Title of Invention	HETEROCYCLIC INHIBITORS OF ERK2
Abstract	1. A compound of formula I': or a pharmaceutically acceptable salt thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and Q'R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 is N and Z2 is CH; T is a linker group selected from -NH-, -CH2- , -CO-, or a saturated or unsaturated C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -CO-, -C(O)C(O)-, -C(O)NR7-, -C(O)NR7NR7-, -CO2,-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-, -NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-; Q' is selected from -CO2-, -C(O)NR7- or -SO2NR7-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R2' is selected from -(CH2)yCH(R5)2 or -(CH2)yCH(R8)CH(R5)2; y is 0-6; R3 is selected from R7, R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2,or -(CH2)y CH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR5, or-(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6; aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and each w is independently selected from 0-4.

Title of Invention

HETEROCYCLIC INHIBITORS OF ERK2

Abstract

1. A compound of formula I': or a pharmaceutically acceptable salt thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and Q'R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 is N and Z2 is CH; T is a linker group selected from -NH-, -CH2- , -CO-, or a saturated or unsaturated C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -CO-, -C(O)C(O)-, -C(O)NR7-, -C(O)NR7NR7-, -CO2,-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-, -NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-; Q' is selected from -CO2-, -C(O)NR7- or -SO2NR7-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R2' is selected from -(CH2)yCH(R5)2 or -(CH2)yCH(R8)CH(R5)2; y is 0-6; R3 is selected from R7, R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2,or -(CH2)y CH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR5, or-(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6; aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and each w is independently selected from 0-4.

