea;
3-{2^yano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-[4-(trifluoro-
methyl)phenyl]benzamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(4-inethyl-
phenyl)benzamide;
N-(4-cyanophenyl)-3-{2-cyano-l-[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
ethyl} benzamide;
3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl}-N-2-naphthyl-
benzamide;
3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]ethyl}-N-l -naphthyl-
benzamide;
3- {2-cyano-l -[4-(7H-pyirolo[2,3-d]pyrimidin-4-yl) -1 H-pyrazol-1 -yl]ethyl} -N,N-dimethyl-
benzamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-pyridin-3-yl-
benzamide;
3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]ethyl}-N-methyl-N-
phenylbenzamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-cyclohexyl-
benzamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(4-phenoxy-
phenyl)benzamide;
N-(3-cyanophenyl)-3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
ethyl}benzamide;
N-biphenyl-4-yl-3-{2-cyano-l-t4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-l-yl]-
ethyl} benzamide;
N-(4-chlorophenyl)-3-{2-cyano-l -[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-lH-pyrazoI-l-yl]-
ethyljbenzamide;
3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yl]ethyl}-N-(3,4-dimethyl-
phenyl)benzamide;
3- {2-cyano-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 -yl]ethyl}-N-(3-methoxy-
phenyl)benzamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(4-methoxy-
phenyl)benzamide;

3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-isoxazol-3-yl-
benzamide;
3-{2-oyano-l-[4-(7H-pyirolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-methyl-N-
phenylbenzenesulfonamide;
3- {2-cyano-l -[4-{7H-pyiTolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-propyl-
benzenesulfonamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyriinidm-4-yl)-lH-pyrazol-l-yl]ethyl}-N-phenyl-
benzenesulfonamide;
3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yljethyl} -N-2-naphthyl-
benzenesulfonamide;
3-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-cyclopropyl-
benzenesulfonamide;
3-[3-(piperidin-l-ylsulfonyl)phenyl]-3-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]propanenitrile;
3-[3-(morpholin-4-ylsulfonyl)phenyl]-3-[4-(7H-pynx)lo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l
yl]propanenitrile;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(4-methyl-
phenyl)benzenesulfonamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(3,4-dimethy]
phenyl)benzenesulfonamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(3-methoxy-
phenyl)benzenesulfonamide;
3-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-(4-methoxy-
phenyl)benzenesulfonamide;
3-{2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-(3,5-
dimethoxyphenyl)benzamide;
3-{2-cyano-l-[4-(7H-pynolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-[4-(dimethyl-
amino)phenyl]benzamide;
3-[3-(benzylsulfonyl)phenyI]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[3-(ben2ylthio)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
4-{[(3-{2-cyano-l-[4-C7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}phenyl)-
sulfonyl]methyl}benzonitrile;
3-{2-cyano-l -[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]ethyl} -N-methyl-
benzenesulfonamide;

3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-l-naphthyl-
benzenesulfonamide;
N-biphenyM-y]-3-{2-cyano-l-[4-(7H-pyrrolo[2J3^]pyrifflidin-4-yl)-lH-pyrazol-l-yl]ethyl}-
benzenesulfonamide;
3-{2^yano-l-[4-(7H-pyrrolot2,3^]pyrimidir,-4-yl)-lH-pyrazol-l-yl]ethyl}-N-[4-(trifluoro-
methoxy)phenyl]benzamide;
3 - {2-cyano-l -t4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl]ethyl} -N-(2-methoxy-
phenyl)benzamide;
3-[3-(benzyloxy)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pynizoI-l-yl]-
propanenitrile;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-cyclohexyI-
benzenesulfonamide;
3-[3-(3,4-dmydroisoquinolin-2(lH)-ylsulfonyl)phenyl]-3-[4-(7H-pyiTolo[2,3-d]pyrimidin-4-
yl)-lH-p yrazol-l-yl]propanenitrile;
3-{2-cyano-l-[4-(7H-pyn-olo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(2-methoxy-
ethyl)benzenesulfonamide;
3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N,N-diethyl-
benzenesulfonamide;
3-{3-[(4-ethylpiperazm-l-yl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl>lH-
pyrazol-1 -yl]propanenitrile;
N-l,3-benzodioxol-5-yl-3-{2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]ethy 1} benzenesulfonamide;
3-{3-[(3-methoxybenzyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-1 -yl]propanenitrile;
3-{3-[(4-methoxybenzyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-1-yl]propanenitrile;
3-{3-[(2,6-dimethylmorpholm-4-yl)sulfonyl]phenyl}-344-(7H-pyrrolo[2,3d]pyrunidin-4-yl)-
1 H-pyrazol-1 -yljpropanenitrile;
3- {3-[(4-oxopiperidin-l -yl)sulfonyl]phenyl} -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-
pyrazol-1 -yl]propanenitrile;
3-[3-(isopropylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-lH-pyrazol-1-ylj-
propanenitrile;
3-{3-[(cyclohexylmethyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-1 -yljpropanenitrile;
3-[3-(octahydroisoqumolin-2(lH)-ylsulfonyl)phenyl]-3-[4-(7H-pyn-olo[2J3-d]pyriniidin-4-
yl)-1H-pyrazol-1 -yl]propanenitrile;