Full Text	CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to US Provisional Patent Application 60/267,818 filed February 9, 2001 and US Provisional Patent Application 60/328,768 filed October 12, 2001, the contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention is in the field of medicinal chemistry and relates to pyrazole compounds that are protein kinase inhibitors, especially inhibitors of ERK, compositions containing such compounds and methods of use. The compounds are useful for treating cancer and other diseases that are alleviated by protein kinase inhibitors. BACKGROUND OF THE INVENTION Mammalian mitogen-activated protein (MAP)1 kinases are serine/threonine kinases that mediate 5 intracellular signal transduction pathways (Cobb and Goldsmith, 1995, J Bio1. Chem., 270, 14843; Davis, 1995, Mol. Reprod. Dev. 42, 459) . Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK2 (extracellular signal 10 regulated kinase) , JNK (Jun N-terminal kinase), and p38 kinases. JNKs and p38 kinases are activated in response to the pro-inflammatory cytokines TNF-alpha and interleukin-l, and by cellular stress such as heat shock, hyperosmolarity, ultraviolet radiation, lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., 1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaud et al. 1995, J Biol. Chem. 270, 7420; Shapiro and Dinarello, 1995, Proc. Natl. Acad. Sex. USA 92, 12230). In contrast, ERKs are activated by mitogens and growth factors (Bokemeyer et al. . 1996, Kidney Int. 49, 1187) . ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thrl83 and Tyrl8 5 are phosphorylated by the upstream MAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylates many regulatory proteins, including the protein kinases Rsk90 (Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al., 1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaud et al. , 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), and c-Myc (Oliver et al. , 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2 is also a downstream target of the Ras/Raf dependent pathways (Moodie et al., 1993, Science 2 60, 1658) and may help relay the signals from these potentially oncogenic proteins. ERK2 has been shown to play a role in the negative growth control of breast cancer cells (Frey and Mulder, 1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breast cancer has been reported (Sivaraman et al., 1997, J Clin. Invest. 99, 1478). Activated ERK2 has also been implicated in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting a role for this kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589). Aurora-2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora- 2 protein has been found to be overexpressed. See Bischoff et al., EMBO J. , 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of a and p isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev. , 10, 508-514 (2000)]. GSK-3 has been implicated in various diseases including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Hag et al., J. Cell Biol. (2000) 151, 117]. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor b-catenin, the translation initiation factor elF2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development. In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)]. However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675]. Therapeutic inhibitors of GSK-3 therefore are considered to be useful for treating diabetic patients suffering from an impaired response to insulin. GSK-3 activity has also been associated with Alzheimer's disease. This disease is characterized by the well-known P-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnormal sites. GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer's disease. Another substrate of GSK-3 is (3-catenin which is degradated after phosphorylation by GSK-3. Reduced levels of ßcatenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)]. As a result of the biological importance of GSK-3, there is current interest in therapeutically effective GSK-3 inhbitors. Small molecules that inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)]. Aryl substituted pyrroles are known in the literature. In particular, tri-aryl pyrroles (US 5,837,719) have been described as having glucagon antagonist activity. 1,5-Diarylpyrazoles have been described as p38 inhibitors (WO 9958523). There is a high unmet medical need to develop new therapeutic treatments that are useful in treating the various conditions associated with ERK2 activation. For many of these conditions the currently available treatment options are inadequate. Accordingly, there is great interest in new and effective inhibitors of protein kinase, including ERK2 inhibitors, that are useful in treating various conditions associated with protein kinase activation. DESCRIPTION OF THE INVENTION It has now been found that compounds of this invention and compositions thereof are effective as protein kinase inhibitors, especially as inhibitors of ERK2. These compounds have the general formula I: or a pharmaceutically acceptable derivative thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and QR2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 and Z2 are each independently selected from N or CH; T and Q are each an independently selected linker group; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -0-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7- , -NR7SO2NR7-, or -S02-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R2 is selected from -(CH2)yR5, - (CH2) yCH (R5) 2; -(CH2)yCH(R8)CH(R5)2, -N(R4)2; or -NR4 (CH2) yN (R4) 2 ; y is 0-6; R3 is selected from R7, R, - (CH2) yCH (R8) R, CN, -(CH2)yCH(R8)CH(R5)2; or - (CH2) yCH (R8)N (R4) 2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -(CH2)yR5, or - (CH2) yCH (R5) 2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, C0N(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2) WN (R4) 2, or (CH2)WSR7; and each w is independently selected from 0-4. As used herein, the following definitions shall apply unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. The term "aliphatic" or "aliphatic group" as used herein means a straight-chain or branched C1-C12 hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. For example, suitable aliphatic groups include, but are not limited to, linear or branched or alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms. The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I. The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl). The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". [0001] The term "heterocycle", "heterocyclyl", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems having five to fourteen ring members in which one or more ring members is a heteroatom, wherein each ring in the system contains 3 to 7 ring members. [0002] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group are selected from halogen, -R°, -OR0, -SR°, 1,2-methylene-dioxy, 1,2- ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), Ph substituted with R°, -O(Ph), 0-(Ph) substituted with R°, -CH2(Ph), -CH2(Ph) substituted with R°, -CH2CH2(Ph), -CH2CH2(Ph) substituted with R°, -N02, -CN, -N(R°)2, -NR°C(O)R°, -NR°C(O)N(R°)2, -NRCCO2R°, -NR°NR°C (O) R°, -NR°NR°C(O)N(R°)2, -NR°NR°CO2R°/ -C(O)C(O)R°, -C (0) CH2C (0) R°, -CO2R°, -C(O)R°, -C(O)N(R°)2, -OC (O) N (R°) 2, -S(O)2R°, -SO2N(R°)2, -S(O)R°, -NR°SO2N(R°)2/ -NR°SO2R0, -C (=S) N (R°) 2, -C(=NH) -N(R°)2, -(CH2)yNHC(O)R°, or - (CH2)yNHC(0)CH(V-R°) (R°) , wherein each R° is independently selected from hydrogen, optionally substituted Ci-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl (Ph), -O(Ph), or -CH2(Ph)- CH2(Ph), wherein y is 0-6; and V is a linker group. Substituents on the aliphatic group of R° are selected from NH2, NH(C1.4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, 0- (C1-4 aliphatic), N02, CN, C02H, CO2(C1-4 aliphatic), -O(halo C1-4 aliphatic), or halo C1-4 aliphatic. An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: =0, =S, =NNHR, =NN(R)2, =N-, =NNHC (o) R, =NNHC02 (alkyl), =NNHS02(alkyl), or =NR, where each.R* is independently selected from hydrogen or an optionally substituted C1-6 aliphatic. Substituents on the aliphatic group of R* are selected from NH2, NH(d-4 aliphatic), N(C1.4 aliphatic)2, halogen, C1.4 aliphatic, OH, O- (C1.4 aliphatic) , No2, CN, CO2H, CO2(C1.4 aliphatic), -O(halo C1-4 aliphatic), or halo C1.4 aliphatic. Substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R+, -N(R+)2, -C(0)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR+SO2R+; wherein R+ is hydrogen, an optionally substituted C1-6 aliphatic, optionally substituted phenyl (Ph), optionally substituted -O(Ph), optionally substituted -CH2(Ph), optionally substituted -CH2CH2(Ph), or an unsubstituted 5- 6 membered heteroaryl or heterocyclic ring. Substituents on the aliphatic group or the phenyl ring of R+ are selected from NH2, NH(C1.4 aliphatic), N(d1.4 aliphatic)2/ halogen, C^ aliphatic, OH, O- (Ci_4 aliphatic) , N02/ CN, C02H, CO2(C1.4 aliphatic), -0(halo C1.4 aliphatic), or halo C1.4 aliphatic. The term "alkylidene chain" refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation. The optional substituents are as described above for an aliphatic group. The term "spacer group" refers to a group that separates and orients other parts of the molecule attached thereto, such that the compound favorably interacts with functional groups in the active site of an enzyme. As used herein, the spacer group separates and orients ring A and QR2 within the active site such that they may form favorable interactions with functional groups which exist within the active site of the ERK2 enzyme. When the spacer group is a 5-membered heteroaromatic ring, ring A and QR2 are attached at non- adjacent positions "B" and "C", and the 5-membered ring is attached to ring A at point "D" and to QR2 at point "E" as illustrated below. Preferably, the distance between "D" and "C" is 3.7A, the distance between "D" and "E" is 5.0A, the distance between "B" and "C" is 2.2A, and the distance between "B" and "E" is 3 . 5A , wherein each of the above described distances is plus/minus 0.2 A. The spacer group itself may also form additional interactions within the active site to further enhance inhibitory activity of the compounds. For example, when Sp is a pyrrole the pyrrole-NH may form an additional hydrogen bond within the active site of the ERK2 enzyme. The term "linker group" means an organic moiety that connects two parts of a compound. Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -NH-, -CH2-, -CO-, or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200. Examples of linkers include a saturated or unsaturated C1-6 alkylidene chain which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -C(0)-, -C(O)C(O)-, -CONR7-, -C0NR7NR7-, -C02-, -OC(O)-, -NR7CO2-, -O-, -NR7CONR7- , -OC(O)NR7-, -NR7NR7-, -NR7C0-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-. As used herein, linker group Q connects Sp with R2. Q may also form additional interactions within the ERK2 binding site to further enhance the inhibitory activity of the compound. When Q is a carbonyl- containing moeity such as -C(O)-, -CO2-, -OC(O)-, -C(O)C(O)-, -CONH-, -CO2NH-, -CONHNH-, -NHCO-, -OC(O)NH-, or -NHCO2-, or a sulfonyl-containing moeity such as -SO2-, -SO2NH-, or -NHSO2-, the carbonyl or sulf onyl oxygen forms a hydrogen-bond with lysine 54 in the ERK2 binding site. When Q is an NH-containing moeity such as -CH2NH- or -NHNH-, the NH-group forms a hydrogen-bond with aspartic acid residue 167 in the ERK2 binding site. When Q is a hydrophobic group such as an alkyl chain, -0-, or -S-, Q forms additional hydrophobic interactions within the ERK2 binding site. R2 forms hydrophobic interactions within the binding site of ERK2, especially with the side-chain carbons of lysine 54 and aspartic acid 167. R2 may also form hydrophobic interactions with the glycine-rich loop which is made up of amino-acid residues 33-38. When R2 is substituted, the substituents may form further interactions within the binding site to enhance the inhibitory activity of the compound. For example, when a substituent on R2 is a hydrogen-bond donor or a hydrogen- bond acceptor, said substituent forms a hydrogen bond with enzyme-bound water molecules that exist in the binding site. As used herein, linker group T, when present, connects Sp with R1. T may also form additional interactions within the ERK2 binding site to further enhance the inhibitory activity of the compound. When T is carbonyl-containing such as -CO-, -C02-, -0C0-, -COCO-, -CONH-, -CO2NH-, -CONHNH-, -NHCO-, or -NHCO2-, or sulfonyl-containing such as -SO2-, -S02NH-, or -NHSO2-, the carbonyl or sulfonyl oxygen forms a hydrogen-bond with the NH of glutamine 105 in the ERK2 binding site. When T is NH-containing such as -CH2NH- or -NHNH-, the NH- group forms a hydrogen-bond with the carbonyl of glutamine 105. When T is a hydrophobic group such as an alkyl chain, -0-, or -S-, T forms additional hydrophobic interactions with the side-chain carbons of glutamine 105 as well as isoleucine 84. The binding interactions described herein between the compounds of this invention and the ERK2 binding site have been determined by molecular modeling programs that are known to those of ordinary skill in the art. These molecular modeling programs include QUANTA [Molecular Simulations, Inc., Burlington, Mass., 1992] and SYBYL [Molecular Modeling Software, Tripos Associates, Inc., St. Louis, Mo., 1992]. As used herein, the amino acid numbering for the ERK2 enzyme corresponds to the Swiss-Prot database entry for accession #P28482. The Swiss-Prot database is an international protein sequence database distributed by the European Bioinformatics Institute (EBI) in Geneva, Switzerland. The database can be found at www.ebi.ac.uk/swissprot. The compounds of this invention are limited to those that are chemically feasible and stable. Therefore, a combination of substituents or variables in the compounds described above is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Compounds of formula I or salts. thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutically acceptable composition. In one embodiment, the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein kinase, particularly ERK- 2, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat or prevent an ERK-2-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient. The term "patient" includes human and veterinary subjects. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Another aspect of this invention relates to a method of treating or preventing an ERK-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound. The term "ERK-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which ERK-2 is known to play a role. The term "ERK -2 - mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an ERK-2 inhibitor. Such conditions include, without limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone- related diseases. The term "cancer" includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon- rectum, large intestine, rectum, brain and central nervous system, and leukemia. The present method is especially useful for treating a disease that is alleviated by the use of an inhibitor of ER.K2 or other protein kinases. Although the present compounds were designed as ERK2 inhibitors, it has been found that certain compounds of this invention also inhibit other protein kinases such as GSK3, Aurora2, Lck, CDK2, and AKT3. Another aspect of the invention relates to inhibiting ERK-2 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of inhibiting ERK-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound. The term "Aurora-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which Aurora is known to play a role. The term "Aurora-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor. Such conditions include, without limitation, cancer. The term "cancer" includes, but is not limited to the following cancers: colon, breast, stomach, and ovarian. Another aspect of the invention relates to inhibiting Aurora-2 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound. The term "GSK-3-mediated condition" or "disease", as used herein, means any disease or other deleterious condition or state in which GSK-3 is known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDS- associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, and baldness. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ßcatenin, which is useful for treating schizophrenia. Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound. Inhibition of ERK2, Aurora2, CDK2, GSK-3, Lck, or AKT3 kinase activity in a biological sample is useful for a variety of purposes which are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ- translplantation, biological specimen storage, and biological assays. -20- The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof. The amount effective to inhibit protein kinase, for example, Aurora-2 and GSK-3, is one that measurably inhibits the kinase activity where compared to the activity of the enzyme in the absence of an inhibitor. Any method may be used to determine inhibition, such as, for example, the Biological Testing Examples described below. Pharmaceutically acceptable carriers that ir.ay be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesior.al and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques"known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation -23- (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, poloxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. In addition to the compounds of this invention, pharmaceutically acceptable derivatives of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified diseases or disorders. A "pharmaceutically acceptable derivative " means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+ (C1.4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. The amount of the protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of the inhibitor will also depend upon the particular compound in the composition. The kinase inhibitors of this invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves,, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re- narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a kinase inhibitor of this invention are another embodiment of the present invention. Depending upon the particular protein kinase- mediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, in the treatment of cancer other chemotherapeutic agents or other anti-proliferative agents may be combined with the protein kinase inhibitors of this invention to treat cancer. These agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives. Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, agents for treating diabetes such as insulin or insulin analogues, in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas; anti- inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti- convulsants, ion channel blockers, riluzole, and anti- Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin. Those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor of this invention in a single composition. Compounds of this invention may exist in alternative tautomeric forms. Unless otherwise indicated, the representation of either tautomer is meant to include the other. Accordingly, the present invention relates to compounds of formula I wherein Ring A is a pyridine (II), pyrimidine (III), or triazine (IV) ring as shown below: or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, R2, UnR3, Q, and T are as described above. Examples of suitable Sp groups of formula I include pyrrole (a) , imidazole (b) , pyrazole (c) , triazole (d) , oxazole (e) , isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h) , furan (i), and thiophene (j), as shown below: wherein each of a through j is optionally substituted with R6. Preferred TmR1 groups of formula I are selected from hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1_6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula I are those listed in Table 1 below. Preferred R3 groups of formula I are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Oberizyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH (CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula I are those listed in Table 1 below. When R2 is R5, preferred R5 groups are pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl, 4-methyl [1,4]diazepan-1-yl, 4-phenyl- piperazine-1-yl, wherein each group is optionally- substituted. When R2 is (CH2)yR5, (CH2) yCH (R5) 2, or -N(R4)2, preferred R5 groups are further selected from pyridin-3- yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4- tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, -CH2OH, -(CH2)2OH, and isopropyl, wherein each group is optionally substituted. Preferred substituents on R5 are -OH, pyridyl, piperidinyl, and optionally substituted phenyl. When R2 is - (CH2)yCH(R8)CH(R5)2, preferred R8 groups are R7 and OR7 such as OH and CH2OH and preferred R5 are as described above. Preferred - (CH2) yCH (R8) CH (R5) 2 groups of formula I are -CH(OH)CH(OH)phenyl and -CH(Me)CH(OH)phenyl. Other preferred -QR2 groups are those listed in Table 1 below. Preferred compounds of formula I are those having one or more, more preferably more than one, and. most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1_4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring,- (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; (c) Q is -CO-, -C02- , -CONH-, -SO2-, -SO2NH-, -OC(O)NH-, -C(O)ONH-, or -CONHNH-; (d) R2 is -NR4(CH2)yN(R4)2, -(CH2)yR5, - (CH2) yCH (R5) 2, or - (CH2)yCH(R8)CH(R5)2; (f) R4 is R, R7, or - (CH2) yCH (R5) 2; and (g) R5 is an optionally substituted group selected from C1-6 aliphatic, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl. More preferred compounds of formula I are those having one or more, more preferably more than one, or most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3 ; (c) Q is -CO-, -CONH-, -S02-, or -SO2NH-; (d) R2 is -(CH2)yR5, - (CH2)yCH(R5)2, or - (CH2)yCH(R8)CH(R5)2, wherein RB is OH or CH2OH; and (e) R5 is -CH2OH, -(CH2)2OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4- phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4- yl, imidazolyl, furan-2-yl, 1,2,3,4- tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl. A preferred embodiment of this invention relates to compounds of formula I' : or a pharmaceutically acceptable derivative thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and Q'R2' are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 and Z2 are each independently selected from N or CH; Q' is selected from -C02-, -C(O)NR7- or -SO2NR7- ; T is a linker group; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -S02-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2/ OR, or OH; R2' is selected from - (CH2) yCH (R5) 2 or - (CH2) yCH (R8) CH (R5) 2 ; y is 0-6; R3 is selected from R7, R, - (CH2) yCH (R8) R, CN, - (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8) N (R4) 2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R -CON(R7)2; -SO2R7, -(CH2)yR5, or - (CH2) yCH (R5) 2 ; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2; OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, S02R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2) WN(R4) 2, or (CH2)WSR7; and each w is independently selected from 0-4. Examples of suitable Sp groups of formula I' include pyrrole (a), imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: wherein each of a through j is optionally substituted with R6. Accordingly, the present invention relates to compounds of formula I' wherein Ring A is a pyridine or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, Q'R2 , and UnR3 are as described above. Preferred R5 groups of formula I' are R or OR7. Examples of such groups include OH, CH2OH, carbocyclic, or optionally substituted 5 or 6-membered aryl or heteroaryl rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula I' are R and OR7, wherein R is an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl, methyl, ethyl, OH, and CH2OH. Preferred substituents on the R5 aryl or heteroaryl ring are halogen, haloalkyl, 0R°, and R°. Preferred TmR1 groups of formula I' are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring.. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula I' are those listed in Table 1 below. Preferred R3 groups of formula I' are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropy1. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH (CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula I' are those listed in Table 1 below. Preferred compounds of formula I' are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmRa is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring. More preferred compounds of formula I' are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH (CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3/ NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q' is C(O)NH. Another preferred embodiment of this invention relates to compounds of formula I": or a pharmaceutically acceptable derivative thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and C(O)NHCH[ (CH2)1-2OH]R5 are attached to Sp at non- adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 and Z2 are each independently selected from N or CH; T is a linker group; U is selected from -NR7-, -NR7C0-, -NR7CONR7-, -NR7CO2-, -0-, -CONR7-, -CO-, -CO2-, -00(0)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -S02-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R3 is selected from R7, R, - (CH2) yCH (R8) R, CN, - (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8) N (R4) 2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2' -SO2R7, -(CH2)yRs, or - (CH2)yCH (Rs) 2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2/ N(R7)2, OR7, SR7, NR7COR7, NR7C0N(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7C0N(R7)2/ CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1.6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2) WN(R4) 2, or (CH2)WSR7; and each w is independently selected from 0-4. Examples of suitable Sp groups of formula I" include pyrrole (a), imidazole (b) , pyrazole (c), triazole (d) , oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: wherein each of a through j is optionally substituted with R6. Accordingly, the present invention relates to compounds of formula I" wherein Ring A is a pyridine (II"), pyrimidine (III"), or triazine (IV") ring as shown below: or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, UnR3, and R5 are as described above. Preferred TVR1 groups of formula I" are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Examples of preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3/ CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula I" are those listed below in Table 1. Preferred R3 groups of formula I" are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropy1. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2- . More preferred UnR3 groups of formula I" are those listed in Table 1 below. Preferred R5 groups of formula I" are optionally substituted 6-membered aryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, and cyclohexyl. Preferred compounds of formula I" are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring,- (b) TmR1 is hydrogen, N{R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) Rs is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. More preferred compounds of formula I" are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring. Another preferred embodiment of this invention relates to compounds of formula I°: or a pharmaceutically acceptable derivative thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and C(O)NHCH(RB)CH(R5)2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 and Z2 are each independently selected from N or CH; T is a linker group; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -S02-; m and n are each independently selected from zer6 or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; y is 0-6; R3 is selected from R7, R, - (CH2) yCH (R8) R, CN, - (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8)N (R4) 2 ; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -(CH2)yR5, or - (CH2)yCH (Rs) 2 ; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7C0R7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted Ci_6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring,- R8 is selected from R, (CH2)WOR7, (CH2) WN (R4) 2, or (CH2)WSR7; and each w is independently selected from 0-4. Examples of suitable Sp groups of formula 1° include pyrrole (a), imidazole (b) , pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g) , 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: wherein each of a through j is optionally substituted with R6. Accordingly, the present invention relates to compounds of formula I° wherein Ring A is a pyridine (II°) , pyrimidine (III°) , or triazine (IV°) ring as shown below: or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, Rs, UnR3, and R8 are as described above. Preferred R5 groups of formula I° are R or OR7. Examples of such groups include OH, CH2OH, carbocyclic, or optionally substituted5 or 6-membered aryl or heteroaryl rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula I° are R and OR7, wherein R is an optionally'substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl,methyl, ethyl, OH, and CH2OH. Preferred substituents on the R5 aryl or heteroaryl ring are halogen, haloalkyl, OR°, and R°. Preferred TmR1 groups of formula 1° are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is cin optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. More preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. Most preferred TmR1 groups of formula I° are those listed in Table 1 below. Preferred R3 groups of formula I° are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3/ OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH (CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula I° are those listed in Table 1 below. Preferred compounds of formula I° are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from Cx.6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted5 or 6-membered aryl or heteroaryl ring. More preferred compounds of formula I° are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH)isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group,- (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) Rs is OH, CH2OH, carbocyclic, or an optionally substitutedphenyl or pyridyl ring. A preferred embodiment relates to compounds of formula III-a: or a pharmaceutically acceptable derivative thereof. Preferred TmR1 groups of formula III-a are hydrogen, N(R4)2' OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1.6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and araino. Examples of such preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3/ CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula Ill-a are those listed in Table 1 below. Preferred R3 groups of formula Ill-a are hydrogen, carbocyclyl, -CH(RB)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups are -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula Ill-a are those listed in Table 1 below. When R2 is R5, preferred R5 groups are pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl- piperazine-1-yl, wherein each group is optionally substituted. When R2 is (CH2)yR5, (CH2) yCH (R5) 2, or -N(R4)2, preferred Rs groups are pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1, 2 , 3 , 4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, -CH2OH, -(CH2)2OH, and isopropyl, wherein each group is optionally substituted. Preferred substituents on R5 are -OH, pyridyl, piperidinyl, and optionally substituted phenyl. When R2 is - (CH2) yCH (R8) CH (R5) 2, preferred R8 groups are R7 and OR7 such as OH and CH2OH. More preferred -QR2 groups are those listed in Table 1 below. Preferred compounds of formula III-a are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or' an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring,- (c) Q is -CO-, -CO2-, -CONH-, -S02-, -SO2NH-, -OC(O)NH-, -C(O)ONH-, or -CONHNH-; (d) R2 is -NR4 (CH2)yN(R4)2, -(CH2)yR5, - (CH2) yCH (Rs) 2; or -(CH2)yCH(R8)CH(R5)2; (f) R4 is R, R7, or - (CH2) yCH (R5) 2; and (g) R5 is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl. More preferred compounds of formula Ill-a are those having one or more, more preferably more than one, or most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3 ; (c) Q is -CO-, -CONH-, -S02-, or -SO2NH-; (d) R2 is -(CH2)yRs, - (CH2)yCH(Rs)2, or - (CH2)yCH(R8)CH(R5)2, wherein R8 is OH or CH2OH; and (e) R5 is -CH2OH, -(CH2)2OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4] diazepan-1-yl, 4- phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4- yl, imidazolyl, furan-2-yl, 1,2,3,4- tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl. Preferred compounds of formula III-a include those of formula III-a': Preferred TmR1 groups of formula III-a' are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, CH2NHCH3, and those listed in Table 1 below. Preferred R3 groups of formula III-a' are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring.. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 of formula III- a' are those listed in Table 1 below. Preferred compounds of formula III-a' are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from Ca.4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1.6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is an optionally substituted6-membered aryl, heteroaryl, or carbocyclic ring. More preferred compounds of formula III-a' are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring. Preferred compounds of formula III-a are further selected from those of formula III-a°: or a pharmaceutically acceptable derivative thereof. Preferred R5 groups of formula III-a° are R or OR7. Examples of such groups include OH, CH2OH, or optionally substituted6-membered aryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula III-a° are R and OR7, wherein R is an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl, methyl, ethyl, OH, and CH2OH. Preferred TmR1 groups of formula III-a° are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula III-a° are those listed in Table 1 below. Preferred R3 groups of formula III-a° are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups are -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula III-a° are those listed in Table 1 below. Preferred compounds of formula III-a° are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C^ aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, and R8 is R7 or OR7. More preferred compounds of formula III-a° are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl or benzyl group;+(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) R5 is OH, CH2OH, phenyl, pyridyl, or cyclohexyl, and R8 is methyl, ethyl, OH, or CH2OH. Preferred compounds of formula III-a are set forth in Table 1 below. More preferred compounds in Table 1 are those of formula III-a' or III-a°. A Compound names for the compounds of formula III-a shown above in Table 1 are set forth in Appendix A. The above formula III-a compounds are those wherein Ring A is a pyrimidine ring and Sp is a pyrrole ring. Inhibitors of formula I wherein Ring A is a pyridine, pyrimidine, or triazine ring having the other Sp rings shown above are otherwise structurally similar to the formula III-a compounds and are represented by the following general formulae Il-b through II-j, Ill-b through III-j, and IV-b through IV-j shown below in Table 2 : compound shown above in Table 2 and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a method of treating or preventing an ERK2-mediated 5 disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of inhibiting ERK2 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable comprising said compound. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable comprising said compound. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof,, which method comprises administering to the patient a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable j composition comprising said compound. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of (3-catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. Another method relates to inhibiting ERK2, Aurora-2, or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound shown above in Table 2, or a pharmaceutically acceptable composition thereof, in an amount effective to inhibit ERK2, Aurora-2, or GSK-3. Each of the aforementioned methods directed to the inhibition of ERK2, Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound shown above in Table 2, as described above. The present compounds may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I through XII and the synthetic examples shown below. Reagents and conditions: (a) TmR1CH2COCl, A1C13/ CH2C12, 2 hours, RT; (b) DMF, 24 hrs, room temperature; (c) (Me2N)2- CHOt-Bu, THF, 24 hrs, room temperature; (d) guanidine, EtOH, 12 hours, reflux; (e) thiourea, EtOH, K2CO3, 12 hrs reflux; (f) m-CPBA, EtOH; (g) UnR3-NH2, DMSO, 130"C. Scheme I above shows a general synthetic route that is used for preparing the pyrrol-3-yl compounds of formula III-a of this invention when R2 is an optionally substituted phenyl group or aliphatic group. In step (a), an optionally substituted acid chloride is combined with compound 1, dichloromethane, and aluminum trichloride to form compound 2. In cases where benzoyl acid chlorides are used, a wide variety of substituents on the phenyl ring are amenable to this reaction. Aliphatic acid chlorides are also used in many cases. Examples of suitable R2 groups include, but are not limited to, those set forth in Table 1 above. The formation of amide 4 is achieved by- treating compound 2 with an amine 3 in DMF. When atnine 3 5 is a primary amine, the reaction proceeds at ambient temperature. When amine 3_ is a. secondary amine, the reaction is heated at 50°C to achieve complete reaction and afford amide 4. The formation of enamine 5 at step (c) is ) achieved by treating amide 4 with (Me2N)2-CHOt-Bu at ambient temperature. Alternatively, the reaction to form enamine 5 at step (c) is also achieved by using dimethylformamide-dimethylacetal (DMF-DMA). The reaction using DMF-DMA typically requires elevated temperature to afford enamine 5 whereas using (Me2N)2-OtBu has the advantage of proceeding at ambient temperature to afford the enamine 5 in higher purity. The formation of the pyrimidine compound 6 at step (d) is achieved by the treatment of enamine 5 with guanidine at elevated temperature. Alternatively, use of a substituted guanidine results in an amino substituent as is illustrated by J3. As an alternative method, in step (e) intermediate _5 may be cyclized with S-methyl thiourea to form the 2-thiomethylpyrimidine 7 which may in turn be oxidized with m-CPBA to the sulfone. The sulfonyl group may be subsequently displaced by an amine to generate the substituted aminopyrimidine 8. The compounds of formula III-a synthesized by this method, as exemplified in Table 1, were isolated by preparatory HPLC (reverse phase, 10—>90% MeCN in water over 15 minutes). The details of the conditions used for producing these compounds are set forth in the Examples. Reagents and conditions: (a) K2CO3, DMA, 100°C. Scheme II above shows a general method for preparing compounds 8 from intermediate 5 and an N- substituted guanidine (9) . Intermediate 5 may be prepared according to Scheme I steps (a), (b), and (c) shown above. Compound 5 is treated with N-substituted guanidine (9) and potassium carbonate in dimethylacetamide to form compound 8. This reaction is amenable to a variety of N-substituted guanidines to form compounds of formula III-a. The details of the conditions used for producing these compounds are set forth in the Examples. Reagents and conditions: (a) A1C13 neat, RT; (b) DMF, 24 hrs, room temperature; (c) polyphosphoric acid, 1 hour, 25-140°C; (d) POClj, DMF, reflux; (e) NH2-UnR3, iPrOH, reflux. Scheme III above shows a general synthetic route that may be used for preparing the pyrrol-3-yl compounds of formula Il-a of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) MeOH, pyridine, Cl2; guanidine; (c) bromine, acetic acid; (d) NaCN, DMF; (e) £, polyphosphoric acid, 1 hour, 25-140°C; (f) POCI3, DMF, reflux; (g) NH2-UnR3, iPrOH, reflux,- (h) SeO2; (i) MeNH. Scheme IV above shows a general synthetic route that may be used for preparing the imidazol-4-yl compounds of formula Il-b of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (e) , (f), and (g) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) MeOH, pyridine, Cl2; (b) 3-, (c) bromine, acetic acid; (d) NaCN, DMF; (e) 6, polyphosphoric acid, 1 hour, 25-140°C; (f) POC13, DMF, reflux; (g) NH2-UnR3, iPrOH, reflux. Scheme V above shows a general synthetic route that may be used for preparing the imidazol-2-yl compounds of formula II-b' of this invention. The conversion of intermediate 5_ to product £ may be achieved through steps (e) , (f) , and (g) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) (b) 3; (c) 5 polyphosphoric acid, 1 hour, 25-140°C; (d) POC13, DMF, reflux; (e) NH2- UnR3, iPrOH, reflux; (f) ceric ammonium nitrate. Scheme VI above shows a general synthetic route that may be used for preparing the pyrazol-3-yl compounds of formula II-c of this invention. The conversion of intermediate 4 to product 7 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) 1,1'-carbonyldiimidazole (CDI), triethylamine, THF; (b) N-butyllithium, THF, -78°C; (c) 6, polyphosphoric acid, 1 hour, 25-140°C; (d) POC13, DMF, reflux; (e) NH2-UnR3, iPrOH, reflux. Scheme VII above shows a general synthetic route that may be used for preparing the oxazol-2-yl compounds of formula II-e' of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. -78°C (b) t-butyllithium, THF, -78°C (c) 6, polyphosphoric acid, 1 hour, 25-140°C (d) POC13, DMF, reflux (e) NH2-R, iPrOH, reflux. 5 Scheme VIII above shows a general synthetic route that may be used for preparing the thiazol-2-yl compounds of formula II-g' of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d) , and (e) according to the method I described in JACS, 1957, pp 79. Reagents and conditions: (a) N-butyllithium, Bu3SnCl ; (b) t-butyllithium, THF, -78°C; (c) MeOCO2Me; (d) 4, Pd(0); (e) 6, polyphosphoric acid, 1 hour, 25-140°C; (f) POC13, DMF, reflux; (g) NH2-UnR3, iPrOH, reflux. Scheme IX above shows a general synthetic route that may be used for preparing the thiazol-4-yl compounds of formula II-g of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (e), (f), and (g) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) CH3OCH2CH2COC1, AlCl3, CH2Cl2, 2.5 hours, RT; (b) DMF, 24 hrs, room temperature; (c) (Me2N)2-CHOt-Bu, THF, 24 hrs, room temperature,- (d) N- substituted guanidine, EtOH, 12 hours, reflux; (e) BBr3, CH2C12, Na2CO3. Scheme X above shows a general synthetic route that is used for preparing compounds of formula III-a where TmR1 is methoxymethyl or hydroxymethyl. In step (a), 3-methoxypropionyl chloride is combined with compound JL, dichloromethane, and aluminum trichloride to form compound .2. The formation of amide £ is achieved by treating compound 2^ with an araine J3 in DMF. When amine 2 is a primary amine, the reaction proceeds at ambient temperature. When amine _3 was a secondary amine, the reaction is heated at 50°C to achieve complete reaction and afford amide 4. The formation of enamine _5 at step (c) is achieved by treating amide 4 with (Me2N) 2-CHOt-Bu at ambient temperature. The formation of the pyrimidine compound 6 at step (d) is achieved by the treatment of enamine 5 with a guanidine at elevated temperature. Alternatively, use of a substituted guanidine results in an amino substituent. To form compounds where lk,TmR1 is hydroxymethyl, intermediate 6 may be treated with BBr3 in dichloromethane to form compounds 7. One of skill in the art would recognize that the hydroxymethyl group of compound 7 could be further derivatized to form a variety of compounds of formula III-a. The details of the conditions used for producing these compounds are set forth in the Examples. Reagents and conditions: (a) RNH2, MeCN, 0 C to 25 C, 12 hours; (b) A1C13, CH2Cl2, 25°C; (c) MeOH:H2O (2:1), 37'C. Scheme XI above shows a general method for preparing the triazine compounds of formula IV-a. Step (a) is performed in the manner described at Scheme I, step (b) above. Step (b) is performed in the manner described at Scheme I, step (a) above. The formation of the triazine ring at step (c) may be performed according to the methods described by Hirsch, J.; Petrakova, E.; Feather, M. S.; J Carbohydr Chem [JCACDM] 1995, 14 (8), 1179-1186. Alternatively, step (c) may be performed according to the methods described by Siddiqui, A. U. ; Satyanarayana, Y.; Rao, U. M. ; Siddiqui, A. H.; J Chem Res, Synop [JRPSDC] 1995 (2), 43. formula I', In I°, III-a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I', I", 1°, III- a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I', I", 1°, III-a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I', I", ID, III- a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I', I", 1°, III-a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ßcatenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula I', I", 1°, Ill-a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I', I", 1°, III- a, Ill-a' , or III-a°, or a pharmaceutically-acceptable composition comprising said compound. The term "CDK-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which CDK-2 is known to play a role. The term "CDK-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor. Such conditions include, without limitation, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M. and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, S., Wang, C, Wu, K. , Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett, M.D., Current Opinion in Oncologic, Endocrine & Metabolic Invescigational Drugs, 2, 40-59 (2000). Another aspect of this invention relates to a method of treating or preventing a Lck-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I', I", l°, lil-a, Ill-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. The terms "Lck-mediated disease" or '"Lck- mediated condition", as used herein, mean any disease state or other deleterious condition in which Lck is known to play a role. The terms "Lck-mediated disease" or "Lck-mediated condition" also mean those diseases or conditions that are alleviated by treatment with an Lck inhibitor. Lck-mediated diseases or conditions include, but are not limited to, autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, and leukemia. The association of Lck with various diseases has been described [Molina et al., Nature, 357, 161 (1992)] . Another aspect of this invention relates to a method of treating or preventing an AKT3-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I', I", 1°, III- a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. The terms "AKT3-mediated disease" or "AKT3- mediated condition", as used herein, mean any disease state or other deleterious condition in which AKT3 is known to play a role. The terms "AKT3-mediated disease" or "AKT3-mediated condition" also mean those diseases or conditions that are alleviated by treatment with an AKT inhibitor. AKT3-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of AKT3 with various diseases has been described [Zang, Q. Y., et al, Oncogene, 19 (2000)] and [Kazuhiko, n., et al, The Journal of Neuroscience, 20 (2000)]. Another method relates to inhibiting ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I', I", 1°, Ill-a, III-a', or III-a°, , or a pharmaceutically acceptable composition comprising said compound, in an amount effective to inhibit ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3. Each of the aforementioned methods directed to the inhibition of ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula I', I", 1°, III-a, III-a', or III-a°, as described above. More preferably, each of the aforementioned methods is carried out with a preferred compound of formula I', I", 1°, III-a', or III-a°, and most preferably with a compound of formula I", 1°, III-a', or Ill-a°. In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. SYNTHETIC EXAMPLES For compounds where the HPLC Method is designated as "A", the following method was utilized: a gradient of water:MeCN, 0.1% TFA (95:5 -» 0:100) was run over 22 minutes at 1 mL/min and 214 nm. For compounds where the HPLC Method is designated as "B", the following method was utilized: a gradient of water.-MeCN, 0.1% TFA (90:10 -> 0:100) was run over 8 minutes at 1 mL/min arid 214 nm. Each of methods A and B utilize the YMC ODS-AQ 55 120A column with a size of 3.0 x 150 mm. As used herein, the term "Rt" refers to the retention time, in minutes, associated with the compound using the designated HPLC method. 2, 2, 2-Trichloro-l- (4-phenyl acetyl-lH-pyrrol-2-yl) - ethanone (1) ¦. In a dry flask, phenylacetyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM) to dissolve the reactants. To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 1 in 60% yield. XH NMR (CDC13) 6 4.0 (s, 2H), 7.1-7.35 (m, 7H), 9.7 (br s, NH). HPLC using method B provided Rt of 4.9 minutes. LC/MS (M+l) 330.2, (M-l) 328.1. 2,2,2-Trichloro-l-(4-(3-Chlorophenyl) acetyl-lH-pyrrol-2- yl)-ethanone (2J .- In a dry flask, 3-chlorophenylacetyl chloride (1 equivalent) was combined with 2- trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 2 . HPLC using method A provided Rt of 15 minutes 1- [5- (2,2,2-Trichloro-acetyl) -lH-pyrrol-3-yl) -propan-1- one (2> : In a dry flask, 3-proprionyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM) . To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 3 4-Phenylacetyl-lff-pyrrole-2-carboxylic acid benzylamide (•4) : To a solution of compound 1 (1 equivalent) in DMF, at ambient temperature, was added benzylamine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 4 was used without purification. HPLC using method B provided Rt of 3.8 minutes. FIA/MS (M+l) 319.3, (M-l) 317.2. 2-(3-Chlorophenyl)l-[5-(morpholine-4-carbonyl)-lH-pyrrol- 3-yl] -ethanone (E) : To a solution of compound 2(1 equivalent) in DMF, at ambient temperature, was added morpholine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 5 was used without purification. FIA/MS (M+l) 333.3, (M-l) 331.2. 1H NMR was consistent with expected structure. . 4-Propionyl-lH-pyrrole-2-carboxylic acid 3,4-difluoro- benzylamide (_6) : To a solution of compound 3_ U equivalent) in DMF, at ambient temperature, was added 3,4-difluorobenzyl amine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 6 was used without purification. 4- (3-Dimethylamino-2-phenyl-acryloyl) -lIf-pyrrole-2- carboxylic acid benzylamide (!) ¦. To a solution of compound 4_ (1 equivalent) in THF, at ambient temperature, was added (Me2N) 2CHOt-Bu (3 equivalents). After 24 hours, the solvent was evaporated and the crude product 1_ was used without purification. XH NMR (CDC13) 5 4.4 (s, 2H.) , 4.8 (s, NH), 6.8-7.4 (m, 13H). 2-(3-Chloro-phenyl)-3-dimethylamino-l-[5-(morpholine-4- carbonyl)-lH-pyrrol-3-yl]-propenone (J3) : To a solution of compound j> (1 equivalent) in THF, at ambient temperature, was added (Me2N) 2CHOt-Bu (3 equivalents) . After 24 hours, the solvent was evaporated and the crude product 8_ was used without purification. HPLC using method B provided Rt of 11.2 minutes. 4- (2-Amino-5-inethyl-pyriinidin-4-yl) -Iff-pyrrole-2- carboxylic acid 3 , 4-difluoro-benzylamide (III-a-74) : Step 1: To a solution of compound 6_ (1 equivalent) in THF, at ambient temperature, was added (Me2N) 2CHOt-Bu (3 equivalents). After 24 hours, the solvent was evaporated and the crude product was utilized without purification. Step 2: To a solution of the compound formed above at Step 1 (1 equivalent) in ethanol, at ambient temperature, was added guanidine (3 equivalents) and the resulting mixture heated at reflux. After 12 hours, the solvent was evaporated and the crude product purified by- preparatory HPLC (reverse phase; 10—>90% MeCN in water; 15 minutes) to afford the desired compound III-a-74. HPLC using method B provided Rt of 7.9 minutes. 1H NMR was consistent with expected structure. FIA/MS Obs. M+l /M- 1. {4- [2-Amino-5- (3-chlorophenyl) -pyrimidine-4-yl] -1H- pyrrol-2-yl}-morpholin-4-yl-methanone (III-a-72): To a solution of compound 8_ (1 equivalent) in ethanol, at ambient temperature, was added guanidine (3 equivalents) and the resulting mixture heated at reflux. After 12 hours, the solvent was evaporated and the crude product purified by preparatory HPLC (reverse phase; 10—>90% MeCN in water; 15 minutes) to afford the desired compound III- a-72. HPLC using method B, Rt=7.9 minutes. 1H NMR was consistent with expected structure. FIA/MS Obs. (M+l) 384.4 amu. N- (2-Hydroxy-l- (3) -phenyl-ethyl) -guanidine»HCl.- (5) - Phenylglycinol (0.38g, 2.7 mmol) and bis-Boc guanidine (AT)-triflate (0.9g, 2.3 mmol) were combined in methyle chloride (anhydrous, 5mL) and stirred at ambient temperature overnight. Completion of the reaction was verified by HPLC. The mixture was diluted with ethyl acetate, washed with 2M sodium bisulfite, brine then dried over MgSO4, filtered and concentrated in vacuo. The bis-Boc guanidine intermediate was treated with 4N HCl/dioxane (5raL) and stirred at room temperature unti] deprotection was complete (48 h) to afford the title compound.. 4- [2- (2-Hydroxy-l- (S) -phenyl-ethylamino) -5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy- 1-(S)-phenyl-ethyl)-amide (III-a-155): 4-(3- Dimethylamino-2-methyl-acryloyl) - 1H~pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide {100 mg, 0.29 mmol) was combined with N-(S)-phenylglycinol guanidine»HCl (126 mg) and potassium carbonate (121 mg) in N,N- dimethylacetamide (2mL). The resulting suspension was heated and stirred at 100° C for 24 hours. The crude material was diluted with ethyl acetate, washed with saturated NaHC03, brine, dried over MgSO4 and concentrated in vacuo. Purification by prep HPLC (Gilson: Column = CombiHT SB-C189 5 [iM 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) followed by preparative TLC (silica, 5% MeOH in CH2C12) afforded compound III-a-155 as a pale yellow solid (8.0 mg). HPLC Method B, Rc=4.76 minutes; MS (FIA) 458.2 (M+l), 456.1 (M-l); XH NMR consistent with structure. 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -phenyl-ethyl)- amide (III-a-162): 4-(3-Dimethylamino-2-methyl-acryloyl)- l#-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)- amide (100 mg, 0.29 mtnol) was combined with cyclopropyl guanidine»HCl (80 mg) and potassium carbonate (121 mg) in N,N-dimethylacetamide (2mL). The resulting suspension was heated and stirred at 100°C for 24 hours. The crude material was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgSO4 then concentrated in vacuo. Purification by preparative TLC (silica, 1:1 EtOAc.-Hexanes) afforded III-a-162 as a yellow solid (7.8 mg). HPLC Method B, Rt=4.29 minutes; LC/MS(m/z) 378.2 (M+l), 376.2 (M-l); JH NMR consistent with structure. 3-Methoxy-l-[5-(2, 2 , 2-trichloro-acetyl)-lH-pyrrol-3-yl]- propan-1-one: To a solution of 2-trichloroacetyl pyrrole 4- (3-Methoxy-propionyl) -lff-pyrrole-2-carboxylic acid (2- hydroxy-1- (S) -phenyl-ethyl) -amide: To a solution of 3- methoxy-1- [5- (2,2, 2-trichloro-acetyl) - 1H-pyrrol-3 -yl] - propan-1-one (3.0 g, 10 ramol) in acetonitrile (50 mL) , cooled to 0°C, was added (S)-( + )-phenyl glycinol (1.2 equivalent, 1.65 g, 12 mmol) and the resulting mixture stirred for 3 days at room temperature. The solvent was removed under reduced pressure and the residue purified by chromatography on silica gel (MeOH 5% in DCM) to afford 5.3 g of the title compound as a white solid. HPLC Method B, Rt=4.2 minutes; LC/MS(m/z) 317.03 (M+l), 315.00 (M-l) ; 1H NMR consistent with structure. (1.0 equivalent, 4.67g, 22 mmol) in methylene chloride (5 mL) was added 3-methoxypropionyl chloride (1.0 equivalent, 22 mmol) then aluminium trichloride (1.0 equivalent, 2.93g, 22 mmol) was added in small portions. After 2.5 hours, the crude mixture was chromatographed on silica gel (MeOH 2% in DCM) to afford 3.0 g of the Friedel-Craft product. 1H NMR consistent with structure. 4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -lff-pyrrole- 2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide: 4-(3-Methoxy-propionyl)-l.H-pyrrole-2-carboxylic acid (2- hydroxy-1-(S)-phenyl-ethyl)-amide was treated with an excess of Bredereck's reagent in THF at room temperature to 50°C for 3 days. The solvent was removed under reduced pressure and the concentrate was used directly in the next step. HPLC Method B, Rt=5.0 minutes "broad peak". 4- (5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)- amide (III-a-164): 4-(3-Dimethylamino-2-methoxymethyl- acryloyl)-l#-pyrrole-2-carboxylic acid (2-hydroxy-l- (S)- phenyl-ethyl)-amide (0.27 mmol) was combined with phenyl guanidine (73 mg) in N,N-dimethylacetamide (2 mL) and the resulting suspension was heated at 90°C for 35 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgS04 and concentrated in vacuo. The crude product was purified by prep HPLC (Gilson: Column = CombiHT SB-C189 5 p.M, 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) to afford III-a-164 as a yellow solid (3.2 mg). LC/MS(m/z) 444.16 (M+l), 442.19 (M-l); HPLC Method B, Rt=5.16 minutes: 1H NMR consistent with structure. 4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)- amide (III-a-165): To a solution of III-a-164 (15 mg, 0.03 mmol) in dichloromethane (2 mL), cooled to -78°C, was added BBr3 (135 \|IL, 0.13 mmol) . After 15 minutes the reaction was allowed to warm to room temperature. After 45 minutes, the reaction was quenched with a saturated solution of sodium carbonate and the resulting mixture was stirred for an additionnal 3 0 minutes before extraction with ethyl acetate. The organic layers were combined and washed with brine then dried over sodium sulfate. The crude mixture was purified by prep TLC (silica, 7% MeOH in CH2Cl2) to afford III-a-165 as a beige solid (1.6 mg) . HPLC Method B, Rt=4.54 minutes; LC/MS (m/z) 430.15 (M+l), 428.03 (M-l); ^ NMR consistent with structure. 4- (2-Amino-5-methoxymethyl-pyrimidin-4-yl) -l.ff-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide (Ill-a- 161): The enamine formed above at Example 16 (0.27 mmol) was combined with guanidine»HCl (51 mg), and K2CO3 (100 mg) in N,N-dimethylacetamide (4 mL). The heterogenous mixture was heated and stirred at 90° C for 3 5 h. The crude material was diluted with ethyl acetate, washed with saturatedd NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. Purification by prep HPLC (Gilson: Column = CombiHT SB-C189 5 fiM, 21.2 mm x 100 mm, eluent = 0.l%TFA MeCN/H2O gradient) afforded III-a-161 as a yellow solid (2.0 mg). LC/MS(m/z) 368.12 (M+l), 366.15 (M-l), Rt (HPLC) =-3.77 min, XH NMR consistent with structure. 4- (2-Mercapto-5-methyl-pyrimidin-4-yl)-Iff-pyrrole-2- carboxylic acid (2-hydroxy-l-(5)-phenyl-ethyl)-amide: 4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -Iff-pyrrol e- 2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide (17.6 mmol, 6.0 g) was combined with thiourea (39 mmol, 3.0 g) and potassium carbonate (53 mmol, 7.3 g) in ethanol (50 mL) and the resulting suspension was heated at 90° C for 24 hrs. The solvent was removed in vacuo and the resulting black solid was diluted with water and the solid was removed by filtration. The solid was washed with ethyl acetate twice and the aqueous solution was acidified to pH 5-6 with HC1(2N). The solid formed was removed by filtration and the aqueous solution was then extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under vacuum to afford the title compound as a brown solid (3.0 g, 48% yield). HPLC Method B, Rt=3 .7 minutes, 1H NMR consistent with structure. 4- (5-Methyl-2-propylsulfanyl-pyrimidin-4-yl) -1H-pyrrole- 2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide: To a solution of 4-(2-mercapto-5-methyl-pyrimidin-4-yl) - lH-pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl- ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueous ammonia (15%) was added at room temperature n-propyliodide (11.6 mmol, 1.1 mL). The solution was stirred overnight at room temperature. The resulting solid was collected by filtration and used directly for the next step. 1H NMR consistent with the structure. 4- [5-Methyl-2- (propane-1-sulfonyl)-pyrimidin-4-yl]~1H- pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -phenyl-ethyl)- amide: The thiopropyl compound (7.7 mmol, 3.05g) prepared at Example 21 above was dissolved in 120 mL of ethanol. To this solution, maintained at room temperature, was added m-CPBA (70% w/w%, 23.1 mmol, 4.0 g). The solution was stirred for an additional 4 hours at room temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate, then washed 4 times with a solution of sodium hydroxide (IN) . The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid (1.7g, 51% yield for 2 steps). HPLC Method B, Rc=5.4 minutes. 1H NMR consistent with the structure. 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide: To a solution of 4-[5-methyl-2-(propane-1-sulfonyl)-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-(S) - phenyl-ethyl)-amide (47 p.mol, 20 mg) in DMSO (1 mL) was added ethylamine (0.5 mmol, 150 \|xL) . The mixture was heated at 130°C for 24 hours to afford the title compound. LC/MS(m/z) 366.2 (M+l); HPLC Method B, Rt=4.2 minutes; 1H NMR consistent with the structure. 4- [2-{N' ,N' -Dimethyl-hydrazino)-5-methyl-pyrimidin-4-yl]- lff-pyrrole-2-carboxylic acid (2-hydroxy-l- (5)-phenyl- ethyl)-amide (III-a-226): To a solution of 4-(3- dimethylamino-2-methoxymethyl-acryloyl)-ltf-pyrrole-2- carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide (0.15 mmol, 50 mg) in DMA (2 mL) was added dimethyl-N,N- aminoguanidine»2HCl (0.17 mmol, 30 mg) and potassium carbonate (0.36 mmol, 50 mg). The reaction mixture was stirred for 48 hrs at 100°C. The solvent was removed by hi-vacuum "GeneVac" and the residue purified by preparative HPLC (Gilson: Column = CombiHT SB-C189 5 J^M 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) followed by preparative TLC (silica, 5% MeOH in CH2C12) "double elutions" afforded compound III-a-226 as a pale yellow solid (1.3 mg). HPLC Method B, Rt=4.03 min.; LC/MS (m/z) 381.1 (M+l), 379.1 (M-l); 2H NMR consistent with structure. Ethanolguanidine: Ethanolamine hydrochloride (2 00 mg, 2 mmol) was added to a mixture of N, N'-di-boc -N'- triflylguanidine (8 00 mg, 2 mmol) and TEA (0.28 mL, 2 mmol) in dichloromethane (10 mL). The mixture was stirred overnight then diluted with EtOAc, washed with sodium bisulfate (2M), saturated sodium bicarbonate, dried over NaS04 and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 20% CH2Cl2/hexane to afford a white solid (0.56 g, 92%). ). 2H NMR (CDC13) : 5 4.18 (q, 2H) , 1.60 (d, 18H), 1.37 (t, 3H). To this bis-Boc guanidine was added 4M HCl/dioxane (5 mL). The mixture was stirred for 24 h and then concentrated to afford the title compound (0.26 g) . H NMR (MeOD) : 5 3.92 (q, 2H), 1.27 (t, 3H) . MS (M+l) 104. 4-(2-Ethanolamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-(s)-phenyl-ethyl)-amide (III-a-195): To a mixture of 4-(3-dimethylamino-2-methyl- acryloyl)-lH-pyrrole-2-carboxylic acid (2-hydroxymethyl- 1- (S) -phenyl-ethyl) amide (0.1 mmol) and K2CO3 (55 mg, 0.4 mmol) in DMF (1 mL) was added ethanolguanidine hydrogen chloride (0.2 mmol). The resulting suspension was stirred for 6 hours at 90 °C. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude residue was purified by preparative HPLC (Gilson: Column = CombiHT SB-C189 5 JIM 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) to afford compound III-a-195 as yellow oil (21 mg). HPLC (method B) Rt = 4.08 min; MS (M+l) 382.1. Ethyl carbamate guanidine: Ethylcarbazate (208 mg, 2 mmol) was added to a solution of N'N'-di-boc N'- triflylguanidine (800 mg, 2 mmol) in dichloromethane (10 mL). The mixture was stirred for overnight then diluted with EtOAc, washed with sodium bisulfat (2M), saturated sodium bicarbonate, dried over anhydrous NaSO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 3 0% EtOAc/hexane to afford a white solid (0.55g). To this bis-boc guanidine was added 4M HCl/Dioxane (5 mL). The mixture was stirred for 24 hours and then concentrated to afford the title compound. 1H NMR (MeOD) : 5 3.4.18 (d, 2H) , 3.26 (s, 1H), 1.28 (t, 3H). MS (M+l) 134. III-a-218 4-(2-Ethyl carbamate-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-(s)-phenyl-ethyl)-amide (III-a-218): To a mixture of 4-(3-dimethylamino-2-methyl- acryloyl)-lH-pyrrole-2-carboxylic acid (2-hydroxymethyl- 1-(S)-phenyl-ethyl) amide (0.1 mmol) and K2CO3 (55 mg, 0.4 mmol) in DMF (1 mL) was added ethyl carbamate guanidine hydrogen chloride (0.2 mmol). The resulting suspension was stirred for 6 hours at 90 °C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC (Gilson: Column = CombiHT SB-C189 5 \|iM 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) to afford compound III-a-218 as a yellow oil (10 mg). HPLC (method B) Rt = 4.03/ MS (M+l) 425.1. ^NMR (MeOD) 8.08 (s, 1H); 7.87 (s, 1H) ; 7.7 (s, 1H) , 7.24-7.5 (m, 5H) ; 5.15 (t, 1H) , 4.2 (m, 2H), 3.85 (m, 2H); 2.5 (s, 3H). Example 2 9 We have prepared other compounds of formula III-a by methods substantially similar to those described in the above Examples 1-28 and those illustrated in Schemes I-XII. The characterization data for these compounds is summarized in Table 3 below and includes LC/MS, HPLC, and 1H NMR data. Where applicable, 1H NMR data is summarized in Table 3 below wherein "Y" designates 1H NMR data is 5 available and was found to be consistant with structure. Compound numbers correspond to the compound numbers listed in Table 1. BIOLOGICAL TESTING The activity of the present compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylatiori activity or ATPase activity of the activated protein kinase. Alternate in vitro assays guantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands. The details of the conditions used for performing these assays are set forth in Examples 3 0 through 37. Example 3 0 ERK INHIBITION ASSAY Compounds were assayed for the inhibition of ERK2 by a spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK2 (10 nM) was incubated with various concentrations of the compound in DMSO (2.5 %) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.5, containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 uM NADH, 150 ug/mL pyruvate kinase, 50 ug/mL lactate dehydrogenase, and 200 uM erktide peptide. The reaction was initiated by the addition of 65 uM ATP. The rate of decrease of absorbance at 34 0 nM was monitored. The IC50 was evaluated from the rate data as a function of inhibitor concentration. Table 4 shows the results of the activity of selected compounds of this invention in the ERK2 inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as "A" provided a percent inhibition less than or equal to 33%; compounds having an activity designated as "B" provided a percent inhibition of between 24% and 66%; and compounds having an activity designated as "C" provided a provided a percent inhibition of between 67% and 100%. Compounds having an activity designated as "D" provided a Xi of less than 0.1 micromolar; compounds having an activity designated as "E" provided a Kj. of between 0.1 and 1.0 micromolar; and compounds having an activity designated as "F" provided a Ki of greater than 1.0 micromolar. Example 31 ERK2 INHIBITION: Cell Proliferation Assay Compounds may be assayed for the inhibition of ERK2 by a cell proliferation assay. In this assay, a complete media is prepared by adding 10% fetal bovine serum and penicillin/streptomycin solution to RPMI 1640 medium (JRH Biosciences). Colon cancer cells (HT-29 cell line) are added to each of 84 wells of a 96 well plate at a seeding density of 10,000 cells/well/150 µL- The cells are allowed to attach to the plate by incubating at 37°C for 2 hours. A solution of test compound is prepared in complete media by serial dilution to obtain the following concentrations: 20 (µM, 6.7 \|J.M, 2.2 (µM, 0.74 (J.M, 0.25 µM, and 0.08 µM. The test compound solution (50 \|iL) is added to each of 72 cell-containing wells. To the 12 remaining cell-containing wells, only complete media (200 µL.) is added to form a control group in order to measure maximal proliferation. To the remaining 12 empty wells, complete media is added to form a vehicle control group in order to measure background. The plates are incubated at 3 7°C for 3 days. A stock solution of 3H-thymidine (1 mCi/mL, New England Nuclear, Boston, MA) is diluted to 20 µCi/mL in RPMI medium then 20 µL of this solution is added to each well. The plates are further incubated at 37°C for 8 hours then harvested and analyzed for 3H-thyraidine uptake using a liquid scintillation counter. Compounds III-a-116, III-a-139, and III-a-136 were each shown to have an IC50 of less than 0.1 µM. Example 32 ERK1 INHIBITION ASSAY Compounds were assayed for the inhibition of ERK1 by a spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK1 (20 nM) was incubated with various concentrations of the compound in DMSO (2.0 %) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.6, containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 uM NADH, 30 ug/mL pyruvate kinase, 10 µg/mL lactate dehydrogenase, and 150 uM erktide peptide. The reaction was initiated by the addition of 140 uM ATP (20 uL) . The rate of decrease of absorbance at 34 0 nM was monitored. The Kj was evaluated from the rate data as a function of inhibitor concentration. Examples of compounds that were found to inhibit ERK1 with an activity of less than 0.1 uM include III-a-202, III-a-204, and III-a-205. Example 33 GSK-3 INHIBITION ASSAY Compounds were screened for their ability to inhibit GSK-3[3 (AA 1-420) activity using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 3 00 uM NADH, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 2 0 uM ATP (Sigma Chemicals, St Louis, MO) and 300 uM peptide (HSSPHQS(PO3H2)EDEEE, American Peptide, Sunnyvale, CA) . Reactions were carried out at 3 0 °C and 2 0 nM GSK-3J3. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 3 00 µM NADH, 3 0 ug/ml pyruvate kinase and 10 ug/ml lactate dehydrogenase. An assay stock buffer solution was prepared containing all of the reagents listed above with the exception of ATP and the test compound of interest. The assay stock buffer solution (175 µi) was incubated in a 96 well plate with 5 ul of the test compound of interest at final concentrations spanning 0.002 uM to 30 uM at 30 °C for 10 min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds in daughter plates. The reaction was initiated by the addition of 20 ul of ATP (final concentration 20 uM). Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at 3 0°C. The Ki values were determined from the rate data as a function of inhibitor concentration. Table 5 shows the results of the activity of selected compounds of this invention in the GSK3 inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as "A" provided a Ki of less than 0.1 micromolar; compounds having an activity designated as "B" provided a Ki of between 0.1 and 1.0 micromolar; and compounds having an activity designated as "C" provided a Ki of greater than 1.0 micromolar. Example 3 4 AURORA-2 INHIBITION ASSAY Compounds were screened in the following manner for their ability to inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 3 0 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 4 0 mM ATP, and 800 uM peptide (LRRASLG, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 uM. The resulting mixture was incubated at 3 0 °C for 10 min. The reaction was initiated by the addition of 10 uL of Aurora-2 stock solution to give a final concentration of 70 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 34 0 ran over a 5 minute read time at 3 0 °C using a BioRad Ultramark plate reader (Hercules, CA) . The Ki values were determined from the rate data as a function of inhibitor concentration. Examples of compounds that were found to inhibit Aurora-2 include III-a-116,- III-a-117, III-a-136, III-a-138, III- a-139, IIl-a-140, and III-a-141. Example 3 5 CDK-2 INHIBITION ASSAY Compounds were screened in the following manner for their ability to inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 1, 2249) . To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 3 00 mM NADH, 3 0 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and 100 uM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 3 0 uM. The resulting mixture was incubated at 3 0 °C for 10 min. The reaction was initiated by the addition of 10 uL of CDK-2/Cyclin A stock solution to give a final concentration of 25 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5-minute read time at 30 °C using a BioRad Ultramark plate reader (Hercules, CA) . The Ki values were determined from the rate data as a function of inhibitor concentration. The following compounds were shown to have Ki values than 0.1 µM for CDK-2: III-a-116, III-a-142, III- a-149, and III-a-152. The following compounds were shown to have Ki values between 0.1 µM and 1 µM for CDK-2: III-a-146, III- a-148, III-a-150, III-a-155, III-a-162, and III-a-174. The following compounds were shown to have Ki values between 1.0 and 20.0 µM for CDK-2: III-a-117, III- a-156, and III-a-159. Example 3 6 LCK INHIBITION ASSAY The compounds were evaluated as inhibitors of human Lck kinase using either a radioactivity-based assay or spectrophotometric assay. Lck Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors of full length bovine thymus Lck kinase (from Upstate Biotechnology, cat. no. 14-106) expressed and purified from baculo viral cells. Lck kinase activity was monitored by following the incorporation of 33P from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu.-Tyr = 4:1 (Sigma, cat. no. ß0275). The following were the final concentrations of the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg/ml BSA, 10 uM ATP (1-2 uCi 33P-ATP per reaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of recombinant human Src kinase. In a typical assay, all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells. Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%. The assay plate was incubated at 30 C for 10 min before initiating the reaction with 33P-ATP. After 20 min of reaction, the reactions were quenched with 150 ul of 10% trichloroacetic acid (TCA) containing 20 mM Na3PO4. The quenched samples were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF/F Glass Fiber Filter, cat no. 7700-3310) installed on a filter plate vacuum manifold. Filter plates were washed four times with 10% TCA containing 20 mM Na3PO4 and then 4 times with methanol. 200ul of scintillation fluid was then added to each well. The plates were sealed and the amount of radioactivity associated with the filters was quantified on a TopCount scintillation counter. The radioactivity incorporated was plotted as a function of the inhibitor concentration. The data was fitted to a competitive inhibition kinetics model to get the Ki for the compound. Lck Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Lck kinase-catalyzed phosphorylation of poly Glu-Tyr substrate was quanitified using a coupled enzyme assay (Fox et al (1998)' Protein Sci 7, 2249) . In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The disappearance of NADH can be conveniently followed at 340 nm. The following were the final concentrations of the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 5 mg/ml poly Glu-Tyr, and 5 0 nM of recombinant human Lck kinase. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 2 00 uM NADH, 3 0 ug/ml pyruvate kinase and 10 ug/ml lactate dehydrogenase. In a typical assay, all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells. Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%. The assay plate was incubated at 30 °C for 10 min before initiating the reaction with 150 uM ATP. The absorbance change at 34 0 nm with time, the rate of the reaction, was monitored on a molecular devices plate reader. The data of rate as a function of the inhibitor concentration was fitted to competitive inhibition kinetics model to get the Ki for the compound. The following compounds were shown to have Ki values than 1 µM for Lck: III-a-170, III-a-171, Ill-a- 172, III-a-173, III-a-181, and III-a-203. The following compounds were shown to have Ki values between l.o and 20.0 µM for Lck: III-a-204, Ill-a- 205, III-a-206, and III-a-207. Example 3 7 AKT3 INHIBITION ASSAY Compounds were screened for their ability to inhibit AKT3 using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 224 9). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgCl2, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 uM ATP (Sigma Chemicals) and 200 uM peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at 30 "C and 45 nM AKT3. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 3 00 uM NADH, 3 0 ug/ML pyruvate kinase and 10 ug/ml lactate dehydrogenase. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of AKT3, DTT, and the test compound of interest. 56 ul of the stock solution was placed in a 384 well plate followed by addition of 1 ul of 2 mM DMSO stock containing the test compound (final compound concentration 30 uM). The plate was preincubated for about 10 minutes at 30°C and the reaction initiated by addition of 10 µl of enzyme (final concentration 45 nM) and 1 mM DTT. Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a 5 minute read time at 30 0C. Compounds showing greater than 50% inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine IC50 values. Selected compounds of this invention that inhibit AKT3 include: III-a-238. While we have presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other embodiments which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example. Appendix A: Names of Table 1 Compound Numbers III-a- 1: 4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid dimethylamide; 2: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-pyrrolidin-l-yl-methanone; 3 •• {4- [2-Amino-5- (3-chloro-2-fluoro-phenyl) -pyrimidin-4- yl]-lH-pyrrol-2-yl}-pyrrolidin-l-yl-methanone; 4: 4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 5: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] - morpholin-4-yl-methanone; 6: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- [1,4' ]bipiperidinyl-l' -yl-methanone; 7: {4- [2-Amino-5- (3, 4-dimethoxy-phenyl) -pyrimidin-4-yl] - lH-pyrrol-2-yl}-(3-hydroxy-piperidin-1-yl) - methanone; 8: {4- [2-Amino-5- (3, 4-dimethoxy-phenyl) --pyrimidin-4-yl] - lH-pyrrol-2-yl}-[1,4']bipiperidinyl-1'-yl-methanone; 9 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] - [1,4']bipiperidinyl-1'-yl-methanone; 10: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-[1,4']bipiperidinyl-1'-yl- methanone; 11: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]- (4-hydroxy-piperidin-1-yl)-methanone; 12 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- [4- (2-fluoro-phenyl)-piperazin-1-yl]-methanone; 13 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- (4-phenyl-piperazin-l-yl)-methanone; 14 .