3-{2-cyano-l-[4-(7H-pyrrdlo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethyl}-N-(2-phenyl-
ethyl)benzenesulfonaroide;
cia-4-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]cyclohexylacetonitrile;
cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethylthiocyanate;
N-5-[(cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)thio]-
4H-I,2,4-triazol-3 -ylpyrimidin-2-amine;
N-5-[(cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yI]cycIohexyImethyl)thio]-
4H-1,2,4-triazol-3 -ylpyrimidin-2-amine;
3-cis-4-[4-(7H-pyiTolo[23-d]pyriniidin-4-yl)-lH-pyrazol-l-yl]cyclohexylpropanenitrile;
5-[2-cis-4-[4H-pyrrolop2,3-d]pyrimidin-4-yl)-IH-pyrazoI-l-yl]cyclohexylethyOthio]-4H-
1 ,2,4-triazol-3-amine;
4-[4-(7H-pyrrolot2,3-d]pyrirnidin-4-yl)-lH-pyrazol-l-yl]cyclohexylideneacetonitrile;
cis-4-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexanecarbonitrile;
2-[(cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)sulfinyl]-
benzonitrile;
2-[(cis-4-[4-(7H-pyrrolo[23-d]pyritnidin-4-yl)-lH-pyrazol-l-yl]cyclohexylmethyl)sulfonyl]-
benzonitrile;
3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclohexylacetonitrile;
5-({cis-4-[4-(7H-pyrrolo[2,3-d3pyrimidin-4-yl)-lH-pyra2ol-l-yl]cyclohexyl}thio)-lH-l,2,4-
triazol-3-amine;
N- {5-[( {cis-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]cyclohexyl}methyl)-
thio]-4H-l,2,4-triazol-3-yI}methanesulfonamide;
[cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-l-(lH-l,2,4-triazol-l-yl)cyclo-
hexyljacetonitrile;
3-[3-(piperazin-l -ylsulfonyl)phenyl]-3-[4-(7H-pyr rolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -
yl]propanenitrile;
3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-3-[3-(thiomorpholin-4-ylsulfonyl)-
phenyl]propanenitri le;
3-{3-[(4-hydroxypiperidin-l-yl)sulfonyl]phenyl}-3 -[4-(7H-pyrrolo[2J3-d]pyrimidin-4-yl)-
lH-pyrazol -l-yl]propanenitrile;
3-[3-(isobutylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanenitrile;
3-[4-(7H-pyrrolo[2)3-d]pyrimidin-4-yl)-lH-pyrazol -1 -yl]-3-{3-[(tetrahydro-2H-pyran-4-
ylmethyl)sul fonyl]phenyl}propanenitrile;
3-{3-[(2-methoxyethyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyriniidin-4-yl)-lH-
pyrazol-1 -yl]propanenitrile;

3-{3-[(3-furylmethyl)sulfonyl]phenyl}-3-[4--(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-
1 -yl]propanenitrile;
3- {3-[(l, 1 -dioxidothiomorpholin-4-yl)sulfonyI]phe nyl} -3-[4-(7H-pyrroIo[2,3-d]pyrimidin-4-
yl)-lH-p yrazol-l-yl]propanenitrile;
3-{3-f(4-acetylpiperazin-l-yl)sulfonyl]phenyl}-3-r4-(7H-pyrTolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-1 -yl]propanenitrile;
3-{3-[(pyridin-4-ylmethyl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-
pyrazol-1 -yl]propanenitrile;
4-[l-(l-phenylbut-3-yn-l-yl)-lH-pyrazol-4-yl]-7H- pyrrolot2,3-d]pyrimidine;
4-(l-{l-[3-(morpholin-4-ylsulfonyl)phenyl]but-3-yn-l-yl}-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-
d]pyrimidine;
3-{l-[4-(7H-pynrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]but-3-yn-l-yl}benzonitrile;
3-{l-[4-(7H-pyn-olo[2,3-d]-pyrimidin-4-yl)-lH-pyrazol-l-yl]but-3-yn-l-yl}benzaldehyde;
methyl 3-(3-cyanophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-
propanoate;
N,N-dimethyl-3-{l-[4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l-yl]but-3-yn-l-yl}-
benzenesulfonamide;
3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 -yl]ethyl) -N-[4-{dimethyl-
amino)phenyl]benzenesulfonamide;
3-{3-methoxy-l-[4-(7H-pyirolo[2,3Kl]pyrimidin-4-yl)-lH-pyrazol-l-yl]propyl}-JV;iV-
dimethylbenzenesulfonamide;
N-phenyl-3-{l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazo]-l-yl]but-3-yn-l-y]}-
benzamide;
4-[l -(3-methoxy-l -phenylpropyl)-lH-pyrazol-4-yl]- 7H-pyrrolo[2,3-d]pyrimidine;
Ar-[4-(dimethylamino)phenyl]-3-{l-[4-(7H-pyn-o]o[2,3-d]-pyrimidin-4-yl)-lH-pyrazol-l-
yl]but-3-yn-l-yl}benzamide;
3-{3-hydroxy-l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-y l)-lH-pyrazol-l-yl]propyl}-iV;7V-
dimethylbenzenesulfonamide;
3-{l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]but-3-en-l -yl}benzonitrile;
4-{l-[l-(3-bromophenyl)but-3-en-l-yl]-lH-pyrazol-4-yl}-7H-pyrroIo[2,3-d]pyrimidine;
3-{4,4-difluoro-l-t4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-l H-pyrazol-1 -yl]but-3-en-l -yl}-
benzonitrile;
4-(i-{4,4-difluoro-l-t3-(morpholin-4-ylsulfonyl)phenyl]but-3-en-l-yl}-lH-pyrazol-4-yl)-7H-
pyrrolo[2,3-d]pyrimidine;
4-(l - {1 -[3-(ethylsulfonyl)phenyl]-4,4-difluorobut-3-en-l -yl} -1 H-pyrazol-4-yl)-7H-pyrrolo-
[2,3-d]pyrimidine;

4-(l-{l-[3-(benzyloxy)phenyl]-4)4-difluorobut-3-en-l-yl}-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-
d]pyrimidine;
441-(2-methoxy-lphenylethyl)-lH-pyrazoM-yl]-7H-pyrrolo[2,3HJ]pyrimidine;
4-(l-{4,4-difluoro-l-[3-(methylsulfonyl)phenyl]but-3-en-l-yl}-lH-pyrazol-4-yl)-7H-
pyrrolo[2,3-d]pyrimidine;
3-{[4-(7H-pynrolo[23-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]methyl}beiizonitrile;
3-{l-[4-(7H-pyrrolo[2,3-d]pyriinidin-4-yl)-lH-pyrazol-l-yl]-ibutyl}ben2onitrile;
4-(l-{l-[3-(ethylsulfonyl)phenyl]-4,4-difluorobutyl}-lH-pyrazoI-4-yl)-7H-pyrrolo[2,3-d]-
pyrimidine;
4-[l-(4,4-difluoro-l-{3-t(2-methoxyethyl)sulfonyl]phenyl}-but-3-en-l-yl)-lH-pyrazol-4-yl]-
7H-pyrrolo[2,3-d]pyrimidine;
4-[l-(l-cyclopentylbut-3-en-l-yl)-lH-pyrazol-4-y]]-7H-pyiTolo[2,3-d]pyrimidine;
4-[l-(l-methylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;
4-[l-(l-cyclopentyl-2-cyclopropylethyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;
4-[ 1 -(1 -cyclopentylbut-3-yn-l -yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;
4-[l-(l-cyclopentylbutyl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin.e;
4-[l-{l-cyclopentyl-4,4-difluorobut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]-
pyrimidin.e;
4-1 -[4,4-difluoro-l -(tetrahydrofuran-3-yl)but-3-en-l -yl]-lH-pyrazo]-4-yl-7H-pyrrolo[2,3-
d]pyrimidine;
4-[l-(l-methylbut-3-en-l-yl)-lH-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;
4-[ 1 -(1 -cyclopropyl-4,4-difluorobut-3-en-l -yl)-l H-pyrazol-4-yl] -7H-pyrrolo[2,3-d]-
pyrimidine;
4-[l-(l-cyclopentyl-4,4-difluorobutyl)-lH-pyTazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;
3-( 1 -methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-1 -yl]propane-
nitrile;
(3R)-and(3S)-4,4-dimethyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]niethyl-7H-pyrroIo[2,3-d3-
pyrimidin-4-yl)-lH-pyrazol-l-yl]pentanenitrile;
l-2-cyano-l-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]ethylcyclopropane-
CEtrbonitrile;
N-[{ 1 -2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidm-4-yl)-lH-pyrazol-l -yl]ethylcyclopentyl)-
methyl]benzamide;
3-l-[(benzyloxy)metoyI]cyclopentyl-3-[4-(7H-pyrTolo[2J3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]propanenitrile;
3-[l^rnethy]sulfonyl)pyn-olidin-3-yl]-3-[4-(7H-pyrTolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-
yl]propanenitrile;

N-cyano-4-cyanomethyl)-4-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl]-lH-pyrazol-l-yl]-
piperidine-1-carboximidamide;
4-l-[2,2,2-trifluoro-l-(lH-imidazol-2-ylmethyl)ethyl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-
d]pyrimidine;
4-(l-(lR)-2,2,2-trifluoro-l-[(4-methyl-l,3-thiazol-2-yl)methyl]ethyl-lH-pyrazol-4-yl)-7H-
pyrrolo[2,3-d]pyrimidine;
4-l-[-1trifluoromethy)but-3-yn-l-yy-lH-pyrazo1-4-yl-7H-pynrolo[2,3-d]pyrimidine;
4-l-[l-(trifluoromethyl)but-3-en-l-yl]-lH-pyrazol1-4-yl-7H-pyrrolo[23-d]pyrimidine;
4-1 -[1 -(trifluoromethyl)butyl]-lH-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine;
4-1 -[4,4-difluoro-l -(trifluoromethyl)but-3-en-l -yl]-l H-pyrazol-4-yl-7H-pyrrolo[2,3-d]-
pyrimidine;
4-l-[4,4-difluoro-l-(trifluororaethyl)butyl]-lH-pyrazol-4-yl-7H-pyrrolot2,3-d]pyrimidine;
3-pyridin-4-yl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]propanenitrilc;
4-2-cyano-l-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l,3-thiazol-2-yl]ethylpyridine-2-
carbonitrile; and
3-pyridin-2-yl-3-[5-(7H-py]ToIo[2,3-d]pyriiiudin-4-yl)-l,3-thiazol--2-yl]propanenitrile;
and pharmaceutically acceptable salts thereof.
47. A composition comprising a compound of any one of claims 1 to 46, or pharmaceutically
acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
48. The composition of claim 47 which is suitable for topical administration.
49. A method of modulating an activity of JAK comprising contacting JAK with a compound c
Formula I:

including pharmaceutically acceptable salt forms or prodrugs thereof, wherein:
A1 and A2 are independently selected from C and N;
T, U, and V are independently selected from O, S, N, CRS, and NR6;
wherein the 5-membered ring formed by A1, A2, U, T, and V is aromatic;