- [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] - [4- (4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-l-yl]- methanone; 15 : [4- (2-Arnino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] - (4-pyridin-2-yl-piperazin-1-yl)-methanone; 16 : (4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrol-2-yl}-morpholin-4-yl-methanone; 17: 4-[2-Amino-5- (3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)- amide; 1_8 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2- yl]-morpholin-4-yl-methanone; 19: 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 20: 4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)- amide; 21: {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-yl]- methanone; 22 : (4- [2-Amino-5- (3 -chloro-phenyl) -pyrimidin-4-yl] -1H-- pyrrol-2-yl}-(4-phenyl-piperazin-1-yl)-methanone; 23: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl] -methanone; 24: {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-(3 , 4-dihydro-lH-isoquinolin-2-yl)- methanone; 25: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)- methanone,- 26: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-morpholin-4-yl-methanone; 27: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-(4-hydroxy-piperidin-l-yl)-methanone; 28 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[1,4']bipiperidinyl-1'-y1-methanone; 29 : 4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid benzyl-methyl-amide; 30 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- [4- (4-methoxy-phenyl)-piperazin-1-yl]-methanone; 31: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] - (2-hydroxymethyl-piperidin-1-yl)-methanone; 32 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- (3,4-dihydro-lH-isoquinolin-2-yl)-methanone; 33 : 4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid benzyl-methyl-amide; 34 : (4- [2-Amino-5-(3 t4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl] -methanone; 35: {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl] - lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinolin-2-yl)- methanone; 36 : 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid benzyl-methyl-amide ,- 37: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl] - (4-phenyl-piperazin-l-yl)-methanone; 38 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-IH-pyrrol-2- yl]- (4-methyl-[1,4]diazepan-1-yl)-methanone; 39 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]- (3,4-dihydro-lH-isoquinolin-2-yl)-methanone; 40: 4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl] -1H- pyrrole-2-carboxylic acid benzyl-methyl-amide; 41: (4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)- methanone; 42 ¦• 4- [2-Amino-5- (3-chloro-2-f luoro-phenyl) -pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid benzyl-methyl- amide; 43: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin-1-yl]- methanone; 44: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4 - yl]-lH-pyrrol-2-yl}-(4-phenyl-piperazin-l-yl)- methanone; 45: [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]- [4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone; 4 6: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]-(3-hydroxy-piperidin-1-yl)-methanone; 47: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]- [4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone; 4 8 .- [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2- yl]- [4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-l- yl]-methanone; 49: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin- 1-yl] -methanone; 50: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-[4-(4-methoxy-phenyl)-piperazin- 1-yl] -methanone; 51: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)- methanone; 52 : l-(4-(4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)- pyrimidin-4-yl]-lH-pyrrole-2-carbonyl}-piperazin-1- yl)-ethanone; 53 .- {4- [2-Amino-5- (3-chloro-2-f luoro-phenyl) -pyrimidin-4- yl]-lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinolin-2- yl)-methanone; 54 : {4~ [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl)-(3-hydroxy-piperidin-l-yl)-methanone; 55 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] - (4-methyl-[1,4]diazepan-1-yl)-methanone; 56 : l-(4-{4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin- 4-yl]-lH-pyrrole-2-carbonyl}-piperazin-1-yl)- ethanone; 57 : {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl] - lH-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)- methanone; 58: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- (3-hydroxy-piperidin-l-yl)-methanone; 59: 4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-- pyrrole-2-carboxylic acid methyl-(2-pyridin-2-yl- ethyl)-amide; 60 : [4- (2-Am'ino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2- yl]-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone; 61: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin- 1-yl] -methanone; 62: 4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- methyl-2-phenyl-ethyl)-methyl-amide; 63: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)- methanone; 64: [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- (4-hydroxy-piperidin-1-yl)-methanone; 65: {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- 1H-pyrrol-2-yl}-(4-hydroxy-piperidin-1-yl)- methanone; 66: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-(4-hydroxy-piperidin-l-yl)- methanone; 67 : (4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)- methanone; 68 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- methanone; 69: 1-{4-[4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H- pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone; 70 : {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1- yl]-methanone; 71 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] - pyrrolidin-1-yl-methanone; 72 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-morpholin-4-yl-methanone; 73 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid benzylamide; 74: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 3,4-difluoro-benzylamide; 75 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 76 : 4 - (2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2 - carboxylic acid 4-fluoro-benzylamide; 77 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 3-chloro-benzylamide; 78 : 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 4-methoxy-benzylamide; 79: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 3-chloro-4-f luoro-benzylamide ,- 80: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide 81: 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide 82: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide; 83: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid . (3-hydroxy-l-phenyl-propyl)-amide; 84: 4- (2,5-Diamino-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 3-chloro-4-fluoro-benzylamide; 85: 4- (2-Amino-5-methylamino-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid 3-chloro-4-fluoro-benzylamide; 86: 4- (5-Acetylamino-2-amino-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid 3-chloro-4-fluoro-benzylamide; 87 : 4- [2-Amino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1H- pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 88 : 4- (2-Amino-5-hydroxy-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid 3-chloro-4-fluoro-benzylamide; 89 : 4- (2-Amino-5-methylaminomethyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 90 : 4- (2-Amino-5-hydroxymethyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 91: 4- [2-Cyclohexylamino-5-(3-methyl-ureido)-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 92: 4- [2-Acetylamino-5-(3-methyl-ureido)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 93 : 4- (5-Hydroxy-2-methanesulfonylamino-pyrimidin-4-yl) - lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide; 94 : 4- (2-Amino-5-methanesulfonyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide; 95 : 4- (2-Amino-5-hydroxymethyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3 , 4-dif luoro-benzylamide ; 96 : 4- (2-Cyclohexylamino-5-methyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide; 97 . 4- [2-Amino-5- (3 , 5-dichloro-phenyl) -pyrimidin-4-yl] - lH-pyrrole-2-carboxylic acid (pyridin-4-ylmethyl)- amide; 18: 4- [5- (3 , 5-Dichloro-phenyl) -2 -phenylamino-pyrimidin-4 - yl]-lH-pyrrole-2-carboxylic acid 3-trifluoromethyl- benzylamide; 99 : 4- [2-Amino-5-(3, 5-dichloro-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid .(2-hydroxy-l-phenyl- ethyl)-amide; 100: 4- [2-Amino-5-(3 , 5-dichloro-phenyl)-pyrimidin-4-yl] - lH-pyrrole-2-carboxylic acid (benzo [1,3]dioxol-5- ylmethyl)-amide; 101: 4- [2-Amino-5-(3 , 5-dichloro-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid (2-dimethylamino-2- pyridin-3-yl-ethyl)-amide; 102 : 4- [2-Amino-5-(3, 5-dichloro-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid 4-methanesulfonyl- benzylamide; 103 : 4- [5- (3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide; 104 : 4- [5- (3 , 5-Dichloro-phenyl)-2-phenylamino-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-morpholin-4- yl-2-pyridin-3-yl-ethyl) -amide; 105 : 4- [2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl) -amide; 106 : 4- (2-Amino-5-propyl-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 107 : 4- (2-Amino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 108 : 4- (5-Methyl-2-methylamino-pyrimidin-4 -yl) -1H- pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)- amide; 109 : 4- (2-Methylamino-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 110 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (2-dimethylamino-ethyl) -amide,- 111: 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid propylamide; 112 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (3-phenyl-propyl)-amide; 113 .- 4- (2-Ethylamino-5-methyl -pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (naphthalen-1-ylmethyl)-amide,- 114 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid cyclopropylamide; 115 : 4- (2-Ethylamino-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid 2-trifluoromethyl-benzylamide; 116 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 117: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 118 : 4- (2-Ethylamino-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (4-methyl-cyclohexyl)-amide; 119 : 4-(5-Ethyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid isopropylamide; 120 : 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-amino-ethyl)-amide; 121: 4- (2-Amino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid benzyl-methyl-amide; 122 : 4- (2-Amino-pyrimidiri-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl- amide; 123 : 1-{4- [4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone; 124 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (3-phenyl-propyl)-amide; 125 : 4- (2-Amino-5-ethyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid [2-(6-methoxy-lH-indol-3-yl)-ethyl]- amide; 126 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-phenoxy-ethyl)-amide; 127 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (1-methyl-3-phenyl- propyl)-amide; 128 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (lH-benzoimidazol-2- ylmethyl)-amide; 129 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (1-hydroxymethyl-3-methyl- butyl)-amide; 130 .- 4- (5-Methyl-2-phenylamino-pyrimidin-4 -yl) -1H- pyrrole-2-carboxylic acid [l-hydroxymethyl-2-(1H- imidazol-4-yl)-ethyl]-amide; 131: 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide; 132 : 4- [2-(2-Diethylamino-ethylamino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid 3,4-difluoro- benzylamide; 133 : 4- [5-Methyl-2-(2-piperidin-l-yl-quinazolin-4- ylamino)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid benzylamide; 134 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-chloro-4-fluoro- phenyl)-2-hydroxy-ethyl]-amide; 135 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-chloro-4-fluoro- phenyl)-2-hydroxy-ethyl]-amide; 136 : 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 137: 4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 138: 4-[2-(3-Hydroxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 139: 4-[2-(Benzo[1,3]dioxol-5-ylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 140: 4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 141: 4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 142: 4- [2- (4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 143: 4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 144: 4- (5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 145: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-fluoro-4-methyl- phenyl)-2-hydroxy-ethyl]-amide; 146: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [2-hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-amide; 147: 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid [1-(3-fluoro-4- methyl-phenyl)-2-hydroxy-ethyl]-amide; 148: 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-amide; 149: 4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 150: 4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 151: 4- [2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 152 : 4- [2- (4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 153: 4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 154: 4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 155: 4- [2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 156: 4- [2- (2-Methoxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl) - amide ,- 157: 4- [5-Methyl-2-(4-trifluoromethoxy-phenylamino)- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 15 8 .- 4- (2-Isobutylamino-5-methyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 159: 4- [2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 160 .- 4- (5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 161: 4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 162 : 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 163: 4- (5-Methyl-2-propylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 164: 4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 165: 4- (5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl) -amide ,• 166 : 4- {2- (2-Hydroxy-l-phenyl-ethylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 167: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl- ethyl)-amide; 168 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl- ethyl)-amide; 169: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-2-phenyl-ethyl)-amide; 170: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2- phenyl-ethyl)-amide; 171: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-IH-pyrrole- 2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2- phenyl-ethyl)-amide; 172 : 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide; 173 .- 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide; 174: 4- [2-(1-Hydroxymethyl-cyclopropylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 175 : 4- [2- (2-Hydroxy-ethylamino) -5-methyl-pyrimidin-4 - yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 176 : 4- [2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 177 : 4- [2- (2-Hydroxy-propylamino) -5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 178 : 4- [2- (2-Hydroxy-propylamino) -5-tnethyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 179 : 4- [2- (2-Hydroxy-cyclohexylamino) -5-methyl-pyrimid.in- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1- phenyl-ethyl)-amide; 121: 4- [2- (2-Hydroxy-l-methyl-ethylamino)-5-methyl- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 121: 4- [2- (3 -Dimethylamino-phenylamino) -5-methyl- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 180: 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl) -methyl- amide; 181 : 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-phenyl-ethyl) -methyl- amide; 183 : 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-2-phenyl-ethyl) -methyl-amide; 184 : { [4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -1H- pyrrole-2-carbonyl] -amino} -phenyl-acetic acid methyl ester; 186: 4- (2-Amino-pyrimidin-4-yl)-lH-pyrrole-2-carboxyIic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl- amide; 187: 4- (2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl- ethyl)-amide; 188: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-pyridin-3-yl-ethyl)- amide; 189 : 4- (2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 190 : 4- (2-Ethylamino-5-methyl-pyritnidin-4-yl) -lH-pyrrole- 2-carboxylic acid [1-(3-fluoro-5-trifluoromethyl- phenyl)-2-hydroxy-ethyl]-amide; 191: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid [1-(3-fluoro-phenyl)-2-hydroxy- ethyl] -amide; 192 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid [1-(2-fluoro-phenyl)-2-hydroxy- ethyl] -amide; 193 : 4- [2-(2-Cyclopropyl-l-hydroxymethyl-ethylamino)-5- methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 194 : 4 - [2- (2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin- 4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl -ethyl) -amide; 195 : 4- (2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl- ethyl)-amide; 196: 4- [2-(1-Hydroxymethyl-2-methyl-propylamino)-5- methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 197: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-oxo-1-phenyl-propyl)-amide; 198 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-IH-pyrrole- 2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl- phenyl)-ethyl]-amide; 199: 4- [2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-amide; 200: 4- [2- (2-Chloro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-amide; 2 01.- 4- [2- (2-Hydroxy-l-phenyl-ethylamino) -5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2- hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide; 200: 4- [2-(3-Dimethylamino-phenylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2- hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide; 202: 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [2-hydroxy-l-(3 - trifluoromethyl-phenyl)-ethyl]-amide; 203: 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [2-hydroxy-l-(2-methoxy- phenyl) -ethyl] -amide; 2 04: 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1K- pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2- hydroxy-ethyl]-amide; 2 05 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl- ethyl)-amide; 206: 4- (2-Methoxyamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 207: 4- (2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 208: 4- [2- (3-Dimethylamino-phenylamino)-5-methyl- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 209: 4- [2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m- tolyl-ethyl)-amide; 210: 4- [2- (2-Hydroxy-l-phenyl-ethylamino)-5-methyl- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 211: 4- [2- (2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m- tolyl-ethyl)-amide; 212: 4- [2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m- tolyl-ethyl)-amide; 213: 4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 214: 4- (5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 215: 4- [5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl] - lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 216: 4-(5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]- pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl) -amide; 217: 4-{5-Methyl-2- [ (tetrahydro-furan-2-ylmethyl)-amino]- pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-pheny1-e thy1)-ami de; 218: N' -{4-[5-(2-Hydroxy-1-phenyl-ethylcarbamoyl) -1H- pyrrol-3-yl]-5-methyl-pyrimidin-2-yl}- hydrazinecarboxylic acid ethyl ester; 219: 4-(5-Methyl-2- [(pyridin-3-ylmethyl)-amino]- pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 220: 4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4- yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 221: 4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl- ethyl)-amide; 222: 4-[2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 22 3 .- 4- (5-Methyl-2-o-tolylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl- ethyl)-amide; 224: 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2- hydroxy-ethyl]-amide; 225: 4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 226: 4-[2-(N',N'-Dimethyl-hydrazino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 227: 4-[5-Methyl-2-(2-trifluoromethyl-phenylamino) - pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 228: 4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl- ethyl)-amide; 229: 4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 230: 4-{2-[1-(3-Chloro-4-fluoro-phenyl)-2-hydroxy- ethylamino]- 5-methyl-pyrimidin-4-yl}-lH-pyrrole-2 - carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 231: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-fluoro-phenyl)-2- hydroxy-ethyl]-amide; 232: 4 - [2 -(1-Hydroxymethyl-propylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [l-(3- chloro-phenyl)-2-hydroxy-ethyl]-amide; 233: 4- [2-(2-Hydroxy-l-hydroxymethyl-ethylamino)-5- methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide; 234: 4- [2-(1-Hydroxymethyl-propylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 235: 4- [2-(2-Hydroxy-1-hydroxymethyl-ethylamino)-5- methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 236: 4-[2-(1-Hydroxymethyl-propylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 237 : 4- [5-Methyl-2- (2-methyl-cyclopropylamino) -pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl) -amide; and 238 : 4- (2-Cyanoamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide. or a pharmaceutically acceptable salt thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and Q'R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 is N and Z2 is CH; T is a linker group selected from -NH-, -CH2- , -CO-, or a saturated or unsaturated C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -CO-, -C(O)C(O)-, -C(O)NR7-, -C(O)NR7NR7-, -CO2,-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-, -NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-; Q' is selected from -CO2-, -C(O)NR7- or -SO2NR7-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R2' is selected from -(CH2)yCH(R5)2 or -(CH2)yCH(R8)CH(R5)2; y is 0-6; R3 is selected from R7, R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2,or -(CH2)y CH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; WE CLAIM: 1. A compound of formula I': each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR5, or-(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6; aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and each w is independently selected from 0-4. 2. The compound as claimed in claim 1, wherein Sp is selected from one of the following: or a pharmaceutically acceptable salt thereof. 3. The compound as claimed in claim 2, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6- membered aryl or heteroaryl ring. 4. The compound as claimed in claim 3, wherein: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1' is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6- membered aryl or heteroaryl ring. 5. The compound as claimed in claim 3, wherein said compound has one or more features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl.. isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group; (b) TmR1 is selected from an optionally substituted phenyl, methyl, ethyl, propyl. cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O) NHCH3, or CH2NHCH3; and (c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q' is -C(O)NH-. 6. The compound as claimed in claim 5, wherein: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group; (b) TmR1 is selected from an optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyh CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O) NHCH3, or CH2NHCH3; and (c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q' is -C(O)NH-. 7. The compound as claimed in claim 2, wherein said compound is of formula I": or a pharmaceutically acceptable salt thereof. 8. The compound as claimed in claim 7, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2:, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. 9. The compound as claimed in claim 8, wherein: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is a an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. 10. The compound as claimed in claim 2, wherein said compound is of formula I°: or a pharmaceutically acceptable salt thereof. 11. The compound as claimed in claim 10, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6- membered aryl or heteroaryl ring. 12. The compound as claimed in claim 11, wherein: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6- membered aryl or heteroaryl ring. 13. A compound of formula III-a': or a pharmaceutically acceptable salt thereof, wherein: T is a linker group selected from -NH-, -CH2-, -CO-, or a saturated or unsaturated C1.6 alkylidene chain, which is optionally substituted, and wherein up to two saturated. carbons of the chain are optionally replaced by -C(O)-, -C(O)C(O)-, -CONR7-, -CONR7NR7-, -CO2-, -OC(O)-, -NR7CO2-, -O-, -NR7CONR\ -OC(O)NR7-: -NR7NR7-, -NR7CO-, -S-, -SO-, -S(O)2-, -NR7-, -SO2NR7-, or -NR7SO2-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R3 is selected from R\ R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2, or -(CH2) yCH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR5, or -(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted Ci.6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)wN(R4)2, or (CH2)«SR7; and each w is independently selected from 0-4. 14. The compound as claimed in claim 13, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroary] ring; and (c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. 15. The compound as claimed in claim 14, wherein: fa) R3 is hydrogen, carbocyclyl. -CH(R8)R. or an optionally substituted group selected from Ci-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR' is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from Ci-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. 16. The compound as claimed in claim 14, wherein said compound has one or more features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR' is selected from an optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O) NHCH3, or CH2NHCH3; and (c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring. 17. The compound as claimed in claim 16, wherein: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl. -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O) NHCH3, or CH2NHCH3; and (c) R5 is cyclohexyl or a substituted or unsubstituted phenyl or pyridyl ring. 18. A compound of formula III-a°: or a pharmaceutically acceptable salt thereof, wherein: T is a linker group selected from -NH-,-CH2-, -CO-, or a saturated or unsaturated C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -CO-, -C(O)(CO)-, -CONR7-, -CONR7NR7-, -CO2-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-, -NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; y is 0-6; R3 is selected from R\ R, -(CH2)yCH(R8)R, CN, -(CH2))CH(R8)CH(R5)2, or -(CH2) yCH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-.6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR\ or -(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6; aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and each w is independently selected from 0-4. 19. The compound as claimed in claim 18, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or a substituted or unsubstituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or a substituted or unsubstituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, and R8 is R7 or OR7. 20. The compound as claimed in claim 19, wherein: a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or a substituted or unsubstituted group selected from C1-4 aliphatic,3-6 membered heterocyclic,or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or a substituted or unsubstituted group selected from C1-.6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, and R8 is R7 or OR7. 21. The compound as claimed in claim 1, selected from the group consisting of: 4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl-amide; 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l - phenyl-ethyl)-amide; 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (3-hydroxy-l - phenyl-propyl)-amide; 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (3-hydroxy-l» phenyl-propyl)-amide; 4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid (2-dimethylamino-2-pyridin-3-yl-ethyl)-amide; 4-[5-(3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-amide; 4-[2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2- carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrroIe-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy- 1 -phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-methyl -amide; 4-(5-Methyl-2-methylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (1 - hydroxymethy 1-3 -methyl -butyl)-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 - hydroxymethyl-2-(lH-imidazol-4-yl)-ethyl]-amide; 4-(5-Methyl-2-methylamino-pyrirnidin-4-yl)-l H-pyrrole-2-carboxylic acid [l-(3- chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid [l-(3- chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4- [2-(3 -Hydroxy-phenylamino)-5 -methyl-pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(Benzo[l,3]dioxol-5-ylamino)-5-methyl-pyrimidin-4-yl]-lH-p>Trole-2- carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; 4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -(3- fluoro-4-methyl-phenyl)-2-hydroxy-ethyl]-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2- hydroxy-1 -(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid [ 1 -(3 -fluoro-4-methy l-phenyl)-2-hydroxy-ethyl] -amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; 4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[5-Methyl-2-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-(2-Isobutylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; 4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Methyl-2-propylamino-pyTimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenyl- ethyl)-methyl-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy- 1-methyl-2-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy- 1 -methyl-2-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy- 2-phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2- phenyl-ethyl)-methyl-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy- l-hydroxymethyl-2-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy- l-hydroxymethyl-2-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (3-hydroxy- 1 -phenyl-propyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (3-hydroxy- 1 -phenyl-propyl)-amide; 4-[2-( 1 -Hydroxymethyl-cyclopropylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-1 -methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; {[4-(2-Ethylamino-5-methyl-p>Timidin-4-yl)-lH-pyrrole-2-carbonyl]-amino}-phenyl- acetic acid methyl ester; 4-[2-(2-Hydroxy-1 -methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-methyl-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-p>Trole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-methyl-amide; 4-(2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy- 1 -pyridin-3-yl-ethyl)-amide; 4-(2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [1 -(3- fluoro-5-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [1-(3- fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid [1 -(2- fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(2-Cyclopropyl-l-hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxyIic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(l -Hydroxymethyl-2-methyl-propylamino)-5-methyl-pyrimidin-4-yl]-1H- pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-oxo-1- phenyl-propyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2-hydroxy- l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pryimidin-4-yl]-1H-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(2-Hydroxy-1 -phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2- carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid [2- hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2- hydroxy-1-(2-methoxy-phenyl)-ethyl] -amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl)-2-hydroxy-ethyl]-amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 4-(2-Methoxyamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-l-phenyl-ethyl)-amide; 4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-f2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yll-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-[2-(2,3-Dirnethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -m-tolyl-ethyl)-amide; 4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyrrole-2- carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; 4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyrrole-2- carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; N'-{4-[5-(2-Hydroxy-l-phenyl-ethylcarbamoyl)-lH-pyrrol-3-yl]-5-methyl-pyrimidin- 2-yl}-hydrazinecarboxylic acid ethyl ester; 4-{5-Methyl-2-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyiTole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Cyanoamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-l-methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -m-tolyl-ethyl)-amide; 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -(3 - chloro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(N',N'-Dimethyl-hydrazino)-5-methyl-pyrimidin-4-ylJ-l H-pyrrole-2-carboxylic acid (2-hydroxy-1-pheny l-ethyl)-amide; 4-[5-Methyl-2-(2-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-{2-[l-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-methyl-pyrimidin-4- yl} -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [l-(3- fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-( 1 -Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid [l-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(2-Hydroxy-1 -hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H- pyrrole-2-carboxylic acid [l-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(l -Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid (2-hydroxy-1-m-tolyl-ethyl)-amide; 4-[2-(2-Hydroxy-1 -hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-l H- pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-[2-(l-Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; and 4-[5-Methyl-2-(2-methyl-cyclopropylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide. 22. A composition comprising a compound as claimed in any one of claims 1-21 and a pharmaceutically acceptable carrier. 23. The composition as claimed in claim 22, comprising an additional therapeutic agent selected from a chemotherapeutic agent or anti-proliferative agent, or an agents for treating diabetes, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, an agent for treating neurlogical disorders, an agent for treating cardiovascular disease, an agent for treating liver disease, cholestyramine, an interferon, an anti-viral agents, an agents for treating blood disorders, or an agent for treating immunodeficiency disorders. 24. The composition as claimed in claim 22, wherein said composition is capable of being used for inhibiting ERK2, GSK-3, Aurora, CDK.2, or Lck activity in a patient. 25. The composition as claimed in claim 24, wherein said composition is used to inhibit ERK2 activity in a patient. 26. The composition as claimed in claim 25, wherein said ERK2 activity is associated with a disease selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, or CNS disorders. 27. The composition as claimed in claim 26, wherein the disease is cancer. 28. The composition as claimed in claim 27, wherein the disease is a cancer selected from breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine: colon-rectum, large intestine, rectum; brain and central nervous system; or leukemia. 29. The composition as claimed in claim 25, wherein the disease is cardiovascular disease. 30. The composition as claimed in claim 29, wherein the disease is a cardiovascular disease selected from restenosis, cardiomegaly, artherosclerosis, myocardial infarction, or congestive heart failure. 31. The composition as claimed in claim 24, wherein said composition is useful for treating a GSK-3 -mediated disease in a patient in need thereof. 32. The composition as claimed in claim 31, wherein said disease is diabetes. 33. The composition as claimed in claim 31, wherein said disease is Alzheimer's disease. 34. The composition as claimed in claim 31, wherein said disease is schizophrenia. 35. The composition as claimed in claim 22, wherein said composition is useful for enhancing glycogen synthesis in a patient in need thereof. 36. The composition as claimed in claim 22, wherein said composition is useful for lowering blood levels of glucose in a patient in need thereof. 37. The composition as claimed in claim 22, wherein said composition is useful for inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof. 38. The composition as claimed in claim 22, wherein said composition is useful for inhibiting the phosphorylation of \|3-catenin in a patient in need thereof. 39. The composition as claimed in claim 24, wherein said composition is useful for treating an Aurora-2-mediated disease in a patient in need thereof. 40. The composition as claimed in claim 39, wherein said disease is selected from colon, breast, stomach, or ovarian cancer. 41. The composition as claimed in claim 24, wherein said composition is useful for treating CDK-2-mediated disease in a patient in need thereof. 42. The composition aas claimed in claim 41, wherein said disease is selected from cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, or an autoimmune disease. 43. The composition as claimed in claim 24, wherein said composition is useful for treating a Lck-mediated disease in a patient in need thereof. 44. The composition as claimed in claim 43, wherein said disease is selected from an autoimmune disease or transplant rejection. 45. A method for screening ERK2, Aurora-2, GSK-3, CDK-2, AKT3, or Lck activity in a biological sample in vitro, wherein said biological sample is selected from the group consisting of a cell culture, an enzyme preparation, a mammalian biopsy, blood, saliva, urine, feces, semen, tears, and any extract thereof, said method comprising the step of contacting said biological sample with a compound as claimed in any one of claims 1-21. 46. A composition for coating an implantable device comprising a compound as claimed in claim 1 and a carrier suitable for coating said implantable device. 47. An implantable device coated with a composition as claimed in claim 46.CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to US Provisional Patent Application 60/267,818 filed February 9, 2001 and US Provisional Patent Application 60/328,768 filed October 12, 2001, the contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention is in the field of medicinal chemistry and relates to pyrazole compounds that are protein kinase inhibitors, especially inhibitors of ERK, compositions containing such compounds and methods of use. The compounds are useful for treating cancer and other diseases that are alleviated by protein kinase inhibitors. BACKGROUND OF THE INVENTION Mammalian mitogen-activated protein (MAP)1 kinases are serine/threonine kinases that mediate 5 intracellular signal transduction pathways (Cobb and Goldsmith, 1995, J Bio1. Chem., 270, 14843; Davis, 1995, Mol. Reprod. Dev. 42, 459) . Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK2 (extracellular signal 10 regulated kinase) , JNK (Jun N-terminal kinase), and p38 kinases. JNKs and p38 kinases are activated in response to the pro-inflammatory cytokines TNF-alpha and interleukin-l, and by cellular stress such as heat shock, hyperosmolarity, ultraviolet radiation, lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., 1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaud et al. 1995, J Biol. Chem. 270, 7420; Shapiro and Dinarello, 1995, Proc. Natl. Acad. Sex. USA 92, 12230). In contrast, ERKs are activated by mitogens and growth factors (Bokemeyer et al. . 1996, Kidney Int. 49, 1187) . ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thrl83 and Tyrl8 5 are phosphorylated by the upstream MAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylates many regulatory proteins, including the protein kinases Rsk90 (Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al., 1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaud et al. , 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), and c-Myc (Oliver et al. , 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2 is also a downstream target of the Ras/Raf dependent pathways (Moodie et al., 1993, Science 2 60, 1658) and may help relay the signals from these potentially oncogenic proteins. ERK2 has been shown to play a role in the negative growth control of breast cancer cells (Frey and Mulder, 1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breast cancer has been reported (Sivaraman et al., 1997, J Clin. Invest. 99, 1478). Activated ERK2 has also been implicated in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting a role for this kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589). Aurora-2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora- 2 protein has been found to be overexpressed. See Bischoff et al., EMBO J. , 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of a and p isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev. , 10, 508-514 (2000)]. GSK-3 has been implicated in various diseases including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Hag et al., J. Cell Biol. (2000) 151, 117]. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor b-catenin, the translation initiation factor elF2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development. In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)]. However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675]. Therapeutic inhibitors of GSK-3 therefore are considered to be useful for treating diabetic patients suffering from an impaired response to insulin. GSK-3 activity has also been associated with Alzheimer's disease. This disease is characterized by the well-known P-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnormal sites. GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer's disease. Another substrate of GSK-3 is (3-catenin which is degradated after phosphorylation by GSK-3. Reduced levels of ßcatenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)]. As a result of the biological importance of GSK-3, there is current interest in therapeutically effective GSK-3 inhbitors. Small molecules that inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)]. Aryl substituted pyrroles are known in the literature. In particular, tri-aryl pyrroles (US 5,837,719) have been described as having glucagon antagonist activity. 1,5-Diarylpyrazoles have been described as p38 inhibitors (WO 9958523). There is a high unmet medical need to develop new therapeutic treatments that are useful in treating the various conditions associated with ERK2 activation. For many of these conditions the currently available treatment options are inadequate. Accordingly, there is great interest in new and effective inhibitors of protein kinase, including ERK2 inhibitors, that are useful in treating various conditions associated with protein kinase activation. DESCRIPTION OF THE INVENTION It has now been found that compounds of this invention and compositions thereof are effective as protein kinase inhibitors, especially as inhibitors of ERK2. These compounds have the general formula I: or a pharmaceutically acceptable derivative thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and QR2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 and Z2 are each independently selected from N or CH; T and Q are each an independently selected linker group; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -0-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7- , -NR7SO2NR7-, or -S02-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R2 is selected from -(CH2)yR5, - (CH2) yCH (R5) 2; -(CH2)yCH(R8)CH(R5)2, -N(R4)2; or -NR4 (CH2) yN (R4) 2 ; y is 0-6; R3 is selected from R7, R, - (CH2) yCH (R8) R, CN, -(CH2)yCH(R8)CH(R5)2; or - (CH2) yCH (R8)N (R4) 2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -(CH2)yR5, or - (CH2) yCH (R5) 2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, C0N(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2) WN (R4) 2, or (CH2)WSR7; and each w is independently selected from 0-4. As used herein, the following definitions shall apply unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. The term "aliphatic" or "aliphatic group" as used herein means a straight-chain or branched C1-C12 hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. For example, suitable aliphatic groups include, but are not limited to, linear or branched or alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms. The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I. The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl). The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". [0001] The term "heterocycle", "heterocyclyl", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems having five to fourteen ring members in which one or more ring members is a heteroatom, wherein each ring in the system contains 3 to 7 ring members. [0002] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group are selected from halogen, -R°, -OR0, -SR°, 1,2-methylene-dioxy, 1,2- ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), Ph substituted with R°, -O(Ph), 0-(Ph) substituted with R°, -CH2(Ph), -CH2(Ph) substituted with R°, -CH2CH2(Ph), -CH2CH2(Ph) substituted with R°, -N02, -CN, -N(R°)2, -NR°C(O)R°, -NR°C(O)N(R°)2, -NRCCO2R°, -NR°NR°C (O) R°, -NR°NR°C(O)N(R°)2, -NR°NR°CO2R°/ -C(O)C(O)R°, -C (0) CH2C (0) R°, -CO2R°, -C(O)R°, -C(O)N(R°)2, -OC (O) N (R°) 2, -S(O)2R°, -SO2N(R°)2, -S(O)R°, -NR°SO2N(R°)2/ -NR°SO2R0, -C (=S) N (R°) 2, -C(=NH) -N(R°)2, -(CH2)yNHC(O)R°, or - (CH2)yNHC(0)CH(V-R°) (R°) , wherein each R° is independently selected from hydrogen, optionally substituted Ci-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl (Ph), -O(Ph), or -CH2(Ph)- CH2(Ph), wherein y is 0-6; and V is a linker group. Substituents on the aliphatic group of R° are selected from NH2, NH(C1.4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, 0- (C1-4 aliphatic), N02, CN, C02H, CO2(C1-4 aliphatic), -O(halo C1-4 aliphatic), or halo C1-4 aliphatic. An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: =0, =S, =NNHR, =NN(R)2, =N-, =NNHC (o) R, =NNHC02 (alkyl), =NNHS02(alkyl), or =NR, where each.R is independently selected from hydrogen or an optionally substituted C1-6 aliphatic. Substituents on the aliphatic group of R* are selected from NH2, NH(d-4 aliphatic), N(C1.4 aliphatic)2, halogen, C1.4 aliphatic, OH, O- (C1.4 aliphatic) , No2, CN, CO2H, CO2(C1.4 aliphatic), -O(halo C1-4 aliphatic), or halo C1.4 aliphatic. Substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R+, -N(R+)2, -C(0)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR+SO2R+; wherein R+ is hydrogen, an optionally substituted C1-6 aliphatic, optionally substituted phenyl (Ph), optionally substituted -O(Ph), optionally substituted -CH2(Ph), optionally substituted -CH2CH2(Ph), or an unsubstituted 5- 6 membered heteroaryl or heterocyclic ring. Substituents on the aliphatic group or the phenyl ring of R+ are selected from NH2, NH(C1.4 aliphatic), N(d1.4 aliphatic)2/ halogen, C^ aliphatic, OH, O- (Ci_4 aliphatic) , N02/ CN, C02H, CO2(C1.4 aliphatic), -0(halo C1.4 aliphatic), or halo C1.4 aliphatic. The term "alkylidene chain" refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation. The optional substituents are as described above for an aliphatic group. The term "spacer group" refers to a group that separates and orients other parts of the molecule attached thereto, such that the compound favorably interacts with functional groups in the active site of an enzyme. As used herein, the spacer group separates and orients ring A and QR2 within the active site such that they may form favorable interactions with functional groups which exist within the active site of the ERK2 enzyme. When the spacer group is a 5-membered heteroaromatic ring, ring A and QR2 are attached at non- adjacent positions "B" and "C", and the 5-membered ring is attached to ring A at point "D" and to QR2 at point "E" as illustrated below. Preferably, the distance between "D" and "C" is 3.7A, the distance between "D" and "E" is 5.0A, the distance between "B" and "C" is 2.2A, and the distance between "B" and "E" is 3 . 5A , wherein each of the above described distances is plus/minus 0.2 A. The spacer group itself may also form additional interactions within the active site to further enhance inhibitory activity of the compounds. For example, when Sp is a pyrrole the pyrrole-NH may form an additional hydrogen bond within the active site of the ERK2 enzyme. The term "linker group" means an organic moiety that connects two parts of a compound. Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -NH-, -CH2-, -CO-, or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200. Examples of linkers include a saturated or unsaturated C1-6 alkylidene chain which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -C(0)-, -C(O)C(O)-, -CONR7-, -C0NR7NR7-, -C02-, -OC(O)-, -NR7CO2-, -O-, -NR7CONR7- , -OC(O)NR7-, -NR7NR7-, -NR7C0-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-. As used herein, linker group Q connects Sp with R2. Q may also form additional interactions within the ERK2 binding site to further enhance the inhibitory activity of the compound. When Q is a carbonyl- containing moeity such as -C(O)-, -CO2-, -OC(O)-, -C(O)C(O)-, -CONH-, -CO2NH-, -CONHNH-, -NHCO-, -OC(O)NH-, or -NHCO2-, or a sulfonyl-containing moeity such as -SO2-, -SO2NH-, or -NHSO2-, the carbonyl or sulf onyl oxygen forms a hydrogen-bond with lysine 54 in the ERK2 binding site. When Q is an NH-containing moeity such as -CH2NH- or -NHNH-, the NH-group forms a hydrogen-bond with aspartic acid residue 167 in the ERK2 binding site. When Q is a hydrophobic group such as an alkyl chain, -0-, or -S-, Q forms additional hydrophobic interactions within the ERK2 binding site. R2 forms hydrophobic interactions within the binding site of ERK2, especially with the side-chain carbons of lysine 54 and aspartic acid 167. R2 may also form hydrophobic interactions with the glycine-rich loop which is made up of amino-acid residues 33-38. When R2 is substituted, the substituents may form further interactions within the binding site to enhance the inhibitory activity of the compound. For example, when a substituent on R2 is a hydrogen-bond donor or a hydrogen- bond acceptor, said substituent forms a hydrogen bond with enzyme-bound water molecules that exist in the binding site. As used herein, linker group T, when present, connects Sp with R1. T may also form additional interactions within the ERK2 binding site to further enhance the inhibitory activity of the compound. When T is carbonyl-containing such as -CO-, -C02-, -0C0-, -COCO-, -CONH-, -CO2NH-, -CONHNH-, -NHCO-, or -NHCO2-, or sulfonyl-containing such as -SO2-, -S02NH-, or -NHSO2-, the carbonyl or sulfonyl oxygen forms a hydrogen-bond with the NH of glutamine 105 in the ERK2 binding site. When T is NH-containing such as -CH2NH- or -NHNH-, the NH- group forms a hydrogen-bond with the carbonyl of glutamine 105. When T is a hydrophobic group such as an alkyl chain, -0-, or -S-, T forms additional hydrophobic interactions with the side-chain carbons of glutamine 105 as well as isoleucine 84. The binding interactions described herein between the compounds of this invention and the ERK2 binding site have been determined by molecular modeling programs that are known to those of ordinary skill in the art. These molecular modeling programs include QUANTA [Molecular Simulations, Inc., Burlington, Mass., 1992] and SYBYL [Molecular Modeling Software, Tripos Associates, Inc., St. Louis, Mo., 1992]. As used herein, the amino acid numbering for the ERK2 enzyme corresponds to the Swiss-Prot database entry for accession #P28482. The Swiss-Prot database is an international protein sequence database distributed by the European Bioinformatics Institute (EBI) in Geneva, Switzerland. The database can be found at www.ebi.ac.uk/swissprot. The compounds of this invention are limited to those that are chemically feasible and stable. Therefore, a combination of substituents or variables in the compounds described above is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Compounds of formula I or salts. thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutically acceptable composition. In one embodiment, the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein kinase, particularly ERK- 2, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat or prevent an ERK-2-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient. The term "patient" includes human and veterinary subjects. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Another aspect of this invention relates to a method of treating or preventing an ERK-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound. The term "ERK-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which ERK-2 is known to play a role. The term "ERK -2 - mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an ERK-2 inhibitor. Such conditions include, without limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone- related diseases. The term "cancer" includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon- rectum, large intestine, rectum, brain and central nervous system, and leukemia. The present method is especially useful for treating a disease that is alleviated by the use of an inhibitor of ER.K2 or other protein kinases. Although the present compounds were designed as ERK2 inhibitors, it has been found that certain compounds of this invention also inhibit other protein kinases such as GSK3, Aurora2, Lck, CDK2, and AKT3. Another aspect of the invention relates to inhibiting ERK-2 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of inhibiting ERK-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound. The term "Aurora-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which Aurora is known to play a role. The term "Aurora-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor. Such conditions include, without limitation, cancer. The term "cancer" includes, but is not limited to the following cancers: colon, breast, stomach, and ovarian. Another aspect of the invention relates to inhibiting Aurora-2 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound. The term "GSK-3-mediated condition" or "disease", as used herein, means any disease or other deleterious condition or state in which GSK-3 is known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDS- associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, and baldness. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ßcatenin, which is useful for treating schizophrenia. Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound. Inhibition of ERK2, Aurora2, CDK2, GSK-3, Lck, or AKT3 kinase activity in a biological sample is useful for a variety of purposes which are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ- translplantation, biological specimen storage, and biological assays. -20- The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof. The amount effective to inhibit protein kinase, for example, Aurora-2 and GSK-3, is one that measurably inhibits the kinase activity where compared to the activity of the enzyme in the absence of an inhibitor. Any method may be used to determine inhibition, such as, for example, the Biological Testing Examples described below. Pharmaceutically acceptable carriers that ir.ay be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesior.al and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques"known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation -23- (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, poloxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. In addition to the compounds of this invention, pharmaceutically acceptable derivatives of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified diseases or disorders. A "pharmaceutically acceptable derivative " means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+ (C1.4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. The amount of the protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of the inhibitor will also depend upon the particular compound in the composition. The kinase inhibitors of this invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves,, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re- narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a kinase inhibitor of this invention are another embodiment of the present invention. Depending upon the particular protein kinase- mediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, in the treatment of cancer other chemotherapeutic agents or other anti-proliferative agents may be combined with the protein kinase inhibitors of this invention to treat cancer. These agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives. Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, agents for treating diabetes such as insulin or insulin analogues, in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas; anti- inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti- convulsants, ion channel blockers, riluzole, and anti- Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin. Those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor of this invention in a single composition. Compounds of this invention may exist in alternative tautomeric forms. Unless otherwise indicated, the representation of either tautomer is meant to include the other. Accordingly, the present invention relates to compounds of formula I wherein Ring A is a pyridine (II), pyrimidine (III), or triazine (IV) ring as shown below: or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, R2, UnR3, Q, and T are as described above. Examples of suitable Sp groups of formula I include pyrrole (a) , imidazole (b) , pyrazole (c) , triazole (d) , oxazole (e) , isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h) , furan (i), and thiophene (j), as shown below: wherein each of a through j is optionally substituted with R6. Preferred TmR1 groups of formula I are selected from hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1_6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula I are those listed in Table 1 below. Preferred R3 groups of formula I are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Oberizyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH (CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula I are those listed in Table 1 below. When R2 is R5, preferred R5 groups are pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl, 4-methyl [1,4]diazepan-1-yl, 4-phenyl- piperazine-1-yl, wherein each group is optionally- substituted. When R2 is (CH2)yR5, (CH2) yCH (R5) 2, or -N(R4)2, preferred R5 groups are further selected from pyridin-3- yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4- tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, -CH2OH, -(CH2)2OH, and isopropyl, wherein each group is optionally substituted. Preferred substituents on R5 are -OH, pyridyl, piperidinyl, and optionally substituted phenyl. When R2 is - (CH2)yCH(R8)CH(R5)2, preferred R8 groups are R7 and OR7 such as OH and CH2OH and preferred R5 are as described above. Preferred - (CH2) yCH (R8) CH (R5) 2 groups of formula I are -CH(OH)CH(OH)phenyl and -CH(Me)CH(OH)phenyl. Other preferred -QR2 groups are those listed in Table 1 below. Preferred compounds of formula I are those having one or more, more preferably more than one, and. most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1_4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring,- (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; (c) Q is -CO-, -C02- , -CONH-, -SO2-, -SO2NH-, -OC(O)NH-, -C(O)ONH-, or -CONHNH-; (d) R2 is -NR4(CH2)yN(R4)2, -(CH2)yR5, - (CH2) yCH (R5) 2, or - (CH2)yCH(R8)CH(R5)2; (f) R4 is R, R7, or - (CH2) yCH (R5) 2; and (g) R5 is an optionally substituted group selected from C1-6 aliphatic, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl. More preferred compounds of formula I are those having one or more, more preferably more than one, or most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3 ; (c) Q is -CO-, -CONH-, -S02-, or -SO2NH-; (d) R2 is -(CH2)yR5, - (CH2)yCH(R5)2, or - (CH2)yCH(R8)CH(R5)2, wherein RB is OH or CH2OH; and (e) R5 is -CH2OH, -(CH2)2OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4- phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4- yl, imidazolyl, furan-2-yl, 1,2,3,4- tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl. A preferred embodiment of this invention relates to compounds of formula I' : or a pharmaceutically acceptable derivative thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and Q'R2' are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 and Z2 are each independently selected from N or CH; Q' is selected from -C02-, -C(O)NR7- or -SO2NR7- ; T is a linker group; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -S02-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2/ OR, or OH; R2' is selected from - (CH2) yCH (R5) 2 or - (CH2) yCH (R8) CH (R5) 2 ; y is 0-6; R3 is selected from R7, R, - (CH2) yCH (R8) R, CN, - (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8) N (R4) 2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R -CON(R7)2; -SO2R7, -(CH2)yR5, or - (CH2) yCH (R5) 2 ; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2; OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, S02R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2) WN(R4) 2, or (CH2)WSR7; and each w is independently selected from 0-4. Examples of suitable Sp groups of formula I' include pyrrole (a), imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: wherein each of a through j is optionally substituted with R6. Accordingly, the present invention relates to compounds of formula I' wherein Ring A is a pyridine or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, Q'R2 , and UnR3 are as described above. Preferred R5 groups of formula I' are R or OR7. Examples of such groups include OH, CH2OH, carbocyclic, or optionally substituted 5 or 6-membered aryl or heteroaryl rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula I' are R and OR7, wherein R is an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl, methyl, ethyl, OH, and CH2OH. Preferred substituents on the R5 aryl or heteroaryl ring are halogen, haloalkyl, 0R°, and R°. Preferred TmR1 groups of formula I' are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring.. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula I' are those listed in Table 1 below. Preferred R3 groups of formula I' are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropy1. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH (CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula I' are those listed in Table 1 below. Preferred compounds of formula I' are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmRa is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring. More preferred compounds of formula I' are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH (CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3/ NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q' is C(O)NH. Another preferred embodiment of this invention relates to compounds of formula I": or a pharmaceutically acceptable derivative thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and C(O)NHCH[ (CH2)1-2OH]R5 are attached to Sp at non- adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 and Z2 are each independently selected from N or CH; T is a linker group; U is selected from -NR7-, -NR7C0-, -NR7CONR7-, -NR7CO2-, -0-, -CONR7-, -CO-, -CO2-, -00(0)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -S02-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R3 is selected from R7, R, - (CH2) yCH (R8) R, CN, - (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8) N (R4) 2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2' -SO2R7, -(CH2)yRs, or - (CH2)yCH (Rs) 2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2/ N(R7)2, OR7, SR7, NR7COR7, NR7C0N(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7C0N(R7)2/ CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1.6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2) WN(R4) 2, or (CH2)WSR7; and each w is independently selected from 0-4. Examples of suitable Sp groups of formula I" include pyrrole (a), imidazole (b) , pyrazole (c), triazole (d) , oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: wherein each of a through j is optionally substituted with R6. Accordingly, the present invention relates to compounds of formula I" wherein Ring A is a pyridine (II"), pyrimidine (III"), or triazine (IV") ring as shown below: or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, UnR3, and R5 are as described above. Preferred TVR1 groups of formula I" are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Examples of preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3/ CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula I" are those listed below in Table 1. Preferred R3 groups of formula I" are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropy1. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2- . More preferred UnR3 groups of formula I" are those listed in Table 1 below. Preferred R5 groups of formula I" are optionally substituted 6-membered aryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, and cyclohexyl. Preferred compounds of formula I" are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring,- (b) TmR1 is hydrogen, N{R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) Rs is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. More preferred compounds of formula I" are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring. Another preferred embodiment of this invention relates to compounds of formula I°: or a pharmaceutically acceptable derivative thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and C(O)NHCH(RB)CH(R5)2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 and Z2 are each independently selected from N or CH; T is a linker group; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -S02-; m and n are each independently selected from zer6 or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; y is 0-6; R3 is selected from R7, R, - (CH2) yCH (R8) R, CN, - (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8)N (R4) 2 ; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -(CH2)yR5, or - (CH2)yCH (Rs) 2 ; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7C0R7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted Ci_6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring,- R8 is selected from R, (CH2)WOR7, (CH2) WN (R4) 2, or (CH2)WSR7; and each w is independently selected from 0-4. Examples of suitable Sp groups of formula 1° include pyrrole (a), imidazole (b) , pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g) , 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: wherein each of a through j is optionally substituted with R6. Accordingly, the present invention relates to compounds of formula I° wherein Ring A is a pyridine (II°) , pyrimidine (III°) , or triazine (IV°) ring as shown below: or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, Rs, UnR3, and R8 are as described above. Preferred R5 groups of formula I° are R or OR7. Examples of such groups include OH, CH2OH, carbocyclic, or optionally substituted5 or 6-membered aryl or heteroaryl rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula I° are R and OR7, wherein R is an optionally'substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl,methyl, ethyl, OH, and CH2OH. Preferred substituents on the R5 aryl or heteroaryl ring are halogen, haloalkyl, OR°, and R°. Preferred TmR1 groups of formula 1° are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is cin optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. More preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. Most preferred TmR1 groups of formula I° are those listed in Table 1 below. Preferred R3 groups of formula I° are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3/ OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH (CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula I° are those listed in Table 1 below. Preferred compounds of formula I° are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from Cx.6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted5 or 6-membered aryl or heteroaryl ring. More preferred compounds of formula I° are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH)isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group,- (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) Rs is OH, CH2OH, carbocyclic, or an optionally substitutedphenyl or pyridyl ring. A preferred embodiment relates to compounds of formula III-a: or a pharmaceutically acceptable derivative thereof. Preferred TmR1 groups of formula III-a are hydrogen, N(R4)2' OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1.6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and araino. Examples of such preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3/ CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula Ill-a are those listed in Table 1 below. Preferred R3 groups of formula Ill-a are hydrogen, carbocyclyl, -CH(RB)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups are -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula Ill-a are those listed in Table 1 below. When R2 is R5, preferred R5 groups are pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl- piperazine-1-yl, wherein each group is optionally substituted. When R2 is (CH2)yR5, (CH2) yCH (R5) 2, or -N(R4)2, preferred Rs groups are pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1, 2 , 3 , 4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, -CH2OH, -(CH2)2OH, and isopropyl, wherein each group is optionally substituted. Preferred substituents on R5 are -OH, pyridyl, piperidinyl, and optionally substituted phenyl. When R2 is - (CH2) yCH (R8) CH (R5) 2, preferred R8 groups are R7 and OR7 such as OH and CH2OH. More preferred -QR2 groups are those listed in Table 1 below. Preferred compounds of formula III-a are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or' an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring,- (c) Q is -CO-, -CO2-, -CONH-, -S02-, -SO2NH-, -OC(O)NH-, -C(O)ONH-, or -CONHNH-; (d) R2 is -NR4 (CH2)yN(R4)2, -(CH2)yR5, - (CH2) yCH (Rs) 2; or -(CH2)yCH(R8)CH(R5)2; (f) R4 is R, R7, or - (CH2) yCH (R5) 2; and (g) R5 is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl. More preferred compounds of formula Ill-a are those having one or more, more preferably more than one, or most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3 ; (c) Q is -CO-, -CONH-, -S02-, or -SO2NH-; (d) R2 is -(CH2)yRs, - (CH2)yCH(Rs)2, or - (CH2)yCH(R8)CH(R5)2, wherein R8 is OH or CH2OH; and (e) R5 is -CH2OH, -(CH2)2OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4] diazepan-1-yl, 4- phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4- yl, imidazolyl, furan-2-yl, 1,2,3,4- tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl. Preferred compounds of formula III-a include those of formula III-a': Preferred TmR1 groups of formula III-a' are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, CH2NHCH3, and those listed in Table 1 below. Preferred R3 groups of formula III-a' are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring.. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups include -CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 of formula III- a' are those listed in Table 1 below. Preferred compounds of formula III-a' are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from Ca.4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1.6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is an optionally substituted6-membered aryl, heteroaryl, or carbocyclic ring. More preferred compounds of formula III-a' are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring. Preferred compounds of formula III-a are further selected from those of formula III-a°: or a pharmaceutically acceptable derivative thereof. Preferred R5 groups of formula III-a° are R or OR7. Examples of such groups include OH, CH2OH, or optionally substituted6-membered aryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula III-a° are R and OR7, wherein R is an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl, methyl, ethyl, OH, and CH2OH. Preferred TmR1 groups of formula III-a° are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula III-a° are those listed in Table 1 below. Preferred R3 groups of formula III-a° are hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples of such groups are -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl. Preferred Un groups, when present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More preferred UnR3 groups of formula III-a° are those listed in Table 1 below. Preferred compounds of formula III-a° are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C^ aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, and R8 is R7 or OR7. More preferred compounds of formula III-a° are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or an optionally substituted phenyl or benzyl group;+(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and (c) R5 is OH, CH2OH, phenyl, pyridyl, or cyclohexyl, and R8 is methyl, ethyl, OH, or CH2OH. Preferred compounds of formula III-a are set forth in Table 1 below. More preferred compounds in Table 1 are those of formula III-a' or III-a°. A Compound names for the compounds of formula III-a shown above in Table 1 are set forth in Appendix A. The above formula III-a compounds are those wherein Ring A is a pyrimidine ring and Sp is a pyrrole ring. Inhibitors of formula I wherein Ring A is a pyridine, pyrimidine, or triazine ring having the other Sp rings shown above are otherwise structurally similar to the formula III-a compounds and are represented by the following general formulae Il-b through II-j, Ill-b through III-j, and IV-b through IV-j shown below in Table 2 : compound shown above in Table 2 and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a method of treating or preventing an ERK2-mediated 5 disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of inhibiting ERK2 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable comprising said compound. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable comprising said compound. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof,, which method comprises administering to the patient a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable j composition comprising said compound. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of (3-catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. Another method relates to inhibiting ERK2, Aurora-2, or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound shown above in Table 2, or a pharmaceutically acceptable composition thereof, in an amount effective to inhibit ERK2, Aurora-2, or GSK-3. Each of the aforementioned methods directed to the inhibition of ERK2, Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound shown above in Table 2, as described above. The present compounds may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I through XII and the synthetic examples shown below. Reagents and conditions: (a) TmR1CH2COCl, A1C13/ CH2C12, 2 hours, RT; (b) DMF, 24 hrs, room temperature; (c) (Me2N)2- CHOt-Bu, THF, 24 hrs, room temperature; (d) guanidine, EtOH, 12 hours, reflux; (e) thiourea, EtOH, K2CO3, 12 hrs reflux; (f) m-CPBA, EtOH; (g) UnR3-NH2, DMSO, 130"C. Scheme I above shows a general synthetic route that is used for preparing the pyrrol-3-yl compounds of formula III-a of this invention when R2 is an optionally substituted phenyl group or aliphatic group. In step (a), an optionally substituted acid chloride is combined with compound 1, dichloromethane, and aluminum trichloride to form compound 2. In cases where benzoyl acid chlorides are used, a wide variety of substituents on the phenyl ring are amenable to this reaction. Aliphatic acid chlorides are also used in many cases. Examples of suitable R2 groups include, but are not limited to, those set forth in Table 1 above. The formation of amide 4 is achieved by- treating compound 2 with an amine 3 in DMF. When atnine 3 5 is a primary amine, the reaction proceeds at ambient temperature. When amine 3_ is a. secondary amine, the reaction is heated at 50°C to achieve complete reaction and afford amide 4. The formation of enamine 5 at step (c) is ) achieved by treating amide 4 with (Me2N)2-CHOt-Bu at ambient temperature. Alternatively, the reaction to form enamine 5 at step (c) is also achieved by using dimethylformamide-dimethylacetal (DMF-DMA). The reaction using DMF-DMA typically requires elevated temperature to afford enamine 5 whereas using (Me2N)2-OtBu has the advantage of proceeding at ambient temperature to afford the enamine 5 in higher purity. The formation of the pyrimidine compound 6 at step (d) is achieved by the treatment of enamine 5 with guanidine at elevated temperature. Alternatively, use of a substituted guanidine results in an amino substituent as is illustrated by J3. As an alternative method, in step (e) intermediate _5 may be cyclized with S-methyl thiourea to form the 2-thiomethylpyrimidine 7 which may in turn be oxidized with m-CPBA to the sulfone. The sulfonyl group may be subsequently displaced by an amine to generate the substituted aminopyrimidine 8. The compounds of formula III-a synthesized by this method, as exemplified in Table 1, were isolated by preparatory HPLC (reverse phase, 10—>90% MeCN in water over 15 minutes). The details of the conditions used for producing these compounds are set forth in the Examples. Reagents and conditions: (a) K2CO3, DMA, 100°C. Scheme II above shows a general method for preparing compounds 8 from intermediate 5 and an N- substituted guanidine (9) . Intermediate 5 may be prepared according to Scheme I steps (a), (b), and (c) shown above. Compound 5 is treated with N-substituted guanidine (9) and potassium carbonate in dimethylacetamide to form compound 8. This reaction is amenable to a variety of N-substituted guanidines to form compounds of formula III-a. The details of the conditions used for producing these compounds are set forth in the Examples. Reagents and conditions: (a) A1C13 neat, RT; (b) DMF, 24 hrs, room temperature; (c) polyphosphoric acid, 1 hour, 25-140°C; (d) POClj, DMF, reflux; (e) NH2-UnR3, iPrOH, reflux. Scheme III above shows a general synthetic route that may be used for preparing the pyrrol-3-yl compounds of formula Il-a of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) MeOH, pyridine, Cl2; guanidine; (c) bromine, acetic acid; (d) NaCN, DMF; (e) £, polyphosphoric acid, 1 hour, 25-140°C; (f) POCI3, DMF, reflux; (g) NH2-UnR3, iPrOH, reflux,- (h) SeO2; (i) MeNH. Scheme IV above shows a general synthetic route that may be used for preparing the imidazol-4-yl compounds of formula Il-b of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (e) , (f), and (g) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) MeOH, pyridine, Cl2; (b) 3-, (c) bromine, acetic acid; (d) NaCN, DMF; (e) 6, polyphosphoric acid, 1 hour, 25-140°C; (f) POC13, DMF, reflux; (g) NH2-UnR3, iPrOH, reflux. Scheme V above shows a general synthetic route that may be used for preparing the imidazol-2-yl compounds of formula II-b' of this invention. The conversion of intermediate 5_ to product £ may be achieved through steps (e) , (f) , and (g) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) (b) 3; (c) 5 polyphosphoric acid, 1 hour, 25-140°C; (d) POC13, DMF, reflux; (e) NH2- UnR3, iPrOH, reflux; (f) ceric ammonium nitrate. Scheme VI above shows a general synthetic route that may be used for preparing the pyrazol-3-yl compounds of formula II-c of this invention. The conversion of intermediate 4 to product 7 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) 1,1'-carbonyldiimidazole (CDI), triethylamine, THF; (b) N-butyllithium, THF, -78°C; (c) 6, polyphosphoric acid, 1 hour, 25-140°C; (d) POC13, DMF, reflux; (e) NH2-UnR3, iPrOH, reflux. Scheme VII above shows a general synthetic route that may be used for preparing the oxazol-2-yl compounds of formula II-e' of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. -78°C (b) t-butyllithium, THF, -78°C (c) 6, polyphosphoric acid, 1 hour, 25-140°C (d) POC13, DMF, reflux (e) NH2-R, iPrOH, reflux. 5 Scheme VIII above shows a general synthetic route that may be used for preparing the thiazol-2-yl compounds of formula II-g' of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d) , and (e) according to the method I described in JACS, 1957, pp 79. Reagents and conditions: (a) N-butyllithium, Bu3SnCl ; (b) t-butyllithium, THF, -78°C; (c) MeOCO2Me; (d) 4, Pd(0); (e) 6, polyphosphoric acid, 1 hour, 25-140°C; (f) POC13, DMF, reflux; (g) NH2-UnR3, iPrOH, reflux. Scheme IX above shows a general synthetic route that may be used for preparing the thiazol-4-yl compounds of formula II-g of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (e), (f), and (g) according to the method described in JACS, 1957, pp 79. Reagents and conditions: (a) CH3OCH2CH2COC1, AlCl3, CH2Cl2, 2.5 hours, RT; (b) DMF, 24 hrs, room temperature; (c) (Me2N)2-CHOt-Bu, THF, 24 hrs, room temperature,- (d) N- substituted guanidine, EtOH, 12 hours, reflux; (e) BBr3, CH2C12, Na2CO3. Scheme X above shows a general synthetic route that is used for preparing compounds of formula III-a where TmR1 is methoxymethyl or hydroxymethyl. In step (a), 3-methoxypropionyl chloride is combined with compound JL, dichloromethane, and aluminum trichloride to form compound .2. The formation of amide £ is achieved by treating compound 2^ with an araine J3 in DMF. When amine 2 is a primary amine, the reaction proceeds at ambient temperature. When amine _3 was a secondary amine, the reaction is heated at 50°C to achieve complete reaction and afford amide 4. The formation of enamine _5 at step (c) is achieved by treating amide 4 with (Me2N) 2-CHOt-Bu at ambient temperature. The formation of the pyrimidine compound 6 at step (d) is achieved by the treatment of enamine 5 with a guanidine at elevated temperature. Alternatively, use of a substituted guanidine results in an amino substituent. To form compounds where lk,TmR1 is hydroxymethyl, intermediate 6 may be treated with BBr3 in dichloromethane to form compounds 7. One of skill in the art would recognize that the hydroxymethyl group of compound 7 could be further derivatized to form a variety of compounds of formula III-a. The details of the conditions used for producing these compounds are set forth in the Examples. Reagents and conditions: (a) RNH2, MeCN, 0 C to 25 C, 12 hours; (b) A1C13, CH2Cl2, 25°C; (c) MeOH:H2O (2:1), 37'C. Scheme XI above shows a general method for preparing the triazine compounds of formula IV-a. Step (a) is performed in the manner described at Scheme I, step (b) above. Step (b) is performed in the manner described at Scheme I, step (a) above. The formation of the triazine ring at step (c) may be performed according to the methods described by Hirsch, J.; Petrakova, E.; Feather, M. S.; J Carbohydr Chem [JCACDM] 1995, 14 (8), 1179-1186. Alternatively, step (c) may be performed according to the methods described by Siddiqui, A. U. ; Satyanarayana, Y.; Rao, U. M. ; Siddiqui, A. H.; J Chem Res, Synop [JRPSDC] 1995 (2), 43. formula I', In I°, III-a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I', I", 1°, III- a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I', I", 1°, III-a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I', I", ID, III- a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I', I", 1°, III-a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ßcatenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula I', I", 1°, Ill-a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I', I", 1°, III- a, Ill-a' , or III-a°, or a pharmaceutically-acceptable composition comprising said compound. The term "CDK-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which CDK-2 is known to play a role. The term "CDK-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor. Such conditions include, without limitation, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M. and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, S., Wang, C, Wu, K. , Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett, M.D., Current Opinion in Oncologic, Endocrine & Metabolic Invescigational Drugs, 2, 40-59 (2000). Another aspect of this invention relates to a method of treating or preventing a Lck-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I', I", l°, lil-a, Ill-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. The terms "Lck-mediated disease" or '"Lck- mediated condition", as used herein, mean any disease state or other deleterious condition in which Lck is known to play a role. The terms "Lck-mediated disease" or "Lck-mediated condition" also mean those diseases or conditions that are alleviated by treatment with an Lck inhibitor. Lck-mediated diseases or conditions include, but are not limited to, autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, and leukemia. The association of Lck with various diseases has been described [Molina et al., Nature, 357, 161 (1992)] . Another aspect of this invention relates to a method of treating or preventing an AKT3-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I', I", 1°, III- a, III-a', or III-a°, or a pharmaceutically acceptable composition comprising said compound. The terms "AKT3-mediated disease" or "AKT3- mediated condition", as used herein, mean any disease state or other deleterious condition in which AKT3 is known to play a role. The terms "AKT3-mediated disease" or "AKT3-mediated condition" also mean those diseases or conditions that are alleviated by treatment with an AKT inhibitor. AKT3-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of AKT3 with various diseases has been described [Zang, Q. Y., et al, Oncogene, 19 (2000)] and [Kazuhiko, n., et al, The Journal of Neuroscience, 20 (2000)]. Another method relates to inhibiting ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I', I", 1°, Ill-a, III-a', or III-a°, , or a pharmaceutically acceptable composition comprising said compound, in an amount effective to inhibit ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3. Each of the aforementioned methods directed to the inhibition of ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula I', I", 1°, III-a, III-a', or III-a°, as described above. More preferably, each of the aforementioned methods is carried out with a preferred compound of formula I', I", 1°, III-a', or III-a°, and most preferably with a compound of formula I", 1°, III-a', or Ill-a°. In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. SYNTHETIC EXAMPLES For compounds where the HPLC Method is designated as "A", the following method was utilized: a gradient of water:MeCN, 0.1% TFA (95:5 -» 0:100) was run over 22 minutes at 1 mL/min and 214 nm. For compounds where the HPLC Method is designated as "B", the following method was utilized: a gradient of water.-MeCN, 0.1% TFA (90:10 -> 0:100) was run over 8 minutes at 1 mL/min arid 214 nm. Each of methods A and B utilize the YMC ODS-AQ 55 120A column with a size of 3.0 x 150 mm. As used herein, the term "Rt" refers to the retention time, in minutes, associated with the compound using the designated HPLC method. 2, 2, 2-Trichloro-l- (4-phenyl acetyl-lH-pyrrol-2-yl) - ethanone (1) ¦. In a dry flask, phenylacetyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM) to dissolve the reactants. To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 1 in 60% yield. XH NMR (CDC13) 6 4.0 (s, 2H), 7.1-7.35 (m, 7H), 9.7 (br s, NH). HPLC using method B provided Rt of 4.9 minutes. LC/MS (M+l) 330.2, (M-l) 328.1. 2,2,2-Trichloro-l-(4-(3-Chlorophenyl) acetyl-lH-pyrrol-2- yl)-ethanone (2J .- In a dry flask, 3-chlorophenylacetyl chloride (1 equivalent) was combined with 2- trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 2 . HPLC using method A provided Rt of 15 minutes 1- [5- (2,2,2-Trichloro-acetyl) -lH-pyrrol-3-yl) -propan-1- one (2> : In a dry flask, 3-proprionyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM) . To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 3 4-Phenylacetyl-lff-pyrrole-2-carboxylic acid benzylamide (•4) : To a solution of compound 1 (1 equivalent) in DMF, at ambient temperature, was added benzylamine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 4 was used without purification. HPLC using method B provided Rt of 3.8 minutes. FIA/MS (M+l) 319.3, (M-l) 317.2. 2-(3-Chlorophenyl)l-[5-(morpholine-4-carbonyl)-lH-pyrrol- 3-yl] -ethanone (E) : To a solution of compound 2(1 equivalent) in DMF, at ambient temperature, was added morpholine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 5 was used without purification. FIA/MS (M+l) 333.3, (M-l) 331.2. 1H NMR was consistent with expected structure. . 4-Propionyl-lH-pyrrole-2-carboxylic acid 3,4-difluoro- benzylamide (_6) : To a solution of compound 3_ U equivalent) in DMF, at ambient temperature, was added 3,4-difluorobenzyl amine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 6 was used without purification. 4- (3-Dimethylamino-2-phenyl-acryloyl) -lIf-pyrrole-2- carboxylic acid benzylamide (!) ¦. To a solution of compound 4_ (1 equivalent) in THF, at ambient temperature, was added (Me2N) 2CHOt-Bu (3 equivalents). After 24 hours, the solvent was evaporated and the crude product 1_ was used without purification. XH NMR (CDC13) 5 4.4 (s, 2H.) , 4.8 (s, NH), 6.8-7.4 (m, 13H). 2-(3-Chloro-phenyl)-3-dimethylamino-l-[5-(morpholine-4- carbonyl)-lH-pyrrol-3-yl]-propenone (J3) : To a solution of compound j> (1 equivalent) in THF, at ambient temperature, was added (Me2N) 2CHOt-Bu (3 equivalents) . After 24 hours, the solvent was evaporated and the crude product 8_ was used without purification. HPLC using method B provided Rt of 11.2 minutes. 4- (2-Amino-5-inethyl-pyriinidin-4-yl) -Iff-pyrrole-2- carboxylic acid 3 , 4-difluoro-benzylamide (III-a-74) : Step 1: To a solution of compound 6_ (1 equivalent) in THF, at ambient temperature, was added (Me2N) 2CHOt-Bu (3 equivalents). After 24 hours, the solvent was evaporated and the crude product was utilized without purification. Step 2: To a solution of the compound formed above at Step 1 (1 equivalent) in ethanol, at ambient temperature, was added guanidine (3 equivalents) and the resulting mixture heated at reflux. After 12 hours, the solvent was evaporated and the crude product purified by- preparatory HPLC (reverse phase; 10—>90% MeCN in water; 15 minutes) to afford the desired compound III-a-74. HPLC using method B provided Rt of 7.9 minutes. 1H NMR was consistent with expected structure. FIA/MS Obs. M+l /M- 1. {4- [2-Amino-5- (3-chlorophenyl) -pyrimidine-4-yl] -1H- pyrrol-2-yl}-morpholin-4-yl-methanone (III-a-72): To a solution of compound 8_ (1 equivalent) in ethanol, at ambient temperature, was added guanidine (3 equivalents) and the resulting mixture heated at reflux. After 12 hours, the solvent was evaporated and the crude product purified by preparatory HPLC (reverse phase; 10—>90% MeCN in water; 15 minutes) to afford the desired compound III- a-72. HPLC using method B, Rt=7.9 minutes. 1H NMR was consistent with expected structure. FIA/MS Obs. (M+l) 384.4 amu. N- (2-Hydroxy-l- (3) -phenyl-ethyl) -guanidine»HCl.- (5) - Phenylglycinol (0.38g, 2.7 mmol) and bis-Boc guanidine (AT)-triflate (0.9g, 2.3 mmol) were combined in methyle chloride (anhydrous, 5mL) and stirred at ambient temperature overnight. Completion of the reaction was verified by HPLC. The mixture was diluted with ethyl acetate, washed with 2M sodium bisulfite, brine then dried over MgSO4, filtered and concentrated in vacuo. The bis-Boc guanidine intermediate was treated with 4N HCl/dioxane (5raL) and stirred at room temperature unti] deprotection was complete (48 h) to afford the title compound.. 4- [2- (2-Hydroxy-l- (S) -phenyl-ethylamino) -5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy- 1-(S)-phenyl-ethyl)-amide (III-a-155): 4-(3- Dimethylamino-2-methyl-acryloyl) - 1H~pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide {100 mg, 0.29 mmol) was combined with N-(S)-phenylglycinol guanidine»HCl (126 mg) and potassium carbonate (121 mg) in N,N- dimethylacetamide (2mL). The resulting suspension was heated and stirred at 100° C for 24 hours. The crude material was diluted with ethyl acetate, washed with saturated NaHC03, brine, dried over MgSO4 and concentrated in vacuo. Purification by prep HPLC (Gilson: Column = CombiHT SB-C189 5 [iM 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) followed by preparative TLC (silica, 5% MeOH in CH2C12) afforded compound III-a-155 as a pale yellow solid (8.0 mg). HPLC Method B, Rc=4.76 minutes; MS (FIA) 458.2 (M+l), 456.1 (M-l); XH NMR consistent with structure. 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -phenyl-ethyl)- amide (III-a-162): 4-(3-Dimethylamino-2-methyl-acryloyl)- l#-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)- amide (100 mg, 0.29 mtnol) was combined with cyclopropyl guanidine»HCl (80 mg) and potassium carbonate (121 mg) in N,N-dimethylacetamide (2mL). The resulting suspension was heated and stirred at 100°C for 24 hours. The crude material was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgSO4 then concentrated in vacuo. Purification by preparative TLC (silica, 1:1 EtOAc.-Hexanes) afforded III-a-162 as a yellow solid (7.8 mg). HPLC Method B, Rt=4.29 minutes; LC/MS(m/z) 378.2 (M+l), 376.2 (M-l); JH NMR consistent with structure. 3-Methoxy-l-[5-(2, 2 , 2-trichloro-acetyl)-lH-pyrrol-3-yl]- propan-1-one: To a solution of 2-trichloroacetyl pyrrole 4- (3-Methoxy-propionyl) -lff-pyrrole-2-carboxylic acid (2- hydroxy-1- (S) -phenyl-ethyl) -amide: To a solution of 3- methoxy-1- [5- (2,2, 2-trichloro-acetyl) - 1H-pyrrol-3 -yl] - propan-1-one (3.0 g, 10 ramol) in acetonitrile (50 mL) , cooled to 0°C, was added (S)-( + )-phenyl glycinol (1.2 equivalent, 1.65 g, 12 mmol) and the resulting mixture stirred for 3 days at room temperature. The solvent was removed under reduced pressure and the residue purified by chromatography on silica gel (MeOH 5% in DCM) to afford 5.3 g of the title compound as a white solid. HPLC Method B, Rt=4.2 minutes; LC/MS(m/z) 317.03 (M+l), 315.00 (M-l) ; 1H NMR consistent with structure. (1.0 equivalent, 4.67g, 22 mmol) in methylene chloride (5 mL) was added 3-methoxypropionyl chloride (1.0 equivalent, 22 mmol) then aluminium trichloride (1.0 equivalent, 2.93g, 22 mmol) was added in small portions. After 2.5 hours, the crude mixture was chromatographed on silica gel (MeOH 2% in DCM) to afford 3.0 g of the Friedel-Craft product. 1H NMR consistent with structure. 4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -lff-pyrrole- 2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide: 4-(3-Methoxy-propionyl)-l.H-pyrrole-2-carboxylic acid (2- hydroxy-1-(S)-phenyl-ethyl)-amide was treated with an excess of Bredereck's reagent in THF at room temperature to 50°C for 3 days. The solvent was removed under reduced pressure and the concentrate was used directly in the next step. HPLC Method B, Rt=5.0 minutes "broad peak". 4- (5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)- amide (III-a-164): 4-(3-Dimethylamino-2-methoxymethyl- acryloyl)-l#-pyrrole-2-carboxylic acid (2-hydroxy-l- (S)- phenyl-ethyl)-amide (0.27 mmol) was combined with phenyl guanidine (73 mg) in N,N-dimethylacetamide (2 mL) and the resulting suspension was heated at 90°C for 35 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgS04 and concentrated in vacuo. The crude product was purified by prep HPLC (Gilson: Column = CombiHT SB-C189 5 p.M, 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) to afford III-a-164 as a yellow solid (3.2 mg). LC/MS(m/z) 444.16 (M+l), 442.19 (M-l); HPLC Method B, Rt=5.16 minutes: 1H NMR consistent with structure. 4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)- amide (III-a-165): To a solution of III-a-164 (15 mg, 0.03 mmol) in dichloromethane (2 mL), cooled to -78°C, was added BBr3 (135 \|IL, 0.13 mmol) . After 15 minutes the reaction was allowed to warm to room temperature. After 45 minutes, the reaction was quenched with a saturated solution of sodium carbonate and the resulting mixture was stirred for an additionnal 3 0 minutes before extraction with ethyl acetate. The organic layers were combined and washed with brine then dried over sodium sulfate. The crude mixture was purified by prep TLC (silica, 7% MeOH in CH2Cl2) to afford III-a-165 as a beige solid (1.6 mg) . HPLC Method B, Rt=4.54 minutes; LC/MS (m/z) 430.15 (M+l), 428.03 (M-l); ^ NMR consistent with structure. 4- (2-Amino-5-methoxymethyl-pyrimidin-4-yl) -l.ff-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide (Ill-a- 161): The enamine formed above at Example 16 (0.27 mmol) was combined with guanidine»HCl (51 mg), and K2CO3 (100 mg) in N,N-dimethylacetamide (4 mL). The heterogenous mixture was heated and stirred at 90° C for 3 5 h. The crude material was diluted with ethyl acetate, washed with saturatedd NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. Purification by prep HPLC (Gilson: Column = CombiHT SB-C189 5 fiM, 21.2 mm x 100 mm, eluent = 0.l%TFA MeCN/H2O gradient) afforded III-a-161 as a yellow solid (2.0 mg). LC/MS(m/z) 368.12 (M+l), 366.15 (M-l), Rt (HPLC) =-3.77 min, XH NMR consistent with structure. 4- (2-Mercapto-5-methyl-pyrimidin-4-yl)-Iff-pyrrole-2- carboxylic acid (2-hydroxy-l-(5)-phenyl-ethyl)-amide: 4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -Iff-pyrrol e- 2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide (17.6 mmol, 6.0 g) was combined with thiourea (39 mmol, 3.0 g) and potassium carbonate (53 mmol, 7.3 g) in ethanol (50 mL) and the resulting suspension was heated at 90° C for 24 hrs. The solvent was removed in vacuo and the resulting black solid was diluted with water and the solid was removed by filtration. The solid was washed with ethyl acetate twice and the aqueous solution was acidified to pH 5-6 with HC1(2N). The solid formed was removed by filtration and the aqueous solution was then extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under vacuum to afford the title compound as a brown solid (3.0 g, 48% yield). HPLC Method B, Rt=3 .7 minutes, 1H NMR consistent with structure. 4- (5-Methyl-2-propylsulfanyl-pyrimidin-4-yl) -1H-pyrrole- 2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide: To a solution of 4-(2-mercapto-5-methyl-pyrimidin-4-yl) - lH-pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl- ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueous ammonia (15%) was added at room temperature n-propyliodide (11.6 mmol, 1.1 mL). The solution was stirred overnight at room temperature. The resulting solid was collected by filtration and used directly for the next step. 1H NMR consistent with the structure. 4- [5-Methyl-2- (propane-1-sulfonyl)-pyrimidin-4-yl]~1H- pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -phenyl-ethyl)- amide: The thiopropyl compound (7.7 mmol, 3.05g) prepared at Example 21 above was dissolved in 120 mL of ethanol. To this solution, maintained at room temperature, was added m-CPBA (70% w/w%, 23.1 mmol, 4.0 g). The solution was stirred for an additional 4 hours at room temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate, then washed 4 times with a solution of sodium hydroxide (IN) . The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid (1.7g, 51% yield for 2 steps). HPLC Method B, Rc=5.4 minutes. 1H NMR consistent with the structure. 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide: To a solution of 4-[5-methyl-2-(propane-1-sulfonyl)-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-(S) - phenyl-ethyl)-amide (47 p.mol, 20 mg) in DMSO (1 mL) was added ethylamine (0.5 mmol, 150 \|xL) . The mixture was heated at 130°C for 24 hours to afford the title compound. LC/MS(m/z) 366.2 (M+l); HPLC Method B, Rt=4.2 minutes; 1H NMR consistent with the structure. 4- [2-{N' ,N' -Dimethyl-hydrazino)-5-methyl-pyrimidin-4-yl]- lff-pyrrole-2-carboxylic acid (2-hydroxy-l- (5)-phenyl- ethyl)-amide (III-a-226): To a solution of 4-(3- dimethylamino-2-methoxymethyl-acryloyl)-ltf-pyrrole-2- carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide (0.15 mmol, 50 mg) in DMA (2 mL) was added dimethyl-N,N- aminoguanidine»2HCl (0.17 mmol, 30 mg) and potassium carbonate (0.36 mmol, 50 mg). The reaction mixture was stirred for 48 hrs at 100°C. The solvent was removed by hi-vacuum "GeneVac" and the residue purified by preparative HPLC (Gilson: Column = CombiHT SB-C189 5 J^M 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) followed by preparative TLC (silica, 5% MeOH in CH2C12) "double elutions" afforded compound III-a-226 as a pale yellow solid (1.3 mg). HPLC Method B, Rt=4.03 min.; LC/MS (m/z) 381.1 (M+l), 379.1 (M-l); 2H NMR consistent with structure. Ethanolguanidine: Ethanolamine hydrochloride (2 00 mg, 2 mmol) was added to a mixture of N, N'-di-boc -N'- triflylguanidine (8 00 mg, 2 mmol) and TEA (0.28 mL, 2 mmol) in dichloromethane (10 mL). The mixture was stirred overnight then diluted with EtOAc, washed with sodium bisulfate (2M), saturated sodium bicarbonate, dried over NaS04 and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 20% CH2Cl2/hexane to afford a white solid (0.56 g, 92%). ). 2H NMR (CDC13) : 5 4.18 (q, 2H) , 1.60 (d, 18H), 1.37 (t, 3H). To this bis-Boc guanidine was added 4M HCl/dioxane (5 mL). The mixture was stirred for 24 h and then concentrated to afford the title compound (0.26 g) . *H NMR (MeOD) : 5 3.92 (q, 2H), 1.27 (t, 3H) . MS (M+l) 104. 4-(2-Ethanolamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-(s)-phenyl-ethyl)-amide (III-a-195): To a mixture of 4-(3-dimethylamino-2-methyl- acryloyl)-lH-pyrrole-2-carboxylic acid (2-hydroxymethyl- 1- (S) -phenyl-ethyl) amide (0.1 mmol) and K2CO3 (55 mg, 0.4 mmol) in DMF (1 mL) was added ethanolguanidine hydrogen chloride (0.2 mmol). The resulting suspension was stirred for 6 hours at 90 °C. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude residue was purified by preparative HPLC (Gilson: Column = CombiHT SB-C189 5 JIM 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) to afford compound III-a-195 as yellow oil (21 mg). HPLC (method B) Rt = 4.08 min; MS (M+l) 382.1. Ethyl carbamate guanidine: Ethylcarbazate (208 mg, 2 mmol) was added to a solution of N'N'-di-boc N'- triflylguanidine (800 mg, 2 mmol) in dichloromethane (10 mL). The mixture was stirred for overnight then diluted with EtOAc, washed with sodium bisulfat (2M), saturated sodium bicarbonate, dried over anhydrous NaSO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 3 0% EtOAc/hexane to afford a white solid (0.55g). To this bis-boc guanidine was added 4M HCl/Dioxane (5 mL). The mixture was stirred for 24 hours and then concentrated to afford the title compound. 1H NMR (MeOD) : 5 3.4.18 (d, 2H) , 3.26 (s, 1H), 1.28 (t, 3H). MS (M+l) 134. III-a-218 4-(2-Ethyl carbamate-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-(s)-phenyl-ethyl)-amide (III-a-218): To a mixture of 4-(3-dimethylamino-2-methyl- acryloyl)-lH-pyrrole-2-carboxylic acid (2-hydroxymethyl- 1-(S)-phenyl-ethyl) amide (0.1 mmol) and K2CO3 (55 mg, 0.4 mmol) in DMF (1 mL) was added ethyl carbamate guanidine hydrogen chloride (0.2 mmol). The resulting suspension was stirred for 6 hours at 90 °C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC (Gilson: Column = CombiHT SB-C189 5 \|iM 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient) to afford compound III-a-218 as a yellow oil (10 mg). HPLC (method B) Rt = 4.03/ MS (M+l) 425.1. ^NMR (MeOD) 8.08 (s, 1H); 7.87 (s, 1H) ; 7.7 (s, 1H) , 7.24-7.5 (m, 5H) ; 5.15 (t, 1H) , 4.2 (m, 2H), 3.85 (m, 2H); 2.5 (s, 3H). Example 2 9 We have prepared other compounds of formula III-a by methods substantially similar to those described in the above Examples 1-28 and those illustrated in Schemes I-XII. The characterization data for these compounds is summarized in Table 3 below and includes LC/MS, HPLC, and 1H NMR data. Where applicable, 1H NMR data is summarized in Table 3 below wherein "Y" designates 1H NMR data is 5 available and was found to be consistant with structure. Compound numbers correspond to the compound numbers listed in Table 1. BIOLOGICAL TESTING The activity of the present compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylatiori activity or ATPase activity of the activated protein kinase. Alternate in vitro assays guantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands. The details of the conditions used for performing these assays are set forth in Examples 3 0 through 37. Example 3 0 ERK INHIBITION ASSAY Compounds were assayed for the inhibition of ERK2 by a spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK2 (10 nM) was incubated with various concentrations of the compound in DMSO (2.5 %) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.5, containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 uM NADH, 150 ug/mL pyruvate kinase, 50 ug/mL lactate dehydrogenase, and 200 uM erktide peptide. The reaction was initiated by the addition of 65 uM ATP. The rate of decrease of absorbance at 34 0 nM was monitored. The IC50 was evaluated from the rate data as a function of inhibitor concentration. Table 4 shows the results of the activity of selected compounds of this invention in the ERK2 inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as "A" provided a percent inhibition less than or equal to 33%; compounds having an activity designated as "B" provided a percent inhibition of between 24% and 66%; and compounds having an activity designated as "C" provided a provided a percent inhibition of between 67% and 100%. Compounds having an activity designated as "D" provided a Xi of less than 0.1 micromolar; compounds having an activity designated as "E" provided a Kj. of between 0.1 and 1.0 micromolar; and compounds having an activity designated as "F" provided a Ki of greater than 1.0 micromolar. Example 31 ERK2 INHIBITION: Cell Proliferation Assay Compounds may be assayed for the inhibition of ERK2 by a cell proliferation assay. In this assay, a complete media is prepared by adding 10% fetal bovine serum and penicillin/streptomycin solution to RPMI 1640 medium (JRH Biosciences). Colon cancer cells (HT-29 cell line) are added to each of 84 wells of a 96 well plate at a seeding density of 10,000 cells/well/150 µL- The cells are allowed to attach to the plate by incubating at 37°C for 2 hours. A solution of test compound is prepared in complete media by serial dilution to obtain the following concentrations: 20 (µM, 6.7 \|J.M, 2.2 (µM, 0.74 (J.M, 0.25 µM, and 0.08 µM. The test compound solution (50 \|iL) is added to each of 72 cell-containing wells. To the 12 remaining cell-containing wells, only complete media (200 µL.) is added to form a control group in order to measure maximal proliferation. To the remaining 12 empty wells, complete media is added to form a vehicle control group in order to measure background. The plates are incubated at 3 7°C for 3 days. A stock solution of 3H-thymidine (1 mCi/mL, New England Nuclear, Boston, MA) is diluted to 20 µCi/mL in RPMI medium then 20 µL of this solution is added to each well. The plates are further incubated at 37°C for 8 hours then harvested and analyzed for 3H-thyraidine uptake using a liquid scintillation counter. Compounds III-a-116, III-a-139, and III-a-136 were each shown to have an IC50 of less than 0.1 µM. Example 32 ERK1 INHIBITION ASSAY Compounds were assayed for the inhibition of ERK1 by a spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK1 (20 nM) was incubated with various concentrations of the compound in DMSO (2.0 %) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.6, containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 uM NADH, 30 ug/mL pyruvate kinase, 10 µg/mL lactate dehydrogenase, and 150 uM erktide peptide. The reaction was initiated by the addition of 140 uM ATP (20 uL) . The rate of decrease of absorbance at 34 0 nM was monitored. The Kj was evaluated from the rate data as a function of inhibitor concentration. Examples of compounds that were found to inhibit ERK1 with an activity of less than 0.1 uM include III-a-202, III-a-204, and III-a-205. Example 33 GSK-3 INHIBITION ASSAY Compounds were screened for their ability to inhibit GSK-3[3 (AA 1-420) activity using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 3 00 uM NADH, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 2 0 uM ATP (Sigma Chemicals, St Louis, MO) and 300 uM peptide (HSSPHQS(PO3H2)EDEEE, American Peptide, Sunnyvale, CA) . Reactions were carried out at 3 0 °C and 2 0 nM GSK-3J3. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 3 00 µM NADH, 3 0 ug/ml pyruvate kinase and 10 ug/ml lactate dehydrogenase. An assay stock buffer solution was prepared containing all of the reagents listed above with the exception of ATP and the test compound of interest. The assay stock buffer solution (175 µi) was incubated in a 96 well plate with 5 ul of the test compound of interest at final concentrations spanning 0.002 uM to 30 uM at 30 °C for 10 min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds in daughter plates. The reaction was initiated by the addition of 20 ul of ATP (final concentration 20 uM). Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at 3 0°C. The Ki values were determined from the rate data as a function of inhibitor concentration. Table 5 shows the results of the activity of selected compounds of this invention in the GSK3 inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as "A" provided a Ki of less than 0.1 micromolar; compounds having an activity designated as "B" provided a Ki of between 0.1 and 1.0 micromolar; and compounds having an activity designated as "C" provided a Ki of greater than 1.0 micromolar. Example 3 4 AURORA-2 INHIBITION ASSAY Compounds were screened in the following manner for their ability to inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 3 0 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 4 0 mM ATP, and 800 uM peptide (LRRASLG, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 uM. The resulting mixture was incubated at 3 0 °C for 10 min. The reaction was initiated by the addition of 10 uL of Aurora-2 stock solution to give a final concentration of 70 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 34 0 ran over a 5 minute read time at 3 0 °C using a BioRad Ultramark plate reader (Hercules, CA) . The Ki values were determined from the rate data as a function of inhibitor concentration. Examples of compounds that were found to inhibit Aurora-2 include III-a-116,- III-a-117, III-a-136, III-a-138, III- a-139, IIl-a-140, and III-a-141. Example 3 5 CDK-2 INHIBITION ASSAY Compounds were screened in the following manner for their ability to inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 1, 2249) . To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 3 00 mM NADH, 3 0 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and 100 uM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 3 0 uM. The resulting mixture was incubated at 3 0 °C for 10 min. The reaction was initiated by the addition of 10 uL of CDK-2/Cyclin A stock solution to give a final concentration of 25 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5-minute read time at 30 °C using a BioRad Ultramark plate reader (Hercules, CA) . The Ki values were determined from the rate data as a function of inhibitor concentration. The following compounds were shown to have Ki values than 0.1 µM for CDK-2: III-a-116, III-a-142, III- a-149, and III-a-152. The following compounds were shown to have Ki values between 0.1 µM and 1 µM for CDK-2: III-a-146, III- a-148, III-a-150, III-a-155, III-a-162, and III-a-174. The following compounds were shown to have Ki values between 1.0 and 20.0 µM for CDK-2: III-a-117, III- a-156, and III-a-159. Example 3 6 LCK INHIBITION ASSAY The compounds were evaluated as inhibitors of human Lck kinase using either a radioactivity-based assay or spectrophotometric assay. Lck Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors of full length bovine thymus Lck kinase (from Upstate Biotechnology, cat. no. 14-106) expressed and purified from baculo viral cells. Lck kinase activity was monitored by following the incorporation of 33P from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu.-Tyr = 4:1 (Sigma, cat. no. ß0275). The following were the final concentrations of the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg/ml BSA, 10 uM ATP (1-2 uCi 33P-ATP per reaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of recombinant human Src kinase. In a typical assay, all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells. Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%. The assay plate was incubated at 30 C for 10 min before initiating the reaction with 33P-ATP. After 20 min of reaction, the reactions were quenched with 150 ul of 10% trichloroacetic acid (TCA) containing 20 mM Na3PO4. The quenched samples were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF/F Glass Fiber Filter, cat no. 7700-3310) installed on a filter plate vacuum manifold. Filter plates were washed four times with 10% TCA containing 20 mM Na3PO4 and then 4 times with methanol. 200ul of scintillation fluid was then added to each well. The plates were sealed and the amount of radioactivity associated with the filters was quantified on a TopCount scintillation counter. The radioactivity incorporated was plotted as a function of the inhibitor concentration. The data was fitted to a competitive inhibition kinetics model to get the Ki for the compound. Lck Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Lck kinase-catalyzed phosphorylation of poly Glu-Tyr substrate was quanitified using a coupled enzyme assay (Fox et al (1998)' Protein Sci 7, 2249) . In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The disappearance of NADH can be conveniently followed at 340 nm. The following were the final concentrations of the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 5 mg/ml poly Glu-Tyr, and 5 0 nM of recombinant human Lck kinase. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 2 00 uM NADH, 3 0 ug/ml pyruvate kinase and 10 ug/ml lactate dehydrogenase. In a typical assay, all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells. Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%. The assay plate was incubated at 30 °C for 10 min before initiating the reaction with 150 uM ATP. The absorbance change at 34 0 nm with time, the rate of the reaction, was monitored on a molecular devices plate reader. The data of rate as a function of the inhibitor concentration was fitted to competitive inhibition kinetics model to get the Ki for the compound. The following compounds were shown to have Ki values than 1 µM for Lck: III-a-170, III-a-171, Ill-a- 172, III-a-173, III-a-181, and III-a-203. The following compounds were shown to have Ki values between l.o and 20.0 µM for Lck: III-a-204, Ill-a- 205, III-a-206, and III-a-207. Example 3 7 AKT3 INHIBITION ASSAY Compounds were screened for their ability to inhibit AKT3 using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 224 9). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgCl2, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 uM ATP (Sigma Chemicals) and 200 uM peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at 30 "C and 45 nM AKT3. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 3 00 uM NADH, 3 0 ug/ML pyruvate kinase and 10 ug/ml lactate dehydrogenase. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of AKT3, DTT, and the test compound of interest. 56 ul of the stock solution was placed in a 384 well plate followed by addition of 1 ul of 2 mM DMSO stock containing the test compound (final compound concentration 30 uM). The plate was preincubated for about 10 minutes at 30°C and the reaction initiated by addition of 10 µl of enzyme (final concentration 45 nM) and 1 mM DTT. Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a 5 minute read time at 30 0C. Compounds showing greater than 50% inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine IC50 values. Selected compounds of this invention that inhibit AKT3 include: III-a-238. While we have presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other embodiments which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example. Appendix A: Names of Table 1 Compound Numbers III-a- 1: 4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid dimethylamide; 2: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-pyrrolidin-l-yl-methanone; 3 •• {4- [2-Amino-5- (3-chloro-2-fluoro-phenyl) -pyrimidin-4- yl]-lH-pyrrol-2-yl}-pyrrolidin-l-yl-methanone; 4: 4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 5: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] - morpholin-4-yl-methanone; 6: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- [1,4' ]bipiperidinyl-l' -yl-methanone; 7: {4- [2-Amino-5- (3, 4-dimethoxy-phenyl) -pyrimidin-4-yl] - lH-pyrrol-2-yl}-(3-hydroxy-piperidin-1-yl) - methanone; 8: {4- [2-Amino-5- (3, 4-dimethoxy-phenyl) --pyrimidin-4-yl] - lH-pyrrol-2-yl}-[1,4']bipiperidinyl-1'-yl-methanone; 9 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] - [1,4']bipiperidinyl-1'-yl-methanone; 10: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-[1,4']bipiperidinyl-1'-yl- methanone; 11: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]- (4-hydroxy-piperidin-1-yl)-methanone; 12 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- [4- (2-fluoro-phenyl)-piperazin-1-yl]-methanone; 13 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- (4-phenyl-piperazin-l-yl)-methanone; 14 .- [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] - [4- (4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-l-yl]- methanone; 15 : [4- (2-Arnino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] - (4-pyridin-2-yl-piperazin-1-yl)-methanone; 16 : (4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrol-2-yl}-morpholin-4-yl-methanone; 17: 4-[2-Amino-5- (3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)- amide; 1_8 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2- yl]-morpholin-4-yl-methanone; 19: 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 20: 4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)- amide; 21: {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-yl]- methanone; 22 : (4- [2-Amino-5- (3 -chloro-phenyl) -pyrimidin-4-yl] -1H-- pyrrol-2-yl}-(4-phenyl-piperazin-1-yl)-methanone; 23: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl] -methanone; 24: {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-(3 , 4-dihydro-lH-isoquinolin-2-yl)- methanone; 25: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)- methanone,- 26: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-morpholin-4-yl-methanone; 27: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-(4-hydroxy-piperidin-l-yl)-methanone; 28 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[1,4']bipiperidinyl-1'-y1-methanone; 29 : 4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid benzyl-methyl-amide; 30 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- [4- (4-methoxy-phenyl)-piperazin-1-yl]-methanone; 31: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] - (2-hydroxymethyl-piperidin-1-yl)-methanone; 32 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- (3,4-dihydro-lH-isoquinolin-2-yl)-methanone; 33 : 4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid benzyl-methyl-amide; 34 : (4- [2-Amino-5-(3 t4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl] -methanone; 35: {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl] - lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinolin-2-yl)- methanone; 36 : 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid benzyl-methyl-amide ,- 37: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl] - (4-phenyl-piperazin-l-yl)-methanone; 38 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-IH-pyrrol-2- yl]- (4-methyl-[1,4]diazepan-1-yl)-methanone; 39 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]- (3,4-dihydro-lH-isoquinolin-2-yl)-methanone; 40: 4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl] -1H- pyrrole-2-carboxylic acid benzyl-methyl-amide; 41: (4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)- methanone; 42 ¦• 4- [2-Amino-5- (3-chloro-2-f luoro-phenyl) -pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid benzyl-methyl- amide; 43: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin-1-yl]- methanone; 44: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4 - yl]-lH-pyrrol-2-yl}-(4-phenyl-piperazin-l-yl)- methanone; 45: [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]- [4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone; 4 6: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]-(3-hydroxy-piperidin-1-yl)-methanone; 47: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2- yl]- [4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone; 4 8 .- [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2- yl]- [4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-l- yl]-methanone; 49: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin- 1-yl] -methanone; 50: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-[4-(4-methoxy-phenyl)-piperazin- 1-yl] -methanone; 51: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)- methanone; 52 : l-(4-(4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)- pyrimidin-4-yl]-lH-pyrrole-2-carbonyl}-piperazin-1- yl)-ethanone; 53 .- {4- [2-Amino-5- (3-chloro-2-f luoro-phenyl) -pyrimidin-4- yl]-lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinolin-2- yl)-methanone; 54 : {4~ [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl)-(3-hydroxy-piperidin-l-yl)-methanone; 55 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] - (4-methyl-[1,4]diazepan-1-yl)-methanone; 56 : l-(4-{4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin- 4-yl]-lH-pyrrole-2-carbonyl}-piperazin-1-yl)- ethanone; 57 : {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl] - lH-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)- methanone; 58: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- (3-hydroxy-piperidin-l-yl)-methanone; 59: 4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-- pyrrole-2-carboxylic acid methyl-(2-pyridin-2-yl- ethyl)-amide; 60 : [4- (2-Am'ino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2- yl]-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone; 61: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin- 1-yl] -methanone; 62: 4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- methyl-2-phenyl-ethyl)-methyl-amide; 63: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)- methanone; 64: [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]- (4-hydroxy-piperidin-1-yl)-methanone; 65: {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- 1H-pyrrol-2-yl}-(4-hydroxy-piperidin-1-yl)- methanone; 66: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4- yl]-lH-pyrrol-2-yl}-(4-hydroxy-piperidin-l-yl)- methanone; 67 : (4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)- methanone; 68 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- methanone; 69: 1-{4-[4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H- pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone; 70 : {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]- lH-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1- yl]-methanone; 71 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] - pyrrolidin-1-yl-methanone; 72 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H- pyrrol-2-yl}-morpholin-4-yl-methanone; 73 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid benzylamide; 74: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 3,4-difluoro-benzylamide; 75 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 76 : 4 - (2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2 - carboxylic acid 4-fluoro-benzylamide; 77 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 3-chloro-benzylamide; 78 : 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 4-methoxy-benzylamide; 79: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 3-chloro-4-f luoro-benzylamide ,- 80: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide 81: 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide 82: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide; 83: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid . (3-hydroxy-l-phenyl-propyl)-amide; 84: 4- (2,5-Diamino-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid 3-chloro-4-fluoro-benzylamide; 85: 4- (2-Amino-5-methylamino-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid 3-chloro-4-fluoro-benzylamide; 86: 4- (5-Acetylamino-2-amino-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid 3-chloro-4-fluoro-benzylamide; 87 : 4- [2-Amino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1H- pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 88 : 4- (2-Amino-5-hydroxy-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid 3-chloro-4-fluoro-benzylamide; 89 : 4- (2-Amino-5-methylaminomethyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 90 : 4- (2-Amino-5-hydroxymethyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 91: 4- [2-Cyclohexylamino-5-(3-methyl-ureido)-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 92: 4- [2-Acetylamino-5-(3-methyl-ureido)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide ; 93 : 4- (5-Hydroxy-2-methanesulfonylamino-pyrimidin-4-yl) - lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide; 94 : 4- (2-Amino-5-methanesulfonyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3-chloro-4-fluoro- benzylamide; 95 : 4- (2-Amino-5-hydroxymethyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3 , 4-dif luoro-benzylamide ; 96 : 4- (2-Cyclohexylamino-5-methyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide; 97 . 4- [2-Amino-5- (3 , 5-dichloro-phenyl) -pyrimidin-4-yl] - lH-pyrrole-2-carboxylic acid (pyridin-4-ylmethyl)- amide; 18: 4- [5- (3 , 5-Dichloro-phenyl) -2 -phenylamino-pyrimidin-4 - yl]-lH-pyrrole-2-carboxylic acid 3-trifluoromethyl- benzylamide; 99 : 4- [2-Amino-5-(3, 5-dichloro-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid .(2-hydroxy-l-phenyl- ethyl)-amide; 100: 4- [2-Amino-5-(3 , 5-dichloro-phenyl)-pyrimidin-4-yl] - lH-pyrrole-2-carboxylic acid (benzo [1,3]dioxol-5- ylmethyl)-amide; 101: 4- [2-Amino-5-(3 , 5-dichloro-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid (2-dimethylamino-2- pyridin-3-yl-ethyl)-amide; 102 : 4- [2-Amino-5-(3, 5-dichloro-phenyl)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid 4-methanesulfonyl- benzylamide; 103 : 4- [5- (3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide; 104 : 4- [5- (3 , 5-Dichloro-phenyl)-2-phenylamino-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-morpholin-4- yl-2-pyridin-3-yl-ethyl) -amide; 105 : 4- [2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl) -amide; 106 : 4- (2-Amino-5-propyl-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 107 : 4- (2-Amino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 108 : 4- (5-Methyl-2-methylamino-pyrimidin-4 -yl) -1H- pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)- amide; 109 : 4- (2-Methylamino-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (2-pyridin-3-yl-ethyl)-amide; 110 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (2-dimethylamino-ethyl) -amide,- 111: 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid propylamide; 112 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (3-phenyl-propyl)-amide; 113 .- 4- (2-Ethylamino-5-methyl -pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (naphthalen-1-ylmethyl)-amide,- 114 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid cyclopropylamide; 115 : 4- (2-Ethylamino-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid 2-trifluoromethyl-benzylamide; 116 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 117: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 118 : 4- (2-Ethylamino-pyrimidin-4-yl) -lH-pyrrole-2- carboxylic acid (4-methyl-cyclohexyl)-amide; 119 : 4-(5-Ethyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid isopropylamide; 120 : 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-amino-ethyl)-amide; 121: 4- (2-Amino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid benzyl-methyl-amide; 122 : 4- (2-Amino-pyrimidiri-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl- amide; 123 : 1-{4- [4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone; 124 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (3-phenyl-propyl)-amide; 125 : 4- (2-Amino-5-ethyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid [2-(6-methoxy-lH-indol-3-yl)-ethyl]- amide; 126 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-phenoxy-ethyl)-amide; 127 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (1-methyl-3-phenyl- propyl)-amide; 128 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (lH-benzoimidazol-2- ylmethyl)-amide; 129 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (1-hydroxymethyl-3-methyl- butyl)-amide; 130 .- 4- (5-Methyl-2-phenylamino-pyrimidin-4 -yl) -1H- pyrrole-2-carboxylic acid [l-hydroxymethyl-2-(1H- imidazol-4-yl)-ethyl]-amide; 131: 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2- carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide; 132 : 4- [2-(2-Diethylamino-ethylamino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid 3,4-difluoro- benzylamide; 133 : 4- [5-Methyl-2-(2-piperidin-l-yl-quinazolin-4- ylamino)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid benzylamide; 134 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-chloro-4-fluoro- phenyl)-2-hydroxy-ethyl]-amide; 135 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-chloro-4-fluoro- phenyl)-2-hydroxy-ethyl]-amide; 136 : 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 137: 4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 138: 4-[2-(3-Hydroxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 139: 4-[2-(Benzo[1,3]dioxol-5-ylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 140: 4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 141: 4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 142: 4- [2- (4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 143: 4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 144: 4- (5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 145: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-fluoro-4-methyl- phenyl)-2-hydroxy-ethyl]-amide; 146: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [2-hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-amide; 147: 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid [1-(3-fluoro-4- methyl-phenyl)-2-hydroxy-ethyl]-amide; 148: 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-amide; 149: 4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 150: 4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 151: 4- [2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 152 : 4- [2- (4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 153: 4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 154: 4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 155: 4- [2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 156: 4- [2- (2-Methoxy-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl) - amide ,- 157: 4- [5-Methyl-2-(4-trifluoromethoxy-phenylamino)- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 15 8 .- 4- (2-Isobutylamino-5-methyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 159: 4- [2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 160 .- 4- (5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 161: 4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 162 : 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 163: 4- (5-Methyl-2-propylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 164: 4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 165: 4- (5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl) -amide ,• 166 : 4- {2- (2-Hydroxy-l-phenyl-ethylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 167: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl- ethyl)-amide; 168 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl- ethyl)-amide; 169: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-2-phenyl-ethyl)-amide; 170: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2- phenyl-ethyl)-amide; 171: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-IH-pyrrole- 2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2- phenyl-ethyl)-amide; 172 : 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide; 173 .- 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide; 174: 4- [2-(1-Hydroxymethyl-cyclopropylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 175 : 4- [2- (2-Hydroxy-ethylamino) -5-methyl-pyrimidin-4 - yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 176 : 4- [2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 177 : 4- [2- (2-Hydroxy-propylamino) -5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 178 : 4- [2- (2-Hydroxy-propylamino) -5-tnethyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 179 : 4- [2- (2-Hydroxy-cyclohexylamino) -5-methyl-pyrimid.in- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1- phenyl-ethyl)-amide; 121: 4- [2- (2-Hydroxy-l-methyl-ethylamino)-5-methyl- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 121: 4- [2- (3 -Dimethylamino-phenylamino) -5-methyl- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 180: 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl) -methyl- amide; 181 : 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-phenyl-ethyl) -methyl- amide; 183 : 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-2-phenyl-ethyl) -methyl-amide; 184 : { [4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -1H- pyrrole-2-carbonyl] -amino} -phenyl-acetic acid methyl ester; 186: 4- (2-Amino-pyrimidin-4-yl)-lH-pyrrole-2-carboxyIic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl- amide; 187: 4- (2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl- ethyl)-amide; 188: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-pyridin-3-yl-ethyl)- amide; 189 : 4- (2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 190 : 4- (2-Ethylamino-5-methyl-pyritnidin-4-yl) -lH-pyrrole- 2-carboxylic acid [1-(3-fluoro-5-trifluoromethyl- phenyl)-2-hydroxy-ethyl]-amide; 191: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid [1-(3-fluoro-phenyl)-2-hydroxy- ethyl] -amide; 192 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid [1-(2-fluoro-phenyl)-2-hydroxy- ethyl] -amide; 193 : 4- [2-(2-Cyclopropyl-l-hydroxymethyl-ethylamino)-5- methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 194 : 4 - [2- (2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin- 4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl -ethyl) -amide; 195 : 4- (2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl- ethyl)-amide; 196: 4- [2-(1-Hydroxymethyl-2-methyl-propylamino)-5- methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 197: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole- 2-carboxylic acid (2-oxo-1-phenyl-propyl)-amide; 198 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-IH-pyrrole- 2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl- phenyl)-ethyl]-amide; 199: 4- [2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-amide; 200: 4- [2- (2-Chloro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-amide; 2 01.- 4- [2- (2-Hydroxy-l-phenyl-ethylamino) -5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2- hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide; 200: 4- [2-(3-Dimethylamino-phenylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2- hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide; 202: 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [2-hydroxy-l-(3 - trifluoromethyl-phenyl)-ethyl]-amide; 203: 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [2-hydroxy-l-(2-methoxy- phenyl) -ethyl] -amide; 2 04: 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1K- pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2- hydroxy-ethyl]-amide; 2 05 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl- ethyl)-amide; 206: 4- (2-Methoxyamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 207: 4- (2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 208: 4- [2- (3-Dimethylamino-phenylamino)-5-methyl- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 209: 4- [2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m- tolyl-ethyl)-amide; 210: 4- [2- (2-Hydroxy-l-phenyl-ethylamino)-5-methyl- pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 211: 4- [2- (2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m- tolyl-ethyl)-amide; 212: 4- [2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m- tolyl-ethyl)-amide; 213: 4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 214: 4- (5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 215: 4- [5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl] - lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl- ethyl)-amide; 216: 4-(5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]- pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl) -amide; 217: 4-{5-Methyl-2- [ (tetrahydro-furan-2-ylmethyl)-amino]- pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-pheny1-e thy1)-ami de; 218: N' -{4-[5-(2-Hydroxy-1-phenyl-ethylcarbamoyl) -1H- pyrrol-3-yl]-5-methyl-pyrimidin-2-yl}- hydrazinecarboxylic acid ethyl ester; 219: 4-(5-Methyl-2- [(pyridin-3-ylmethyl)-amino]- pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 220: 4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4- yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 221: 4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl- ethyl)-amide; 222: 4-[2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 22 3 .- 4- (5-Methyl-2-o-tolylamino-pyrimidin-4-yl) -1H- pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl- ethyl)-amide; 224: 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2- hydroxy-ethyl]-amide; 225: 4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4- yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 226: 4-[2-(N',N'-Dimethyl-hydrazino)-5-methyl-pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl)-amide; 227: 4-[5-Methyl-2-(2-trifluoromethyl-phenylamino) - pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 228: 4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]- lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl- ethyl)-amide; 229: 4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 230: 4-{2-[1-(3-Chloro-4-fluoro-phenyl)-2-hydroxy- ethylamino]- 5-methyl-pyrimidin-4-yl}-lH-pyrrole-2 - carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 231: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H- pyrrole-2-carboxylic acid [1-(3-fluoro-phenyl)-2- hydroxy-ethyl]-amide; 232: 4 - [2 -(1-Hydroxymethyl-propylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [l-(3- chloro-phenyl)-2-hydroxy-ethyl]-amide; 233: 4- [2-(2-Hydroxy-l-hydroxymethyl-ethylamino)-5- methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide; 234: 4- [2-(1-Hydroxymethyl-propylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 235: 4- [2-(2-Hydroxy-1-hydroxymethyl-ethylamino)-5- methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 236: 4-[2-(1-Hydroxymethyl-propylamino)-5-methyl- pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 237 : 4- [5-Methyl-2- (2-methyl-cyclopropylamino) -pyrimidin- 4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l- phenyl-ethyl) -amide; and 238 : 4- (2-Cyanoamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole- 2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide. or a pharmaceutically acceptable salt thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and Q'R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 is N and Z2 is CH; T is a linker group selected from -NH-, -CH2- , -CO-, or a saturated or unsaturated C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -CO-, -C(O)C(O)-, -C(O)NR7-, -C(O)NR7NR7-, -CO2,-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-, -NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-; Q' is selected from -CO2-, -C(O)NR7- or -SO2NR7-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R2' is selected from -(CH2)yCH(R5)2 or -(CH2)yCH(R8)CH(R5)2; y is 0-6; R3 is selected from R7, R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2,or -(CH2)y CH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; WE CLAIM: 1. A compound of formula I': each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR5, or-(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6; aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and each w is independently selected from 0-4. 2. The compound as claimed in claim 1, wherein Sp is selected from one of the following: or a pharmaceutically acceptable salt thereof. 3. The compound as claimed in claim 2, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6- membered aryl or heteroaryl ring. 4. The compound as claimed in claim 3, wherein: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1' is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6- membered aryl or heteroaryl ring. 5. The compound as claimed in claim 3, wherein said compound has one or more features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl.. isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group; (b) TmR1 is selected from an optionally substituted phenyl, methyl, ethyl, propyl. cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O) NHCH3, or CH2NHCH3; and (c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q' is -C(O)NH-. 6. The compound as claimed in claim 5, wherein: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group; (b) TmR1 is selected from an optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyh CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O) NHCH3, or CH2NHCH3; and (c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q' is -C(O)NH-. 7. The compound as claimed in claim 2, wherein said compound is of formula I": or a pharmaceutically acceptable salt thereof. 8. The compound as claimed in claim 7, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2:, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. 9. The compound as claimed in claim 8, wherein: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is a an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. 10. The compound as claimed in claim 2, wherein said compound is of formula I°: or a pharmaceutically acceptable salt thereof. 11. The compound as claimed in claim 10, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6- membered aryl or heteroaryl ring. 12. The compound as claimed in claim 11, wherein: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6- membered aryl or heteroaryl ring. 13. A compound of formula III-a': or a pharmaceutically acceptable salt thereof, wherein: T is a linker group selected from -NH-, -CH2-, -CO-, or a saturated or unsaturated C1.6 alkylidene chain, which is optionally substituted, and wherein up to two saturated. carbons of the chain are optionally replaced by -C(O)-, -C(O)C(O)-, -CONR7-, -CONR7NR7-, -CO2-, -OC(O)-, -NR7CO2-, -O-, -NR7CONR\ -OC(O)NR7-: -NR7NR7-, -NR7CO-, -S-, -SO-, -S(O)2-, -NR7-, -SO2NR7-, or -NR7SO2-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R3 is selected from R\ R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2, or -(CH2) yCH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR5, or -(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted Ci.6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)wN(R4)2, or (CH2)«SR7; and each w is independently selected from 0-4. 14. The compound as claimed in claim 13, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroary] ring; and (c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. 15. The compound as claimed in claim 14, wherein: fa) R3 is hydrogen, carbocyclyl. -CH(R8)R. or an optionally substituted group selected from Ci-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR' is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from Ci-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring. 16. The compound as claimed in claim 14, wherein said compound has one or more features selected from the group consisting of: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR' is selected from an optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O) NHCH3, or CH2NHCH3; and (c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring. 17. The compound as claimed in claim 16, wherein: (a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl. -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH) isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or benzyl group; (b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O) NHCH3, or CH2NHCH3; and (c) R5 is cyclohexyl or a substituted or unsubstituted phenyl or pyridyl ring. 18. A compound of formula III-a°: or a pharmaceutically acceptable salt thereof, wherein: T is a linker group selected from -NH-,-CH2-, -CO-, or a saturated or unsaturated C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -CO-, -C(O)(CO)-, -CONR7-, -CONR7NR7-, -CO2-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-, -NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; y is 0-6; R3 is selected from R\ R, -(CH2)yCH(R8)R, CN, -(CH2))CH(R8)CH(R5)2, or -(CH2) yCH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-.6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR\ or -(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6; aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and each w is independently selected from 0-4. 19. The compound as claimed in claim 18, wherein said compound has one or more features selected from the group consisting of: (a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or a substituted or unsubstituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or a substituted or unsubstituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, and R8 is R7 or OR7. 20. The compound as claimed in claim 19, wherein: a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or a substituted or unsubstituted group selected from C1-4 aliphatic,3-6 membered heterocyclic,or a 5-6 membered aryl or heteroaryl ring; (b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or a substituted or unsubstituted group selected from C1-.6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and (c) R5 is R or OR7, and R8 is R7 or OR7. 21. The compound as claimed in claim 1, selected from the group consisting of: 4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl-amide; 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l - phenyl-ethyl)-amide; 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (3-hydroxy-l - phenyl-propyl)-amide; 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (3-hydroxy-l» phenyl-propyl)-amide; 4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid (2-dimethylamino-2-pyridin-3-yl-ethyl)-amide; 4-[5-(3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-amide; 4-[2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2- carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrroIe-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy- 1 -phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-methyl -amide; 4-(5-Methyl-2-methylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (1 - hydroxymethy 1-3 -methyl -butyl)-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 - hydroxymethyl-2-(lH-imidazol-4-yl)-ethyl]-amide; 4-(5-Methyl-2-methylamino-pyrirnidin-4-yl)-l H-pyrrole-2-carboxylic acid [l-(3- chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid [l-(3- chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4- [2-(3 -Hydroxy-phenylamino)-5 -methyl-pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(Benzo[l,3]dioxol-5-ylamino)-5-methyl-pyrimidin-4-yl]-lH-p>Trole-2- carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; 4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -(3- fluoro-4-methyl-phenyl)-2-hydroxy-ethyl]-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2- hydroxy-1 -(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid [ 1 -(3 -fluoro-4-methy l-phenyl)-2-hydroxy-ethyl] -amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; 4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[5-Methyl-2-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-(2-Isobutylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; 4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Methyl-2-propylamino-pyTimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenyl- ethyl)-methyl-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy- 1-methyl-2-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy- 1 -methyl-2-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy- 2-phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2- phenyl-ethyl)-methyl-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy- l-hydroxymethyl-2-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy- l-hydroxymethyl-2-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (3-hydroxy- 1 -phenyl-propyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (3-hydroxy- 1 -phenyl-propyl)-amide; 4-[2-( 1 -Hydroxymethyl-cyclopropylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-1 -methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; {[4-(2-Ethylamino-5-methyl-p>Timidin-4-yl)-lH-pyrrole-2-carbonyl]-amino}-phenyl- acetic acid methyl ester; 4-[2-(2-Hydroxy-1 -methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-methyl-amide; 4-(2-Amino-pyrimidin-4-yl)-1 H-p>Trole-2-carboxylic acid (2-hydroxy-1 -methyl-2- phenyl-ethyl)-methyl-amide; 4-(2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy- 1 -pyridin-3-yl-ethyl)-amide; 4-(2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [1 -(3- fluoro-5-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [1-(3- fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid [1 -(2- fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(2-Cyclopropyl-l-hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH- pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxyIic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(l -Hydroxymethyl-2-methyl-propylamino)-5-methyl-pyrimidin-4-yl]-1H- pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-oxo-1- phenyl-propyl)-amide; 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2-hydroxy- l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pryimidin-4-yl]-1H-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(2-Hydroxy-1 -phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2- carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid [2- hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2- hydroxy-1-(2-methoxy-phenyl)-ethyl] -amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl)-2-hydroxy-ethyl]-amide; 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2- hydroxy-1-m-tolyl-ethyl)-amide; 4-(2-Methoxyamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-l-phenyl-ethyl)-amide; 4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-f2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yll-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-[2-(2,3-Dirnethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -m-tolyl-ethyl)-amide; 4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1-phenyl-ethyl)-amide; 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyrrole-2- carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; 4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyrrole-2- carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide; N'-{4-[5-(2-Hydroxy-l-phenyl-ethylcarbamoyl)-lH-pyrrol-3-yl]-5-methyl-pyrimidin- 2-yl}-hydrazinecarboxylic acid ethyl ester; 4-{5-Methyl-2-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyiTole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-(2-Cyanoamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2- hydroxy-1 -phenyl-ethyl)-amide; 4-[2-(2-Hydroxy-l-methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide; 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2- hydroxy-1 -m-tolyl-ethyl)-amide; 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -(3 - chloro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[2-(N',N'-Dimethyl-hydrazino)-5-methyl-pyrimidin-4-ylJ-l H-pyrrole-2-carboxylic acid (2-hydroxy-1-pheny l-ethyl)-amide; 4-[5-Methyl-2-(2-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; 4-{2-[l-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-methyl-pyrimidin-4- yl} -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide; 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [l-(3- fluoro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-( 1 -Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid [l-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(2-Hydroxy-1 -hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H- pyrrole-2-carboxylic acid [l-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide; 4-[2-(l -Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2- carboxylic acid (2-hydroxy-1-m-tolyl-ethyl)-amide; 4-[2-(2-Hydroxy-1 -hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-l H- pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide; 4-[2-(l-Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; and 4-[5-Methyl-2-(2-methyl-cyclopropylamino)-pyrimidin-4-yl]-lH-pyrrole-2- carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide. 22. A composition comprising a compound as claimed in any one of claims 1-21 and a pharmaceutically acceptable carrier. 23. The composition as claimed in claim 22, comprising an additional therapeutic agent selected from a chemotherapeutic agent or anti-proliferative agent, or an agents for treating diabetes, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, an agent for treating neurlogical disorders, an agent for treating cardiovascular disease, an agent for treating liver disease, cholestyramine, an interferon, an anti-viral agents, an agents for treating blood disorders, or an agent for treating immunodeficiency disorders. 24. The composition as claimed in claim 22, wherein said composition is capable of being used for inhibiting ERK2, GSK-3, Aurora, CDK.2, or Lck activity in a patient. 25. The composition as claimed in claim 24, wherein said composition is used to inhibit ERK2 activity in a patient. 26. The composition as claimed in claim 25, wherein said ERK2 activity is associated with a disease selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, or CNS disorders. 27. The composition as claimed in claim 26, wherein the disease is cancer. 28. The composition as claimed in claim 27, wherein the disease is a cancer selected from breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine: colon-rectum, large intestine, rectum; brain and central nervous system; or leukemia. 29. The composition as claimed in claim 25, wherein the disease is cardiovascular disease. 30. The composition as claimed in claim 29, wherein the disease is a cardiovascular disease selected from restenosis, cardiomegaly, artherosclerosis, myocardial infarction, or congestive heart failure. 31. The composition as claimed in claim 24, wherein said composition is useful for treating a GSK-3 -mediated disease in a patient in need thereof. 32. The composition as claimed in claim 31, wherein said disease is diabetes. 33. The composition as claimed in claim 31, wherein said disease is Alzheimer's disease. 34. The composition as claimed in claim 31, wherein said disease is schizophrenia. 35. The composition as claimed in claim 22, wherein said composition is useful for enhancing glycogen synthesis in a patient in need thereof. 36. The composition as claimed in claim 22, wherein said composition is useful for lowering blood levels of glucose in a patient in need thereof. 37. The composition as claimed in claim 22, wherein said composition is useful for inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof. 38. The composition as claimed in claim 22, wherein said composition is useful for inhibiting the phosphorylation of \|3-catenin in a patient in need thereof. 39. The composition as claimed in claim 24, wherein said composition is useful for treating an Aurora-2-mediated disease in a patient in need thereof. 40. The composition as claimed in claim 39, wherein said disease is selected from colon, breast, stomach, or ovarian cancer. 41. The composition as claimed in claim 24, wherein said composition is useful for treating CDK-2-mediated disease in a patient in need thereof. 42. The composition aas claimed in claim 41, wherein said disease is selected from cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, or an autoimmune disease. 43. The composition as claimed in claim 24, wherein said composition is useful for treating a Lck-mediated disease in a patient in need thereof. 44. The composition as claimed in claim 43, wherein said disease is selected from an autoimmune disease or transplant rejection. 45. A method for screening ERK2, Aurora-2, GSK-3, CDK-2, AKT3, or Lck activity in a biological sample in vitro, wherein said biological sample is selected from the group consisting of a cell culture, an enzyme preparation, a mammalian biopsy, blood, saliva, urine, feces, semen, tears, and any extract thereof, said method comprising the step of contacting said biological sample with a compound as claimed in any one of claims 1-21. 46. A composition for coating an implantable device comprising a compound as claimed in claim 1 and a carrier suitable for coating said implantable device. 47. An implantable device coated with a composition as claimed in claim 46. 1. A compound of formula I': or a pharmaceutically acceptable salt thereof, wherein: Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and Q'R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6; Z1 is N and Z2 is CH; T is a linker group selected from -NH-, -CH2- , -CO-, or a saturated or unsaturated C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by -CO-, -C(O)C(O)-, -C(O)NR7-, -C(O)NR7NR7-, -CO2,-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-, -NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-; Q' is selected from -CO2-, -C(O)NR7- or -SO2NR7-; U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-; m and n are each independently selected from zero or one; R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH; R2' is selected from -(CH2)yCH(R5)2 or -(CH2)yCH(R8)CH(R5)2; y is 0-6; R3 is selected from R7, R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2,or -(CH2)y CH(R8)N(R4)2; each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, - (CH2)yR5, or-(CH2)yCH(R5)2; each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N (R7)2; each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7NR7SO2R7, COR7, CN, or SO2N(R7)2; each R7 is independently selected from hydrogen or an optionally substituted C1-6; aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and each w is independently selected from 0-4.