X is N or CR4;
Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R12)p -(C3-10 cycloalkylene)-
(CR11R12)q (CR11R12)q-(arylene)-(CR11R12)q) (CR11Rl2)p-(G1-10heterocycloaIkylene)(CR11R12)q
(CR11R12)q-(heteroarylene)-(CR11R21)q, CR11R21)POCR11R21)q CR11R21)pSCR11R21)q,
CR11R21)qC(O)CR11R21)q, CR11R21)pC(O)NReCR11R21)q,, CR11R21)pC(O)O(CR11R21)qq>
CR11R21)POC(O)CR11R21)q, (CR11R12)qOC(O)NRc(CR11R21)q, (CR11R12)qNRCCR11R21)q
CR11R21)qC(O)NRd(CR11R12)p , CR11R21)qS(O)CR11R21)q, (CR11R12)p S(O)NRc(CR11R12)q,
CR11R21)qS(O)2CR11R21)q, or (CR11R12)qS(O)2NRc(CR11R12),, wherein saidC1-4alkylene, C2-8
alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is
optionally substituted with 1,2, or 3 substituents independently selected from -D'-D2-D3-D4;
Z is H, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4
hydroxyalkyl,C1-4cyanoalkyl, -C-R1, =N-R!, Cyl, CN, NO2, OR", SRa, C(O)Rb, CCONRHd.
C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcWd, NRcC(O)Rb, NR1C(O0NRcRd, NRcC(O)ORa,
C(=NR1)NRcRd, NRcC(=NR')NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb,
C(=NO(C1-6 alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C1-4alkyl,
C2-4 alkenyl, C2-4 alkynyl,C1-4 haloalkyl, halosulfanyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, Cy1 CN,
NO2 ORa, SRa, C(O)Rb, C(O)NScBd. C(O)ORa, OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb,
NRcC(O)IMRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRa, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-4alkyl))Rb, and S(O)2NRcRd;
wherein when Z is H, n is 1;
or the -(Y)n-Z moiety is taken together with i) A2 to which the moiety is attached, ii) R5 or R6
of either T or V, and iii) the C or N atom to which the R5 or R6 of either T or V is attached to form a
4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring
formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or S substituents independently selected
from-(W)m-Q;
W is C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, O, S, C(O), C(O)NR°\ C(O)O, OC(O),
OC(O)NRC, NRC, NRc'C(O)NRd', S(O), S(O)NRC, S(O)2, or S(O)2NRC';
Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, halosulfanyl, aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-6 alkenyl, C2-8 alkynyl, C1-8
haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalky] is optionally substituted with 1,2, 3 or 4
substituents independently selected from halo,C1-4alkyl, C2-4 alkenyl, C1-4alkynyl,C1-4haloalkyl,
halosulfanyl,C1-4hydroxyalkyl,C1-4cyanoalkyl, Cy2, CN, NO2, OR"', SRa\ C(O)Rb', C(O)NRcRd',
C(O)ORa', OC(O)Rb, OC(O)NRcRd, NRcRd. NR°'C(O)Rb',NRCC(O)NRcRd,NRcC(O)OR0,
S(O)Rb>, S(O)NRc'Rd', S(O)2Rb>, NRc>S(O)2Rb', and S(O)2NRcRd;

Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl, each optionally substituted by 1,2, 3, 4 or 5 substituents independently selected
from halo,C1-4alkyl,C1-4alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C\^
cyanoalkyl, CN,NO2, OR"", SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", OC(O)Rb", OC(O)NRc"Rd",
NRc"Rd", NRc"C(O)Rb", NRc"C(O)ORa", NRcS(O)R1", NRc"S(O)2Rb", S(O)Rb.", S(O)NRc"Rd",
S(O)2Rb", and S(O)2NRcRd;
R1, R2, R3, and R4 are independently selected from H, halo,C1-4alkyl, C2-4 alkenyl,C1-4alkynyl, C1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7,
SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)RS, OC(O)NR9R10, NR9R10, NR9C(O)R8, NRCC(O)OR7,
S(O)R8, S(O)NER9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10;
Rs is H, halo,C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4, haloalkyl, halosulfanyl, CN, NO2,
OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8,
NR9C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, or S(O)2NR9R10;
R6 is H, C1-6 alkyl,C1-4alkenyl, C2-4 alkynyl,C1-4 haloalkyl, OR7, C(O)R8, C(O)NR9R10,
C(O)OR7, S(O)R8, S(O)NR9R10, S(O)2R8, or S(O)2NR9R10;
R7 is H, C1-4alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R8 isH, C1-8 alkyl, C1-4haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R9 and R10 are independently selected from H, C1-10 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6alkylcarbonyl, arylcarbonyl, C1-4 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
or R9 and R10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group;
Ru and R12 are independently selected from H and -E1-B2-E3-E4;
D1 and E1 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein
each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1,2 or 3 substituents independently selected from
halo, CN, NO2, N3, SCN, OH, C1-6alkyl, C1-6haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy,
amino, C1-6 alkylamino, and C2-8 dialkylamino;
D2 and E2 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene,C1-4alkynylene, (C1-4alkylene)r-O-( C1-6alkylene)s, (C1-6 alkylene)r-S-(C1-6 alkylene)s, (C1-6
alkylene)r-NRe-(C1-4 alkylene)s, (C1-6 alkylene)r-CO-(C1-6 alkylene)s, (C1-6alkylene)r-COO-(C1-6
alkylene)5, (C1-6alkylene)r-CONRc-(C1-6 alkylene)s, (C1-4alkylene)r-SO-(C1-6 alkylene)s, (C1-6
alkylene)r-S02-(C1-4alkylene)S, (C1-4alkylene)rSONRe-(C1-6 alkylene)s, and (C1-4alkylene)r-
NReCONRf-(C1-6 alkylene)s, wherein each of the C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene is

optionally substituted by 1,2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN,
OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-4alkoxy, C1-4 haloalkoxy, amino, C1-6 alkylamino,
and C2-8 dialkylamino;
D3 and E3 are independently absent or independently selected from C1-6alkylene, C2-6
alkenylene, C2-6 alkynylene, aiylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein
each of the C^alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from
halo, CN, NO2,N3, SCN, OH, C1-6 alkyl, C1-6haloalkyl, C2-8 alkoxyalkyl, C1-4alkoxy, C1-6 haloalkoxy,
amino, C1-6 alkylamino, and C2-8 dialkylamino;
D4 and E4 are independently selected from H, halo,C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN, NO2, OR", SR", C(O)Rb,
C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NR°Rd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(0)ORa,
C(=NR1)NRcRd, NRCO(-NR1)NRI!R-, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb,
C(=NO(C1-6alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1, 2, 3,4,5, or 6 substituents independently selected from halo,C1-4alkyl,
C2-4 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN,
NO2, ORa, SRa, C(O)Rb, C(O)NReR NRcC(O)NReRd, NRCC(O)OR85 C(=NR1)NRcRd, NRcC(=NR')NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C2-6 alkyl))Rb, and S(O)2NRcRd;
Ra is H, Cy', -(C1-6 alkyl)-Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein
said C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6 haloalkyl, halosulfanyl,
aryl, arylalkyl, hcteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rb is H, Cy1, -(C1-4alkyl)-Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein
said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6
haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Ra' and Ra" are independently selected from H, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1,2, or 3 substituents independently selected
from OH, CN, amino, halo, C1-6 alkyl, C1-4 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rb and Rb" are independently selected from H, C1-6 alkyl, C1-6haloalkyl,C1-4alkenyl,
C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,

cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, Chalky!, C1-6haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Re and Rd are independently selected from H, Cy\ -(C1-4alkyl)-Cy1, C1-10 alkyl, C1-6
haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-8 alkrenyl, or C2-6
alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy\ -(C1-6
alkyl)-Cy1 OH, CN, amino, halo, C1-6 alkyl, C1-6haloalkyl, C1-6 haloalkyl,and halosulfanyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently
selected from Cy1, -(C1-6 alkyO-Cy1, OH, CN, amino, halo, C1-6alkyl, C1-4haloalkyl, C1-6haloalkyl,
and halosulfanyl;
Rc and Rd are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc' and Rd> together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc" and Rd" are independently selected from H, C1-10 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10 alkyl, C1-6 haloalkyl,C1-4alkenyl, C2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-4 alkyl, C1-4 haloalkyl, halosulfanyl, C1-4 haloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc" and Rd" together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-6alkyl, C1-4 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R! is H, CN, NO2 or C1-6alkyl;
Rc and Rf are independently selected from H and C1-6 alkyl;
R' is H, CN,or NO2;

m is 0 or 1;
n is 0 or 1;
p is 0, 1, 2, 3,4, 5, or 6;
q is O, 1,2, 3,4, 5 or 6;
r is 0 or 1; and
s is 0 or 1.
50. The method of claim 49 wherein said JAK is JAK1, JAK2, JAK3 or TYK2.
51. The method of claim 49 wherein said JAK is JAK1 or JAK2.
52. The method of claim 49 wherein said JAK is JAK2.
53. The method of claim 49 wherein said modulating is inhibiting.
54. The method of claim 49 wherein said compound is a selective inhibitor of JAK2 over JAK1,
JAK3 and TYK2.
55. A method of treating a disease in a patient, wherein said disease is associated with JAK
activity, comprising administering to said patient a therapeutically effective amount of a compound of
Formula I:

including pharmaceutically acceptable salt forms or prbdrugs thereof, wherein:
A1 and A2 are independently selected from C and N;
T, U, and V are independently selected from O, S, N, CR5, and NR6;
wherein the 5-membered ring formed by A1, A2, U, T, and V is aromatic;
X is N or CR4;
Y is C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene, (CR11R21)p-(C3-10 cycloalkylene)-
(CRllR12)q,(CR1IRl2)p-(arylene)-(CR11R12)q,(CR11R12)p -(C1-10 heterocycloalkylene)-(CR11R12)p )
(CR11R12)q (heteroarylene(CR11R12)q (CR11R12)qO(CR11R12)Q, (CR11R12)qS(CR11R12)q,