Full Text

CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to US
Provisional Patent Application 60/267,818 filed February
9, 2001 and US Provisional Patent Application 60/328,768
filed October 12, 2001, the contents of which are
incorporated herein by reference.
FIELD OF THE INVENTION
The present invention is in the field of
medicinal chemistry and relates to pyrazole compounds
that are protein kinase inhibitors, especially inhibitors
of ERK, compositions containing such compounds and
methods of use. The compounds are useful for treating
cancer and other diseases that are alleviated by protein
kinase inhibitors.
BACKGROUND OF THE INVENTION
Mammalian mitogen-activated protein (MAP)1
kinases are serine/threonine kinases that mediate
5 intracellular signal transduction pathways (Cobb and
Goldsmith, 1995, J Bio1. Chem., 270, 14843; Davis, 1995,
Mol. Reprod. Dev. 42, 459) . Members of the MAP kinase
family share sequence similarity and conserved structural
domains, and include the ERK2 (extracellular signal
10 regulated kinase) , JNK (Jun N-terminal kinase), and p38
kinases. JNKs and p38 kinases are activated in response
to the pro-inflammatory cytokines TNF-alpha and
interleukin-l, and by cellular stress such as heat shock,
hyperosmolarity, ultraviolet radiation,
lipopolysaccharides and inhibitors of protein synthesis
(Derijard et al., 1994, Cell 76, 1025; Han et al., 1994,
Science 265, 808; Raingeaud et al. 1995, J Biol. Chem.
270, 7420; Shapiro and Dinarello, 1995, Proc. Natl. Acad.
Sex. USA 92, 12230). In contrast, ERKs are activated by
mitogens and growth factors (Bokemeyer et al. . 1996,
Kidney Int. 49, 1187) .
ERK2 is a widely distributed protein kinase
that achieves maximum activity when both Thrl83 and
Tyrl8 5 are phosphorylated by the upstream MAP kinase
kinase, MEK1 (Anderson et al., 1990, Nature 343, 651;
Crews et al., 1992, Science 258, 478). Upon activation,
ERK2 phosphorylates many regulatory proteins, including
the protein kinases Rsk90 (Bjorbaek et al., 1995, J.
Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al., 1994,
Cell 78, 1027), and transcription factors such as ATF2
(Raingeaud et al. , 1996, Mol. Cell Biol. 16, 1247), Elk-1
(Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc.
Natl. Acad. Sci. USA 90, 10952), and c-Myc (Oliver et
al. , 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2 is
also a downstream target of the Ras/Raf dependent
pathways (Moodie et al., 1993, Science 2 60, 1658) and may
help relay the signals from these potentially oncogenic
proteins. ERK2 has been shown to play a role in the
negative growth control of breast cancer cells (Frey and
Mulder, 1997, Cancer Res. 57, 628) and hyperexpression of
ERK2 in human breast cancer has been reported (Sivaraman
et al., 1997, J Clin. Invest. 99, 1478). Activated ERK2
has also been implicated in the proliferation of
endothelin-stimulated airway smooth muscle cells,
suggesting a role for this kinase in asthma (Whelchel et
al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589).
Aurora-2 is a serine/threonine protein kinase
that has been implicated in human cancer, such as colon,
breast and other solid tumors. This kinase is believed
to be involved in protein phosphorylation events that
regulate the cell cycle. Specifically, Aurora-2 may play
a role in controlling the accurate segregation of
chromosomes during mitosis. Misregulation of the cell
cycle can lead to cellular proliferation and other
abnormalities. In human colon cancer tissue, the aurora-
2 protein has been found to be overexpressed. See
Bischoff et al., EMBO J. , 1998, 17, 3052-3065; Schumacher
et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et
al., J. Biol. Chem., 1997, 272, 13766-13771.
Glycogen synthase kinase-3 (GSK-3) is a
serine/threonine protein kinase comprised of a and p
isoforms that are each encoded by distinct genes [Coghlan
et al., Chemistry & Biology, 7, 793-803 (2000); Kim and
Kimmel, Curr. Opinion Genetics Dev. , 10, 508-514 (2000)].
GSK-3 has been implicated in various diseases including
diabetes, Alzheimer's disease, CNS disorders such as
manic depressive disorder and neurodegenerative diseases,
and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675;
and Hag et al., J. Cell Biol. (2000) 151, 117]. These
diseases may be caused by, or result in, the abnormal
operation of certain cell signaling pathways in which
GSK-3 plays a role. GSK-3 has been found to
phosphorylate and modulate the activity of a number of
regulatory proteins. These proteins include glycogen
synthase which is the rate limiting enzyme necessary for
glycogen synthesis, the microtubule associated protein
Tau, the gene transcription factor b-catenin, the
translation initiation factor elF2B, as well as ATP
citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc,
c-Myb, CREB, and CEPBa. These diverse protein targets
implicate GSK-3 in many aspects of cellular metabolism,
proliferation, differentiation and development.
In a GSK-3 mediated pathway that is relevant
for the treatment of type II diabetes, insulin-induced
signaling leads to cellular glucose uptake and glycogen
synthesis. Along this pathway, GSK-3 is a negative
regulator of the insulin-induced signal. Normally, the
presence of insulin causes inhibition of GSK-3 mediated
phosphorylation and deactivation of glycogen synthase.
The inhibition of GSK-3 leads to increased glycogen
synthesis and glucose uptake [Klein et al., PNAS, 93,
8455-9 (1996); Cross et al., Biochem. J., 303, 21-26
(1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993);
Massillon et al., Biochem J. 299, 123-128 (1994)].
However, in a diabetic patient where the insulin response
is impaired, glycogen synthesis and glucose uptake fail
to increase despite the presence of relatively high blood
levels of insulin. This leads to abnormally high blood
levels of glucose with acute and long term effects that
may ultimately result in cardiovascular disease, renal
failure and blindness. In such patients, the normal
insulin-induced inhibition of GSK-3 fails to occur. It
has also been reported that in patients with type II
diabetes, GSK-3 is overexpressed [WO 00/38675].
Therapeutic inhibitors of GSK-3 therefore are considered
to be useful for treating diabetic patients suffering
from an impaired response to insulin.
GSK-3 activity has also been associated with
Alzheimer's disease. This disease is characterized by
the well-known P-amyloid peptide and the formation of
intracellular neurofibrillary tangles. The
neurofibrillary tangles contain hyperphosphorylated Tau
protein where Tau is phosphorylated on abnormal sites.
GSK-3 has been shown to phosphorylate these abnormal
sites in cell and animal models. Furthermore, inhibition
of GSK-3 has been shown to prevent hyperphosphorylation
of Tau in cells [Lovestone et al., Current Biology 4,
1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55
(1997)]. Therefore, it is believed that GSK-3 activity
may promote generation of the neurofibrillary tangles and
the progression of Alzheimer's disease.
Another substrate of GSK-3 is (3-catenin which
is degradated after phosphorylation by GSK-3. Reduced
levels of ßcatenin have been reported in schizophrenic
patients and have also been associated with other
diseases related to increase in neuronal cell death
[Zhong et al., Nature, 395, 698-702 (1998); Takashima et
al., PNAS, 90, 7789-93 (1993); Pei et al., J.
Neuropathol. Exp, 56, 70-78 (1997)].
As a result of the biological importance of
GSK-3, there is current interest in therapeutically
effective GSK-3 inhbitors. Small molecules that inhibit
GSK-3 have recently been reported [WO 99/65897 (Chiron)
and WO 00/38675 (SmithKline Beecham)].
Aryl substituted pyrroles are known in the
literature. In particular, tri-aryl pyrroles (US
5,837,719) have been described as having glucagon
antagonist activity. 1,5-Diarylpyrazoles have been
described as p38 inhibitors (WO 9958523).
There is a high unmet medical need to develop
new therapeutic treatments that are useful in treating
the various conditions associated with ERK2 activation.
For many of these conditions the currently available
treatment options are inadequate.
Accordingly, there is great interest in new and
effective inhibitors of protein kinase, including ERK2
inhibitors, that are useful in treating various
conditions associated with protein kinase activation.
DESCRIPTION OF THE INVENTION
It has now been found that compounds of this
invention and compositions thereof are effective as
protein kinase inhibitors, especially as inhibitors of
ERK2. These compounds have the general formula I:
or a pharmaceutically acceptable derivative thereof,
wherein:
Sp is a spacer group comprising a 5-membered
heteroaromatic ring, wherein Ring A and QR2 are
attached to Sp at non-adjacent positions; and wherein
Sp has up to two R6 substituents, provided that two
substitutable carbon ring atoms in Sp are not
simultaneously substituted by R6;
Z1 and Z2 are each independently selected from N or CH;
T and Q are each an independently selected linker group;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-,
-0-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7- ,
-NR7SO2NR7-, or -S02-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR,
or OH;
R2 is selected from -(CH2)yR5, - (CH2) yCH (R5) 2;
-(CH2)yCH(R8)CH(R5)2, -N(R4)2; or -NR4 (CH2) yN (R4) 2 ;
y is 0-6;
R3 is selected from R7, R, - (CH2) yCH (R8) R, CN,
-(CH2)yCH(R8)CH(R5)2; or - (CH2) yCH (R8)N (R4) 2;
each R is independently selected from an optionally
substituted group selected from C1-6 aliphatic, C6-10
aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R,
-CON(R7)2, -SO2R7, -(CH2)yR5, or - (CH2) yCH (R5) 2;
each R5 is independently selected from R, OR, CO2R,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2,
C0N(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2) WN (R4) 2, or (CH2)WSR7;
and
each w is independently selected from 0-4.
As used herein, the following definitions shall
apply unless otherwise indicated. The phrase "optionally
substituted" is used interchangeably with the phrase
"substituted or unsubstituted" or with the term
"(un)substituted." Unless otherwise indicated, an
optionally substituted group may have a substituent at
each substitutable position of the group, and each
substitution is independent of the other.
The term "aliphatic" or "aliphatic group" as
used herein means a straight-chain or branched C1-C12
hydrocarbon chain that is completely saturated or that
contains one or more units of unsaturation, or a
monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon
that is completely saturated or that contains one or more
units of unsaturation, but which is not aromatic (also
referred to herein as "carbocycle" or "cycloalkyl"), that
has a single point of attachment to the rest of the
molecule wherein any individual ring in said bicyclic
ring system has 3-7 members. For example, suitable
aliphatic groups include, but are not limited to, linear
or branched or alkyl, alkenyl, alkynyl groups and hybrids
thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or
(cycloalkyl)alkenyl.
The terms "alkyl", "alkoxy", "hydroxyalkyl",
"alkoxyalkyl", and "alkoxycarbonyl", used alone or as
part of a larger moiety includes both straight and
branched chains containing one to twelve carbon atoms.
The terms "alkenyl" and "alkynyl" used alone or as part
of a larger moiety shall include both straight and
branched chains containing two to twelve carbon atoms.
The terms "haloalkyl", "haloalkenyl" and
"haloalkoxy" means alkyl, alkenyl or alkoxy, as the case
may be, substituted with one or more halogen atoms. The
term "halogen" means F, Cl, Br, or I.
The term "heteroatom" means nitrogen, oxygen,
or sulfur and includes any oxidized form of nitrogen and
sulfur, and the quaternized form of any basic nitrogen.
Also the term "nitrogen" includes a substitutable
nitrogen of a heterocyclic ring. As an example, in a
saturated or partially unsaturated ring having 0-3
heteroatoms selected from oxygen, sulfur or nitrogen, the
nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as
in pyrrolidinyl) or NR+ (as in N-substituted
pyrrolidinyl).
The term "aryl" used alone or as part of a
larger moiety as in "aralkyl", "aralkoxy", or
"aryloxyalkyl", refers to monocyclic, bicyclic and
tricyclic ring systems having a total of five to fourteen
ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3
to 7 ring members. The term "aryl" may be used
interchangeably with the term "aryl ring".
[0001] The term "heterocycle",
"heterocyclyl", or "heterocyclic" as used herein means
non-aromatic, monocyclic, bicyclic or tricyclic ring
systems having five to fourteen ring members in which one
or more ring members is a heteroatom, wherein each ring
in the system contains 3 to 7 ring members.
[0002] The term "heteroaryl", used alone or
as part of a larger moiety as in "heteroaralkyl" or
"heteroarylalkoxy", refers to monocyclic, bicyclic and
tricyclic ring systems having a total of five to fourteen
ring members, wherein at least one ring in the system is
aromatic, at least one ring in the system contains one or
more heteroatoms, and wherein each ring in the system
contains 3 to 7 ring members. The term "heteroaryl" may
be used interchangeably with the term "heteroaryl ring"
or the term "heteroaromatic".
An aryl (including aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including
heteroaralkyl and heteroarylalkoxy and the like) group
may contain one or more substituents. Suitable
substituents on the unsaturated carbon atom of an aryl,
heteroaryl, aralkyl, or heteroaralkyl group are selected
from halogen, -R°, -OR0, -SR°, 1,2-methylene-dioxy, 1,2-
ethylenedioxy, protected OH (such as acyloxy), phenyl
(Ph), Ph substituted with R°, -O(Ph), 0-(Ph) substituted
with R°, -CH2(Ph), -CH2(Ph) substituted with R°,
-CH2CH2(Ph), -CH2CH2(Ph) substituted with R°, -N02, -CN,
-N(R°)2, -NR°C(O)R°, -NR°C(O)N(R°)2, -NRCCO2R°, -NR°NR°C (O) R°,
-NR°NR°C(O)N(R°)2, -NR°NR°CO2R°/ -C(O)C(O)R°, -C (0) CH2C (0) R°,
-CO2R°, -C(O)R°, -C(O)N(R°)2, -OC (O) N (R°) 2, -S(O)2R°,
-SO2N(R°)2, -S(O)R°, -NR°SO2N(R°)2/ -NR°SO2R0, -C (=S) N (R°) 2,
-C(=NH) -N(R°)2, -(CH2)yNHC(O)R°, or
- (CH2)yNHC(0)CH(V-R°) (R°) , wherein each R° is independently
selected from hydrogen, optionally substituted Ci-6
aliphatic, an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring, phenyl (Ph), -O(Ph), or -CH2(Ph)-
CH2(Ph), wherein y is 0-6; and V is a linker group.
Substituents on the aliphatic group of R° are selected
from NH2, NH(C1.4 aliphatic), N(C1-4 aliphatic)2, halogen,
C1-4 aliphatic, OH, 0- (C1-4 aliphatic), N02, CN, C02H,
CO2(C1-4 aliphatic), -O(halo C1-4 aliphatic), or halo C1-4
aliphatic.
An aliphatic group or a non-aromatic
heterocyclic ring may contain one or more substituents.
Suitable substituents on the saturated carbon of an
aliphatic group or of a non-aromatic heterocyclic ring
are selected from those listed above for the unsaturated
carbon of an aryl or heteroaryl group and the following:
=0, =S, =NNHR*, =NN(R*)2, =N-, =NNHC (o) R*, =NNHC02 (alkyl),
=NNHS02(alkyl), or =NR*, where each.R* is independently
selected from hydrogen or an optionally substituted C1-6
aliphatic. Substituents on the aliphatic group of R* are
selected from NH2, NH(d-4 aliphatic), N(C1.4 aliphatic)2,
halogen, C1.4 aliphatic, OH, O- (C1.4 aliphatic) , No2, CN,
CO2H, CO2(C1.4 aliphatic), -O(halo C1-4 aliphatic), or halo
C1.4 aliphatic.
Substituents on the nitrogen of a non-aromatic
heterocyclic ring are selected from -R+, -N(R+)2, -C(0)R+,
-CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2,
-C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR+SO2R+; wherein R+ is
hydrogen, an optionally substituted C1-6 aliphatic,
optionally substituted phenyl (Ph), optionally
substituted -O(Ph), optionally substituted -CH2(Ph),
optionally substituted -CH2CH2(Ph), or an unsubstituted 5-
6 membered heteroaryl or heterocyclic ring. Substituents
on the aliphatic group or the phenyl ring of R+ are
selected from NH2, NH(C1.4 aliphatic), N(d1.4 aliphatic)2/
halogen, C^ aliphatic, OH, O- (Ci_4 aliphatic) , N02/ CN,
C02H, CO2(C1.4 aliphatic), -0(halo C1.4 aliphatic), or halo
C1.4 aliphatic.
The term "alkylidene chain" refers to an
optionally substituted, straight or branched carbon chain
that may be fully saturated or have one or more units of
unsaturation. The optional substituents are as described
above for an aliphatic group.
The term "spacer group" refers to a group that
separates and orients other parts of the molecule
attached thereto, such that the compound favorably
interacts with functional groups in the active site of an
enzyme. As used herein, the spacer group separates and
orients ring A and QR2 within the active site such that
they may form favorable interactions with functional
groups which exist within the active site of the ERK2
enzyme. When the spacer group is a 5-membered
heteroaromatic ring, ring A and QR2 are attached at non-
adjacent positions "B" and "C", and the 5-membered ring
is attached to ring A at point "D" and to QR2 at point "E"
as illustrated below.
Preferably, the distance between "D" and "C" is 3.7A, the
distance between "D" and "E" is 5.0A, the distance
between "B" and "C" is 2.2A, and the distance between "B"
and "E" is 3 . 5A , wherein each of the above described
distances is plus/minus 0.2 A.
The spacer group itself may also form
additional interactions within the active site to further
enhance inhibitory activity of the compounds. For
example, when Sp is a pyrrole the pyrrole-NH may form an
additional hydrogen bond within the active site of the
ERK2 enzyme.
The term "linker group" means an organic moiety
that connects two parts of a compound. Linkers are
typically comprised of an atom such as oxygen or sulfur,
a unit such as -NH-, -CH2-, -CO-, or a chain of atoms,
such as an alkylidene chain. The molecular mass of a
linker is typically in the range of about 14 to 200.
Examples of linkers include a saturated or unsaturated
C1-6 alkylidene chain which is optionally substituted, and
wherein up to two saturated carbons of the chain are
optionally replaced by -C(0)-, -C(O)C(O)-, -CONR7-,
-C0NR7NR7-, -C02-, -OC(O)-, -NR7CO2-, -O-, -NR7CONR7- ,
-OC(O)NR7-, -NR7NR7-, -NR7C0-, -S-, -SO-, -SO2-, -NR7-,
-SO2NR7-, or -NR7SO2-.
As used herein, linker group Q connects Sp with
R2. Q may also form additional interactions within the
ERK2 binding site to further enhance the inhibitory
activity of the compound. When Q is a carbonyl-
containing moeity such as -C(O)-, -CO2-, -OC(O)-,
-C(O)C(O)-, -CONH-, -CO2NH-, -CONHNH-, -NHCO-, -OC(O)NH-,
or -NHCO2-, or a sulfonyl-containing moeity such as -SO2-,
-SO2NH-, or -NHSO2-, the carbonyl or sulf onyl oxygen forms
a hydrogen-bond with lysine 54 in the ERK2 binding site.
When Q is an NH-containing moeity such as -CH2NH- or
-NHNH-, the NH-group forms a hydrogen-bond with aspartic
acid residue 167 in the ERK2 binding site. When Q is a
hydrophobic group such as an alkyl chain, -0-, or -S-, Q
forms additional hydrophobic interactions within the ERK2
binding site.
R2 forms hydrophobic interactions within the
binding site of ERK2, especially with the side-chain
carbons of lysine 54 and aspartic acid 167. R2 may also
form hydrophobic interactions with the glycine-rich loop
which is made up of amino-acid residues 33-38. When R2 is
substituted, the substituents may form further
interactions within the binding site to enhance the
inhibitory activity of the compound. For example, when a
substituent on R2 is a hydrogen-bond donor or a hydrogen-
bond acceptor, said substituent forms a hydrogen bond
with enzyme-bound water molecules that exist in the
binding site.
As used herein, linker group T, when present,
connects Sp with R1. T may also form additional
interactions within the ERK2 binding site to further
enhance the inhibitory activity of the compound. When T
is carbonyl-containing such as -CO-, -C02-, -0C0-, -COCO-,
-CONH-, -CO2NH-, -CONHNH-, -NHCO-, or -NHCO2-, or
sulfonyl-containing such as -SO2-, -S02NH-, or -NHSO2-,
the carbonyl or sulfonyl oxygen forms a hydrogen-bond
with the NH of glutamine 105 in the ERK2 binding site.
When T is NH-containing such as -CH2NH- or -NHNH-, the NH-
group forms a hydrogen-bond with the carbonyl of
glutamine 105. When T is a hydrophobic group such as an
alkyl chain, -0-, or -S-, T forms additional hydrophobic
interactions with the side-chain carbons of glutamine 105
as well as isoleucine 84.
The binding interactions described herein
between the compounds of this invention and the ERK2
binding site have been determined by molecular modeling
programs that are known to those of ordinary skill in the
art. These molecular modeling programs include QUANTA
[Molecular Simulations, Inc., Burlington, Mass., 1992]
and SYBYL [Molecular Modeling Software, Tripos
Associates, Inc., St. Louis, Mo., 1992]. As used herein,
the amino acid numbering for the ERK2 enzyme corresponds
to the Swiss-Prot database entry for accession #P28482.
The Swiss-Prot database is an international protein
sequence database distributed by the European
Bioinformatics Institute (EBI) in Geneva, Switzerland.
The database can be found at www.ebi.ac.uk/swissprot.
The compounds of this invention are limited to
those that are chemically feasible and stable.
Therefore, a combination of substituents or variables in
the compounds described above is permissible only if such
a combination results in a stable or chemically feasible
compound. A stable compound or chemically feasible
compound is one in which the chemical structure is not
substantially altered when kept at a temperature of 40 °C
or less, in the absence of moisture or other chemically
reactive conditions, for at least a week.
Unless otherwise stated, structures depicted
herein are also meant to include all stereochemical forms
of the structure; i.e., the R and S configurations for
each asymmetric center. Therefore, single stereochemical
isomers as well as enantiomeric and diastereomeric
mixtures of the present compounds are within the scope of
the invention. Unless otherwise stated, structures
depicted herein are also meant to include compounds which
differ only in the presence of one or more isotopically
enriched atoms. For example, compounds having the
present structures except for the replacement of a
hydrogen by a deuterium or tritium, or the replacement of
a carbon by a 13C- or 14C-enriched carbon are within the
scope of this invention.
Compounds of formula I or salts. thereof may be
formulated into compositions. In a preferred embodiment,
the composition is a pharmaceutically acceptable
composition. In one embodiment, the composition
comprises an amount of the protein kinase inhibitor
effective to inhibit a protein kinase, particularly ERK-
2, in a biological sample or in a patient. In another
embodiment, compounds of this invention and
pharmaceutical compositions thereof, which comprise an
amount of the protein kinase inhibitor effective to treat
or prevent an ERK-2-mediated condition and a
pharmaceutically acceptable carrier, adjuvant, or
vehicle, may be formulated for administration to a
patient.
The term "patient" includes human and
veterinary subjects.
The term "biological sample", as used herein,
includes, without limitation, cell cultures or extracts
thereof; preparations of an enzyme suitable for in vitro
assay; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen,
tears, or other body fluids or extracts thereof.
Another aspect of this invention relates to a
method of treating or preventing an ERK-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I or a
pharmaceutically acceptable comprising said compound.
The term "ERK-2-mediated condition" or
"disease", as used herein, means any disease or other
deleterious condition in which ERK-2 is known to play a
role. The term "ERK -2 - mediated condition" or "disease"
also means those diseases or conditions that are
alleviated by treatment with an ERK-2 inhibitor. Such
conditions include, without limitation, cancer, stroke,
diabetes, hepatomegaly, cardiovascular disease including
cardiomegaly, Alzheimer's disease, cystic fibrosis, viral
disease, autoimmune diseases, atherosclerosis,
restenosis, psoriasis, allergic disorders including
asthma, inflammation, neurological disorders and hormone-
related diseases. The term "cancer" includes, but is not
limited to the following cancers: breast, ovary, cervix,
prostate, testis, genitourinary tract, esophagus, larynx,
glioblastoma, neuroblastoma, stomach, skin,
keratoacanthoma, lung, epidermoid carcinoma, large cell
carcinoma, small cell carcinoma, lung adenocarcinoma,
bone, colon, adenoma, pancreas, adenocarcinoma, thyroid,
follicular carcinoma, undifferentiated carcinoma,
papillary carcinoma, seminoma, melanoma, sarcoma, bladder
carcinoma, liver carcinoma and biliary passages, kidney
carcinoma, myeloid disorders, lymphoid disorders,
Hodgkin's, hairy cells, buccal cavity and pharynx (oral),
lip, tongue, mouth, pharynx, small intestine, colon-
rectum, large intestine, rectum, brain and central
nervous system, and leukemia.
The present method is especially useful for
treating a disease that is alleviated by the use of an
inhibitor of ER.K2 or other protein kinases. Although the
present compounds were designed as ERK2 inhibitors, it
has been found that certain compounds of this invention
also inhibit other protein kinases such as GSK3, Aurora2,
Lck, CDK2, and AKT3.
Another aspect of the invention relates to
inhibiting ERK-2 activity in a biological sample, which
method comprises contacting the biological sample with a
compound of formula I, or a pharmaceutically acceptable
composition comprising said compound.
Another aspect of this invention relates to a
method of inhibiting ERK-2 activity in a patient, which
method comprises administering to the patient a compound
of formula I or a pharmaceutically acceptable composition
comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I or a
pharmaceutically acceptable comprising said compound.
The term "Aurora-2-mediated condition" or
"disease", as used herein, means any disease or other
deleterious condition in which Aurora is known to play a
role. The term "Aurora-2-mediated condition" or
"disease" also means those diseases or conditions that
are alleviated by treatment with an Aurora-2 inhibitor.
Such conditions include, without limitation, cancer. The
term "cancer" includes, but is not limited to the
following cancers: colon, breast, stomach, and ovarian.
Another aspect of the invention relates to
inhibiting Aurora-2 activity in a biological sample,
which method comprises contacting the biological sample
with a compound of formula I, or a pharmaceutically
acceptable composition comprising said compound.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula I or a pharmaceutically acceptable
composition comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I or a
pharmaceutically acceptable comprising said compound.
The term "GSK-3-mediated condition" or
"disease", as used herein, means any disease or other
deleterious condition or state in which GSK-3 is known to
play a role. Such diseases or conditions include,
without limitation, diabetes, Alzheimer's disease,
Huntington's Disease, Parkinson's Disease, AIDS-
associated dementia, amyotrophic lateral sclerosis (AML),
multiple sclerosis (MS), schizophrenia, cardiomycete
hypertrophy, reperfusion/ischemia, and baldness.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
I or a pharmaceutically acceptable thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of ßcatenin, which is useful for
treating schizophrenia.
Another aspect of the invention relates to
inhibiting GSK-3 activity in a biological sample, which
method comprises contacting the biological sample with a
compound of formula I.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula I or a pharmaceutically acceptable composition
comprising said compound.
Inhibition of ERK2, Aurora2, CDK2, GSK-3, Lck,
or AKT3 kinase activity in a biological sample is useful
for a variety of purposes which are known to one of skill
in the art. Examples of such purposes include, but are
not limited to, blood transfusion, organ-
translplantation, biological specimen storage, and
biological assays.
-20-
The term "pharmaceutically acceptable carrier,
adjuvant, or vehicle" refers to a non-toxic carrier,
adjuvant, or vehicle that may be administered to a
patient, together with a compound of this invention, and
which does not destroy the pharmacological activity
thereof.
The amount effective to inhibit protein kinase,
for example, Aurora-2 and GSK-3, is one that measurably
inhibits the kinase activity where compared to the
activity of the enzyme in the absence of an inhibitor.
Any method may be used to determine inhibition, such as,
for example, the Biological Testing Examples described
below.
Pharmaceutically acceptable carriers that ir.ay
be used in these pharmaceutical compositions include, but
are not limited to, ion exchangers, alumina, aluminum
stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine,
sorbic acid, potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as protamine sulfate, disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
The compositions of the present invention may
be administered orally, parenterally, by inhalation
spray, topically, rectally, nasally, buccally, vaginally
or via an implanted reservoir. The term "parenteral" as
used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesior.al
and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally,
intraperitoneally or intravenously.
Sterile injectable forms of the compositions of
this invention may be aqueous or oleaginous suspension.
These suspensions may be formulated according to
techniques"known in the art using suitable dispersing or
wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally-
acceptable diluent or solvent, for example as a solution
in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water. Ringer's
solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed
as a solvent or suspending medium. For this purpose, any
bland fixed oil may be employed including synthetic mono-
or di-glycerides. Fatty acids, such as oleic acid and
its glyceride derivatives are useful in the preparation
of injectables, as are natural pharmaceutically-
acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil
solutions or suspensions may also contain a long-chain
alcohol diluent or dispersant, such as carboxymethyl
cellulose or similar dispersing agents which are commonly
used in the formulation of pharmaceutically acceptable
dosage forms including emulsions and suspensions. Other
commonly used surfactants, such as Tweens, Spans and
other emulsifying agents or bioavailability enhancers
which are commonly used in the manufacture of
pharmaceutically acceptable solid, liquid, or other
dosage forms may also be used for the purposes of
formulation.
The pharmaceutical compositions of this
invention may be orally administered in any orally
acceptable dosage form including, but not limited to,
capsules, tablets, aqueous suspensions or solutions. In
the case of tablets for oral use, carriers commonly used
include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added.
For oral administration in a capsule form, useful
diluents include lactose and dried cornstarch. When
aqueous suspensions are required for oral use, the active
ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
Alternatively, the pharmaceutical compositions
of this invention may be administered in the form of
suppositories for rectal administration. These can be
prepared by mixing the agent with a suitable non-
irritating excipient which is solid at room temperature
but liquid at rectal temperature and therefore will melt
in the rectum to release the drug. Such materials
include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this
invention may also be administered topically, especially
when the target of treatment includes areas or organs
readily accessible by topical application, including
diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily
prepared for each of these areas or organs.
Topical application for the lower intestinal
tract can be effected in a rectal suppository formulation
-23-
(see above) or in a suitable enema formulation.
Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical
compositions may be formulated in a suitable ointment
containing the active component suspended or dissolved in
one or more carriers. Carriers for topical
administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, poloxypropylene compound, emulsifying
wax and water. Alternatively, the pharmaceutical
compositions can be formulated in a suitable lotion or
cream containing the active components suspended or
dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60,
cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,
benzyl alcohol and water.
For ophthalmic use, the pharmaceutical
compositions may be formulated as micronized suspensions
in isotonic, pH adjusted sterile saline, or, preferably,
as solutions in isotonic, pH adjusted sterile saline,
either with or without a preservative such as
benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated
in an ointment such as petrolatum.
The pharmaceutical compositions of this
invention may also be administered by nasal aerosol or
inhalation. Such compositions are prepared according to
techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or
dispersing agents.
In addition to the compounds of this invention,
pharmaceutically acceptable derivatives of the compounds
of this invention may also be employed in compositions to
treat or prevent the above-identified diseases or
disorders.
A "pharmaceutically acceptable derivative "
means any pharmaceutically acceptable salt, ester, salt
of an ester or other derivative of a compound of this
invention which, upon administration to a recipient, is
capable of providing, either directly or indirectly, a
compound of this invention or an inhibitorily active
metabolite or residue thereof. Particularly favored
derivatives are those that increase the bioavailability
of the compounds of this invention when such compounds
are administered to a patient (e.g., by allowing an
orally administered compound to be more readily absorbed
into the blood) or which enhance delivery of the parent
compound to a biological compartment (e.g., the brain or
lymphatic system) relative to the parent species.
Pharmaceutically acceptable salts of the
compounds of this invention include those derived from
pharmaceutically acceptable inorganic and organic acids
and bases. Examples of suitable acid salts include
acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate,
camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate,
fumarate, glucoheptanoate, glycerophosphate, glycolate,
hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, malonate, methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, oxalate,
palmoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, salicylate,
succinate, sulfate, tartrate, thiocyanate, tosylate and
undecanoate. Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, may be employed
in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include
alkali metal (e.g., sodium and potassium), alkaline earth
metal (e.g., magnesium), ammonium and N+ (C1.4 alkyl)4
salts. This invention also envisions the quaternization
of any basic nitrogen-containing groups of the compounds
disclosed herein. Water or oil-soluble or dispersible
products may be obtained by such quaternization.
The amount of the protein kinase inhibitor that
may be combined with the carrier materials to produce a
single dosage form will vary depending upon the patient
treated and the particular mode of administration.
Preferably, the compositions should be formulated so that
a dosage of between 0.01 - 100 mg/kg body weight/day of
the inhibitor can be administered to a patient receiving
these compositions.
It should also be understood that a specific
dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and
the judgment of the treating physician and the severity
of the particular disease being treated. The amount of
the inhibitor will also depend upon the particular
compound in the composition.
The kinase inhibitors of this invention or
pharmaceutical compositions thereof may also be
incorporated into compositions for coating an implantable
medical device, such as prostheses, artificial valves,,
vascular grafts, stents and catheters. Vascular stents,
for example, have been used to overcome restenosis (re-
narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk
clot formation or platelet activation. These unwanted
effects may be prevented or mitigated by pre-coating the
device with a pharmaceutically acceptable composition
comprising a kinase inhibitor. Suitable coatings and the
general preparation of coated implantable devices are
described in US Patents 6,099,562; 5,886,026; and
5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene
glycol, polylactic acid, ethylene vinyl acetate, and
mixtures thereof. The coatings may optionally be further
covered by a suitable topcoat of fluorosilicone,
polysaccarides, polyethylene glycol, phospholipids or
combinations thereof to impart controlled release
characteristics in the composition. Implantable devices
coated with a kinase inhibitor of this invention are
another embodiment of the present invention.
Depending upon the particular protein kinase-
mediated condition to be treated or prevented, additional
therapeutic agents, which are normally administered to
treat or prevent that condition, may be administered
together with the inhibitors of this invention. For
example, in the treatment of cancer other
chemotherapeutic agents or other anti-proliferative
agents may be combined with the protein kinase inhibitors
of this invention to treat cancer. These agents include,
without limitation, adriamycin, dexamethasone,
vincristine, cyclophosphamide, fluorouracil, topotecan,
taxol, interferons, and platinum derivatives.
Other examples of agents the inhibitors of this
invention may also be combined with include, without
limitation, agents for treating diabetes such as insulin
or insulin analogues, in injectable or inhalation form,
glitazones, alpha glucosidase inhibitors, biguanides,
insulin sensitizers, and sulfonyl ureas; anti-
inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive
agents such as cyclosporin, tacrolimus, rapamycin,
mycophenolate mofetil, interferons, corticosteroids,
cyclophophamide, azathioprine, and sulfasalazine;
neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-
convulsants, ion channel blockers, riluzole, and anti-
Parkinsonian agents; agents for treating cardiovascular
disease such as beta-blockers, ACE inhibitors, diuretics,
nitrates, calcium channel blockers, and statins; agents
for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents;
agents for treating blood disorders such as
corticosteroids, anti-leukemic agents, and growth
factors; and agents for treating immunodeficiency
disorders such as gamma globulin.
Those additional agents may be administered
separately from the protein kinase inhibitor-containing
composition, as part of a multiple dosage regimen.
Alternatively, those agents may be part of a single
dosage form, mixed together with the protein kinase
inhibitor of this invention in a single composition.
Compounds of this invention may exist in
alternative tautomeric forms. Unless otherwise
indicated, the representation of either tautomer is meant
to include the other.
Accordingly, the present invention relates to
compounds of formula I wherein Ring A is a pyridine (II),
pyrimidine (III), or triazine (IV) ring as shown below:
or a pharmaceutically acceptable derivative thereof,
wherein Sp, TmR1, R2, UnR3, Q, and T are as described
above.
Examples of suitable Sp groups of formula I
include pyrrole (a) , imidazole (b) , pyrazole (c) ,
triazole (d) , oxazole (e) , isoxazole (f), 1,3-thiazole
(g), 1,2-thiazole (h) , furan (i), and thiophene (j), as
shown below:
wherein each of a through j is optionally substituted
with R6.
Preferred TmR1 groups of formula I are selected
from hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1_6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Preferred TmR1
groups are methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
and CH2NHCH3. More preferred TmR1 groups of formula I are
those listed in Table 1 below.
Preferred R3 groups of formula I are hydrogen,
carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and
isopropyl. When R3 is optionally substituted phenyl,
preferred substituents on the phenyl ring are halogen,
alkyl, alkoxy, haloalkyl, Oberizyl, Ophenyl, OCF3, OH,
SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples
of such groups include -CH (CH2OH)phenyl, -CH (CH2OH) ethyl,
-CH(CH2OH)2, -CH(CH2OH) isopropyl, and
-CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when
present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2-. More
preferred UnR3 groups of formula I are those listed in
Table 1 below.
When R2 is R5, preferred R5 groups are
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and
piperazin-1-yl, 4-methyl [1,4]diazepan-1-yl, 4-phenyl-
piperazine-1-yl, wherein each group is optionally-
substituted. When R2 is (CH2)yR5, (CH2) yCH (R5) 2, or -N(R4)2,
preferred R5 groups are further selected from pyridin-3-
yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-
tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl,
phenyl, benzyl, -CH2OH, -(CH2)2OH, and isopropyl, wherein
each group is optionally substituted. Preferred
substituents on R5 are -OH, pyridyl, piperidinyl, and
optionally substituted phenyl. When R2 is
- (CH2)yCH(R8)CH(R5)2, preferred R8 groups are R7 and OR7
such as OH and CH2OH and preferred R5 are as described
above. Preferred - (CH2) yCH (R8) CH (R5) 2 groups of formula I
are -CH(OH)CH(OH)phenyl and -CH(Me)CH(OH)phenyl. Other
preferred -QR2 groups are those listed in Table 1 below.
Preferred compounds of formula I are those
having one or more, more preferably more than one, and.
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1_4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring,-
(b) TmR1 is hydrogen, amino, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring;
(c) Q is -CO-, -C02- , -CONH-, -SO2-, -SO2NH-,
-OC(O)NH-, -C(O)ONH-, or -CONHNH-;
(d) R2 is -NR4(CH2)yN(R4)2, -(CH2)yR5, - (CH2) yCH (R5) 2, or
- (CH2)yCH(R8)CH(R5)2;
(f) R4 is R, R7, or - (CH2) yCH (R5) 2; and
(g) R5 is an optionally substituted group selected
from C1-6 aliphatic, phenyl, 5-6 membered
heteroaryl, or 5-6 membered heterocyclyl.
More preferred compounds of formula I are those
having one or more, more preferably more than one, or
most preferably all, of the features selected from the
group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl, benzyl, or
isoxazolyl group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3 ;
(c) Q is -CO-, -CONH-, -S02-, or -SO2NH-;
(d) R2 is -(CH2)yR5, - (CH2)yCH(R5)2, or
- (CH2)yCH(R8)CH(R5)2, wherein RB is OH or CH2OH;
and
(e) R5 is -CH2OH, -(CH2)2OH, isopropyl, or an
optionally substituted group selected from
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl,
piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-
phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-
yl, imidazolyl, furan-2-yl, 1,2,3,4-
tetrahydroisoquinoline, tetrahydrofuran-2-yl,
cyclohexyl, phenyl, or benzyl.
A preferred embodiment of this invention
relates to compounds of formula I' :
or a pharmaceutically acceptable derivative thereof,
wherein:
Sp is a spacer group comprising a 5-membered
heteroaromatic ring, wherein Ring A and Q'R2' are
attached to Sp at non-adjacent positions; and wherein
Sp has up to two R6 substituents, provided that two
substitutable carbon ring atoms in Sp are not
simultaneously substituted by R6;
Z1 and Z2 are each independently selected from N or CH;
Q' is selected from -C02-, -C(O)NR7- or -SO2NR7- ;
T is a linker group;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-,
-O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-,
-NR7SO2NR7-, or -S02-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2/ OR,
or OH;
R2' is selected from - (CH2) yCH (R5) 2 or - (CH2) yCH (R8) CH (R5) 2 ;
y is 0-6;
R3 is selected from R7, R, - (CH2) yCH (R8) R, CN,
- (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8) N (R4) 2;
each R is independently selected from an optionally
substituted group selected from C1-6 aliphatic, C6_10
aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R
-CON(R7)2; -SO2R7, -(CH2)yR5, or - (CH2) yCH (R5) 2 ;
each R5 is independently selected from R, OR, CO2R,
(CH2)yN(R7)2, N(R7)2; OR7, SR7, NR7COR7, NR7CON(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2,
CON(R7)2, S02R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2) WN(R4) 2, or (CH2)WSR7;
and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula I'
include pyrrole (a), imidazole (b), pyrazole (c),
triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole
(g), 1,2-thiazole (h), furan (i), and thiophene (j), as
shown below:
wherein each of a through j is optionally substituted
with R6.
Accordingly, the present invention relates to
compounds of formula I' wherein Ring A is a pyridine
or a pharmaceutically acceptable derivative thereof,
wherein Sp, TmR1, Q'R2 , and UnR3 are as described above.
Preferred R5 groups of formula I' are R or OR7.
Examples of such groups include OH, CH2OH, carbocyclic, or
optionally substituted 5 or 6-membered aryl or heteroaryl
rings, such as phenyl, pyridyl, and cyclohexyl.
Preferred R8 groups of formula I' are R and OR7, wherein R
is an optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6 membered
aryl or heteroaryl ring. Examples of such groups include
phenyl, methyl, ethyl, OH, and CH2OH. Preferred
substituents on the R5 aryl or heteroaryl ring are
halogen, haloalkyl, 0R°, and R°.
Preferred TmR1 groups of formula I' are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring.. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Preferred TmR1
groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
and CH2NHCH3. More preferred TmR1 groups of formula I' are
those listed in Table 1 below.
Preferred R3 groups of formula I' are hydrogen,
carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and
isopropy1. When R3 is optionally substituted phenyl,
preferred substituents on the phenyl ring are halogen,
alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH,
SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples
of such groups include -CH (CH2OH) phenyl, -CH (CH2OH) ethyl,
-CH(CH2OH)2, -CH(CH2OH) isopropyl, and
-CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when
present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More
preferred UnR3 groups of formula I' are those listed in
Table 1 below.
Preferred compounds of formula I' are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmRa is hydrogen, amino, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an
optionally substituted 5 or 6-membered aryl or
heteroaryl ring.

More preferred compounds of formula I' are
those having one or more, more preferably more than one,
and most preferably all, of the features selected from
the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH (CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl, benzyl, or
isoxazolyl group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3/ NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, carbocyclic, or an optionally
substituted phenyl or pyridyl ring, and Q' is
C(O)NH.
Another preferred embodiment of this invention
relates to compounds of formula I":
or a pharmaceutically acceptable derivative thereof,
wherein:
Sp is a spacer group comprising a 5-membered
heteroaromatic ring, wherein Ring A and
C(O)NHCH[ (CH2)1-2OH]R5 are attached to Sp at non-
adjacent positions; and wherein Sp has up to two R6
substituents, provided that two substitutable carbon
ring atoms in Sp are not simultaneously substituted by
R6;
Z1 and Z2 are each independently selected from N or CH;
T is a linker group;
U is selected from -NR7-, -NR7C0-, -NR7CONR7-, -NR7CO2-,
-0-, -CONR7-, -CO-, -CO2-, -00(0)-, -NR7SO2-, -SO2NR7-,
-NR7SO2NR7-, or -S02-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR,
or OH;
R3 is selected from R7, R, - (CH2) yCH (R8) R, CN,
- (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8) N (R4) 2;
each R is independently selected from an optionally
substituted group selected from C1-6 aliphatic, C6.10
aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R,
-CON(R7)2' -SO2R7, -(CH2)yRs, or - (CH2)yCH (Rs) 2;
each R5 is independently selected from R, OR, CO2R,
(CH2)yN(R7)2/ N(R7)2, OR7, SR7, NR7COR7, NR7C0N(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7C0N(R7)2/
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an
optionally substituted C1.6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2) WN(R4) 2, or (CH2)WSR7;
and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula I"
include pyrrole (a), imidazole (b) , pyrazole (c),
triazole (d) , oxazole (e), isoxazole (f), 1,3-thiazole
(g), 1,2-thiazole (h), furan (i), and thiophene (j), as
shown below:
wherein each of a through j is optionally substituted
with R6.
Accordingly, the present invention relates to
compounds of formula I" wherein Ring A is a pyridine
(II"), pyrimidine (III"), or triazine (IV") ring as shown
below:
or a pharmaceutically acceptable derivative thereof,
wherein Sp, TmR1, UnR3, and R5 are as described above.
Preferred TVR1 groups of formula I" are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Examples of
preferred TmR1 groups include methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH2OCH3/ CH2OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of
formula I" are those listed below in Table 1.
Preferred R3 groups of formula I" are hydrogen,
carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and
isopropy1. When R3 is optionally substituted phenyl,
preferred substituents on the phenyl ring are halogen,
alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH,
SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples
of such groups include -CH(CH2OH) phenyl, -CH (CH2OH) ethyl,
-CH(CH2OH)2, -CH(CH2OH) isopropyl, and
-CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when
present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2- . More
preferred UnR3 groups of formula I" are those listed in
Table 1 below.
Preferred R5 groups of formula I" are optionally
substituted 6-membered aryl, heteroaryl, and carbocyclic
rings, such as phenyl, pyridyl, and cyclohexyl.

Preferred compounds of formula I" are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring,-
(b) TmR1 is hydrogen, N{R4)2, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and
(c) Rs is an optionally substituted 6-membered aryl,
heteroaryl, or carbocyclic ring.
More preferred compounds of formula I" are
those having one or more, more preferably more than one,
and most preferably all, of the features selected from
the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl or benzyl
group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or an optionally substituted
phenyl or pyridylring.
Another preferred embodiment of this invention
relates to compounds of formula I°:
or a pharmaceutically acceptable derivative thereof,
wherein:
Sp is a spacer group comprising a 5-membered
heteroaromatic ring, wherein Ring A and
C(O)NHCH(RB)CH(R5)2 are attached to Sp at non-adjacent
positions; and wherein Sp has up to two R6
substituents, provided that two substitutable carbon
ring atoms in Sp are not simultaneously substituted by
R6;
Z1 and Z2 are each independently selected from N or CH;
T is a linker group;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-,
-O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-,
-NR7SO2NR7-, or -S02-;
m and n are each independently selected from zer6 or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR,
or OH;
y is 0-6;
R3 is selected from R7, R, - (CH2) yCH (R8) R, CN,
- (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8)N (R4) 2 ;
each R4 is independently selected from R, R7, -COR7, -CO2R,
-CON(R7)2, -SO2R7, -(CH2)yR5, or - (CH2)yCH (Rs) 2 ;
each R is independently selected from an optionally
substituted group selected from C1-6 aliphatic, C6-10
aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms;
each R5 is independently selected from R, OR, CO2R,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7C0R7, NR7CON(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an
optionally substituted Ci_6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring,-
R8 is selected from R, (CH2)WOR7, (CH2) WN (R4) 2, or (CH2)WSR7;
and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula 1°
include pyrrole (a), imidazole (b) , pyrazole (c),
triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole
(g) , 1,2-thiazole (h), furan (i), and thiophene (j), as
shown below:
wherein each of a through j is optionally substituted
with R6.
Accordingly, the present invention relates to
compounds of formula I° wherein Ring A is a pyridine
(II°) , pyrimidine (III°) , or triazine (IV°) ring as shown
below:
or a pharmaceutically acceptable derivative thereof,
wherein Sp, TmR1, Rs, UnR3, and R8 are as described above.
Preferred R5 groups of formula I° are R or OR7.
Examples of such groups include OH, CH2OH, carbocyclic, or
optionally substituted5 or 6-membered aryl or heteroaryl
rings, such as phenyl, pyridyl, and cyclohexyl.
Preferred R8 groups of formula I° are R and OR7, wherein R
is an optionally'substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6 membered
aryl or heteroaryl ring. Examples of such groups include
phenyl,methyl, ethyl, OH, and CH2OH. Preferred
substituents on the R5 aryl or heteroaryl ring are
halogen, haloalkyl, OR°, and R°.
Preferred TmR1 groups of formula 1° are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is cin
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. More preferred
TmR1 groups are methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
and CH2NHCH3. Most preferred TmR1 groups of formula I° are
those listed in Table 1 below.
Preferred R3 groups of formula I° are hydrogen,
carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and
isopropyl. When R3 is optionally substituted phenyl,
preferred substituents on the phenyl ring are halogen,
alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3/ OH,
SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples
of such groups include -CH (CH2OH) phenyl, -CH (CH2OH) ethyl,
-CH(CH2OH)2, -CH(CH2OH) isopropyl, and
-CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when
present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More
preferred UnR3 groups of formula I° are those listed in
Table 1 below.
Preferred compounds of formula I° are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from Cx.6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and