(CR11R12)qC(O)(CR11R12)q (CR11R12)p C(O)NRc(CR11R12)q, (CR11R12)pC(O)O(CR11R12)p ,
(CR11'R12)p OCCO)(CR11R12)q, (CR11R12)q)OC(O)NR.c(CR11R12)q, (CR11R12)pNRC(CR11R12)q,
(CR11R12)qNRcC(O)NRd(CR11R12)q, (CR11Rl2)pS(O)(CR11R12)q (CR11R12)qS(O)NRc(CR11R12)q
(CR11R12)qs(CR11R12)q,, or (CR11'R12)p S(O)NRc(CR11R12)q, wherein said C1-8 alkylene, C2-8
alkenylene, C2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is
optionally substituted with 1, 2, or 3 substituents independently selected from -D'-D2-D3-D4;
Z is H, halo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl,C1-4haloalkyl, halosulfanyl,C1-4hydroxyalkyl, C1-4 cyanoalkyl, =C-R\ =N-R\ Cy1, CN, NO2, ORa, SRa, C(O)Rb, C(O)NR°Rd,
C(O)OR\ OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NR°Rd, NRcC(O)ORa,
C(=NR1)NRcRd NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb,
C(=NO(C1-6 alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-6 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl,
C2-4 alkenyl, C2-6 alkynyl, C1-6 1-4 haloalkyl, halosulfanyl, C1-4 hydroxyalkyl,C1-4cyanoalkyl, Cy1, CN,
NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)OR", OC(O)Rb, OC(O)NRcRd, NR^, NRcC(O)Rb,
NR"C(O)NRCR-, NRcC(O)ORa, C(=MRi)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl))Rb, and S(O)2NRcRd;
wherein when Z is H, n is 1;
or the -(Y)n-Z moiety is taken together with i) A2 to which the moiety is attached, ii) R3 or R6
of either T or V, and iii) the C or N atom to which the Rs or R6 of either T or V is attached to form a
4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring
formed by A1, A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected
from -(W)m-Q;
W is C1-8 alkylenyl, C2-8 alkenylenyl, C2-8 alkynylenyl, O, S, C(O), C(O)NRC, C(O)O, OC(O),
OC(O)NRe>, NRC', NRc'C(O)NRd>, S(O), S(O)NRC S(O)2, or S(O)2NRC";
Q is H, halo, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, halosulfanyl, aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8
haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1,2,3 or 4
substituents independently selected from halo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,
halosulfanyl,C1-4hydroxyalkyl, C1-6 cyanoalkyl, Cy2, CN, NO2, ORa>, SRa%, C(O)Rb', C(O)NRc>Rd',
C(O)ORa>, OC(O)Rb', OC(O)NRcRd,NRcRd',NRc'C(O)Rb>, NRc'C(O)NRc'Rd', NRcC(O)ORa',
S(O)Rb', S(O)NRc'Rd', S(O)2Rb\ NRc'S(O)2Rb', and S(O)2NRc>Rd>;
Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected
from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, halosulfanyl, C1-4hydroxyalkyl, C1-4
cyanoalkyl, CN, NO2, ORa", SRa", C(O)Rb", C(O)NRc"Rd", C(O)ORa", OC(O)Rb", OC(O)NRc"Rd",

NRc"Rd", NRc"C(O)Rb' NRc"C(O)ORa", NRc"S(O)Rb", NRcSCO)2Rb", S(O)Rb' S(O)NRc"Rd",
S(O)2Rb", and S(O)2NRc"Rd>;
R1, R2, R and R4 are independently selected from H, halo, C1-4 alkyl, C2-6 alkenyl, C2-4
alkynyl,C1-4haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OR7,
SR7, C(O)R8, C(O)NR9R10, C(O)OR7 OC(O)R8, OC(O)NR9R10, NR'R10, NR9C(O)R8, NRCC(O)OR7,
S(O)R8, S(O)NR9R10, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R10;
R5 is H, halo,C1-4alkyl, C2-4 alkenyl,C1-4alkynyl, C1-4 haloalkyl, halosulfanyl, CN, NO2,
OR7, SR7, C(O)R8, C(O)NR9R10, C(O)OR7, OC(O)R8, OC(O)NR9R10, NR9R10, NR9C(O)R8,
NR'C(O)OR7, S{O)R8, S(O)NR9R10, S(O)2R8, NR'SCOaR8, or S(O)2NR9R10;
R6 is H,C1-4alkyl,C1-4alkenyl, C2-6 C1-4 alkynyl, C1-6 haloalkyl, OR7, C(O)R8, C(O)NR9R10,
C(O)OR7, S(O)R8, S(O)NR9R10, SCO)2R8, or S(O)NR9R10;
R7 is H, C1-4alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R8 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
R9 and R10 are independently selected from H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, C1-4alkylcarbonyl, arylcarbonyl, C1-6alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
or R9 and R10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group;
Rn and R12 are independently selected from H and -E1-E2-E3-E4;
D1 and E1 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein
each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1,2 or 3 substituents independently selected from
halo, CN, NO2, N3, SCN, OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy,
amino, C1-6alkylamino, and C2-8dialkylamino;
D2 and E2 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, (C1-6 alkylene),-O-(C1-6 alkylene)s, (C1-6 alkylene)r-S-(C1-6 alkylene)s, (C1-6
alkylene)r-NRe-(C1-6alkylene)s, (C1-6 alkylene)r-CO-(C1-6 alkylene)s, (C1-6 alkylene)r-COO-(C1-6
alkylene),, (C1-6alkylene)r-CONRe-(C1-6 alkylene)s> (C1-6alkylene)t-SO-(C1-6alkylene)s, (C1-6
alkylene)r-SO2-(C1-6 alkylene)s, (C1-6alkylene)r-SONRe-(C1-6alkylene)s, and (C1-6 alkylene)r-
NRcCONRf-(C1-6 alkylene),, wherein each of the C1-4 alkylene, C2-6 alkenylene, and C2-6 alkynylene is
optionally substituted by 1,2 or 3 substituents independently selected from halo, CN, NO2, N3, SCN,
OH, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C1-6alkoxy, C1-4haloalkoxy, amino, C1-4 alkylamino,
and C2-6 dialkylamino;

D3 and E3 are independently absent or independently selected from C1-6 alkylene, C2-6
alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein
each of the C1-4alkylene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from
halo, CN, NO2, N3, SCN, OH, C1-6alkyl, C1-4haloalkyl. C2-8 alkoxyalkyl, C1-4alkoxy, C1-6 haloalkoxy,
amino, C1-6 alkylamino, and C2-8 dialkylamino;
D4 and E4 are independently selected from H, halo,C1-4 alkyl, C2-4 alkenyl, C2-6 alkynyl, C1-4
haloalkyl, halosulfanyl,C1-4 hydroxyalkyl,C1-4 cyanoalkyl, Cy1, CN, NO2, OR8, SRa, C(O)Rb,
C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NReC(O)ORa,
C(=NR1)NRcRd, NRcC(=NR1)NR°Rd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, C(=NOH)Rb,
C(=NO(C1-6alkyl)Rb, and S(O)2NRcRd, wherein said C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, is
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1-4 alkyl,
C2-4 alkenyl,C1-4alkynyl, C1-4haloalkyl, halosulfanyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, Cy1, CN,
NO2, OR8, SRa, C(O)Rb, C(O)NR°Rd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRTcRd, NRcC(O)Rb,
NRcC(O)NRcRd, NRcC(O)ORa, C(=NR1)NRcRd, NRcC(=NR1)NRcRd, S(O)Rb, S(O)NRTR.d, S(O)2Rb,
NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C1-6alkyl))Rb, and S(O)2NRcRd;
Ra is H, Cy1, -(C1-6 alkyl)-Cy1, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein
said C1-6 alkyl, C1-6 haloalkyl, C1-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rb is H, Cy1, -(C1-6 alkyO-Cy1, C168 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein
said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1,2, or 3
substituents independently selected from OH, CN, amino, halo, C1-8 alkyl, C1-6 haloalkyl, C1-6
haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Ra and Ra" are independently selected from H, C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with I, 2, or 3 substituents independently selected
from OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rb> and Rb" are independently selected from H, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl,
C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl, wherein said C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from

OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc and Rd are independently selected from H,Cy1,-(C1-6 alkyl)-Cy1, C1-10 alkyl, C1-6
haloalkyl, C2-6 alkenyl, C2-6 alkynyl, wherein said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6
alkynyl, is optionally substituted with. 1,2, or 3 substituents independently selected from Cy1, -C1-6
alkyl)-Cy1, OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6 haloalkyl,and halosulfanyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently
selected from Cy1, -(C1-8alkyl)-Cy', OH, CN, amino, halo, C1-4 alkyl, C1-6 haloalkyl, C1-6haloalkyl,
and halosulfanyl;
Rc> and Rd' are independently selected from H, C1-10alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10alkyl, C1-4haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1,2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-6 alkyl, C1-6haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc' and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-4 alkyl, C1-6haloalkyl, C1-6 haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc" and Rd" are independently selected from H, C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C1-10alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from
OH, CN, amino, halo, C1-6 alkyl, C1-6 haloalkyl, halosulfanyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or Rc" and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-
membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C1-6alkyl, C1-4haloalkyl, C1-6haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rl is H, CN, NOz, or C1-6 alkyl;
Re and Rf are independently selected from H and C1-6 alkyl;
Ri is H,CN,or NO2;
m is 0 or 1;
n is 0 or 1;

p is 0,1, 2, 3,4, 5, or 6;
q is O, 1,2, 3,4, 5 or 6;
r is O or 1; and
s is O or 1.
56. The method of claim 55 wherein said disease is allograft rejection or graft versus host disease.
57. The method of claim 55 wherein said disease is an autoimmune disease.
58. The method of claim 57 wherein said autoimmune disease is a skin disorder, multiple
sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease,
Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune
thyroid disorder.
59. The method of claim 57 wherein said autoimmune disease is bullous skin disorder.
60. The method of claim 59 wherein said bullous skin disorder is pemphigus vulgaris (PV) or
bullous pemphigoid (BP).
61. The method of claim 55 wherein said disease is a skin disorder.
62. The method of claim 61 wherein said skin disorder is atopic dermatitis, psoriasis, skin
sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
63. The method of claim 55 wherein said disease is a viral disease.
64. The method of claim 63 wherein said viral disease is Epstein Barr Virus (EBV), Hepatitis B,
Hepatitis C, HIV, HTLV 1, Varicell-Zoster Virus (VZV) or Human Papilloma Virus (HPV).
65. The method of claim 55 wherein said disease is cancer.
66. The method of claim 65 wherein said cancer is a solid tumor
67. The method of claim 66 wherein said cancer is prostate cancer, renal cancer, hepatic cancer,
breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease or pancreatic
cancer.