(c) R5 is R or OR7, wherein R is carbocyclic, or an
optionally substituted5 or 6-membered aryl or
heteroaryl ring.
More preferred compounds of formula I° are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH)isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl, benzyl, or
isoxazolyl group,-
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) Rs is OH, CH2OH, carbocyclic, or an optionally
substitutedphenyl or pyridyl ring.
A preferred embodiment relates to compounds of
formula III-a:
or a pharmaceutically acceptable derivative thereof.
Preferred TmR1 groups of formula III-a are
hydrogen, N(R4)2' OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1.6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and araino. Examples of such
preferred TmR1 groups include methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH2OCH3/ CH2OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of
formula Ill-a are those listed in Table 1 below.
Preferred R3 groups of formula Ill-a are
hydrogen, carbocyclyl, -CH(RB)R, or an optionally
substituted group selected from C1-4 aliphatic, 3-6
membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring. Examples of such groups include methyl,
ethyl, propyl, cyclopropyl, cyclohexyl, benzyl,
isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is
optionally substituted phenyl, preferred substituents on
the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,
Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy.
When R3 is -CH(R8)R, examples of such groups are
-CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl.
Preferred Un groups, when present, are -CH2-, -O-, -NR7-,
-NHCO-, and -NHCO2-. More preferred UnR3 groups of
formula Ill-a are those listed in Table 1 below.
When R2 is R5, preferred R5 groups are
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and
piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-
piperazine-1-yl, wherein each group is optionally
substituted. When R2 is (CH2)yR5, (CH2) yCH (R5) 2, or -N(R4)2,
preferred Rs groups are pyridin-3-yl, pyridin-4-yl,
imidazolyl, furan-2-yl, 1, 2 , 3 , 4-tetrahydroisoquinoline,
tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, -CH2OH,
-(CH2)2OH, and isopropyl, wherein each group is optionally
substituted. Preferred substituents on R5 are -OH,
pyridyl, piperidinyl, and optionally substituted phenyl.
When R2 is - (CH2) yCH (R8) CH (R5) 2, preferred R8 groups are R7
and OR7 such as OH and CH2OH. More preferred -QR2 groups
are those listed in Table 1 below.
Preferred compounds of formula III-a are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered
carbocyclyl, or' an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring,-
(c) Q is -CO-, -CO2-, -CONH-, -S02-, -SO2NH-,
-OC(O)NH-, -C(O)ONH-, or -CONHNH-;
(d) R2 is -NR4 (CH2)yN(R4)2, -(CH2)yR5, - (CH2) yCH (Rs) 2; or
-(CH2)yCH(R8)CH(R5)2;
(f) R4 is R, R7, or - (CH2) yCH (R5) 2; and
(g) R5 is an optionally substituted group selected
from phenyl, 5-6 membered heteroaryl, or 5-6
membered heterocyclyl.
More preferred compounds of formula Ill-a are
those having one or more, more preferably more than one,
or most preferably all, of the features selected from the
group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl or benzyl
group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3 ;
(c) Q is -CO-, -CONH-, -S02-, or -SO2NH-;
(d) R2 is -(CH2)yRs, - (CH2)yCH(Rs)2, or
- (CH2)yCH(R8)CH(R5)2, wherein R8 is OH or CH2OH;
and
(e) R5 is -CH2OH, -(CH2)2OH, isopropyl, or an
optionally substituted group selected from
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl,
piperazin-1-yl, 4-methyl[1,4] diazepan-1-yl, 4-
phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-
yl, imidazolyl, furan-2-yl, 1,2,3,4-
tetrahydroisoquinoline, tetrahydrofuran-2-yl,
cyclohexyl, phenyl, or benzyl.
Preferred compounds of formula III-a include
those of formula III-a':
Preferred TmR1 groups of formula III-a' are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Preferred TmR1
groups are methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
CH2NHCH3, and those listed in Table 1 below.
Preferred R3 groups of formula III-a' are
hydrogen, carbocyclyl, -CH(R8)R, or an optionally
substituted group selected from C1-4 aliphatic, 3-6
membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring.. Examples of such groups include methyl,
ethyl, propyl, cyclopropyl, cyclohexyl, benzyl,
isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is
optionally substituted phenyl, preferred substituents on
the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,
Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy.
When R3 is -CH(R8)R, examples of such groups include
-CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl.
Preferred Un groups, when present, are -CH2-, -0-, -NR7-,
-NHCO-, and -NHCO2-. More preferred UnR3 of formula III-
a' are those listed in Table 1 below.
Preferred compounds of formula III-a' are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from Ca.4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1.6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and
(c) R5 is an optionally substituted6-membered aryl,
heteroaryl, or carbocyclic ring.
More preferred compounds of formula III-a' are
those having one or more, more preferably more than one,
and most preferably all, of the features selected from
the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl or benzyl
group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or an optionally substituted
phenyl or pyridylring.
Preferred compounds of formula III-a are
further selected from those of formula III-a°:
or a pharmaceutically acceptable derivative thereof.
Preferred R5 groups of formula III-a° are R or
OR7. Examples of such groups include OH, CH2OH, or
optionally substituted6-membered aryl, heteroaryl, and
carbocyclic rings, such as phenyl, pyridyl, and
cyclohexyl. Preferred R8 groups of formula III-a° are R
and OR7, wherein R is an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include phenyl, methyl, ethyl, OH, and CH2OH.
Preferred TmR1 groups of formula III-a° are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Preferred TmR1
groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
and CH2NHCH3. More preferred TmR1 groups of formula III-a°
are those listed in Table 1 below.
Preferred R3 groups of formula III-a° are
hydrogen, carbocyclyl, -CH(R8)R, or an optionally
substituted group selected from C1-4 aliphatic, 3-6
membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring. Examples of such groups include methyl,
ethyl, propyl, cyclopropyl, cyclohexyl, benzyl,
isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is
optionally substituted phenyl, preferred substituents on
the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,
Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy.
When R3 is -CH(R8)R, examples of such groups are
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl.
Preferred Un groups, when present, are -CH2-, -0-, -NR7-,
-NHCO-, and -NHCO2-. More preferred UnR3 groups of
formula III-a° are those listed in Table 1 below.
Preferred compounds of formula III-a° are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C^
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and
(c) R5 is R or OR7, and R8 is R7 or OR7.
More preferred compounds of formula III-a° are
those having one or more, more preferably more than one,
and most preferably all, of the features selected from
the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl or benzyl
group;+(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, phenyl, pyridyl, or cyclohexyl,
and R8 is methyl, ethyl, OH, or CH2OH.
Preferred compounds of formula III-a are set
forth in Table 1 below. More preferred compounds in
Table 1 are those of formula III-a' or III-a°.
A Compound names for the compounds of formula III-a
shown above in Table 1 are set forth in Appendix A.
The above formula III-a compounds are those
wherein Ring A is a pyrimidine ring and Sp is a pyrrole
ring. Inhibitors of formula I wherein Ring A is a
pyridine, pyrimidine, or triazine ring having the other
Sp rings shown above are otherwise structurally similar
to the formula III-a compounds and are represented by the
following general formulae Il-b through II-j, Ill-b
through III-j, and IV-b through IV-j shown below in Table
2 :
compound shown above in Table 2 and a pharmaceutically
acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an ERK2-mediated
5 disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound shown above in Table 2 or
a pharmaceutically acceptable composition comprising said
compound.
Another aspect of this invention relates to a
method of inhibiting ERK2 activity in a patient, which
method comprises administering to the patient a compound
shown above in Table 2 or a pharmaceutically acceptable
composition comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound shown above in Table 2 or
a pharmaceutically acceptable comprising said compound.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound shown above in Table 2 or a pharmaceutically
acceptable composition comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated
disease, which method comprises administering to a
patient in need of such treatment a therapeutically
effective amount of a compound shown above in Table 2 or
a pharmaceutically acceptable comprising said compound.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,,
which method comprises administering to the patient a
therapeutically effective amount of a compound shown
above in Table 2 or a pharmaceutically acceptable
j composition comprising said compound. This method is
especially useful for diabetic patients. Another method
relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of (3-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
shown above in Table 2 or a pharmaceutically acceptable
composition comprising said compound.
Another method relates to inhibiting ERK2,
Aurora-2, or GSK-3 activity in a biological sample, which
method comprises contacting the biological sample with a
compound shown above in Table 2, or a pharmaceutically
acceptable composition thereof, in an amount effective to
inhibit ERK2, Aurora-2, or GSK-3.
Each of the aforementioned methods directed to
the inhibition of ERK2, Aurora-2 or GSK-3, or the
treatment of a disease alleviated thereby, is preferably
carried out with a preferred compound shown above in
Table 2, as described above.
The present compounds may be prepared in
general by methods known to those skilled in the art for
analogous compounds, as illustrated by the general
Schemes I through XII and the synthetic examples shown
below.
Reagents and conditions: (a) TmR1CH2COCl, A1C13/ CH2C12, 2
hours, RT; (b) DMF, 24 hrs, room temperature; (c) (Me2N)2-
CHOt-Bu, THF, 24 hrs, room temperature; (d) guanidine,
EtOH, 12 hours, reflux; (e) thiourea, EtOH, K2CO3, 12 hrs
reflux; (f) m-CPBA, EtOH; (g) UnR3-NH2, DMSO, 130"C.
Scheme I above shows a general synthetic route
that is used for preparing the pyrrol-3-yl compounds of
formula III-a of this invention when R2 is an optionally
substituted phenyl group or aliphatic group. In step
(a), an optionally substituted acid chloride is combined
with compound 1, dichloromethane, and aluminum
trichloride to form compound 2. In cases where benzoyl
acid chlorides are used, a wide variety of substituents
on the phenyl ring are amenable to this reaction.
Aliphatic acid chlorides are also used in many cases.
Examples of suitable R2 groups include, but are not
limited to, those set forth in Table 1 above.
The formation of amide 4 is achieved by-
treating compound 2 with an amine 3 in DMF. When atnine 3
5 is a primary amine, the reaction proceeds at ambient
temperature. When amine 3_ is a. secondary amine, the
reaction is heated at 50°C to achieve complete reaction
and afford amide 4.
The formation of enamine 5 at step (c) is
) achieved by treating amide 4 with (Me2N)2-CHOt-Bu at
ambient temperature. Alternatively, the reaction to form
enamine 5 at step (c) is also achieved by using
dimethylformamide-dimethylacetal (DMF-DMA). The reaction
using DMF-DMA typically requires elevated temperature to
afford enamine 5 whereas using (Me2N)2-OtBu has the
advantage of proceeding at ambient temperature to afford
the enamine 5 in higher purity.
The formation of the pyrimidine compound 6 at
step (d) is achieved by the treatment of enamine 5 with
guanidine at elevated temperature. Alternatively, use of
a substituted guanidine results in an amino substituent
as is illustrated by J3.
As an alternative method, in step (e)
intermediate _5 may be cyclized with S-methyl thiourea to
form the 2-thiomethylpyrimidine 7 which may in turn be
oxidized with m-CPBA to the sulfone. The sulfonyl group
may be subsequently displaced by an amine to generate the
substituted aminopyrimidine 8.
The compounds of formula III-a synthesized by
this method, as exemplified in Table 1, were isolated by
preparatory HPLC (reverse phase, 10—>90% MeCN in water
over 15 minutes). The details of the conditions used for
producing these compounds are set forth in the Examples.
Reagents and conditions: (a) K2CO3, DMA, 100°C.
Scheme II above shows a general method for
preparing compounds 8 from intermediate 5 and an N-
substituted guanidine (9) . Intermediate 5 may be
prepared according to Scheme I steps (a), (b), and (c)
shown above. Compound 5 is treated with N-substituted
guanidine (9) and potassium carbonate in
dimethylacetamide to form compound 8. This reaction is
amenable to a variety of N-substituted guanidines to form
compounds of formula III-a. The details of the
conditions used for producing these compounds are set
forth in the Examples.
Reagents and conditions: (a) A1C13 neat, RT; (b) DMF, 24
hrs, room temperature; (c) polyphosphoric acid, 1 hour,
25-140°C; (d) POClj, DMF, reflux; (e) NH2-UnR3, iPrOH,
reflux.
Scheme III above shows a general synthetic
route that may be used for preparing the pyrrol-3-yl
compounds of formula Il-a of this invention. The
conversion of intermediate 5 to product 8 may be achieved
through steps (c), (d), and (e) according to the method
described in JACS, 1957, pp 79.
Reagents and conditions: (a) MeOH, pyridine, Cl2; guanidine; (c) bromine, acetic acid; (d) NaCN, DMF; (e)
£, polyphosphoric acid, 1 hour, 25-140°C; (f) POCI3, DMF,
reflux; (g) NH2-UnR3, iPrOH, reflux,- (h) SeO2; (i) MeNH.
Scheme IV above shows a general synthetic route
that may be used for preparing the imidazol-4-yl
compounds of formula Il-b of this invention. The
conversion of intermediate 5 to product 8 may be achieved
through steps (e) , (f), and (g) according to the method
described in JACS, 1957, pp 79.
Reagents and conditions: (a) MeOH, pyridine, Cl2; (b) 3-,
(c) bromine, acetic acid; (d) NaCN, DMF; (e) 6,
polyphosphoric acid, 1 hour, 25-140°C; (f) POC13, DMF,
reflux; (g) NH2-UnR3, iPrOH, reflux.
Scheme V above shows a general synthetic route
that may be used for preparing the imidazol-2-yl
compounds of formula II-b' of this invention. The
conversion of intermediate 5_ to product £ may be achieved
through steps (e) , (f) , and (g) according to the method
described in JACS, 1957, pp 79.
Reagents and conditions: (a) (b) 3; (c) 5 polyphosphoric
acid, 1 hour, 25-140°C; (d) POC13, DMF, reflux; (e) NH2-
UnR3, iPrOH, reflux; (f) ceric ammonium nitrate.
Scheme VI above shows a general synthetic route
that may be used for preparing the pyrazol-3-yl compounds
of formula II-c of this invention. The conversion of
intermediate 4 to product 7 may be achieved through steps
(c), (d), and (e) according to the method described in
JACS, 1957, pp 79.
Reagents and conditions: (a) 1,1'-carbonyldiimidazole
(CDI), triethylamine, THF; (b) N-butyllithium, THF, -78°C;
(c) 6, polyphosphoric acid, 1 hour, 25-140°C; (d) POC13,
DMF, reflux; (e) NH2-UnR3, iPrOH, reflux.
Scheme VII above shows a general synthetic
route that may be used for preparing the oxazol-2-yl
compounds of formula II-e' of this invention. The
conversion of intermediate 5 to product 8 may be achieved
through steps (c), (d), and (e) according to the method
described in JACS, 1957, pp 79.
-78°C (b) t-butyllithium, THF, -78°C (c) 6, polyphosphoric
acid, 1 hour, 25-140°C (d) POC13, DMF, reflux (e) NH2-R,
iPrOH, reflux.
5 Scheme VIII above shows a general synthetic
route that may be used for preparing the thiazol-2-yl
compounds of formula II-g' of this invention. The
conversion of intermediate 5 to product 8 may be achieved
through steps (c), (d) , and (e) according to the method
I described in JACS, 1957, pp 79.
Reagents and conditions: (a) N-butyllithium, Bu3SnCl ;
(b) t-butyllithium, THF, -78°C; (c) MeOCO2Me; (d) 4,
Pd(0); (e) 6, polyphosphoric acid, 1 hour, 25-140°C; (f)
POC13, DMF, reflux; (g) NH2-UnR3, iPrOH, reflux.
Scheme IX above shows a general synthetic route
that may be used for preparing the thiazol-4-yl compounds
of formula II-g of this invention. The conversion of
intermediate 5 to product 8 may be achieved through steps
(e), (f), and (g) according to the method described in
JACS, 1957, pp 79.
Reagents and conditions: (a) CH3OCH2CH2COC1, AlCl3, CH2Cl2,
2.5 hours, RT; (b) DMF, 24 hrs, room temperature; (c)
(Me2N)2-CHOt-Bu, THF, 24 hrs, room temperature,- (d) N-
substituted guanidine, EtOH, 12 hours, reflux; (e) BBr3,
CH2C12, Na2CO3.
Scheme X above shows a general synthetic route
that is used for preparing compounds of formula III-a
where TmR1 is methoxymethyl or hydroxymethyl. In step
(a), 3-methoxypropionyl chloride is combined with
compound JL, dichloromethane, and aluminum trichloride to
form compound .2.
The formation of amide £ is achieved by
treating compound 2^ with an araine J3 in DMF. When amine 2
is a primary amine, the reaction proceeds at ambient
temperature. When amine _3 was a secondary amine, the
reaction is heated at 50°C to achieve complete reaction
and afford amide 4. The formation of enamine _5 at step
(c) is achieved by treating amide 4 with (Me2N) 2-CHOt-Bu
at ambient temperature.
The formation of the pyrimidine compound 6 at
step (d) is achieved by the treatment of enamine 5 with a
guanidine at elevated temperature. Alternatively, use of
a substituted guanidine results in an amino substituent.
To form compounds where lk,TmR1 is hydroxymethyl,
intermediate 6 may be treated with BBr3 in dichloromethane
to form compounds 7. One of skill in the art would
recognize that the hydroxymethyl group of compound 7
could be further derivatized to form a variety of
compounds of formula III-a. The details of the
conditions used for producing these compounds are set
forth in the Examples.
Reagents and conditions: (a) RNH2, MeCN, 0 C to 25 C, 12
hours; (b) A1C13, CH2Cl2, 25°C; (c) MeOH:H2O (2:1), 37'C.
Scheme XI above shows a general method for
preparing the triazine compounds of formula IV-a. Step
(a) is performed in the manner described at Scheme I,
step (b) above. Step (b) is performed in the manner
described at Scheme I, step (a) above. The formation of
the triazine ring at step (c) may be performed according
to the methods described by Hirsch, J.; Petrakova, E.;
Feather, M. S.; J Carbohydr Chem [JCACDM] 1995, 14 (8),
1179-1186. Alternatively, step (c) may be performed
according to the methods described by Siddiqui, A. U. ;
Satyanarayana, Y.; Rao, U. M. ; Siddiqui, A. H.; J Chem
Res, Synop [JRPSDC] 1995 (2), 43.
formula I', In I°, III-a, III-a', or III-a°, or a
pharmaceutically acceptable composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I', I", 1°, III-
a, III-a', or III-a°, or a pharmaceutically acceptable
composition comprising said compound.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula I', I", 1°, III-a, III-a', or III-a°,
or a pharmaceutically acceptable composition comprising
said compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated
disease, which method comprises administering to a
patient in need of such treatment a therapeutically
effective amount of a compound of formula I', I", ID, III-
a, III-a', or III-a°, or a pharmaceutically acceptable
composition comprising said compound.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
I', I", 1°, III-a, III-a', or III-a°, or a
pharmaceutically acceptable composition comprising said
compound. This method is especially useful for diabetic
patients. Another method relates to inhibiting the
production of hyperphosphorylated Tau protein, which is
useful in halting or slowing the progression of
Alzheimer's disease. Another method relates to
inhibiting the phosphorylation of ßcatenin, which is
useful for treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula I', I", 1°, Ill-a, III-a', or III-a°, or a
pharmaceutically acceptable composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a CDK-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I', I", 1°, III-
a, Ill-a' , or III-a°, or a pharmaceutically-acceptable
composition comprising said compound.
The term "CDK-2-mediated condition" or
"disease", as used herein, means any disease or other
deleterious condition in which CDK-2 is known to play a
role. The term "CDK-2-mediated condition" or "disease"
also means those diseases or conditions that are
alleviated by treatment with a CDK-2 inhibitor. Such
conditions include, without limitation, cancer,
Alzheimer's disease, restenosis, angiogenesis,
glomerulonephritis, cytomegalovirus, HIV, herpes,
psoriasis, atherosclerosis, alopecia, and autoimmune
diseases such as rheumatoid arthritis. See Fischer, P.M.
and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245
(2000); Mani, S., Wang, C, Wu, K. , Francis, R. and
Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000);
Fry, D.W. and Garrett, M.D., Current Opinion in
Oncologic, Endocrine & Metabolic Invescigational Drugs,
2, 40-59 (2000).
Another aspect of this invention relates to a
method of treating or preventing a Lck-mediated disease,
which method comprises administering to a patient in need
of such a treatment a therapeutically effective amount of
a compound of formula I', I", l°, lil-a, Ill-a', or
III-a°, or a pharmaceutically acceptable composition
comprising said compound.
The terms "Lck-mediated disease" or '"Lck-
mediated condition", as used herein, mean any disease
state or other deleterious condition in which Lck is
known to play a role. The terms "Lck-mediated disease"
or "Lck-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with an Lck
inhibitor. Lck-mediated diseases or conditions include,
but are not limited to, autoimmune diseases such as
transplant rejection, allergies, rheumatoid arthritis,
and leukemia. The association of Lck with various
diseases has been described [Molina et al., Nature, 357,
161 (1992)] .
Another aspect of this invention relates to a
method of treating or preventing an AKT3-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I', I", 1°, III-
a, III-a', or III-a°, or a pharmaceutically acceptable
composition comprising said compound.
The terms "AKT3-mediated disease" or "AKT3-
mediated condition", as used herein, mean any disease
state or other deleterious condition in which AKT3 is
known to play a role. The terms "AKT3-mediated disease"
or "AKT3-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with an AKT
inhibitor. AKT3-mediated diseases or conditions include,
but are not limited to, proliferative disorders, cancer,
and neurodegenerative disorders. The association of AKT3
with various diseases has been described [Zang, Q. Y., et
al, Oncogene, 19 (2000)] and [Kazuhiko, n., et al, The
Journal of Neuroscience, 20 (2000)].
Another method relates to inhibiting ERK2,
Aurora-2, CDK-2, Lck, AKT3, or GSK-3 activity in a
biological sample, which method comprises contacting the
biological sample with a compound of formula I', I", 1°,
Ill-a, III-a', or III-a°, , or a pharmaceutically
acceptable composition comprising said compound, in an
amount effective to inhibit ERK2, Aurora-2, CDK-2, Lck,
AKT3, or GSK-3.
Each of the aforementioned methods directed to
the inhibition of ERK2, Aurora-2, CDK-2, Lck, AKT3, or
GSK-3, or the treatment of a disease alleviated thereby,
is preferably carried out with a preferred compound of
formula I', I", 1°, III-a, III-a', or III-a°, as described
above. More preferably, each of the aforementioned
methods is carried out with a preferred compound of
formula I', I", 1°, III-a', or III-a°, and most preferably
with a compound of formula I", 1°, III-a', or Ill-a°.
In order that the invention described herein
may be more fully understood, the following examples are
set forth. It should be understood that these examples
are for illustrative purposes only and are not to be
construed as limiting this invention in any manner.
SYNTHETIC EXAMPLES
For compounds where the HPLC Method is
designated as "A", the following method was utilized: a
gradient of water:MeCN, 0.1% TFA (95:5 -» 0:100) was run
over 22 minutes at 1 mL/min and 214 nm. For compounds
where the HPLC Method is designated as "B", the following
method was utilized: a gradient of water.-MeCN, 0.1% TFA
(90:10 -> 0:100) was run over 8 minutes at 1 mL/min arid
214 nm. Each of methods A and B utilize the YMC ODS-AQ
55 120A column with a size of 3.0 x 150 mm. As used
herein, the term "Rt" refers to the retention time, in
minutes, associated with the compound using the
designated HPLC method.
2, 2, 2-Trichloro-l- (4-phenyl acetyl-lH-pyrrol-2-yl) -
ethanone (1) ¦. In a dry flask, phenylacetyl chloride (1
equivalent) was combined with 2-trichloroacetyl pyrrole
(1 equivalent) in a minimum amount of dichloromethane
(DCM) to dissolve the reactants. To the resulting
solution, at ambient temperature, was added aluminum
trichloride (1 equivalent). After 2 hours, the reaction
mixture was applied directly onto a silica gel column.
Gradient elution with 10% ethyl acetate to 50% ethyl
acetate in hexanes provided compound 1 in 60% yield. XH
NMR (CDC13) 6 4.0 (s, 2H), 7.1-7.35 (m, 7H), 9.7 (br s,
NH). HPLC using method B provided Rt of 4.9 minutes.
LC/MS (M+l) 330.2, (M-l) 328.1.
2,2,2-Trichloro-l-(4-(3-Chlorophenyl) acetyl-lH-pyrrol-2-
yl)-ethanone (2J .- In a dry flask, 3-chlorophenylacetyl
chloride (1 equivalent) was combined with 2-
trichloroacetyl pyrrole (1 equivalent) in a minimum
amount of dichloromethane (DCM). To the resulting
solution, at ambient temperature, was added aluminum
trichloride (1 equivalent). After 2 hours, the reaction
mixture was applied directly onto a silica gel column.
Gradient elution with 10% ethyl acetate to 50% ethyl
acetate in hexanes provided compound 2 . HPLC using
method A provided Rt of 15 minutes
1- [5- (2,2,2-Trichloro-acetyl) -lH-pyrrol-3-yl) -propan-1-
one (2> : In a dry flask, 3-proprionyl chloride (1
equivalent) was combined with 2-trichloroacetyl pyrrole
(1 equivalent) in a minimum amount of dichloromethane
(DCM) . To the resulting solution, at ambient
temperature, was added aluminum trichloride (1
equivalent). After 2 hours, the reaction mixture was
applied directly onto a silica gel column. Gradient
elution with 10% ethyl acetate to 50% ethyl acetate in
hexanes provided compound 3
4-Phenylacetyl-lff-pyrrole-2-carboxylic acid benzylamide
(•4) : To a solution of compound 1 (1 equivalent) in DMF,
at ambient temperature, was added benzylamine (1.2
equivalents). After 24 hours, the solvent was evaporated
and the crude product 4 was used without purification.
HPLC using method B provided Rt of 3.8 minutes. FIA/MS
(M+l) 319.3, (M-l) 317.2.
2-(3-Chlorophenyl)l-[5-(morpholine-4-carbonyl)-lH-pyrrol-
3-yl] -ethanone (E) : To a solution of compound 2(1
equivalent) in DMF, at ambient temperature, was added
morpholine (1.2 equivalents). After 24 hours, the
solvent was evaporated and the crude product 5 was used
without purification. FIA/MS (M+l) 333.3, (M-l) 331.2.
1H NMR was consistent with expected structure. .
4-Propionyl-lH-pyrrole-2-carboxylic acid 3,4-difluoro-
benzylamide (_6) : To a solution of compound 3_ U
equivalent) in DMF, at ambient temperature, was added
3,4-difluorobenzyl amine (1.2 equivalents). After 24
hours, the solvent was evaporated and the crude product 6
was used without purification.
4- (3-Dimethylamino-2-phenyl-acryloyl) -lIf-pyrrole-2-
carboxylic acid benzylamide (!) ¦. To a solution of
compound 4_ (1 equivalent) in THF, at ambient temperature,
was added (Me2N) 2CHOt-Bu (3 equivalents). After 24 hours,
the solvent was evaporated and the crude product 1_ was
used without purification. XH NMR (CDC13) 5 4.4 (s, 2H.) ,
4.8 (s, NH), 6.8-7.4 (m, 13H).
2-(3-Chloro-phenyl)-3-dimethylamino-l-[5-(morpholine-4-
carbonyl)-lH-pyrrol-3-yl]-propenone (J3) : To a solution of
compound j> (1 equivalent) in THF, at ambient temperature,
was added (Me2N) 2CHOt-Bu (3 equivalents) . After 24 hours,
the solvent was evaporated and the crude product 8_ was
used without purification. HPLC using method B provided Rt
of 11.2 minutes.
4- (2-Amino-5-inethyl-pyriinidin-4-yl) -Iff-pyrrole-2-
carboxylic acid 3 , 4-difluoro-benzylamide (III-a-74) :
Step 1: To a solution of compound 6_ (1 equivalent) in
THF, at ambient temperature, was added (Me2N) 2CHOt-Bu (3
equivalents). After 24 hours, the solvent was evaporated
and the crude product was utilized without purification.
Step 2: To a solution of the compound formed above at
Step 1 (1 equivalent) in ethanol, at ambient temperature,
was added guanidine (3 equivalents) and the resulting
mixture heated at reflux. After 12 hours, the solvent
was evaporated and the crude product purified by-
preparatory HPLC (reverse phase; 10—>90% MeCN in water; 15
minutes) to afford the desired compound III-a-74. HPLC
using method B provided Rt of 7.9 minutes. 1H NMR was
consistent with expected structure. FIA/MS Obs. M+l /M-
1.
{4- [2-Amino-5- (3-chlorophenyl) -pyrimidine-4-yl] -1H-
pyrrol-2-yl}-morpholin-4-yl-methanone (III-a-72): To a
solution of compound 8_ (1 equivalent) in ethanol, at
ambient temperature, was added guanidine (3 equivalents)
and the resulting mixture heated at reflux. After 12
hours, the solvent was evaporated and the crude product
purified by preparatory HPLC (reverse phase; 10—>90% MeCN
in water; 15 minutes) to afford the desired compound III-
a-72. HPLC using method B, Rt=7.9 minutes. 1H NMR was
consistent with expected structure. FIA/MS Obs. (M+l)
384.4 amu.
N- (2-Hydroxy-l- (3) -phenyl-ethyl) -guanidine»HCl.- (5) -
Phenylglycinol (0.38g, 2.7 mmol) and bis-Boc guanidine
(AT)-triflate (0.9g, 2.3 mmol) were combined in methyle
chloride (anhydrous, 5mL) and stirred at ambient
temperature overnight. Completion of the reaction was
verified by HPLC. The mixture was diluted with ethyl
acetate, washed with 2M sodium bisulfite, brine then
dried over MgSO4, filtered and concentrated in vacuo.
The bis-Boc guanidine intermediate was treated with 4N
HCl/dioxane (5raL) and stirred at room temperature unti]
deprotection was complete (48 h) to afford the title
compound..
4- [2- (2-Hydroxy-l- (S) -phenyl-ethylamino) -5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-
1-(S)-phenyl-ethyl)-amide (III-a-155): 4-(3-
Dimethylamino-2-methyl-acryloyl) - 1H~pyrrole-2-carboxylic
acid (2-hydroxy-l-phenyl-ethyl)-amide {100 mg, 0.29 mmol)
was combined with N-(S)-phenylglycinol guanidine»HCl (126
mg) and potassium carbonate (121 mg) in N,N-
dimethylacetamide (2mL). The resulting suspension was
heated and stirred at 100° C for 24 hours. The crude
material was diluted with ethyl acetate, washed with
saturated NaHC03, brine, dried over MgSO4 and concentrated
in vacuo. Purification by prep HPLC (Gilson: Column =
CombiHT SB-C189 5 [iM 21.2 mm x 100 mm, eluent = 0.1%TFA
MeCN/H2O gradient) followed by preparative TLC (silica,
5% MeOH in CH2C12) afforded compound III-a-155 as a pale
yellow solid (8.0 mg). HPLC Method B, Rc=4.76 minutes; MS
(FIA) 458.2 (M+l), 456.1 (M-l); XH NMR consistent with
structure.
4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -phenyl-ethyl)-
amide (III-a-162): 4-(3-Dimethylamino-2-methyl-acryloyl)-
l#-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-
amide (100 mg, 0.29 mtnol) was combined with cyclopropyl
guanidine»HCl (80 mg) and potassium carbonate (121 mg) in
N,N-dimethylacetamide (2mL). The resulting suspension
was heated and stirred at 100°C for 24 hours. The crude
material was diluted with ethyl acetate, washed with
saturated NaHCO3 and brine, dried over MgSO4 then
concentrated in vacuo. Purification by preparative TLC
(silica, 1:1 EtOAc.-Hexanes) afforded III-a-162 as a
yellow solid (7.8 mg). HPLC Method B, Rt=4.29 minutes;
LC/MS(m/z) 378.2 (M+l), 376.2 (M-l); JH NMR consistent
with structure.
3-Methoxy-l-[5-(2, 2 , 2-trichloro-acetyl)-lH-pyrrol-3-yl]-
propan-1-one: To a solution of 2-trichloroacetyl pyrrole
4- (3-Methoxy-propionyl) -lff-pyrrole-2-carboxylic acid (2-
hydroxy-1- (S) -phenyl-ethyl) -amide: To a solution of 3-
methoxy-1- [5- (2,2, 2-trichloro-acetyl) - 1H-pyrrol-3 -yl] -
propan-1-one (3.0 g, 10 ramol) in acetonitrile (50 mL) ,
cooled to 0°C, was added (S)-( + )-phenyl glycinol (1.2
equivalent, 1.65 g, 12 mmol) and the resulting mixture
stirred for 3 days at room temperature. The solvent was
removed under reduced pressure and the residue purified
by chromatography on silica gel (MeOH 5% in DCM) to
afford 5.3 g of the title compound as a white solid.
HPLC Method B, Rt=4.2 minutes; LC/MS(m/z) 317.03 (M+l),
315.00 (M-l) ; 1H NMR consistent with structure.
(1.0 equivalent, 4.67g, 22 mmol) in methylene chloride (5
mL) was added 3-methoxypropionyl chloride (1.0
equivalent, 22 mmol) then aluminium trichloride (1.0
equivalent, 2.93g, 22 mmol) was added in small portions.
After 2.5 hours, the crude mixture was chromatographed on
silica gel (MeOH 2% in DCM) to afford 3.0 g of the
Friedel-Craft product. 1H NMR consistent with structure.
4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -lff-pyrrole-
2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide:
4-(3-Methoxy-propionyl)-l.H-pyrrole-2-carboxylic acid (2-
hydroxy-1-(S)-phenyl-ethyl)-amide was treated with an
excess of Bredereck's reagent in THF at room temperature
to 50°C for 3 days. The solvent was removed under
reduced pressure and the concentrate was used directly in
the next step. HPLC Method B, Rt=5.0 minutes "broad
peak".
4- (5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-
amide (III-a-164): 4-(3-Dimethylamino-2-methoxymethyl-
acryloyl)-l#-pyrrole-2-carboxylic acid (2-hydroxy-l- (S)-
phenyl-ethyl)-amide (0.27 mmol) was combined with phenyl
guanidine (73 mg) in N,N-dimethylacetamide (2 mL) and the
resulting suspension was heated at 90°C for 35 hours.
The reaction mixture was diluted with ethyl acetate,
washed with saturated NaHCO3 and brine, dried over MgS04
and concentrated in vacuo. The crude product was
purified by prep HPLC (Gilson: Column = CombiHT SB-C189 5
p.M, 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient)
to afford III-a-164 as a yellow solid (3.2 mg).
LC/MS(m/z) 444.16 (M+l), 442.19 (M-l); HPLC Method B,
Rt=5.16 minutes: 1H NMR consistent with structure.
4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-
amide (III-a-165): To a solution of III-a-164 (15 mg,
0.03 mmol) in dichloromethane (2 mL), cooled to -78°C,
was added BBr3 (135 |IL, 0.13 mmol) . After 15 minutes the
reaction was allowed to warm to room temperature. After
45 minutes, the reaction was quenched with a saturated
solution of sodium carbonate and the resulting mixture
was stirred for an additionnal 3 0 minutes before
extraction with ethyl acetate. The organic layers were
combined and washed with brine then dried over sodium
sulfate. The crude mixture was purified by prep TLC
(silica, 7% MeOH in CH2Cl2) to afford III-a-165 as a beige
solid (1.6 mg) . HPLC Method B, Rt=4.54 minutes; LC/MS
(m/z) 430.15 (M+l), 428.03 (M-l); ^ NMR consistent with
structure.
4- (2-Amino-5-methoxymethyl-pyrimidin-4-yl) -l.ff-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide (Ill-a-
161): The enamine formed above at Example 16 (0.27 mmol)
was combined with guanidine»HCl (51 mg), and K2CO3 (100
mg) in N,N-dimethylacetamide (4 mL). The heterogenous
mixture was heated and stirred at 90° C for 3 5 h. The
crude material was diluted with ethyl acetate, washed
with saturatedd NaHCO3 and brine, dried (MgSO4) and
concentrated in vacuo. Purification by prep HPLC
(Gilson: Column = CombiHT SB-C189 5 fiM, 21.2 mm x 100 mm,
eluent = 0.l%TFA MeCN/H2O gradient) afforded III-a-161 as
a yellow solid (2.0 mg). LC/MS(m/z) 368.12 (M+l), 366.15
(M-l), Rt (HPLC) =-3.77 min, XH NMR consistent with
structure.
4- (2-Mercapto-5-methyl-pyrimidin-4-yl)-Iff-pyrrole-2-
carboxylic acid (2-hydroxy-l-(5)-phenyl-ethyl)-amide:
4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -Iff-pyrrol e-
2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide
(17.6 mmol, 6.0 g) was combined with thiourea (39 mmol,
3.0 g) and potassium carbonate (53 mmol, 7.3 g) in
ethanol (50 mL) and the resulting suspension was heated
at 90° C for 24 hrs. The solvent was removed in vacuo and
the resulting black solid was diluted with water and the
solid was removed by filtration. The solid was washed
with ethyl acetate twice and the aqueous solution was
acidified to pH 5-6 with HC1(2N). The solid formed was
removed by filtration and the aqueous solution was then
extracted twice with ethyl acetate. The combined organic
phases were dried over sodium sulfate. The solvent was
removed under vacuum to afford the title compound as a
brown solid (3.0 g, 48% yield). HPLC Method B, Rt=3 .7
minutes, 1H NMR consistent with structure.
4- (5-Methyl-2-propylsulfanyl-pyrimidin-4-yl) -1H-pyrrole-
2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide:
To a solution of 4-(2-mercapto-5-methyl-pyrimidin-4-yl) -
lH-pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-
ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueous ammonia
(15%) was added at room temperature n-propyliodide (11.6
mmol, 1.1 mL). The solution was stirred overnight at
room temperature. The resulting solid was collected by
filtration and used directly for the next step. 1H NMR
consistent with the structure.
4- [5-Methyl-2- (propane-1-sulfonyl)-pyrimidin-4-yl]~1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -phenyl-ethyl)-
amide: The thiopropyl compound (7.7 mmol, 3.05g) prepared
at Example 21 above was dissolved in 120 mL of ethanol.
To this solution, maintained at room temperature, was
added m-CPBA (70% w/w%, 23.1 mmol, 4.0 g). The solution
was stirred for an additional 4 hours at room
temperature. The solvent was removed in vacuo and the
residue dissolved in ethyl acetate, then washed 4 times
with a solution of sodium hydroxide (IN) . The organic
phase was dried over sodium sulfate and concentrated in
vacuo to afford the title compound as a white solid
(1.7g, 51% yield for 2 steps). HPLC Method B, Rc=5.4
minutes. 1H NMR consistent with the structure.
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide: To a
solution of 4-[5-methyl-2-(propane-1-sulfonyl)-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -
phenyl-ethyl)-amide (47 p.mol, 20 mg) in DMSO (1 mL) was
added ethylamine (0.5 mmol, 150 |xL) . The mixture was
heated at 130°C for 24 hours to afford the title
compound. LC/MS(m/z) 366.2 (M+l); HPLC Method B, Rt=4.2
minutes; 1H NMR consistent with the structure.

4- [2-{N' ,N' -Dimethyl-hydrazino)-5-methyl-pyrimidin-4-yl]-
lff-pyrrole-2-carboxylic acid (2-hydroxy-l- (5)-phenyl-
ethyl)-amide (III-a-226): To a solution of 4-(3-
dimethylamino-2-methoxymethyl-acryloyl)-ltf-pyrrole-2-
carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide
(0.15 mmol, 50 mg) in DMA (2 mL) was added dimethyl-N,N-
aminoguanidine»2HCl (0.17 mmol, 30 mg) and potassium
carbonate (0.36 mmol, 50 mg). The reaction mixture was
stirred for 48 hrs at 100°C. The solvent was removed by
hi-vacuum "GeneVac" and the residue purified by
preparative HPLC (Gilson: Column = CombiHT SB-C189 5 J^M
21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient)
followed by preparative TLC (silica, 5% MeOH in CH2C12)
"double elutions" afforded compound III-a-226 as a pale
yellow solid (1.3 mg). HPLC Method B, Rt=4.03 min.; LC/MS
(m/z) 381.1 (M+l), 379.1 (M-l); 2H NMR consistent with
structure.

Ethanolguanidine: Ethanolamine hydrochloride (2 00 mg, 2
mmol) was added to a mixture of N, N'-di-boc -N'-
triflylguanidine (8 00 mg, 2 mmol) and TEA (0.28 mL, 2
mmol) in dichloromethane (10 mL). The mixture was
stirred overnight then diluted with EtOAc, washed with
sodium bisulfate (2M), saturated sodium bicarbonate,
dried over NaS04 and concentrated in vacuo. The crude
residue was purified by flash column chromatography
eluting with 20% CH2Cl2/hexane to afford a white solid
(0.56 g, 92%). ). 2H NMR (CDC13) : 5 4.18 (q, 2H) , 1.60 (d,
18H), 1.37 (t, 3H). To this bis-Boc guanidine was added
4M HCl/dioxane (5 mL). The mixture was stirred for 24 h
and then concentrated to afford the title compound (0.26
g) . *H NMR (MeOD) : 5 3.92 (q, 2H), 1.27 (t, 3H) . MS (M+l)
104.

4-(2-Ethanolamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-(s)-phenyl-ethyl)-amide
(III-a-195): To a mixture of 4-(3-dimethylamino-2-methyl-
acryloyl)-lH-pyrrole-2-carboxylic acid (2-hydroxymethyl-
1- (S) -phenyl-ethyl) amide (0.1 mmol) and K2CO3 (55 mg, 0.4
mmol) in DMF (1 mL) was added ethanolguanidine hydrogen
chloride (0.2 mmol). The resulting suspension was
stirred for 6 hours at 90 °C. The reaction mixture was
filtered and the filtrate concentrated in vacuo. The
crude residue was purified by preparative HPLC (Gilson:
Column = CombiHT SB-C189 5 JIM 21.2 mm x 100 mm, eluent =
0.1%TFA MeCN/H2O gradient) to afford compound III-a-195
as yellow oil (21 mg). HPLC (method B) Rt = 4.08 min; MS
(M+l) 382.1.

Ethyl carbamate guanidine: Ethylcarbazate (208 mg, 2
mmol) was added to a solution of N'N'-di-boc N'-
triflylguanidine (800 mg, 2 mmol) in dichloromethane (10
mL). The mixture was stirred for overnight then diluted
with EtOAc, washed with sodium bisulfat (2M), saturated
sodium bicarbonate, dried over anhydrous NaSO4 and
concentrated in vacuo. The crude residue was purified by
flash column chromatography eluting with 3 0% EtOAc/hexane
to afford a white solid (0.55g). To this bis-boc
guanidine was added 4M HCl/Dioxane (5 mL). The mixture
was stirred for 24 hours and then concentrated to afford
the title compound. 1H NMR (MeOD) : 5 3.4.18 (d, 2H) , 3.26
(s, 1H), 1.28 (t, 3H). MS (M+l) 134.

III-a-218
4-(2-Ethyl carbamate-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-(s)-phenyl-ethyl)-amide
(III-a-218): To a mixture of 4-(3-dimethylamino-2-methyl-
acryloyl)-lH-pyrrole-2-carboxylic acid (2-hydroxymethyl-
1-(S)-phenyl-ethyl) amide (0.1 mmol) and K2CO3 (55 mg, 0.4
mmol) in DMF (1 mL) was added ethyl carbamate guanidine
hydrogen chloride (0.2 mmol). The resulting suspension
was stirred for 6 hours at 90 °C. The reaction mixture
was filtered and the filtrate was concentrated in vacuo.
The crude residue was purified by preparative HPLC
(Gilson: Column = CombiHT SB-C189 5 |iM 21.2 mm x 100 mm,
eluent = 0.1%TFA MeCN/H2O gradient) to afford compound
III-a-218 as a yellow oil (10 mg). HPLC (method B) Rt =
4.03/ MS (M+l) 425.1. ^NMR (MeOD) 8.08 (s, 1H); 7.87 (s,
1H) ; 7.7 (s, 1H) , 7.24-7.5 (m, 5H) ; 5.15 (t, 1H) , 4.2 (m,
2H), 3.85 (m, 2H); 2.5 (s, 3H).
Example 2 9
We have prepared other compounds of formula
III-a by methods substantially similar to those described
in the above Examples 1-28 and those illustrated in
Schemes I-XII. The characterization data for these
compounds is summarized in Table 3 below and includes
LC/MS, HPLC, and 1H NMR data.
Where applicable, 1H NMR data is summarized in
Table 3 below wherein "Y" designates 1H NMR data is
5 available and was found to be consistant with structure.
Compound numbers correspond to the compound numbers
listed in Table 1.
BIOLOGICAL TESTING
The activity of the present compounds as
protein kinase inhibitors may be assayed in vitro, in
vivo or in a cell line. In vitro assays include assays
that determine inhibition of either the phosphorylatiori
activity or ATPase activity of the activated protein
kinase. Alternate in vitro assays guantitate the ability
of the inhibitor to bind to the protein kinase.
Inhibitor binding may be measured by radiolabelling the
inhibitor prior to binding, isolating the
inhibitor/protein kinase complex and determining the
amount of radiolabel bound. Alternatively, inhibitor
binding may be determined by running a competition
experiment where new inhibitors are incubated with the
protein kinase bound to known radioligands. The details
of the conditions used for performing these assays are
set forth in Examples 3 0 through 37.
Example 3 0
ERK INHIBITION ASSAY
Compounds were assayed for the inhibition of
ERK2 by a spectrophotometric coupled-enzyme assay (Fox et
al (1998) Protein Sci 7, 2249). In this assay, a fixed
concentration of activated ERK2 (10 nM) was incubated
with various concentrations of the compound in DMSO (2.5
%) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.5,
containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200
uM NADH, 150 ug/mL pyruvate kinase, 50 ug/mL lactate
dehydrogenase, and 200 uM erktide peptide. The reaction
was initiated by the addition of 65 uM ATP. The rate of
decrease of absorbance at 34 0 nM was monitored. The IC50
was evaluated from the rate data as a function of
inhibitor concentration.
Table 4 shows the results of the activity of
selected compounds of this invention in the ERK2
inhibition assay. The compound numbers correspond to the
compound numbers in Table 1. Compounds having an
activity designated as "A" provided a percent inhibition
less than or equal to 33%; compounds having an activity
designated as "B" provided a percent inhibition of
between 24% and 66%; and compounds having an activity
designated as "C" provided a provided a percent
inhibition of between 67% and 100%. Compounds having an
activity designated as "D" provided a Xi of less than 0.1
micromolar; compounds having an activity designated as
"E" provided a Kj. of between 0.1 and 1.0 micromolar; and
compounds having an activity designated as "F" provided a
Ki of greater than 1.0 micromolar.
Example 31
ERK2 INHIBITION: Cell Proliferation Assay
Compounds may be assayed for the inhibition of
ERK2 by a cell proliferation assay. In this assay, a
complete media is prepared by adding 10% fetal bovine
serum and penicillin/streptomycin solution to RPMI 1640
medium (JRH Biosciences). Colon cancer cells (HT-29 cell
line) are added to each of 84 wells of a 96 well plate at
a seeding density of 10,000 cells/well/150 µL- The cells
are allowed to attach to the plate by incubating at 37°C
for 2 hours. A solution of test compound is prepared in
complete media by serial dilution to obtain the following
concentrations: 20 (µM, 6.7 |J.M, 2.2 (µM, 0.74 (J.M, 0.25 µM,
and 0.08 µM. The test compound solution (50 |iL) is added
to each of 72 cell-containing wells. To the 12 remaining
cell-containing wells, only complete media (200 µL.) is
added to form a control group in order to measure maximal
proliferation. To the remaining 12 empty wells, complete
media is added to form a vehicle control group in order
to measure background. The plates are incubated at 3 7°C
for 3 days. A stock solution of 3H-thymidine (1 mCi/mL,
New England Nuclear, Boston, MA) is diluted to 20 µCi/mL
in RPMI medium then 20 µL of this solution is added to
each well. The plates are further incubated at 37°C for 8
hours then harvested and analyzed for 3H-thyraidine uptake
using a liquid scintillation counter.
Compounds III-a-116, III-a-139, and III-a-136
were each shown to have an IC50 of less than 0.1 µM.
Example 32
ERK1 INHIBITION ASSAY
Compounds were assayed for the inhibition of
ERK1 by a spectrophotometric coupled-enzyme assay (Fox et
al (1998) Protein Sci 7, 2249). In this assay, a fixed
concentration of activated ERK1 (20 nM) was incubated
with various concentrations of the compound in DMSO (2.0
%) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.6,
containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200
uM NADH, 30 ug/mL pyruvate kinase, 10 µg/mL lactate
dehydrogenase, and 150 uM erktide peptide. The reaction
was initiated by the addition of 140 uM ATP (20 uL) . The
rate of decrease of absorbance at 34 0 nM was monitored.
The Kj was evaluated from the rate data as a function of
inhibitor concentration.
Examples of compounds that were found to
inhibit ERK1 with an activity of less than 0.1 uM include
III-a-202, III-a-204, and III-a-205.
Example 33
GSK-3 INHIBITION ASSAY
Compounds were screened for their ability to
inhibit GSK-3[3 (AA 1-420) activity using a standard
coupled enzyme system (Fox et al. (1998) Protein Sci. 7,
2249). Reactions were carried out in a solution
containing 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl,
3 00 uM NADH, 1 mM DTT and 1.5% DMSO. Final substrate
concentrations in the assay were 2 0 uM ATP (Sigma
Chemicals, St Louis, MO) and 300 uM peptide
(HSSPHQS(PO3H2)EDEEE, American Peptide, Sunnyvale, CA) .
Reactions were carried out at 3 0 °C and 2 0 nM GSK-3J3.
Final concentrations of the components of the coupled
enzyme system were 2.5 mM phosphoenolpyruvate, 3 00 µM
NADH, 3 0 ug/ml pyruvate kinase and 10 ug/ml lactate
dehydrogenase.
An assay stock buffer solution was prepared
containing all of the reagents listed above with the
exception of ATP and the test compound of interest. The
assay stock buffer solution (175 µi) was incubated in a
96 well plate with 5 ul of the test compound of interest
at final concentrations spanning 0.002 uM to 30 uM at 30
°C for 10 min. Typically, a 12 point titration was
conducted by preparing serial dilutions (from 10 mM
compound stocks) with DMSO of the test compounds in
daughter plates. The reaction was initiated by the
addition of 20 ul of ATP (final concentration 20 uM).
Rates of reaction were obtained using a Molecular Devices
Spectramax plate reader (Sunnyvale, CA) over 10 min at
3 0°C. The Ki values were determined from the rate data as
a function of inhibitor concentration.
Table 5 shows the results of the activity of
selected compounds of this invention in the GSK3
inhibition assay. The compound numbers correspond to the
compound numbers in Table 1. Compounds having an
activity designated as "A" provided a Ki of less than 0.1
micromolar; compounds having an activity designated as
"B" provided a Ki of between 0.1 and 1.0 micromolar; and
compounds having an activity designated as "C" provided a
Ki of greater than 1.0 micromolar.
Example 3 4
AURORA-2 INHIBITION ASSAY
Compounds were screened in the following manner
for their ability to inhibit Aurora-2 using a standard
coupled enzyme assay (Fox et al (1998) Protein Sci 7,
2249).
To an assay stock buffer solution containing
0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM
phosphoenolpyruvate, 300 mM NADH, 3 0 mg/ml pyruvate
kinase, 10 mg/ml lactate dehydrogenase, 4 0 mM ATP, and
800 uM peptide (LRRASLG, American Peptide, Sunnyvale, CA)
was added a DMSO solution of a compound of the present
invention to a final concentration of 30 uM. The
resulting mixture was incubated at 3 0 °C for 10 min. The
reaction was initiated by the addition of 10 uL of
Aurora-2 stock solution to give a final concentration of
70 nM in the assay. The rates of reaction were obtained
by monitoring absorbance at 34 0 ran over a 5 minute read
time at 3 0 °C using a BioRad Ultramark plate reader
(Hercules, CA) . The Ki values were determined from the
rate data as a function of inhibitor concentration.
Examples of compounds that were found to inhibit Aurora-2
include III-a-116,- III-a-117, III-a-136, III-a-138, III-
a-139, IIl-a-140, and III-a-141.
Example 3 5
CDK-2 INHIBITION ASSAY
Compounds were screened in the following manner
for their ability to inhibit CDK-2 using a standard
coupled enzyme assay (Fox et al (1998) Protein Sci 1,
2249) .
To an assay stock buffer solution containing
0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM
phosphoenolpyruvate, 3 00 mM NADH, 3 0 mg/ml pyruvate
kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and
100 uM peptide (MAHHHRSPRKRAKKK, American Peptide,
Sunnyvale, CA) was added a DMSO solution of a compound of
the present invention to a final concentration of 3 0 uM.
The resulting mixture was incubated at 3 0 °C for 10 min.
The reaction was initiated by the addition of
10 uL of CDK-2/Cyclin A stock solution to give a final
concentration of 25 nM in the assay. The rates of
reaction were obtained by monitoring absorbance at 340 nm
over a 5-minute read time at 30 °C using a BioRad
Ultramark plate reader (Hercules, CA) . The Ki values were
determined from the rate data as a function of inhibitor
concentration.
The following compounds were shown to have Ki
values than 0.1 µM for CDK-2: III-a-116, III-a-142, III-
a-149, and III-a-152.
The following compounds were shown to have Ki
values between 0.1 µM and 1 µM for CDK-2: III-a-146, III-
a-148, III-a-150, III-a-155, III-a-162, and III-a-174.
The following compounds were shown to have Ki
values between 1.0 and 20.0 µM for CDK-2: III-a-117, III-
a-156, and III-a-159.
Example 3 6
LCK INHIBITION ASSAY
The compounds were evaluated as inhibitors of
human Lck kinase using either a radioactivity-based assay
or spectrophotometric assay.
Lck Inhibition Assay A: Radioactivity-based Assay
The compounds were assayed as inhibitors of
full length bovine thymus Lck kinase (from Upstate
Biotechnology, cat. no. 14-106) expressed and purified
from baculo viral cells. Lck kinase activity was
monitored by following the incorporation of 33P from ATP
into the tyrosine of a random poly Glu-Tyr polymer
substrate of composition, Glu.-Tyr = 4:1 (Sigma, cat. no.
ß0275). The following were the final concentrations of
the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2,
2 mM DTT, 0.25 mg/ml BSA, 10 uM ATP (1-2 uCi 33P-ATP per
reaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of
recombinant human Src kinase. In a typical assay, all
the reaction components with the exception of ATP were
pre-mixed and aliquoted into assay plate wells.
Inhibitors dissolved in DMSO were added to the wells to
give a final DMSO concentration of 2.5%. The assay plate
was incubated at 30 C for 10 min before initiating the
reaction with 33P-ATP. After 20 min of reaction, the
reactions were quenched with 150 ul of 10%
trichloroacetic acid (TCA) containing 20 mM Na3PO4. The
quenched samples were then transferred to a 96-well
filter plate (Whatman, UNI-Filter GF/F Glass Fiber
Filter, cat no. 7700-3310) installed on a filter plate
vacuum manifold. Filter plates were washed four times
with 10% TCA containing 20 mM Na3PO4 and then 4 times with
methanol. 200ul of scintillation fluid was then added to
each well. The plates were sealed and the amount of
radioactivity associated with the filters was quantified
on a TopCount scintillation counter. The radioactivity
incorporated was plotted as a function of the inhibitor
concentration. The data was fitted to a competitive
inhibition kinetics model to get the Ki for the compound.
Lck Inhibition Assay B: Spectrophotometric Assay
The ADP produced from ATP by the human
recombinant Lck kinase-catalyzed phosphorylation of poly
Glu-Tyr substrate was quanitified using a coupled enzyme
assay (Fox et al (1998)' Protein Sci 7, 2249) . In this
assay one molecule of NADH is oxidised to NAD for every
molecule of ADP produced in the kinase reaction. The
disappearance of NADH can be conveniently followed at 340
nm.
The following were the final concentrations of
the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2,
2 mM DTT, 5 mg/ml poly Glu-Tyr, and 5 0 nM of recombinant
human Lck kinase. Final concentrations of the components
of the coupled enzyme system were 2.5 mM
phosphoenolpyruvate, 2 00 uM NADH, 3 0 ug/ml pyruvate
kinase and 10 ug/ml lactate dehydrogenase.
In a typical assay, all the reaction components
with the exception of ATP were pre-mixed and aliquoted
into assay plate wells. Inhibitors dissolved in DMSO
were added to the wells to give a final DMSO
concentration of 2.5%. The assay plate was incubated at
30 °C for 10 min before initiating the reaction with 150
uM ATP. The absorbance change at 34 0 nm with time, the
rate of the reaction, was monitored on a molecular
devices plate reader. The data of rate as a function of
the inhibitor concentration was fitted to competitive
inhibition kinetics model to get the Ki for the compound.
The following compounds were shown to have Ki
values than 1 µM for Lck: III-a-170, III-a-171, Ill-a-
172, III-a-173, III-a-181, and III-a-203.
The following compounds were shown to have Ki
values between l.o and 20.0 µM for Lck: III-a-204, Ill-a-
205, III-a-206, and III-a-207.
Example 3 7
AKT3 INHIBITION ASSAY
Compounds were screened for their ability to
inhibit AKT3 using a standard coupled enzyme assay (Fox
et al., Protein Sci., (1998) 7, 224 9). Assays were
carried out in a mixture of 100 mM HEPES 7.5, 10 mM
MgCl2, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final
substrate concentrations in the assay were 170 uM ATP
(Sigma Chemicals) and 200 uM peptide (RPRAATF, American
Peptide, Sunnyvale, CA). Assays were carried out at 30
"C and 45 nM AKT3. Final concentrations of the
components of the coupled enzyme system were 2.5 mM
phosphoenolpyruvate, 3 00 uM NADH, 3 0 ug/ML pyruvate
kinase and 10 ug/ml lactate dehydrogenase.
An assay stock buffer solution was prepared
containing all of the reagents listed above, with the
exception of AKT3, DTT, and the test compound of
interest. 56 ul of the stock solution was placed in a
384 well plate followed by addition of 1 ul of 2 mM DMSO
stock containing the test compound (final compound
concentration 30 uM). The plate was preincubated for
about 10 minutes at 30°C and the reaction initiated by
addition of 10 µl of enzyme (final concentration 45 nM)
and 1 mM DTT. Rates of reaction were obtained using a
BioRad Ultramark plate reader (Hercules, CA) over a 5
minute read time at 30 0C. Compounds showing greater than
50% inhibition versus standard wells containing the assay
mixture and DMSO without test compound were titrated to
determine IC50 values.

Selected compounds of this invention that
inhibit AKT3 include: III-a-238.
While we have presented a number of embodiments
of this invention, it is apparent that our basic
construction can be altered to provide other embodiments
which utilize the compounds and methods of this
invention. Therefore, it will be appreciated that the
scope of this invention is to be defined by the appended
claims rather than by the specific embodiments which have
been represented by way of example.
Appendix A: Names of Table 1 Compound Numbers III-a-
1: 4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid dimethylamide;
2: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-pyrrolidin-l-yl-methanone;
3 •• {4- [2-Amino-5- (3-chloro-2-fluoro-phenyl) -pyrimidin-4-
yl]-lH-pyrrol-2-yl}-pyrrolidin-l-yl-methanone;
4: 4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
5: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -
morpholin-4-yl-methanone;
6: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
[1,4' ]bipiperidinyl-l' -yl-methanone;
7: {4- [2-Amino-5- (3, 4-dimethoxy-phenyl) -pyrimidin-4-yl] -
lH-pyrrol-2-yl}-(3-hydroxy-piperidin-1-yl) -
methanone;
8: {4- [2-Amino-5- (3, 4-dimethoxy-phenyl) --pyrimidin-4-yl] -
lH-pyrrol-2-yl}-[1,4']bipiperidinyl-1'-yl-methanone;
9 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -
[1,4']bipiperidinyl-1'-yl-methanone;
10: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-[1,4']bipiperidinyl-1'-yl-
methanone;
11: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]- (4-hydroxy-piperidin-1-yl)-methanone;
12 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
[4- (2-fluoro-phenyl)-piperazin-1-yl]-methanone;
13 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
(4-phenyl-piperazin-l-yl)-methanone;
14 .- [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -
[4- (4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-l-yl]-
methanone;
15 : [4- (2-Arnino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -
(4-pyridin-2-yl-piperazin-1-yl)-methanone;
16 : (4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrol-2-yl}-morpholin-4-yl-methanone;
17: 4-[2-Amino-5- (3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)-
amide;
1_8 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-
yl]-morpholin-4-yl-methanone;
19: 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
20: 4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)-
amide;
21: {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-yl]-
methanone;
22 : (4- [2-Amino-5- (3 -chloro-phenyl) -pyrimidin-4-yl] -1H--
pyrrol-2-yl}-(4-phenyl-piperazin-1-yl)-methanone;
23: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-
pyridin-1-yl] -methanone;
24: {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-(3 , 4-dihydro-lH-isoquinolin-2-yl)-
methanone;
25: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)-
methanone,-
26: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-morpholin-4-yl-methanone;
27: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-(4-hydroxy-piperidin-l-yl)-methanone;
28 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[1,4']bipiperidinyl-1'-y1-methanone;
29 : 4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid benzyl-methyl-amide;
30 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
[4- (4-methoxy-phenyl)-piperazin-1-yl]-methanone;
31: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] -
(2-hydroxymethyl-piperidin-1-yl)-methanone;
32 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
(3,4-dihydro-lH-isoquinolin-2-yl)-methanone;
33 : 4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid benzyl-methyl-amide;
34 : (4- [2-Amino-5-(3 t4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-
pyridin-1-yl] -methanone;
35: {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl] -
lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinolin-2-yl)-
methanone;
36 : 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid benzyl-methyl-amide ,-
37: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl] - (4-phenyl-piperazin-l-yl)-methanone;
38 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-IH-pyrrol-2-
yl]- (4-methyl-[1,4]diazepan-1-yl)-methanone;
39 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]- (3,4-dihydro-lH-isoquinolin-2-yl)-methanone;
40: 4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl] -1H-
pyrrole-2-carboxylic acid benzyl-methyl-amide;
41: (4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-
methanone;
42 ¦• 4- [2-Amino-5- (3-chloro-2-f luoro-phenyl) -pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid benzyl-methyl-
amide;
43: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-
methanone;
44: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4 -
yl]-lH-pyrrol-2-yl}-(4-phenyl-piperazin-l-yl)-
methanone;
45: [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]- [4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;
4 6: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]-(3-hydroxy-piperidin-1-yl)-methanone;
47: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]- [4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;
4 8 .- [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-
yl]- [4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-l-
yl]-methanone;
49: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-
1-yl] -methanone;
50: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-[4-(4-methoxy-phenyl)-piperazin-
1-yl] -methanone;
51: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-
methanone;
52 : l-(4-(4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-
pyrimidin-4-yl]-lH-pyrrole-2-carbonyl}-piperazin-1-
yl)-ethanone;
53 .- {4- [2-Amino-5- (3-chloro-2-f luoro-phenyl) -pyrimidin-4-
yl]-lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinolin-2-
yl)-methanone;
54 : {4~ [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl)-(3-hydroxy-piperidin-l-yl)-methanone;
55 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] -
(4-methyl-[1,4]diazepan-1-yl)-methanone;
56 : l-(4-{4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-
4-yl]-lH-pyrrole-2-carbonyl}-piperazin-1-yl)-
ethanone;
57 : {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl] -
lH-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-
methanone;
58: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
(3-hydroxy-piperidin-l-yl)-methanone;
59: 4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H--
pyrrole-2-carboxylic acid methyl-(2-pyridin-2-yl-
ethyl)-amide;
60 : [4- (2-Am'ino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-
yl]-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone;
61: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin-
1-yl] -methanone;
62: 4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
methyl-2-phenyl-ethyl)-methyl-amide;
63: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)-
methanone;
64: [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
(4-hydroxy-piperidin-1-yl)-methanone;
65: {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
1H-pyrrol-2-yl}-(4-hydroxy-piperidin-1-yl)-
methanone;
66: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-(4-hydroxy-piperidin-l-yl)-
methanone;
67 : (4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)-
methanone;
68 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-
methanone;
69: 1-{4-[4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-
pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone;
70 : {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-
yl]-methanone;
71 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] -
pyrrolidin-1-yl-methanone;
72 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-morpholin-4-yl-methanone;
73 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid benzylamide;
74: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 3,4-difluoro-benzylamide;
75 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
76 : 4 - (2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2 -
carboxylic acid 4-fluoro-benzylamide;
77 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 3-chloro-benzylamide;
78 : 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 4-methoxy-benzylamide;
79: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 3-chloro-4-f luoro-benzylamide ,-
80: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide
81: 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide
82: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide;
83: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid . (3-hydroxy-l-phenyl-propyl)-amide;
84: 4- (2,5-Diamino-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 3-chloro-4-fluoro-benzylamide;
85: 4- (2-Amino-5-methylamino-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
86: 4- (5-Acetylamino-2-amino-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
87 : 4- [2-Amino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1H-
pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
88 : 4- (2-Amino-5-hydroxy-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid 3-chloro-4-fluoro-benzylamide;
89 : 4- (2-Amino-5-methylaminomethyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
90 : 4- (2-Amino-5-hydroxymethyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
91: 4- [2-Cyclohexylamino-5-(3-methyl-ureido)-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
92: 4- [2-Acetylamino-5-(3-methyl-ureido)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
93 : 4- (5-Hydroxy-2-methanesulfonylamino-pyrimidin-4-yl) -
lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide;
94 : 4- (2-Amino-5-methanesulfonyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide;
95 : 4- (2-Amino-5-hydroxymethyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3 , 4-dif luoro-benzylamide ;
96 : 4- (2-Cyclohexylamino-5-methyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide;
97 . 4- [2-Amino-5- (3 , 5-dichloro-phenyl) -pyrimidin-4-yl] -
lH-pyrrole-2-carboxylic acid (pyridin-4-ylmethyl)-
amide;
18: 4- [5- (3 , 5-Dichloro-phenyl) -2 -phenylamino-pyrimidin-4 -
yl]-lH-pyrrole-2-carboxylic acid 3-trifluoromethyl-
benzylamide;
99 : 4- [2-Amino-5-(3, 5-dichloro-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid .(2-hydroxy-l-phenyl-
ethyl)-amide;
100: 4- [2-Amino-5-(3 , 5-dichloro-phenyl)-pyrimidin-4-yl] -
lH-pyrrole-2-carboxylic acid (benzo [1,3]dioxol-5-
ylmethyl)-amide;
101: 4- [2-Amino-5-(3 , 5-dichloro-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid (2-dimethylamino-2-
pyridin-3-yl-ethyl)-amide;
102 : 4- [2-Amino-5-(3, 5-dichloro-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid 4-methanesulfonyl-
benzylamide;
103 : 4- [5- (3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid
(benzo [1,3] dioxol-5-ylmethyl) -amide;
104 : 4- [5- (3 , 5-Dichloro-phenyl)-2-phenylamino-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-morpholin-4-
yl-2-pyridin-3-yl-ethyl) -amide;
105 : 4- [2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl) -amide;
106 : 4- (2-Amino-5-propyl-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
107 : 4- (2-Amino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
108 : 4- (5-Methyl-2-methylamino-pyrimidin-4 -yl) -1H-
pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)-
amide;
109 : 4- (2-Methylamino-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
110 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (2-dimethylamino-ethyl) -amide,-
111: 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid propylamide;
112 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (3-phenyl-propyl)-amide;
113 .- 4- (2-Ethylamino-5-methyl -pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (naphthalen-1-ylmethyl)-amide,-
114 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid cyclopropylamide;
115 : 4- (2-Ethylamino-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid 2-trifluoromethyl-benzylamide;
116 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
117: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
118 : 4- (2-Ethylamino-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (4-methyl-cyclohexyl)-amide;
119 : 4-(5-Ethyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid isopropylamide;
120 : 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-amino-ethyl)-amide;
121: 4- (2-Amino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic
acid benzyl-methyl-amide;
122 : 4- (2-Amino-pyrimidiri-4-yl)-lH-pyrrole-2-carboxylic
acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl-
amide;
123 : 1-{4- [4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone;
124 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (3-phenyl-propyl)-amide;
125 : 4- (2-Amino-5-ethyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid [2-(6-methoxy-lH-indol-3-yl)-ethyl]-
amide;
126 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-phenoxy-ethyl)-amide;
127 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (1-methyl-3-phenyl-
propyl)-amide;
128 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (lH-benzoimidazol-2-
ylmethyl)-amide;
129 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (1-hydroxymethyl-3-methyl-
butyl)-amide;
130 .- 4- (5-Methyl-2-phenylamino-pyrimidin-4 -yl) -1H-
pyrrole-2-carboxylic acid [l-hydroxymethyl-2-(1H-
imidazol-4-yl)-ethyl]-amide;
131: 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide;
132 : 4- [2-(2-Diethylamino-ethylamino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid 3,4-difluoro-
benzylamide;
133 : 4- [5-Methyl-2-(2-piperidin-l-yl-quinazolin-4-
ylamino)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid benzylamide;
134 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-chloro-4-fluoro-
phenyl)-2-hydroxy-ethyl]-amide;
135 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-chloro-4-fluoro-
phenyl)-2-hydroxy-ethyl]-amide;
136 : 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
137: 4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
138: 4-[2-(3-Hydroxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
139: 4-[2-(Benzo[1,3]dioxol-5-ylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
140: 4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
141: 4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
142: 4- [2- (4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
143: 4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
144: 4- (5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
145: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-fluoro-4-methyl-
phenyl)-2-hydroxy-ethyl]-amide;
146: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [2-hydroxy-l-(3-
trifluoromethyl-phenyl)-ethyl]-amide;
147: 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid [1-(3-fluoro-4-
methyl-phenyl)-2-hydroxy-ethyl]-amide;
148: 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-
trifluoromethyl-phenyl)-ethyl]-amide;
149: 4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
150: 4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
151: 4- [2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
152 : 4- [2- (4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
153: 4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
154: 4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
155: 4- [2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
156: 4- [2- (2-Methoxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl) - amide ,-
157: 4- [5-Methyl-2-(4-trifluoromethoxy-phenylamino)-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
15 8 .- 4- (2-Isobutylamino-5-methyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
159: 4- [2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
160 .- 4- (5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
161: 4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
162 : 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
163: 4- (5-Methyl-2-propylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
164: 4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
165: 4- (5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl) -amide ,•
166 : 4- {2- (2-Hydroxy-l-phenyl-ethylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
167: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-
ethyl)-amide;
168 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-
ethyl)-amide;
169: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-2-phenyl-ethyl)-amide;
170: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2-
phenyl-ethyl)-amide;
171: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-IH-pyrrole-
2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2-
phenyl-ethyl)-amide;
172 : 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide;
173 .- 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide;
174: 4- [2-(1-Hydroxymethyl-cyclopropylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
175 : 4- [2- (2-Hydroxy-ethylamino) -5-methyl-pyrimidin-4 -
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
176 : 4- [2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
177 : 4- [2- (2-Hydroxy-propylamino) -5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
178 : 4- [2- (2-Hydroxy-propylamino) -5-tnethyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
179 : 4- [2- (2-Hydroxy-cyclohexylamino) -5-methyl-pyrimid.in-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1-
phenyl-ethyl)-amide;
121: 4- [2- (2-Hydroxy-l-methyl-ethylamino)-5-methyl-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
121: 4- [2- (3 -Dimethylamino-phenylamino) -5-methyl-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
180: 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic
acid (2-hydroxy-l-methyl-2-phenyl-ethyl) -methyl-
amide;
181 : 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -methyl-2-phenyl-ethyl) -methyl-
amide;
183 : 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic
acid (2-hydroxy-2-phenyl-ethyl) -methyl-amide;
184 : { [4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -1H-
pyrrole-2-carbonyl] -amino} -phenyl-acetic acid methyl
ester;
186: 4- (2-Amino-pyrimidin-4-yl)-lH-pyrrole-2-carboxyIic
acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl-
amide;
187: 4- (2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-
ethyl)-amide;
188: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-pyridin-3-yl-ethyl)-
amide;
189 : 4- (2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
190 : 4- (2-Ethylamino-5-methyl-pyritnidin-4-yl) -lH-pyrrole-
2-carboxylic acid [1-(3-fluoro-5-trifluoromethyl-
phenyl)-2-hydroxy-ethyl]-amide;
191: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid [1-(3-fluoro-phenyl)-2-hydroxy-
ethyl] -amide;
192 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid [1-(2-fluoro-phenyl)-2-hydroxy-
ethyl] -amide;
193 : 4- [2-(2-Cyclopropyl-l-hydroxymethyl-ethylamino)-5-
methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid
(2-hydroxy-1-phenyl-ethyl)-amide;
194 : 4 - [2- (2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-
4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl -ethyl) -amide;
195 : 4- (2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-
ethyl)-amide;
196: 4- [2-(1-Hydroxymethyl-2-methyl-propylamino)-5-
methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid
(2-hydroxy-l-phenyl-ethyl)-amide;
197: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-oxo-1-phenyl-propyl)-amide;
198 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-IH-pyrrole-
2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-
phenyl)-ethyl]-amide;
199: 4- [2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-
trifluoromethyl-phenyl)-ethyl]-amide;
200: 4- [2- (2-Chloro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-
trifluoromethyl-phenyl)-ethyl]-amide;
2 01.- 4- [2- (2-Hydroxy-l-phenyl-ethylamino) -5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2-
hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;
200: 4- [2-(3-Dimethylamino-phenylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2-
hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;
202: 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [2-hydroxy-l-(3 -
trifluoromethyl-phenyl)-ethyl]-amide;
203: 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [2-hydroxy-l-(2-methoxy-
phenyl) -ethyl] -amide;
2 04: 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1K-
pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2-
hydroxy-ethyl]-amide;
2 05 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-
ethyl)-amide;
206: 4- (2-Methoxyamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
207: 4- (2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
208: 4- [2- (3-Dimethylamino-phenylamino)-5-methyl-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
209: 4- [2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m-
tolyl-ethyl)-amide;
210: 4- [2- (2-Hydroxy-l-phenyl-ethylamino)-5-methyl-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
211: 4- [2- (2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m-
tolyl-ethyl)-amide;
212: 4- [2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m-
tolyl-ethyl)-amide;
213: 4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
214: 4- (5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
215: 4- [5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl] -
lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
216: 4-(5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-
pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl) -amide;
217: 4-{5-Methyl-2- [ (tetrahydro-furan-2-ylmethyl)-amino]-
pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-pheny1-e thy1)-ami de;
218: N' -{4-[5-(2-Hydroxy-1-phenyl-ethylcarbamoyl) -1H-
pyrrol-3-yl]-5-methyl-pyrimidin-2-yl}-
hydrazinecarboxylic acid ethyl ester;
219: 4-(5-Methyl-2- [(pyridin-3-ylmethyl)-amino]-
pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
220: 4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4-
yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
221: 4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-
ethyl)-amide;
222: 4-[2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
22 3 .- 4- (5-Methyl-2-o-tolylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-
ethyl)-amide;
224: 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2-
hydroxy-ethyl]-amide;
225: 4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
226: 4-[2-(N',N'-Dimethyl-hydrazino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
227: 4-[5-Methyl-2-(2-trifluoromethyl-phenylamino) -
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
228: 4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-
ethyl)-amide;
229: 4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
230: 4-{2-[1-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-
ethylamino]- 5-methyl-pyrimidin-4-yl}-lH-pyrrole-2 -
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
231: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-fluoro-phenyl)-2-
hydroxy-ethyl]-amide;
232: 4 - [2 -(1-Hydroxymethyl-propylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [l-(3-
chloro-phenyl)-2-hydroxy-ethyl]-amide;
233: 4- [2-(2-Hydroxy-l-hydroxymethyl-ethylamino)-5-
methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid
[1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;
234: 4- [2-(1-Hydroxymethyl-propylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
235: 4- [2-(2-Hydroxy-1-hydroxymethyl-ethylamino)-5-
methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid
(2-hydroxy-l-phenyl-ethyl)-amide;
236: 4-[2-(1-Hydroxymethyl-propylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
237 : 4- [5-Methyl-2- (2-methyl-cyclopropylamino) -pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl) -amide; and
238 : 4- (2-Cyanoamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide.
or a pharmaceutically acceptable salt thereof, wherein:
Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring
A and Q'R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to
two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not
simultaneously substituted by R6;
Z1 is N and Z2 is CH;
T is a linker group selected from -NH-, -CH2- , -CO-, or a saturated or unsaturated
C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated
carbons of the chain are optionally replaced by -CO-, -C(O)C(O)-, -C(O)NR7-,
-C(O)NR7NR7-, -CO2,-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-,
-NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-;
Q' is selected from -CO2-, -C(O)NR7- or -SO2NR7-;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-,
-CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
R2' is selected from -(CH2)yCH(R5)2 or -(CH2)yCH(R8)CH(R5)2;
y is 0-6;
R3 is selected from R7, R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2,or -(CH2)y
CH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from
C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl
ring having 3-10 ring atoms;
WE CLAIM:
1. A compound of formula I':
each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -
(CH2)yR5, or-(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7,
SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N
(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7,
NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6;
aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen
to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and
each w is independently selected from 0-4.
2. The compound as claimed in claim 1, wherein Sp is selected from one of the
following:
or a pharmaceutically acceptable salt thereof.
3. The compound as claimed in claim 2, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-
membered aryl or heteroaryl ring.
4. The compound as claimed in claim 3, wherein:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1' is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-
membered aryl or heteroaryl ring.
5. The compound as claimed in claim 3, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl..
isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH)
isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl,
or isoxazolyl group;
(b) TmR1 is selected from an optionally substituted phenyl, methyl, ethyl, propyl.
cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)
NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl
ring, and Q' is -C(O)NH-.
6. The compound as claimed in claim 5, wherein:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH)
isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl,
or isoxazolyl group;
(b) TmR1 is selected from an optionally substituted phenyl, methyl, ethyl, propyl,
cyclopropyl, cyclohexyh CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)
NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl
ring, and Q' is -C(O)NH-.
7. The compound as claimed in claim 2, wherein said compound is of formula I":
or a pharmaceutically acceptable salt thereof.
8. The compound as claimed in claim 7, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1 is hydrogen, N(R4)2:, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
9. The compound as claimed in claim 8, wherein:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is a an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
10. The compound as claimed in claim 2, wherein said compound is of formula I°:
or a pharmaceutically acceptable salt thereof.
11. The compound as claimed in claim 10, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-
membered aryl or heteroaryl ring.
12. The compound as claimed in claim 11, wherein:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-
membered aryl or heteroaryl ring.
13. A compound of formula III-a':
or a pharmaceutically acceptable salt thereof, wherein:
T is a linker group selected from -NH-, -CH2-, -CO-, or a saturated or unsaturated C1.6
alkylidene chain, which is optionally substituted, and wherein up to two saturated.
carbons of the chain are optionally replaced by -C(O)-, -C(O)C(O)-, -CONR7-,
-CONR7NR7-, -CO2-, -OC(O)-, -NR7CO2-, -O-, -NR7CONR\ -OC(O)NR7-:
-NR7NR7-, -NR7CO-, -S-, -SO-, -S(O)2-, -NR7-, -SO2NR7-, or -NR7SO2-;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-,
-CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
R3 is selected from R\ R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2, or -(CH2)
yCH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from
C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl
ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -
(CH2)yR5, or -(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7,
SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N
(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7,
NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted Ci.6
aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen
to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2)wN(R4)2, or (CH2)«SR7; and
each w is independently selected from 0-4.
14. The compound as claimed in claim 13, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroary]
ring; and
(c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
15. The compound as claimed in claim 14, wherein:
fa) R3 is hydrogen, carbocyclyl. -CH(R8)R. or an optionally substituted group selected
from Ci-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR' is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from Ci-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
16. The compound as claimed in claim 14, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH)
isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or
benzyl group;
(b) TmR' is selected from an optionally substituted phenyl, methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)
NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring.
17. The compound as claimed in claim 16, wherein:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
isopropyl. -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH)
isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or
benzyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)
NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or a substituted or unsubstituted phenyl or pyridyl ring.
18. A compound of formula III-a°:
or a pharmaceutically acceptable salt thereof, wherein:
T is a linker group selected from -NH-,-CH2-, -CO-, or a saturated or unsaturated C1-6
alkylidene chain, which is optionally substituted, and wherein up to two saturated
carbons of the chain are optionally replaced by -CO-, -C(O)(CO)-, -CONR7-,
-CONR7NR7-, -CO2-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-,
-NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-,
-CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
y is 0-6;
R3 is selected from R\ R, -(CH2)yCH(R8)R, CN, -(CH2))CH(R8)CH(R5)2, or -(CH2)
yCH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from
C1-.6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl
ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -
(CH2)yR\ or -(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7,
SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N
(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7,
NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6;
aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen
to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and
each w is independently selected from 0-4.
19. The compound as claimed in claim 18, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or a substituted or unsubstituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or a substituted or
unsubstituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, and R8 is R7 or OR7.
20. The compound as claimed in claim 19, wherein:
a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or a substituted or unsubstituted group
selected from C1-4 aliphatic,3-6 membered heterocyclic,or a 5-6 membered aryl or
heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or a substituted or
unsubstituted group selected from C1-.6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, and R8 is R7 or OR7.
21. The compound as claimed in claim 1, selected from the group consisting of:
4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl-amide;
4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l -
phenyl-ethyl)-amide;
4-(2-Amino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (3-hydroxy-l -
phenyl-propyl)-amide;
4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (3-hydroxy-l»
phenyl-propyl)-amide;
4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid
(2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid
(2-dimethylamino-2-pyridin-3-yl-ethyl)-amide;
4-[5-(3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-amide;
4-[2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-
carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrroIe-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-
1 -phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-methyl -amide;
4-(5-Methyl-2-methylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (1 -
hydroxymethy 1-3 -methyl -butyl)-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -
hydroxymethyl-2-(lH-imidazol-4-yl)-ethyl]-amide;
4-(5-Methyl-2-methylamino-pyrirnidin-4-yl)-l H-pyrrole-2-carboxylic acid [l-(3-
chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid [l-(3-
chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid
(2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4- [2-(3 -Hydroxy-phenylamino)-5 -methyl-pyrimidin-4-yl] -1H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(Benzo[l,3]dioxol-5-ylamino)-5-methyl-pyrimidin-4-yl]-lH-p>Trole-2-
carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide;
4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -(3-
fluoro-4-methyl-phenyl)-2-hydroxy-ethyl]-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2-
hydroxy-1 -(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid
[ 1 -(3 -fluoro-4-methy l-phenyl)-2-hydroxy-ethyl] -amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid
[2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide;
4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[5-Methyl-2-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-(2-Isobutylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid
(2-hydroxy- l-phenyl-ethyl)-amide;
4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Methyl-2-propylamino-pyTimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenyl-
ethyl)-methyl-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-
1-methyl-2-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-
1 -methyl-2-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-
2-phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-
phenyl-ethyl)-methyl-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-
l-hydroxymethyl-2-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-
l-hydroxymethyl-2-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (3-hydroxy-
1 -phenyl-propyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (3-hydroxy-
1 -phenyl-propyl)-amide;
4-[2-( 1 -Hydroxymethyl-cyclopropylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid
(2-hydroxy-1-phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-1 -methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid
(2-hydroxy-1 -phenyl-ethyl)-amide;
{[4-(2-Ethylamino-5-methyl-p>Timidin-4-yl)-lH-pyrrole-2-carbonyl]-amino}-phenyl-
acetic acid methyl ester;
4-[2-(2-Hydroxy-1 -methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-methyl-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-p>Trole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-methyl-amide;
4-(2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-
1 -pyridin-3-yl-ethyl)-amide;
4-(2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [1 -(3-
fluoro-5-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [1-(3-
fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid [1 -(2-
fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(2-Cyclopropyl-l-hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxyIic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(l -Hydroxymethyl-2-methyl-propylamino)-5-methyl-pyrimidin-4-yl]-1H-
pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-oxo-1-
phenyl-propyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2-hydroxy-
l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pryimidin-4-yl]-1H-pyrrole-2-carboxylic acid
[2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid
[2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(2-Hydroxy-1 -phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-
carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid [2-
hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2-
hydroxy-1-(2-methoxy-phenyl)-ethyl] -amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid [1-
(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
4-(2-Methoxyamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-l-phenyl-ethyl)-amide;
4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide;
4-f2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yll-l H-pyrrole-2-carboxylic acid
(2-hydroxy-l-m-tolyl-ethyl)-amide;
4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide;
4-[2-(2,3-Dirnethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic
acid (2-hydroxy-l-m-tolyl-ethyl)-amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid
(2-hydroxy-1 -m-tolyl-ethyl)-amide;
4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyrrole-2-
carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide;
4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyrrole-2-
carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide;
N'-{4-[5-(2-Hydroxy-l-phenyl-ethylcarbamoyl)-lH-pyrrol-3-yl]-5-methyl-pyrimidin-
2-yl}-hydrazinecarboxylic acid ethyl ester;
4-{5-Methyl-2-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyiTole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Cyanoamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-l-methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide;
4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -m-tolyl-ethyl)-amide;
4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -(3 -
chloro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(N',N'-Dimethyl-hydrazino)-5-methyl-pyrimidin-4-ylJ-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1-pheny l-ethyl)-amide;
4-[5-Methyl-2-(2-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid
(2-hydroxy-1 -phenyl-ethyl)-amide;
4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-{2-[l-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-methyl-pyrimidin-4-
yl} -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [l-(3-
fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-( 1 -Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid [l-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(2-Hydroxy-1 -hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-
pyrrole-2-carboxylic acid [l-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(l -Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid (2-hydroxy-1-m-tolyl-ethyl)-amide;
4-[2-(2-Hydroxy-1 -hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-
pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-[2-(l-Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; and
4-[5-Methyl-2-(2-methyl-cyclopropylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide.
22. A composition comprising a compound as claimed in any one of claims 1-21 and
a pharmaceutically acceptable carrier.
23. The composition as claimed in claim 22, comprising an additional therapeutic
agent selected from a chemotherapeutic agent or anti-proliferative agent, or an agents
for treating diabetes, an anti-inflammatory agent, an immunomodulatory or
immunosuppressive agent, an agent for treating neurlogical disorders, an agent for
treating cardiovascular disease, an agent for treating liver disease, cholestyramine, an
interferon, an anti-viral agents, an agents for treating blood disorders, or an agent for
treating immunodeficiency disorders.
24. The composition as claimed in claim 22, wherein said composition is capable of
being used for inhibiting ERK2, GSK-3, Aurora, CDK.2, or Lck activity in a patient.
25. The composition as claimed in claim 24, wherein said composition is used to
inhibit ERK2 activity in a patient.
26. The composition as claimed in claim 25, wherein said ERK2 activity is
associated with a disease selected from cancer, stroke, diabetes, hepatomegaly,
cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease,
autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders,
inflammation, neurological disorders, a hormone-related disease, conditions
associated with organ transplantation, immunodeficiency disorders, destructive bone
disorders, proliferative disorders, infectious diseases, conditions associated with cell
death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML),
liver disease, pathologic immune conditions involving T cell activation, or CNS
disorders.
27. The composition as claimed in claim 26, wherein the disease is cancer.
28. The composition as claimed in claim 27, wherein the disease is a cancer selected
from breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx,
glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid
carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone;
colon, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma,
undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma;
bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid
disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx
(oral), lip, tongue, mouth, pharynx; small intestine: colon-rectum, large intestine,
rectum; brain and central nervous system; or leukemia.
29. The composition as claimed in claim 25, wherein the disease is cardiovascular
disease.
30. The composition as claimed in claim 29, wherein the disease is a cardiovascular
disease selected from restenosis, cardiomegaly, artherosclerosis, myocardial
infarction, or congestive heart failure.
31. The composition as claimed in claim 24, wherein said composition is useful for
treating a GSK-3 -mediated disease in a patient in need thereof.
32. The composition as claimed in claim 31, wherein said disease is diabetes.
33. The composition as claimed in claim 31, wherein said disease is Alzheimer's
disease.
34. The composition as claimed in claim 31, wherein said disease is schizophrenia.
35. The composition as claimed in claim 22, wherein said composition is useful for
enhancing glycogen synthesis in a patient in need thereof.
36. The composition as claimed in claim 22, wherein said composition is useful for
lowering blood levels of glucose in a patient in need thereof.
37. The composition as claimed in claim 22, wherein said composition is useful for
inhibiting the production of hyperphosphorylated Tau protein in a patient in need
thereof.
38. The composition as claimed in claim 22, wherein said composition is useful for
inhibiting the phosphorylation of |3-catenin in a patient in need thereof.
39. The composition as claimed in claim 24, wherein said composition is useful for
treating an Aurora-2-mediated disease in a patient in need thereof.
40. The composition as claimed in claim 39, wherein said disease is selected from
colon, breast, stomach, or ovarian cancer.
41. The composition as claimed in claim 24, wherein said composition is useful for
treating CDK-2-mediated disease in a patient in need thereof.
42. The composition aas claimed in claim 41, wherein said disease is selected from
cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,
cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, or an autoimmune
disease.
43. The composition as claimed in claim 24, wherein said composition is useful for
treating a Lck-mediated disease in a patient in need thereof.
44. The composition as claimed in claim 43, wherein said disease is selected from an
autoimmune disease or transplant rejection.
45. A method for screening ERK2, Aurora-2, GSK-3, CDK-2, AKT3, or Lck activity
in a biological sample in vitro, wherein said biological sample is selected from the
group consisting of a cell culture, an enzyme preparation, a mammalian biopsy,
blood, saliva, urine, feces, semen, tears, and any extract thereof, said method
comprising the step of contacting said biological sample with a compound as claimed
in any one of claims 1-21.
46. A composition for coating an implantable device comprising a compound as
claimed in claim 1 and a carrier suitable for coating said implantable device.
47. An implantable device coated with a composition as claimed in claim 46.CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to US
Provisional Patent Application 60/267,818 filed February
9, 2001 and US Provisional Patent Application 60/328,768
filed October 12, 2001, the contents of which are
incorporated herein by reference.
FIELD OF THE INVENTION
The present invention is in the field of
medicinal chemistry and relates to pyrazole compounds
that are protein kinase inhibitors, especially inhibitors
of ERK, compositions containing such compounds and
methods of use. The compounds are useful for treating
cancer and other diseases that are alleviated by protein
kinase inhibitors.
BACKGROUND OF THE INVENTION
Mammalian mitogen-activated protein (MAP)1
kinases are serine/threonine kinases that mediate
5 intracellular signal transduction pathways (Cobb and
Goldsmith, 1995, J Bio1. Chem., 270, 14843; Davis, 1995,
Mol. Reprod. Dev. 42, 459) . Members of the MAP kinase
family share sequence similarity and conserved structural
domains, and include the ERK2 (extracellular signal
10 regulated kinase) , JNK (Jun N-terminal kinase), and p38
kinases. JNKs and p38 kinases are activated in response
to the pro-inflammatory cytokines TNF-alpha and
interleukin-l, and by cellular stress such as heat shock,
hyperosmolarity, ultraviolet radiation,
lipopolysaccharides and inhibitors of protein synthesis
(Derijard et al., 1994, Cell 76, 1025; Han et al., 1994,
Science 265, 808; Raingeaud et al. 1995, J Biol. Chem.
270, 7420; Shapiro and Dinarello, 1995, Proc. Natl. Acad.
Sex. USA 92, 12230). In contrast, ERKs are activated by
mitogens and growth factors (Bokemeyer et al. . 1996,
Kidney Int. 49, 1187) .
ERK2 is a widely distributed protein kinase
that achieves maximum activity when both Thrl83 and
Tyrl8 5 are phosphorylated by the upstream MAP kinase
kinase, MEK1 (Anderson et al., 1990, Nature 343, 651;
Crews et al., 1992, Science 258, 478). Upon activation,
ERK2 phosphorylates many regulatory proteins, including
the protein kinases Rsk90 (Bjorbaek et al., 1995, J.
Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al., 1994,
Cell 78, 1027), and transcription factors such as ATF2
(Raingeaud et al. , 1996, Mol. Cell Biol. 16, 1247), Elk-1
(Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc.
Natl. Acad. Sci. USA 90, 10952), and c-Myc (Oliver et
al. , 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2 is
also a downstream target of the Ras/Raf dependent
pathways (Moodie et al., 1993, Science 2 60, 1658) and may
help relay the signals from these potentially oncogenic
proteins. ERK2 has been shown to play a role in the
negative growth control of breast cancer cells (Frey and
Mulder, 1997, Cancer Res. 57, 628) and hyperexpression of
ERK2 in human breast cancer has been reported (Sivaraman
et al., 1997, J Clin. Invest. 99, 1478). Activated ERK2
has also been implicated in the proliferation of
endothelin-stimulated airway smooth muscle cells,
suggesting a role for this kinase in asthma (Whelchel et
al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589).
Aurora-2 is a serine/threonine protein kinase
that has been implicated in human cancer, such as colon,
breast and other solid tumors. This kinase is believed
to be involved in protein phosphorylation events that
regulate the cell cycle. Specifically, Aurora-2 may play
a role in controlling the accurate segregation of
chromosomes during mitosis. Misregulation of the cell
cycle can lead to cellular proliferation and other
abnormalities. In human colon cancer tissue, the aurora-
2 protein has been found to be overexpressed. See
Bischoff et al., EMBO J. , 1998, 17, 3052-3065; Schumacher
et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et
al., J. Biol. Chem., 1997, 272, 13766-13771.
Glycogen synthase kinase-3 (GSK-3) is a
serine/threonine protein kinase comprised of a and p
isoforms that are each encoded by distinct genes [Coghlan
et al., Chemistry & Biology, 7, 793-803 (2000); Kim and
Kimmel, Curr. Opinion Genetics Dev. , 10, 508-514 (2000)].
GSK-3 has been implicated in various diseases including
diabetes, Alzheimer's disease, CNS disorders such as
manic depressive disorder and neurodegenerative diseases,
and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675;
and Hag et al., J. Cell Biol. (2000) 151, 117]. These
diseases may be caused by, or result in, the abnormal
operation of certain cell signaling pathways in which
GSK-3 plays a role. GSK-3 has been found to
phosphorylate and modulate the activity of a number of
regulatory proteins. These proteins include glycogen
synthase which is the rate limiting enzyme necessary for
glycogen synthesis, the microtubule associated protein
Tau, the gene transcription factor b-catenin, the
translation initiation factor elF2B, as well as ATP
citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc,
c-Myb, CREB, and CEPBa. These diverse protein targets
implicate GSK-3 in many aspects of cellular metabolism,
proliferation, differentiation and development.
In a GSK-3 mediated pathway that is relevant
for the treatment of type II diabetes, insulin-induced
signaling leads to cellular glucose uptake and glycogen
synthesis. Along this pathway, GSK-3 is a negative
regulator of the insulin-induced signal. Normally, the
presence of insulin causes inhibition of GSK-3 mediated
phosphorylation and deactivation of glycogen synthase.
The inhibition of GSK-3 leads to increased glycogen
synthesis and glucose uptake [Klein et al., PNAS, 93,
8455-9 (1996); Cross et al., Biochem. J., 303, 21-26
(1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993);
Massillon et al., Biochem J. 299, 123-128 (1994)].
However, in a diabetic patient where the insulin response
is impaired, glycogen synthesis and glucose uptake fail
to increase despite the presence of relatively high blood
levels of insulin. This leads to abnormally high blood
levels of glucose with acute and long term effects that
may ultimately result in cardiovascular disease, renal
failure and blindness. In such patients, the normal
insulin-induced inhibition of GSK-3 fails to occur. It
has also been reported that in patients with type II
diabetes, GSK-3 is overexpressed [WO 00/38675].
Therapeutic inhibitors of GSK-3 therefore are considered
to be useful for treating diabetic patients suffering
from an impaired response to insulin.
GSK-3 activity has also been associated with
Alzheimer's disease. This disease is characterized by
the well-known P-amyloid peptide and the formation of
intracellular neurofibrillary tangles. The
neurofibrillary tangles contain hyperphosphorylated Tau
protein where Tau is phosphorylated on abnormal sites.
GSK-3 has been shown to phosphorylate these abnormal
sites in cell and animal models. Furthermore, inhibition
of GSK-3 has been shown to prevent hyperphosphorylation
of Tau in cells [Lovestone et al., Current Biology 4,
1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55
(1997)]. Therefore, it is believed that GSK-3 activity
may promote generation of the neurofibrillary tangles and
the progression of Alzheimer's disease.
Another substrate of GSK-3 is (3-catenin which
is degradated after phosphorylation by GSK-3. Reduced
levels of ßcatenin have been reported in schizophrenic
patients and have also been associated with other
diseases related to increase in neuronal cell death
[Zhong et al., Nature, 395, 698-702 (1998); Takashima et
al., PNAS, 90, 7789-93 (1993); Pei et al., J.
Neuropathol. Exp, 56, 70-78 (1997)].
As a result of the biological importance of
GSK-3, there is current interest in therapeutically
effective GSK-3 inhbitors. Small molecules that inhibit
GSK-3 have recently been reported [WO 99/65897 (Chiron)
and WO 00/38675 (SmithKline Beecham)].
Aryl substituted pyrroles are known in the
literature. In particular, tri-aryl pyrroles (US
5,837,719) have been described as having glucagon
antagonist activity. 1,5-Diarylpyrazoles have been
described as p38 inhibitors (WO 9958523).
There is a high unmet medical need to develop
new therapeutic treatments that are useful in treating
the various conditions associated with ERK2 activation.
For many of these conditions the currently available
treatment options are inadequate.
Accordingly, there is great interest in new and
effective inhibitors of protein kinase, including ERK2
inhibitors, that are useful in treating various
conditions associated with protein kinase activation.
DESCRIPTION OF THE INVENTION
It has now been found that compounds of this
invention and compositions thereof are effective as
protein kinase inhibitors, especially as inhibitors of
ERK2. These compounds have the general formula I:
or a pharmaceutically acceptable derivative thereof,
wherein:
Sp is a spacer group comprising a 5-membered
heteroaromatic ring, wherein Ring A and QR2 are
attached to Sp at non-adjacent positions; and wherein
Sp has up to two R6 substituents, provided that two
substitutable carbon ring atoms in Sp are not
simultaneously substituted by R6;
Z1 and Z2 are each independently selected from N or CH;
T and Q are each an independently selected linker group;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-,
-0-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7- ,
-NR7SO2NR7-, or -S02-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR,
or OH;
R2 is selected from -(CH2)yR5, - (CH2) yCH (R5) 2;
-(CH2)yCH(R8)CH(R5)2, -N(R4)2; or -NR4 (CH2) yN (R4) 2 ;
y is 0-6;
R3 is selected from R7, R, - (CH2) yCH (R8) R, CN,
-(CH2)yCH(R8)CH(R5)2; or - (CH2) yCH (R8)N (R4) 2;
each R is independently selected from an optionally
substituted group selected from C1-6 aliphatic, C6-10
aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R,
-CON(R7)2, -SO2R7, -(CH2)yR5, or - (CH2) yCH (R5) 2;
each R5 is independently selected from R, OR, CO2R,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2,
C0N(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2) WN (R4) 2, or (CH2)WSR7;
and
each w is independently selected from 0-4.
As used herein, the following definitions shall
apply unless otherwise indicated. The phrase "optionally
substituted" is used interchangeably with the phrase
"substituted or unsubstituted" or with the term
"(un)substituted." Unless otherwise indicated, an
optionally substituted group may have a substituent at
each substitutable position of the group, and each
substitution is independent of the other.
The term "aliphatic" or "aliphatic group" as
used herein means a straight-chain or branched C1-C12
hydrocarbon chain that is completely saturated or that
contains one or more units of unsaturation, or a
monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon
that is completely saturated or that contains one or more
units of unsaturation, but which is not aromatic (also
referred to herein as "carbocycle" or "cycloalkyl"), that
has a single point of attachment to the rest of the
molecule wherein any individual ring in said bicyclic
ring system has 3-7 members. For example, suitable
aliphatic groups include, but are not limited to, linear
or branched or alkyl, alkenyl, alkynyl groups and hybrids
thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or
(cycloalkyl)alkenyl.
The terms "alkyl", "alkoxy", "hydroxyalkyl",
"alkoxyalkyl", and "alkoxycarbonyl", used alone or as
part of a larger moiety includes both straight and
branched chains containing one to twelve carbon atoms.
The terms "alkenyl" and "alkynyl" used alone or as part
of a larger moiety shall include both straight and
branched chains containing two to twelve carbon atoms.
The terms "haloalkyl", "haloalkenyl" and
"haloalkoxy" means alkyl, alkenyl or alkoxy, as the case
may be, substituted with one or more halogen atoms. The
term "halogen" means F, Cl, Br, or I.
The term "heteroatom" means nitrogen, oxygen,
or sulfur and includes any oxidized form of nitrogen and
sulfur, and the quaternized form of any basic nitrogen.
Also the term "nitrogen" includes a substitutable
nitrogen of a heterocyclic ring. As an example, in a
saturated or partially unsaturated ring having 0-3
heteroatoms selected from oxygen, sulfur or nitrogen, the
nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as
in pyrrolidinyl) or NR+ (as in N-substituted
pyrrolidinyl).
The term "aryl" used alone or as part of a
larger moiety as in "aralkyl", "aralkoxy", or
"aryloxyalkyl", refers to monocyclic, bicyclic and
tricyclic ring systems having a total of five to fourteen
ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3
to 7 ring members. The term "aryl" may be used
interchangeably with the term "aryl ring".
[0001] The term "heterocycle",
"heterocyclyl", or "heterocyclic" as used herein means
non-aromatic, monocyclic, bicyclic or tricyclic ring
systems having five to fourteen ring members in which one
or more ring members is a heteroatom, wherein each ring
in the system contains 3 to 7 ring members.
[0002] The term "heteroaryl", used alone or
as part of a larger moiety as in "heteroaralkyl" or
"heteroarylalkoxy", refers to monocyclic, bicyclic and
tricyclic ring systems having a total of five to fourteen
ring members, wherein at least one ring in the system is
aromatic, at least one ring in the system contains one or
more heteroatoms, and wherein each ring in the system
contains 3 to 7 ring members. The term "heteroaryl" may
be used interchangeably with the term "heteroaryl ring"
or the term "heteroaromatic".
An aryl (including aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including
heteroaralkyl and heteroarylalkoxy and the like) group
may contain one or more substituents. Suitable
substituents on the unsaturated carbon atom of an aryl,
heteroaryl, aralkyl, or heteroaralkyl group are selected
from halogen, -R°, -OR0, -SR°, 1,2-methylene-dioxy, 1,2-
ethylenedioxy, protected OH (such as acyloxy), phenyl
(Ph), Ph substituted with R°, -O(Ph), 0-(Ph) substituted
with R°, -CH2(Ph), -CH2(Ph) substituted with R°,
-CH2CH2(Ph), -CH2CH2(Ph) substituted with R°, -N02, -CN,
-N(R°)2, -NR°C(O)R°, -NR°C(O)N(R°)2, -NRCCO2R°, -NR°NR°C (O) R°,
-NR°NR°C(O)N(R°)2, -NR°NR°CO2R°/ -C(O)C(O)R°, -C (0) CH2C (0) R°,
-CO2R°, -C(O)R°, -C(O)N(R°)2, -OC (O) N (R°) 2, -S(O)2R°,
-SO2N(R°)2, -S(O)R°, -NR°SO2N(R°)2/ -NR°SO2R0, -C (=S) N (R°) 2,
-C(=NH) -N(R°)2, -(CH2)yNHC(O)R°, or
- (CH2)yNHC(0)CH(V-R°) (R°) , wherein each R° is independently
selected from hydrogen, optionally substituted Ci-6
aliphatic, an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring, phenyl (Ph), -O(Ph), or -CH2(Ph)-
CH2(Ph), wherein y is 0-6; and V is a linker group.
Substituents on the aliphatic group of R° are selected
from NH2, NH(C1.4 aliphatic), N(C1-4 aliphatic)2, halogen,
C1-4 aliphatic, OH, 0- (C1-4 aliphatic), N02, CN, C02H,
CO2(C1-4 aliphatic), -O(halo C1-4 aliphatic), or halo C1-4
aliphatic.
An aliphatic group or a non-aromatic
heterocyclic ring may contain one or more substituents.
Suitable substituents on the saturated carbon of an
aliphatic group or of a non-aromatic heterocyclic ring
are selected from those listed above for the unsaturated
carbon of an aryl or heteroaryl group and the following:
=0, =S, =NNHR*, =NN(R*)2, =N-, =NNHC (o) R*, =NNHC02 (alkyl),
=NNHS02(alkyl), or =NR*, where each.R* is independently
selected from hydrogen or an optionally substituted C1-6
aliphatic. Substituents on the aliphatic group of R* are
selected from NH2, NH(d-4 aliphatic), N(C1.4 aliphatic)2,
halogen, C1.4 aliphatic, OH, O- (C1.4 aliphatic) , No2, CN,
CO2H, CO2(C1.4 aliphatic), -O(halo C1-4 aliphatic), or halo
C1.4 aliphatic.
Substituents on the nitrogen of a non-aromatic
heterocyclic ring are selected from -R+, -N(R+)2, -C(0)R+,
-CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2,
-C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR+SO2R+; wherein R+ is
hydrogen, an optionally substituted C1-6 aliphatic,
optionally substituted phenyl (Ph), optionally
substituted -O(Ph), optionally substituted -CH2(Ph),
optionally substituted -CH2CH2(Ph), or an unsubstituted 5-
6 membered heteroaryl or heterocyclic ring. Substituents
on the aliphatic group or the phenyl ring of R+ are
selected from NH2, NH(C1.4 aliphatic), N(d1.4 aliphatic)2/
halogen, C^ aliphatic, OH, O- (Ci_4 aliphatic) , N02/ CN,
C02H, CO2(C1.4 aliphatic), -0(halo C1.4 aliphatic), or halo
C1.4 aliphatic.
The term "alkylidene chain" refers to an
optionally substituted, straight or branched carbon chain
that may be fully saturated or have one or more units of
unsaturation. The optional substituents are as described
above for an aliphatic group.
The term "spacer group" refers to a group that
separates and orients other parts of the molecule
attached thereto, such that the compound favorably
interacts with functional groups in the active site of an
enzyme. As used herein, the spacer group separates and
orients ring A and QR2 within the active site such that
they may form favorable interactions with functional
groups which exist within the active site of the ERK2
enzyme. When the spacer group is a 5-membered
heteroaromatic ring, ring A and QR2 are attached at non-
adjacent positions "B" and "C", and the 5-membered ring
is attached to ring A at point "D" and to QR2 at point "E"
as illustrated below.
Preferably, the distance between "D" and "C" is 3.7A, the
distance between "D" and "E" is 5.0A, the distance
between "B" and "C" is 2.2A, and the distance between "B"
and "E" is 3 . 5A , wherein each of the above described
distances is plus/minus 0.2 A.
The spacer group itself may also form
additional interactions within the active site to further
enhance inhibitory activity of the compounds. For
example, when Sp is a pyrrole the pyrrole-NH may form an
additional hydrogen bond within the active site of the
ERK2 enzyme.
The term "linker group" means an organic moiety
that connects two parts of a compound. Linkers are
typically comprised of an atom such as oxygen or sulfur,
a unit such as -NH-, -CH2-, -CO-, or a chain of atoms,
such as an alkylidene chain. The molecular mass of a
linker is typically in the range of about 14 to 200.
Examples of linkers include a saturated or unsaturated
C1-6 alkylidene chain which is optionally substituted, and
wherein up to two saturated carbons of the chain are
optionally replaced by -C(0)-, -C(O)C(O)-, -CONR7-,
-C0NR7NR7-, -C02-, -OC(O)-, -NR7CO2-, -O-, -NR7CONR7- ,
-OC(O)NR7-, -NR7NR7-, -NR7C0-, -S-, -SO-, -SO2-, -NR7-,
-SO2NR7-, or -NR7SO2-.
As used herein, linker group Q connects Sp with
R2. Q may also form additional interactions within the
ERK2 binding site to further enhance the inhibitory
activity of the compound. When Q is a carbonyl-
containing moeity such as -C(O)-, -CO2-, -OC(O)-,
-C(O)C(O)-, -CONH-, -CO2NH-, -CONHNH-, -NHCO-, -OC(O)NH-,
or -NHCO2-, or a sulfonyl-containing moeity such as -SO2-,
-SO2NH-, or -NHSO2-, the carbonyl or sulf onyl oxygen forms
a hydrogen-bond with lysine 54 in the ERK2 binding site.
When Q is an NH-containing moeity such as -CH2NH- or
-NHNH-, the NH-group forms a hydrogen-bond with aspartic
acid residue 167 in the ERK2 binding site. When Q is a
hydrophobic group such as an alkyl chain, -0-, or -S-, Q
forms additional hydrophobic interactions within the ERK2
binding site.
R2 forms hydrophobic interactions within the
binding site of ERK2, especially with the side-chain
carbons of lysine 54 and aspartic acid 167. R2 may also
form hydrophobic interactions with the glycine-rich loop
which is made up of amino-acid residues 33-38. When R2 is
substituted, the substituents may form further
interactions within the binding site to enhance the
inhibitory activity of the compound. For example, when a
substituent on R2 is a hydrogen-bond donor or a hydrogen-
bond acceptor, said substituent forms a hydrogen bond
with enzyme-bound water molecules that exist in the
binding site.
As used herein, linker group T, when present,
connects Sp with R1. T may also form additional
interactions within the ERK2 binding site to further
enhance the inhibitory activity of the compound. When T
is carbonyl-containing such as -CO-, -C02-, -0C0-, -COCO-,
-CONH-, -CO2NH-, -CONHNH-, -NHCO-, or -NHCO2-, or
sulfonyl-containing such as -SO2-, -S02NH-, or -NHSO2-,
the carbonyl or sulfonyl oxygen forms a hydrogen-bond
with the NH of glutamine 105 in the ERK2 binding site.
When T is NH-containing such as -CH2NH- or -NHNH-, the NH-
group forms a hydrogen-bond with the carbonyl of
glutamine 105. When T is a hydrophobic group such as an
alkyl chain, -0-, or -S-, T forms additional hydrophobic
interactions with the side-chain carbons of glutamine 105
as well as isoleucine 84.
The binding interactions described herein
between the compounds of this invention and the ERK2
binding site have been determined by molecular modeling
programs that are known to those of ordinary skill in the
art. These molecular modeling programs include QUANTA
[Molecular Simulations, Inc., Burlington, Mass., 1992]
and SYBYL [Molecular Modeling Software, Tripos
Associates, Inc., St. Louis, Mo., 1992]. As used herein,
the amino acid numbering for the ERK2 enzyme corresponds
to the Swiss-Prot database entry for accession #P28482.
The Swiss-Prot database is an international protein
sequence database distributed by the European
Bioinformatics Institute (EBI) in Geneva, Switzerland.
The database can be found at www.ebi.ac.uk/swissprot.
The compounds of this invention are limited to
those that are chemically feasible and stable.
Therefore, a combination of substituents or variables in
the compounds described above is permissible only if such
a combination results in a stable or chemically feasible
compound. A stable compound or chemically feasible
compound is one in which the chemical structure is not
substantially altered when kept at a temperature of 40 °C
or less, in the absence of moisture or other chemically
reactive conditions, for at least a week.
Unless otherwise stated, structures depicted
herein are also meant to include all stereochemical forms
of the structure; i.e., the R and S configurations for
each asymmetric center. Therefore, single stereochemical
isomers as well as enantiomeric and diastereomeric
mixtures of the present compounds are within the scope of
the invention. Unless otherwise stated, structures
depicted herein are also meant to include compounds which
differ only in the presence of one or more isotopically
enriched atoms. For example, compounds having the
present structures except for the replacement of a
hydrogen by a deuterium or tritium, or the replacement of
a carbon by a 13C- or 14C-enriched carbon are within the
scope of this invention.
Compounds of formula I or salts. thereof may be
formulated into compositions. In a preferred embodiment,
the composition is a pharmaceutically acceptable
composition. In one embodiment, the composition
comprises an amount of the protein kinase inhibitor
effective to inhibit a protein kinase, particularly ERK-
2, in a biological sample or in a patient. In another
embodiment, compounds of this invention and
pharmaceutical compositions thereof, which comprise an
amount of the protein kinase inhibitor effective to treat
or prevent an ERK-2-mediated condition and a
pharmaceutically acceptable carrier, adjuvant, or
vehicle, may be formulated for administration to a
patient.
The term "patient" includes human and
veterinary subjects.
The term "biological sample", as used herein,
includes, without limitation, cell cultures or extracts
thereof; preparations of an enzyme suitable for in vitro
assay; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen,
tears, or other body fluids or extracts thereof.
Another aspect of this invention relates to a
method of treating or preventing an ERK-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I or a
pharmaceutically acceptable comprising said compound.
The term "ERK-2-mediated condition" or
"disease", as used herein, means any disease or other
deleterious condition in which ERK-2 is known to play a
role. The term "ERK -2 - mediated condition" or "disease"
also means those diseases or conditions that are
alleviated by treatment with an ERK-2 inhibitor. Such
conditions include, without limitation, cancer, stroke,
diabetes, hepatomegaly, cardiovascular disease including
cardiomegaly, Alzheimer's disease, cystic fibrosis, viral
disease, autoimmune diseases, atherosclerosis,
restenosis, psoriasis, allergic disorders including
asthma, inflammation, neurological disorders and hormone-
related diseases. The term "cancer" includes, but is not
limited to the following cancers: breast, ovary, cervix,
prostate, testis, genitourinary tract, esophagus, larynx,
glioblastoma, neuroblastoma, stomach, skin,
keratoacanthoma, lung, epidermoid carcinoma, large cell
carcinoma, small cell carcinoma, lung adenocarcinoma,
bone, colon, adenoma, pancreas, adenocarcinoma, thyroid,
follicular carcinoma, undifferentiated carcinoma,
papillary carcinoma, seminoma, melanoma, sarcoma, bladder
carcinoma, liver carcinoma and biliary passages, kidney
carcinoma, myeloid disorders, lymphoid disorders,
Hodgkin's, hairy cells, buccal cavity and pharynx (oral),
lip, tongue, mouth, pharynx, small intestine, colon-
rectum, large intestine, rectum, brain and central
nervous system, and leukemia.
The present method is especially useful for
treating a disease that is alleviated by the use of an
inhibitor of ER.K2 or other protein kinases. Although the
present compounds were designed as ERK2 inhibitors, it
has been found that certain compounds of this invention
also inhibit other protein kinases such as GSK3, Aurora2,
Lck, CDK2, and AKT3.
Another aspect of the invention relates to
inhibiting ERK-2 activity in a biological sample, which
method comprises contacting the biological sample with a
compound of formula I, or a pharmaceutically acceptable
composition comprising said compound.
Another aspect of this invention relates to a
method of inhibiting ERK-2 activity in a patient, which
method comprises administering to the patient a compound
of formula I or a pharmaceutically acceptable composition
comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I or a
pharmaceutically acceptable comprising said compound.
The term "Aurora-2-mediated condition" or
"disease", as used herein, means any disease or other
deleterious condition in which Aurora is known to play a
role. The term "Aurora-2-mediated condition" or
"disease" also means those diseases or conditions that
are alleviated by treatment with an Aurora-2 inhibitor.
Such conditions include, without limitation, cancer. The
term "cancer" includes, but is not limited to the
following cancers: colon, breast, stomach, and ovarian.
Another aspect of the invention relates to
inhibiting Aurora-2 activity in a biological sample,
which method comprises contacting the biological sample
with a compound of formula I, or a pharmaceutically
acceptable composition comprising said compound.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula I or a pharmaceutically acceptable
composition comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I or a
pharmaceutically acceptable comprising said compound.
The term "GSK-3-mediated condition" or
"disease", as used herein, means any disease or other
deleterious condition or state in which GSK-3 is known to
play a role. Such diseases or conditions include,
without limitation, diabetes, Alzheimer's disease,
Huntington's Disease, Parkinson's Disease, AIDS-
associated dementia, amyotrophic lateral sclerosis (AML),
multiple sclerosis (MS), schizophrenia, cardiomycete
hypertrophy, reperfusion/ischemia, and baldness.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
I or a pharmaceutically acceptable thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of ßcatenin, which is useful for
treating schizophrenia.
Another aspect of the invention relates to
inhibiting GSK-3 activity in a biological sample, which
method comprises contacting the biological sample with a
compound of formula I.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula I or a pharmaceutically acceptable composition
comprising said compound.
Inhibition of ERK2, Aurora2, CDK2, GSK-3, Lck,
or AKT3 kinase activity in a biological sample is useful
for a variety of purposes which are known to one of skill
in the art. Examples of such purposes include, but are
not limited to, blood transfusion, organ-
translplantation, biological specimen storage, and
biological assays.
-20-
The term "pharmaceutically acceptable carrier,
adjuvant, or vehicle" refers to a non-toxic carrier,
adjuvant, or vehicle that may be administered to a
patient, together with a compound of this invention, and
which does not destroy the pharmacological activity
thereof.
The amount effective to inhibit protein kinase,
for example, Aurora-2 and GSK-3, is one that measurably
inhibits the kinase activity where compared to the
activity of the enzyme in the absence of an inhibitor.
Any method may be used to determine inhibition, such as,
for example, the Biological Testing Examples described
below.
Pharmaceutically acceptable carriers that ir.ay
be used in these pharmaceutical compositions include, but
are not limited to, ion exchangers, alumina, aluminum
stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine,
sorbic acid, potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as protamine sulfate, disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
The compositions of the present invention may
be administered orally, parenterally, by inhalation
spray, topically, rectally, nasally, buccally, vaginally
or via an implanted reservoir. The term "parenteral" as
used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesior.al
and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally,
intraperitoneally or intravenously.
Sterile injectable forms of the compositions of
this invention may be aqueous or oleaginous suspension.
These suspensions may be formulated according to
techniques"known in the art using suitable dispersing or
wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally-
acceptable diluent or solvent, for example as a solution
in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water. Ringer's
solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed
as a solvent or suspending medium. For this purpose, any
bland fixed oil may be employed including synthetic mono-
or di-glycerides. Fatty acids, such as oleic acid and
its glyceride derivatives are useful in the preparation
of injectables, as are natural pharmaceutically-
acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil
solutions or suspensions may also contain a long-chain
alcohol diluent or dispersant, such as carboxymethyl
cellulose or similar dispersing agents which are commonly
used in the formulation of pharmaceutically acceptable
dosage forms including emulsions and suspensions. Other
commonly used surfactants, such as Tweens, Spans and
other emulsifying agents or bioavailability enhancers
which are commonly used in the manufacture of
pharmaceutically acceptable solid, liquid, or other
dosage forms may also be used for the purposes of
formulation.
The pharmaceutical compositions of this
invention may be orally administered in any orally
acceptable dosage form including, but not limited to,
capsules, tablets, aqueous suspensions or solutions. In
the case of tablets for oral use, carriers commonly used
include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added.
For oral administration in a capsule form, useful
diluents include lactose and dried cornstarch. When
aqueous suspensions are required for oral use, the active
ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
Alternatively, the pharmaceutical compositions
of this invention may be administered in the form of
suppositories for rectal administration. These can be
prepared by mixing the agent with a suitable non-
irritating excipient which is solid at room temperature
but liquid at rectal temperature and therefore will melt
in the rectum to release the drug. Such materials
include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this
invention may also be administered topically, especially
when the target of treatment includes areas or organs
readily accessible by topical application, including
diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily
prepared for each of these areas or organs.
Topical application for the lower intestinal
tract can be effected in a rectal suppository formulation
-23-
(see above) or in a suitable enema formulation.
Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical
compositions may be formulated in a suitable ointment
containing the active component suspended or dissolved in
one or more carriers. Carriers for topical
administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, poloxypropylene compound, emulsifying
wax and water. Alternatively, the pharmaceutical
compositions can be formulated in a suitable lotion or
cream containing the active components suspended or
dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60,
cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,
benzyl alcohol and water.
For ophthalmic use, the pharmaceutical
compositions may be formulated as micronized suspensions
in isotonic, pH adjusted sterile saline, or, preferably,
as solutions in isotonic, pH adjusted sterile saline,
either with or without a preservative such as
benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated
in an ointment such as petrolatum.
The pharmaceutical compositions of this
invention may also be administered by nasal aerosol or
inhalation. Such compositions are prepared according to
techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or
dispersing agents.
In addition to the compounds of this invention,
pharmaceutically acceptable derivatives of the compounds
of this invention may also be employed in compositions to
treat or prevent the above-identified diseases or
disorders.
A "pharmaceutically acceptable derivative "
means any pharmaceutically acceptable salt, ester, salt
of an ester or other derivative of a compound of this
invention which, upon administration to a recipient, is
capable of providing, either directly or indirectly, a
compound of this invention or an inhibitorily active
metabolite or residue thereof. Particularly favored
derivatives are those that increase the bioavailability
of the compounds of this invention when such compounds
are administered to a patient (e.g., by allowing an
orally administered compound to be more readily absorbed
into the blood) or which enhance delivery of the parent
compound to a biological compartment (e.g., the brain or
lymphatic system) relative to the parent species.
Pharmaceutically acceptable salts of the
compounds of this invention include those derived from
pharmaceutically acceptable inorganic and organic acids
and bases. Examples of suitable acid salts include
acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate,
camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate,
fumarate, glucoheptanoate, glycerophosphate, glycolate,
hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, malonate, methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, oxalate,
palmoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, salicylate,
succinate, sulfate, tartrate, thiocyanate, tosylate and
undecanoate. Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, may be employed
in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include
alkali metal (e.g., sodium and potassium), alkaline earth
metal (e.g., magnesium), ammonium and N+ (C1.4 alkyl)4
salts. This invention also envisions the quaternization
of any basic nitrogen-containing groups of the compounds
disclosed herein. Water or oil-soluble or dispersible
products may be obtained by such quaternization.
The amount of the protein kinase inhibitor that
may be combined with the carrier materials to produce a
single dosage form will vary depending upon the patient
treated and the particular mode of administration.
Preferably, the compositions should be formulated so that
a dosage of between 0.01 - 100 mg/kg body weight/day of
the inhibitor can be administered to a patient receiving
these compositions.
It should also be understood that a specific
dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and
the judgment of the treating physician and the severity
of the particular disease being treated. The amount of
the inhibitor will also depend upon the particular
compound in the composition.
The kinase inhibitors of this invention or
pharmaceutical compositions thereof may also be
incorporated into compositions for coating an implantable
medical device, such as prostheses, artificial valves,,
vascular grafts, stents and catheters. Vascular stents,
for example, have been used to overcome restenosis (re-
narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk
clot formation or platelet activation. These unwanted
effects may be prevented or mitigated by pre-coating the
device with a pharmaceutically acceptable composition
comprising a kinase inhibitor. Suitable coatings and the
general preparation of coated implantable devices are
described in US Patents 6,099,562; 5,886,026; and
5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene
glycol, polylactic acid, ethylene vinyl acetate, and
mixtures thereof. The coatings may optionally be further
covered by a suitable topcoat of fluorosilicone,
polysaccarides, polyethylene glycol, phospholipids or
combinations thereof to impart controlled release
characteristics in the composition. Implantable devices
coated with a kinase inhibitor of this invention are
another embodiment of the present invention.
Depending upon the particular protein kinase-
mediated condition to be treated or prevented, additional
therapeutic agents, which are normally administered to
treat or prevent that condition, may be administered
together with the inhibitors of this invention. For
example, in the treatment of cancer other
chemotherapeutic agents or other anti-proliferative
agents may be combined with the protein kinase inhibitors
of this invention to treat cancer. These agents include,
without limitation, adriamycin, dexamethasone,
vincristine, cyclophosphamide, fluorouracil, topotecan,
taxol, interferons, and platinum derivatives.
Other examples of agents the inhibitors of this
invention may also be combined with include, without
limitation, agents for treating diabetes such as insulin
or insulin analogues, in injectable or inhalation form,
glitazones, alpha glucosidase inhibitors, biguanides,
insulin sensitizers, and sulfonyl ureas; anti-
inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive
agents such as cyclosporin, tacrolimus, rapamycin,
mycophenolate mofetil, interferons, corticosteroids,
cyclophophamide, azathioprine, and sulfasalazine;
neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-
convulsants, ion channel blockers, riluzole, and anti-
Parkinsonian agents; agents for treating cardiovascular
disease such as beta-blockers, ACE inhibitors, diuretics,
nitrates, calcium channel blockers, and statins; agents
for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents;
agents for treating blood disorders such as
corticosteroids, anti-leukemic agents, and growth
factors; and agents for treating immunodeficiency
disorders such as gamma globulin.
Those additional agents may be administered
separately from the protein kinase inhibitor-containing
composition, as part of a multiple dosage regimen.
Alternatively, those agents may be part of a single
dosage form, mixed together with the protein kinase
inhibitor of this invention in a single composition.
Compounds of this invention may exist in
alternative tautomeric forms. Unless otherwise
indicated, the representation of either tautomer is meant
to include the other.
Accordingly, the present invention relates to
compounds of formula I wherein Ring A is a pyridine (II),
pyrimidine (III), or triazine (IV) ring as shown below:
or a pharmaceutically acceptable derivative thereof,
wherein Sp, TmR1, R2, UnR3, Q, and T are as described
above.
Examples of suitable Sp groups of formula I
include pyrrole (a) , imidazole (b) , pyrazole (c) ,
triazole (d) , oxazole (e) , isoxazole (f), 1,3-thiazole
(g), 1,2-thiazole (h) , furan (i), and thiophene (j), as
shown below:
wherein each of a through j is optionally substituted
with R6.
Preferred TmR1 groups of formula I are selected
from hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1_6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Preferred TmR1
groups are methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
and CH2NHCH3. More preferred TmR1 groups of formula I are
those listed in Table 1 below.
Preferred R3 groups of formula I are hydrogen,
carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and
isopropyl. When R3 is optionally substituted phenyl,
preferred substituents on the phenyl ring are halogen,
alkyl, alkoxy, haloalkyl, Oberizyl, Ophenyl, OCF3, OH,
SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples
of such groups include -CH (CH2OH)phenyl, -CH (CH2OH) ethyl,
-CH(CH2OH)2, -CH(CH2OH) isopropyl, and
-CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when
present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2-. More
preferred UnR3 groups of formula I are those listed in
Table 1 below.
When R2 is R5, preferred R5 groups are
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and
piperazin-1-yl, 4-methyl [1,4]diazepan-1-yl, 4-phenyl-
piperazine-1-yl, wherein each group is optionally-
substituted. When R2 is (CH2)yR5, (CH2) yCH (R5) 2, or -N(R4)2,
preferred R5 groups are further selected from pyridin-3-
yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-
tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl,
phenyl, benzyl, -CH2OH, -(CH2)2OH, and isopropyl, wherein
each group is optionally substituted. Preferred
substituents on R5 are -OH, pyridyl, piperidinyl, and
optionally substituted phenyl. When R2 is
- (CH2)yCH(R8)CH(R5)2, preferred R8 groups are R7 and OR7
such as OH and CH2OH and preferred R5 are as described
above. Preferred - (CH2) yCH (R8) CH (R5) 2 groups of formula I
are -CH(OH)CH(OH)phenyl and -CH(Me)CH(OH)phenyl. Other
preferred -QR2 groups are those listed in Table 1 below.
Preferred compounds of formula I are those
having one or more, more preferably more than one, and.
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1_4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring,-
(b) TmR1 is hydrogen, amino, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring;
(c) Q is -CO-, -C02- , -CONH-, -SO2-, -SO2NH-,
-OC(O)NH-, -C(O)ONH-, or -CONHNH-;
(d) R2 is -NR4(CH2)yN(R4)2, -(CH2)yR5, - (CH2) yCH (R5) 2, or
- (CH2)yCH(R8)CH(R5)2;
(f) R4 is R, R7, or - (CH2) yCH (R5) 2; and
(g) R5 is an optionally substituted group selected
from C1-6 aliphatic, phenyl, 5-6 membered
heteroaryl, or 5-6 membered heterocyclyl.
More preferred compounds of formula I are those
having one or more, more preferably more than one, or
most preferably all, of the features selected from the
group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl, benzyl, or
isoxazolyl group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3 ;
(c) Q is -CO-, -CONH-, -S02-, or -SO2NH-;
(d) R2 is -(CH2)yR5, - (CH2)yCH(R5)2, or
- (CH2)yCH(R8)CH(R5)2, wherein RB is OH or CH2OH;
and
(e) R5 is -CH2OH, -(CH2)2OH, isopropyl, or an
optionally substituted group selected from
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl,
piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-
phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-
yl, imidazolyl, furan-2-yl, 1,2,3,4-
tetrahydroisoquinoline, tetrahydrofuran-2-yl,
cyclohexyl, phenyl, or benzyl.
A preferred embodiment of this invention
relates to compounds of formula I' :
or a pharmaceutically acceptable derivative thereof,
wherein:
Sp is a spacer group comprising a 5-membered
heteroaromatic ring, wherein Ring A and Q'R2' are
attached to Sp at non-adjacent positions; and wherein
Sp has up to two R6 substituents, provided that two
substitutable carbon ring atoms in Sp are not
simultaneously substituted by R6;
Z1 and Z2 are each independently selected from N or CH;
Q' is selected from -C02-, -C(O)NR7- or -SO2NR7- ;
T is a linker group;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-,
-O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-,
-NR7SO2NR7-, or -S02-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2/ OR,
or OH;
R2' is selected from - (CH2) yCH (R5) 2 or - (CH2) yCH (R8) CH (R5) 2 ;
y is 0-6;
R3 is selected from R7, R, - (CH2) yCH (R8) R, CN,
- (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8) N (R4) 2;
each R is independently selected from an optionally
substituted group selected from C1-6 aliphatic, C6_10
aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R
-CON(R7)2; -SO2R7, -(CH2)yR5, or - (CH2) yCH (R5) 2 ;
each R5 is independently selected from R, OR, CO2R,
(CH2)yN(R7)2, N(R7)2; OR7, SR7, NR7COR7, NR7CON(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2,
CON(R7)2, S02R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2) WN(R4) 2, or (CH2)WSR7;
and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula I'
include pyrrole (a), imidazole (b), pyrazole (c),
triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole
(g), 1,2-thiazole (h), furan (i), and thiophene (j), as
shown below:
wherein each of a through j is optionally substituted
with R6.
Accordingly, the present invention relates to
compounds of formula I' wherein Ring A is a pyridine
or a pharmaceutically acceptable derivative thereof,
wherein Sp, TmR1, Q'R2 , and UnR3 are as described above.
Preferred R5 groups of formula I' are R or OR7.
Examples of such groups include OH, CH2OH, carbocyclic, or
optionally substituted 5 or 6-membered aryl or heteroaryl
rings, such as phenyl, pyridyl, and cyclohexyl.
Preferred R8 groups of formula I' are R and OR7, wherein R
is an optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6 membered
aryl or heteroaryl ring. Examples of such groups include
phenyl, methyl, ethyl, OH, and CH2OH. Preferred
substituents on the R5 aryl or heteroaryl ring are
halogen, haloalkyl, 0R°, and R°.
Preferred TmR1 groups of formula I' are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring.. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Preferred TmR1
groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
and CH2NHCH3. More preferred TmR1 groups of formula I' are
those listed in Table 1 below.
Preferred R3 groups of formula I' are hydrogen,
carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and
isopropy1. When R3 is optionally substituted phenyl,
preferred substituents on the phenyl ring are halogen,
alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH,
SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples
of such groups include -CH (CH2OH) phenyl, -CH (CH2OH) ethyl,
-CH(CH2OH)2, -CH(CH2OH) isopropyl, and
-CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when
present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More
preferred UnR3 groups of formula I' are those listed in
Table 1 below.
Preferred compounds of formula I' are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmRa is hydrogen, amino, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an
optionally substituted 5 or 6-membered aryl or
heteroaryl ring.