68. The method of claim 66 wherein said cancer is prostate cancer.
69. The method of claim 65 wherein said cancer is hematological.
70. The method of claim 69 wherein said cancer is lymphoma, leukemia, or multiple myeloma.
71. The method of claim 69 wherein said cancer is a skin cancer.
72. The method of claim 71 wherein said skin cancer is cutaneous T-cell lymphoma or cutaneous
B-cell lymphoma.
73. The method of claim 69 wherein said cancer is multiple myeloma.
74. The method of claim 55 said disease is characterized by a mutant JAK2.
75. The method of claim 74 wherein at least one mutation of said mutant JAK2 resides in the
pseudo-kinase domain of said JAK2.
76. The method of claim 55 wherein said disease is a myeloproliferative disorder.
77. The method of claim 76 wherein said myeloproliferative disorder (MPD) is polycythemia
vera (PV), essential thrombocythemia (ET), mycloid metaplasia with myelofibrosis (MMM), chronic
myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic
syndrome (HES), or systemic mast cell disease (SMCD).
78. The method of claim 55 wherein said disease is an inflammatory disease.
79. The method of claim 78 wherein said disease is an inflammatory disease of the eye.
80. The method of claim 79 wherein said disease is iritis, uveitis, scleritis, or conjunctivitis..
81. The method of claim 78 wherein said disease is an inflammatory disease of the respiratory
tract.
82. The method of claim 81 wherein said inflammatory disease concerns the upper respiratory
tract.

83. The method of claim 81 wherein said inflammatory disease concerns the lower respiratory
tract.
84. The method of claim 55 wherein said inflammatory disease is an inflammatory myopathy.
85. The method of claim 84 wherein said inflammatory disease is myocarditis.
86. The method of claim 55 wherein said disease is ischemia reperfusion or related to an ischemic
event.
87. The method of claim 55 wherein said disease is anorexia or cachexia resulting from or
associated with cancer.
88. The method of claim 55 wherein said disease is fatigue resulting from or associated
with cancer.

The present invention provides heteroaryl substituted
pyrrolo[2,3-b]pyridines (I) and heteroaryl substituted pyrrolo[2,3-b]pyrim-
idines that modulate the activity of Janus kinases and are useful in the
treatment of diseases related to activity of Janus kinases including, for
example, immune-related diseases, skin disorders, myeloid proliferative
disorders, cancer, and other diseases.

Documents:

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Patent Number

269841

Indian Patent Application Number

2365/KOLNP/2008

PG Journal Number

46/2015

Publication Date

13-Nov-2015

Grant Date

10-Nov-2015

Date of Filing

12-Jun-2008

Name of Patentee

INCYTE CORPORATION

Applicant Address

EXPERIMENTAL STATION, ROUTE 141 & HENRY CLAY ROAD, BUILDING E336, WILMINGTON, DE

Inventors:

#	Inventor's Name	Inventor's Address
1	WANG, HAISHENG	207 HOCKESSIN CIRCLE, HOCKESSIN, DE 19707
2	FALAHATPISHEH, NIKOO	1822 FOULK ROAD, WILMINGTON, DE 19810
3	MADUSKUIE, THOMAS P.	613 FOULKSTONE ROAD, WILMINTON, DE 19803
4	RAFALSKI, MARIA	908 FAIRTHORNE AVENUE, GREENVILLE, DE 19807
5	ARVANITIS, ARGYRIOS G.	101 WILLOW GLEN DRIVE, KENNETT SQUARE, PA 19348
6	JALLURI, RAVI KUMAR	234 HONEY LOCUST DRIVE, AVONDALE, PA 19311
7	FRIDMAN JORDAN S	50 WILLOW CREEK LANE, NEWARK, DE 19711
8	ROGERS, JAMES D.	2 HILLSIDE LANE, LANDENBERG, PA 19350
9	STORACE, LOUIS	1409 BOHEMIA MILL ROAD, MIDDLETOWN, DE 19709
10	VADDI, KRISHNA	108 FOREST DRIVE, KENNETT SQUARE, PA 19348
11	SHEPARD, STACEY	3407 AVALON CT., VOORHEES, NJ 08043

PCT International Classification Number

C07D 471/04

PCT International Application Number

PCT/US2006/047369

PCT International Filing date

2006-12-12

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/859404	2006-11-16	U.S.A.
2	60/749905	2005-12-13	U.S.A.
3	60/856872	2006-11-03	U.S.A.
4	60/810231	2006-06-02	U.S.A.
5	60/850625	2006-10-10	U.S.A.