More preferred compounds of formula I' are
those having one or more, more preferably more than one,
and most preferably all, of the features selected from
the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH (CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl, benzyl, or
isoxazolyl group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3/ NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, carbocyclic, or an optionally
substituted phenyl or pyridyl ring, and Q' is
C(O)NH.
Another preferred embodiment of this invention
relates to compounds of formula I":
or a pharmaceutically acceptable derivative thereof,
wherein:
Sp is a spacer group comprising a 5-membered
heteroaromatic ring, wherein Ring A and
C(O)NHCH[ (CH2)1-2OH]R5 are attached to Sp at non-
adjacent positions; and wherein Sp has up to two R6
substituents, provided that two substitutable carbon
ring atoms in Sp are not simultaneously substituted by
R6;
Z1 and Z2 are each independently selected from N or CH;
T is a linker group;
U is selected from -NR7-, -NR7C0-, -NR7CONR7-, -NR7CO2-,
-0-, -CONR7-, -CO-, -CO2-, -00(0)-, -NR7SO2-, -SO2NR7-,
-NR7SO2NR7-, or -S02-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR,
or OH;
R3 is selected from R7, R, - (CH2) yCH (R8) R, CN,
- (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8) N (R4) 2;
each R is independently selected from an optionally
substituted group selected from C1-6 aliphatic, C6.10
aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R,
-CON(R7)2' -SO2R7, -(CH2)yRs, or - (CH2)yCH (Rs) 2;
each R5 is independently selected from R, OR, CO2R,
(CH2)yN(R7)2/ N(R7)2, OR7, SR7, NR7COR7, NR7C0N(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7C0N(R7)2/
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an
optionally substituted C1.6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2) WN(R4) 2, or (CH2)WSR7;
and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula I"
include pyrrole (a), imidazole (b) , pyrazole (c),
triazole (d) , oxazole (e), isoxazole (f), 1,3-thiazole
(g), 1,2-thiazole (h), furan (i), and thiophene (j), as
shown below:
wherein each of a through j is optionally substituted
with R6.
Accordingly, the present invention relates to
compounds of formula I" wherein Ring A is a pyridine
(II"), pyrimidine (III"), or triazine (IV") ring as shown
below:
or a pharmaceutically acceptable derivative thereof,
wherein Sp, TmR1, UnR3, and R5 are as described above.
Preferred TVR1 groups of formula I" are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Examples of
preferred TmR1 groups include methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH2OCH3/ CH2OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of
formula I" are those listed below in Table 1.
Preferred R3 groups of formula I" are hydrogen,
carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and
isopropy1. When R3 is optionally substituted phenyl,
preferred substituents on the phenyl ring are halogen,
alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH,
SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples
of such groups include -CH(CH2OH) phenyl, -CH (CH2OH) ethyl,
-CH(CH2OH)2, -CH(CH2OH) isopropyl, and
-CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when
present, are -CH2-, -O-, -NR7-, -NHCO-, and -NHCO2- . More
preferred UnR3 groups of formula I" are those listed in
Table 1 below.
Preferred R5 groups of formula I" are optionally
substituted 6-membered aryl, heteroaryl, and carbocyclic
rings, such as phenyl, pyridyl, and cyclohexyl.

Preferred compounds of formula I" are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring,-
(b) TmR1 is hydrogen, N{R4)2, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and
(c) Rs is an optionally substituted 6-membered aryl,
heteroaryl, or carbocyclic ring.
More preferred compounds of formula I" are
those having one or more, more preferably more than one,
and most preferably all, of the features selected from
the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl or benzyl
group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or an optionally substituted
phenyl or pyridylring.
Another preferred embodiment of this invention
relates to compounds of formula I°:
or a pharmaceutically acceptable derivative thereof,
wherein:
Sp is a spacer group comprising a 5-membered
heteroaromatic ring, wherein Ring A and
C(O)NHCH(RB)CH(R5)2 are attached to Sp at non-adjacent
positions; and wherein Sp has up to two R6
substituents, provided that two substitutable carbon
ring atoms in Sp are not simultaneously substituted by
R6;
Z1 and Z2 are each independently selected from N or CH;
T is a linker group;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-,
-O-, -CONR7-, -CO-, -CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-,
-NR7SO2NR7-, or -S02-;
m and n are each independently selected from zer6 or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR,
or OH;
y is 0-6;
R3 is selected from R7, R, - (CH2) yCH (R8) R, CN,
- (CH2)yCH(R8)CH(R5)2, or - (CH2) yCH (R8)N (R4) 2 ;
each R4 is independently selected from R, R7, -COR7, -CO2R,
-CON(R7)2, -SO2R7, -(CH2)yR5, or - (CH2)yCH (Rs) 2 ;
each R is independently selected from an optionally
substituted group selected from C1-6 aliphatic, C6-10
aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms;
each R5 is independently selected from R, OR, CO2R,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl,
(CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7C0R7, NR7CON(R7)2,
CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an
optionally substituted Ci_6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring,-
R8 is selected from R, (CH2)WOR7, (CH2) WN (R4) 2, or (CH2)WSR7;
and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula 1°
include pyrrole (a), imidazole (b) , pyrazole (c),
triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole
(g) , 1,2-thiazole (h), furan (i), and thiophene (j), as
shown below:
wherein each of a through j is optionally substituted
with R6.
Accordingly, the present invention relates to
compounds of formula I° wherein Ring A is a pyridine
(II°) , pyrimidine (III°) , or triazine (IV°) ring as shown
below:
or a pharmaceutically acceptable derivative thereof,
wherein Sp, TmR1, Rs, UnR3, and R8 are as described above.
Preferred R5 groups of formula I° are R or OR7.
Examples of such groups include OH, CH2OH, carbocyclic, or
optionally substituted5 or 6-membered aryl or heteroaryl
rings, such as phenyl, pyridyl, and cyclohexyl.
Preferred R8 groups of formula I° are R and OR7, wherein R
is an optionally'substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6 membered
aryl or heteroaryl ring. Examples of such groups include
phenyl,methyl, ethyl, OH, and CH2OH. Preferred
substituents on the R5 aryl or heteroaryl ring are
halogen, haloalkyl, OR°, and R°.
Preferred TmR1 groups of formula 1° are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is cin
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. More preferred
TmR1 groups are methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
and CH2NHCH3. Most preferred TmR1 groups of formula I° are
those listed in Table 1 below.
Preferred R3 groups of formula I° are hydrogen,
carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and
isopropyl. When R3 is optionally substituted phenyl,
preferred substituents on the phenyl ring are halogen,
alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3/ OH,
SO2NH2, and methylene dioxy. When R3 is -CH(R8)R, examples
of such groups include -CH (CH2OH) phenyl, -CH (CH2OH) ethyl,
-CH(CH2OH)2, -CH(CH2OH) isopropyl, and
-CH(CH2OH) CH2cyclopropyl. Preferred Un groups, when
present, are -CH2-, -0-, -NR7-, -NHCO-, and -NHCO2-. More
preferred UnR3 groups of formula I° are those listed in
Table 1 below.
Preferred compounds of formula I° are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from Cx.6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and

(c) R5 is R or OR7, wherein R is carbocyclic, or an
optionally substituted5 or 6-membered aryl or
heteroaryl ring.
More preferred compounds of formula I° are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH)isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl, benzyl, or
isoxazolyl group,-
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) Rs is OH, CH2OH, carbocyclic, or an optionally
substitutedphenyl or pyridyl ring.
A preferred embodiment relates to compounds of
formula III-a:
or a pharmaceutically acceptable derivative thereof.
Preferred TmR1 groups of formula III-a are
hydrogen, N(R4)2' OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1.6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and araino. Examples of such
preferred TmR1 groups include methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH2OCH3/ CH2OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of
formula Ill-a are those listed in Table 1 below.
Preferred R3 groups of formula Ill-a are
hydrogen, carbocyclyl, -CH(RB)R, or an optionally
substituted group selected from C1-4 aliphatic, 3-6
membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring. Examples of such groups include methyl,
ethyl, propyl, cyclopropyl, cyclohexyl, benzyl,
isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is
optionally substituted phenyl, preferred substituents on
the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,
Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy.
When R3 is -CH(R8)R, examples of such groups are
-CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl.
Preferred Un groups, when present, are -CH2-, -O-, -NR7-,
-NHCO-, and -NHCO2-. More preferred UnR3 groups of
formula Ill-a are those listed in Table 1 below.
When R2 is R5, preferred R5 groups are
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and
piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-
piperazine-1-yl, wherein each group is optionally
substituted. When R2 is (CH2)yR5, (CH2) yCH (R5) 2, or -N(R4)2,
preferred Rs groups are pyridin-3-yl, pyridin-4-yl,
imidazolyl, furan-2-yl, 1, 2 , 3 , 4-tetrahydroisoquinoline,
tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, -CH2OH,
-(CH2)2OH, and isopropyl, wherein each group is optionally
substituted. Preferred substituents on R5 are -OH,
pyridyl, piperidinyl, and optionally substituted phenyl.
When R2 is - (CH2) yCH (R8) CH (R5) 2, preferred R8 groups are R7
and OR7 such as OH and CH2OH. More preferred -QR2 groups
are those listed in Table 1 below.
Preferred compounds of formula III-a are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C1-4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered
carbocyclyl, or' an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring,-
(c) Q is -CO-, -CO2-, -CONH-, -S02-, -SO2NH-,
-OC(O)NH-, -C(O)ONH-, or -CONHNH-;
(d) R2 is -NR4 (CH2)yN(R4)2, -(CH2)yR5, - (CH2) yCH (Rs) 2; or
-(CH2)yCH(R8)CH(R5)2;
(f) R4 is R, R7, or - (CH2) yCH (R5) 2; and
(g) R5 is an optionally substituted group selected
from phenyl, 5-6 membered heteroaryl, or 5-6
membered heterocyclyl.
More preferred compounds of formula Ill-a are
those having one or more, more preferably more than one,
or most preferably all, of the features selected from the
group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl or benzyl
group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3 ;
(c) Q is -CO-, -CONH-, -S02-, or -SO2NH-;
(d) R2 is -(CH2)yRs, - (CH2)yCH(Rs)2, or
- (CH2)yCH(R8)CH(R5)2, wherein R8 is OH or CH2OH;
and
(e) R5 is -CH2OH, -(CH2)2OH, isopropyl, or an
optionally substituted group selected from
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl,
piperazin-1-yl, 4-methyl[1,4] diazepan-1-yl, 4-
phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-
yl, imidazolyl, furan-2-yl, 1,2,3,4-
tetrahydroisoquinoline, tetrahydrofuran-2-yl,
cyclohexyl, phenyl, or benzyl.
Preferred compounds of formula III-a include
those of formula III-a':
Preferred TmR1 groups of formula III-a' are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Preferred TmR1
groups are methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
CH2NHCH3, and those listed in Table 1 below.
Preferred R3 groups of formula III-a' are
hydrogen, carbocyclyl, -CH(R8)R, or an optionally
substituted group selected from C1-4 aliphatic, 3-6
membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring.. Examples of such groups include methyl,
ethyl, propyl, cyclopropyl, cyclohexyl, benzyl,
isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is
optionally substituted phenyl, preferred substituents on
the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,
Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy.
When R3 is -CH(R8)R, examples of such groups include
-CH(CH2OH) phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl.
Preferred Un groups, when present, are -CH2-, -0-, -NR7-,
-NHCO-, and -NHCO2-. More preferred UnR3 of formula III-
a' are those listed in Table 1 below.
Preferred compounds of formula III-a' are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from Ca.4
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1.6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and
(c) R5 is an optionally substituted6-membered aryl,
heteroaryl, or carbocyclic ring.
More preferred compounds of formula III-a' are
those having one or more, more preferably more than one,
and most preferably all, of the features selected from
the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl or benzyl
group;
(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or an optionally substituted
phenyl or pyridylring.
Preferred compounds of formula III-a are
further selected from those of formula III-a°:
or a pharmaceutically acceptable derivative thereof.
Preferred R5 groups of formula III-a° are R or
OR7. Examples of such groups include OH, CH2OH, or
optionally substituted6-membered aryl, heteroaryl, and
carbocyclic rings, such as phenyl, pyridyl, and
cyclohexyl. Preferred R8 groups of formula III-a° are R
and OR7, wherein R is an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic,
or a 5-6 membered aryl or heteroaryl ring. Examples of
such groups include phenyl, methyl, ethyl, OH, and CH2OH.
Preferred TmR1 groups of formula III-a° are
hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an
optionally substituted group selected from C1-6 aliphatic
or a 5-6 membered aryl or heteroaryl ring. When R1 is an
optionally substituted phenyl or aliphatic group,
preferred substituents on the phenyl or aliphatic group
are R7, halo, nitro, alkoxy, and amino. Preferred TmR1
groups include methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3,
and CH2NHCH3. More preferred TmR1 groups of formula III-a°
are those listed in Table 1 below.
Preferred R3 groups of formula III-a° are
hydrogen, carbocyclyl, -CH(R8)R, or an optionally
substituted group selected from C1-4 aliphatic, 3-6
membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring. Examples of such groups include methyl,
ethyl, propyl, cyclopropyl, cyclohexyl, benzyl,
isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is
optionally substituted phenyl, preferred substituents on
the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,
Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy.
When R3 is -CH(R8)R, examples of such groups are
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, and -CH (CH2OH) CH2cyclopropyl.
Preferred Un groups, when present, are -CH2-, -0-, -NR7-,
-NHCO-, and -NHCO2-. More preferred UnR3 groups of
formula III-a° are those listed in Table 1 below.
Preferred compounds of formula III-a° are those
having one or more, more preferably more than one, and
most preferably all, of the features selected from the
group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an
optionally substituted group selected from C^
aliphatic, 3-6 membered heterocyclic, or a 5-6
membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered
carbocyclyl, or an optionally substituted group
selected from C1-6 aliphatic or a 5-6 membered
aryl or heteroaryl ring; and
(c) R5 is R or OR7, and R8 is R7 or OR7.
More preferred compounds of formula III-a° are
those having one or more, more preferably more than one,
and most preferably all, of the features selected from
the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl,
propyl, cyclopropyl, cyclohexyl, isopropyl,
-CH(CH2OH)phenyl, -CH (CH2OH) ethyl, -CH(CH2OH)2,
-CH(CH2OH) isopropyl, -CH (CH2OH) CH2cyclopropyl, or
an optionally substituted phenyl or benzyl
group;+(b) TmR1 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc,
NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, phenyl, pyridyl, or cyclohexyl,
and R8 is methyl, ethyl, OH, or CH2OH.
Preferred compounds of formula III-a are set
forth in Table 1 below. More preferred compounds in
Table 1 are those of formula III-a' or III-a°.
A Compound names for the compounds of formula III-a
shown above in Table 1 are set forth in Appendix A.
The above formula III-a compounds are those
wherein Ring A is a pyrimidine ring and Sp is a pyrrole
ring. Inhibitors of formula I wherein Ring A is a
pyridine, pyrimidine, or triazine ring having the other
Sp rings shown above are otherwise structurally similar
to the formula III-a compounds and are represented by the
following general formulae Il-b through II-j, Ill-b
through III-j, and IV-b through IV-j shown below in Table
2 :
compound shown above in Table 2 and a pharmaceutically
acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an ERK2-mediated
5 disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound shown above in Table 2 or
a pharmaceutically acceptable composition comprising said
compound.
Another aspect of this invention relates to a
method of inhibiting ERK2 activity in a patient, which
method comprises administering to the patient a compound
shown above in Table 2 or a pharmaceutically acceptable
composition comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound shown above in Table 2 or
a pharmaceutically acceptable comprising said compound.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound shown above in Table 2 or a pharmaceutically
acceptable composition comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated
disease, which method comprises administering to a
patient in need of such treatment a therapeutically
effective amount of a compound shown above in Table 2 or
a pharmaceutically acceptable comprising said compound.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,,
which method comprises administering to the patient a
therapeutically effective amount of a compound shown
above in Table 2 or a pharmaceutically acceptable
j composition comprising said compound. This method is
especially useful for diabetic patients. Another method
relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of (3-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
shown above in Table 2 or a pharmaceutically acceptable
composition comprising said compound.
Another method relates to inhibiting ERK2,
Aurora-2, or GSK-3 activity in a biological sample, which
method comprises contacting the biological sample with a
compound shown above in Table 2, or a pharmaceutically
acceptable composition thereof, in an amount effective to
inhibit ERK2, Aurora-2, or GSK-3.
Each of the aforementioned methods directed to
the inhibition of ERK2, Aurora-2 or GSK-3, or the
treatment of a disease alleviated thereby, is preferably
carried out with a preferred compound shown above in
Table 2, as described above.
The present compounds may be prepared in
general by methods known to those skilled in the art for
analogous compounds, as illustrated by the general
Schemes I through XII and the synthetic examples shown
below.
Reagents and conditions: (a) TmR1CH2COCl, A1C13/ CH2C12, 2
hours, RT; (b) DMF, 24 hrs, room temperature; (c) (Me2N)2-
CHOt-Bu, THF, 24 hrs, room temperature; (d) guanidine,
EtOH, 12 hours, reflux; (e) thiourea, EtOH, K2CO3, 12 hrs
reflux; (f) m-CPBA, EtOH; (g) UnR3-NH2, DMSO, 130"C.
Scheme I above shows a general synthetic route
that is used for preparing the pyrrol-3-yl compounds of
formula III-a of this invention when R2 is an optionally
substituted phenyl group or aliphatic group. In step
(a), an optionally substituted acid chloride is combined
with compound 1, dichloromethane, and aluminum
trichloride to form compound 2. In cases where benzoyl
acid chlorides are used, a wide variety of substituents
on the phenyl ring are amenable to this reaction.
Aliphatic acid chlorides are also used in many cases.
Examples of suitable R2 groups include, but are not
limited to, those set forth in Table 1 above.
The formation of amide 4 is achieved by-
treating compound 2 with an amine 3 in DMF. When atnine 3
5 is a primary amine, the reaction proceeds at ambient
temperature. When amine 3_ is a. secondary amine, the
reaction is heated at 50°C to achieve complete reaction
and afford amide 4.
The formation of enamine 5 at step (c) is
) achieved by treating amide 4 with (Me2N)2-CHOt-Bu at
ambient temperature. Alternatively, the reaction to form
enamine 5 at step (c) is also achieved by using
dimethylformamide-dimethylacetal (DMF-DMA). The reaction
using DMF-DMA typically requires elevated temperature to
afford enamine 5 whereas using (Me2N)2-OtBu has the
advantage of proceeding at ambient temperature to afford
the enamine 5 in higher purity.
The formation of the pyrimidine compound 6 at
step (d) is achieved by the treatment of enamine 5 with
guanidine at elevated temperature. Alternatively, use of
a substituted guanidine results in an amino substituent
as is illustrated by J3.
As an alternative method, in step (e)
intermediate _5 may be cyclized with S-methyl thiourea to
form the 2-thiomethylpyrimidine 7 which may in turn be
oxidized with m-CPBA to the sulfone. The sulfonyl group
may be subsequently displaced by an amine to generate the
substituted aminopyrimidine 8.
The compounds of formula III-a synthesized by
this method, as exemplified in Table 1, were isolated by
preparatory HPLC (reverse phase, 10—>90% MeCN in water
over 15 minutes). The details of the conditions used for
producing these compounds are set forth in the Examples.
Reagents and conditions: (a) K2CO3, DMA, 100°C.
Scheme II above shows a general method for
preparing compounds 8 from intermediate 5 and an N-
substituted guanidine (9) . Intermediate 5 may be
prepared according to Scheme I steps (a), (b), and (c)
shown above. Compound 5 is treated with N-substituted
guanidine (9) and potassium carbonate in
dimethylacetamide to form compound 8. This reaction is
amenable to a variety of N-substituted guanidines to form
compounds of formula III-a. The details of the
conditions used for producing these compounds are set
forth in the Examples.
Reagents and conditions: (a) A1C13 neat, RT; (b) DMF, 24
hrs, room temperature; (c) polyphosphoric acid, 1 hour,
25-140°C; (d) POClj, DMF, reflux; (e) NH2-UnR3, iPrOH,
reflux.
Scheme III above shows a general synthetic
route that may be used for preparing the pyrrol-3-yl
compounds of formula Il-a of this invention. The
conversion of intermediate 5 to product 8 may be achieved
through steps (c), (d), and (e) according to the method
described in JACS, 1957, pp 79.
Reagents and conditions: (a) MeOH, pyridine, Cl2; guanidine; (c) bromine, acetic acid; (d) NaCN, DMF; (e)
£, polyphosphoric acid, 1 hour, 25-140°C; (f) POCI3, DMF,
reflux; (g) NH2-UnR3, iPrOH, reflux,- (h) SeO2; (i) MeNH.
Scheme IV above shows a general synthetic route
that may be used for preparing the imidazol-4-yl
compounds of formula Il-b of this invention. The
conversion of intermediate 5 to product 8 may be achieved
through steps (e) , (f), and (g) according to the method
described in JACS, 1957, pp 79.
Reagents and conditions: (a) MeOH, pyridine, Cl2; (b) 3-,
(c) bromine, acetic acid; (d) NaCN, DMF; (e) 6,
polyphosphoric acid, 1 hour, 25-140°C; (f) POC13, DMF,
reflux; (g) NH2-UnR3, iPrOH, reflux.
Scheme V above shows a general synthetic route
that may be used for preparing the imidazol-2-yl
compounds of formula II-b' of this invention. The
conversion of intermediate 5_ to product £ may be achieved
through steps (e) , (f) , and (g) according to the method
described in JACS, 1957, pp 79.
Reagents and conditions: (a) (b) 3; (c) 5 polyphosphoric
acid, 1 hour, 25-140°C; (d) POC13, DMF, reflux; (e) NH2-
UnR3, iPrOH, reflux; (f) ceric ammonium nitrate.
Scheme VI above shows a general synthetic route
that may be used for preparing the pyrazol-3-yl compounds
of formula II-c of this invention. The conversion of
intermediate 4 to product 7 may be achieved through steps
(c), (d), and (e) according to the method described in
JACS, 1957, pp 79.
Reagents and conditions: (a) 1,1'-carbonyldiimidazole
(CDI), triethylamine, THF; (b) N-butyllithium, THF, -78°C;
(c) 6, polyphosphoric acid, 1 hour, 25-140°C; (d) POC13,
DMF, reflux; (e) NH2-UnR3, iPrOH, reflux.
Scheme VII above shows a general synthetic
route that may be used for preparing the oxazol-2-yl
compounds of formula II-e' of this invention. The
conversion of intermediate 5 to product 8 may be achieved
through steps (c), (d), and (e) according to the method
described in JACS, 1957, pp 79.
-78°C (b) t-butyllithium, THF, -78°C (c) 6, polyphosphoric
acid, 1 hour, 25-140°C (d) POC13, DMF, reflux (e) NH2-R,
iPrOH, reflux.
5 Scheme VIII above shows a general synthetic
route that may be used for preparing the thiazol-2-yl
compounds of formula II-g' of this invention. The
conversion of intermediate 5 to product 8 may be achieved
through steps (c), (d) , and (e) according to the method
I described in JACS, 1957, pp 79.
Reagents and conditions: (a) N-butyllithium, Bu3SnCl ;
(b) t-butyllithium, THF, -78°C; (c) MeOCO2Me; (d) 4,
Pd(0); (e) 6, polyphosphoric acid, 1 hour, 25-140°C; (f)
POC13, DMF, reflux; (g) NH2-UnR3, iPrOH, reflux.
Scheme IX above shows a general synthetic route
that may be used for preparing the thiazol-4-yl compounds
of formula II-g of this invention. The conversion of
intermediate 5 to product 8 may be achieved through steps
(e), (f), and (g) according to the method described in
JACS, 1957, pp 79.
Reagents and conditions: (a) CH3OCH2CH2COC1, AlCl3, CH2Cl2,
2.5 hours, RT; (b) DMF, 24 hrs, room temperature; (c)
(Me2N)2-CHOt-Bu, THF, 24 hrs, room temperature,- (d) N-
substituted guanidine, EtOH, 12 hours, reflux; (e) BBr3,
CH2C12, Na2CO3.
Scheme X above shows a general synthetic route
that is used for preparing compounds of formula III-a
where TmR1 is methoxymethyl or hydroxymethyl. In step
(a), 3-methoxypropionyl chloride is combined with
compound JL, dichloromethane, and aluminum trichloride to
form compound .2.
The formation of amide £ is achieved by
treating compound 2^ with an araine J3 in DMF. When amine 2
is a primary amine, the reaction proceeds at ambient
temperature. When amine _3 was a secondary amine, the
reaction is heated at 50°C to achieve complete reaction
and afford amide 4. The formation of enamine _5 at step
(c) is achieved by treating amide 4 with (Me2N) 2-CHOt-Bu
at ambient temperature.
The formation of the pyrimidine compound 6 at
step (d) is achieved by the treatment of enamine 5 with a
guanidine at elevated temperature. Alternatively, use of
a substituted guanidine results in an amino substituent.
To form compounds where lk,TmR1 is hydroxymethyl,
intermediate 6 may be treated with BBr3 in dichloromethane
to form compounds 7. One of skill in the art would
recognize that the hydroxymethyl group of compound 7
could be further derivatized to form a variety of
compounds of formula III-a. The details of the
conditions used for producing these compounds are set
forth in the Examples.
Reagents and conditions: (a) RNH2, MeCN, 0 C to 25 C, 12
hours; (b) A1C13, CH2Cl2, 25°C; (c) MeOH:H2O (2:1), 37'C.
Scheme XI above shows a general method for
preparing the triazine compounds of formula IV-a. Step
(a) is performed in the manner described at Scheme I,
step (b) above. Step (b) is performed in the manner
described at Scheme I, step (a) above. The formation of
the triazine ring at step (c) may be performed according
to the methods described by Hirsch, J.; Petrakova, E.;
Feather, M. S.; J Carbohydr Chem [JCACDM] 1995, 14 (8),
1179-1186. Alternatively, step (c) may be performed
according to the methods described by Siddiqui, A. U. ;
Satyanarayana, Y.; Rao, U. M. ; Siddiqui, A. H.; J Chem
Res, Synop [JRPSDC] 1995 (2), 43.
formula I', In I°, III-a, III-a', or III-a°, or a
pharmaceutically acceptable composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I', I", 1°, III-
a, III-a', or III-a°, or a pharmaceutically acceptable
composition comprising said compound.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula I', I", 1°, III-a, III-a', or III-a°,
or a pharmaceutically acceptable composition comprising
said compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated
disease, which method comprises administering to a
patient in need of such treatment a therapeutically
effective amount of a compound of formula I', I", ID, III-
a, III-a', or III-a°, or a pharmaceutically acceptable
composition comprising said compound.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
I', I", 1°, III-a, III-a', or III-a°, or a
pharmaceutically acceptable composition comprising said
compound. This method is especially useful for diabetic
patients. Another method relates to inhibiting the
production of hyperphosphorylated Tau protein, which is
useful in halting or slowing the progression of
Alzheimer's disease. Another method relates to
inhibiting the phosphorylation of ßcatenin, which is
useful for treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula I', I", 1°, Ill-a, III-a', or III-a°, or a
pharmaceutically acceptable composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a CDK-2-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I', I", 1°, III-
a, Ill-a' , or III-a°, or a pharmaceutically-acceptable
composition comprising said compound.
The term "CDK-2-mediated condition" or
"disease", as used herein, means any disease or other
deleterious condition in which CDK-2 is known to play a
role. The term "CDK-2-mediated condition" or "disease"
also means those diseases or conditions that are
alleviated by treatment with a CDK-2 inhibitor. Such
conditions include, without limitation, cancer,
Alzheimer's disease, restenosis, angiogenesis,
glomerulonephritis, cytomegalovirus, HIV, herpes,
psoriasis, atherosclerosis, alopecia, and autoimmune
diseases such as rheumatoid arthritis. See Fischer, P.M.
and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245
(2000); Mani, S., Wang, C, Wu, K. , Francis, R. and
Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000);
Fry, D.W. and Garrett, M.D., Current Opinion in
Oncologic, Endocrine & Metabolic Invescigational Drugs,
2, 40-59 (2000).
Another aspect of this invention relates to a
method of treating or preventing a Lck-mediated disease,
which method comprises administering to a patient in need
of such a treatment a therapeutically effective amount of
a compound of formula I', I", l°, lil-a, Ill-a', or
III-a°, or a pharmaceutically acceptable composition
comprising said compound.
The terms "Lck-mediated disease" or '"Lck-
mediated condition", as used herein, mean any disease
state or other deleterious condition in which Lck is
known to play a role. The terms "Lck-mediated disease"
or "Lck-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with an Lck
inhibitor. Lck-mediated diseases or conditions include,
but are not limited to, autoimmune diseases such as
transplant rejection, allergies, rheumatoid arthritis,
and leukemia. The association of Lck with various
diseases has been described [Molina et al., Nature, 357,
161 (1992)] .
Another aspect of this invention relates to a
method of treating or preventing an AKT3-mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amount of a compound of formula I', I", 1°, III-
a, III-a', or III-a°, or a pharmaceutically acceptable
composition comprising said compound.
The terms "AKT3-mediated disease" or "AKT3-
mediated condition", as used herein, mean any disease
state or other deleterious condition in which AKT3 is
known to play a role. The terms "AKT3-mediated disease"
or "AKT3-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with an AKT
inhibitor. AKT3-mediated diseases or conditions include,
but are not limited to, proliferative disorders, cancer,
and neurodegenerative disorders. The association of AKT3
with various diseases has been described [Zang, Q. Y., et
al, Oncogene, 19 (2000)] and [Kazuhiko, n., et al, The
Journal of Neuroscience, 20 (2000)].
Another method relates to inhibiting ERK2,
Aurora-2, CDK-2, Lck, AKT3, or GSK-3 activity in a
biological sample, which method comprises contacting the
biological sample with a compound of formula I', I", 1°,
Ill-a, III-a', or III-a°, , or a pharmaceutically
acceptable composition comprising said compound, in an
amount effective to inhibit ERK2, Aurora-2, CDK-2, Lck,
AKT3, or GSK-3.
Each of the aforementioned methods directed to
the inhibition of ERK2, Aurora-2, CDK-2, Lck, AKT3, or
GSK-3, or the treatment of a disease alleviated thereby,
is preferably carried out with a preferred compound of
formula I', I", 1°, III-a, III-a', or III-a°, as described
above. More preferably, each of the aforementioned
methods is carried out with a preferred compound of
formula I', I", 1°, III-a', or III-a°, and most preferably
with a compound of formula I", 1°, III-a', or Ill-a°.
In order that the invention described herein
may be more fully understood, the following examples are
set forth. It should be understood that these examples
are for illustrative purposes only and are not to be
construed as limiting this invention in any manner.
SYNTHETIC EXAMPLES
For compounds where the HPLC Method is
designated as "A", the following method was utilized: a
gradient of water:MeCN, 0.1% TFA (95:5 -» 0:100) was run
over 22 minutes at 1 mL/min and 214 nm. For compounds
where the HPLC Method is designated as "B", the following
method was utilized: a gradient of water.-MeCN, 0.1% TFA
(90:10 -> 0:100) was run over 8 minutes at 1 mL/min arid
214 nm. Each of methods A and B utilize the YMC ODS-AQ
55 120A column with a size of 3.0 x 150 mm. As used
herein, the term "Rt" refers to the retention time, in
minutes, associated with the compound using the
designated HPLC method.
2, 2, 2-Trichloro-l- (4-phenyl acetyl-lH-pyrrol-2-yl) -
ethanone (1) ¦. In a dry flask, phenylacetyl chloride (1
equivalent) was combined with 2-trichloroacetyl pyrrole
(1 equivalent) in a minimum amount of dichloromethane
(DCM) to dissolve the reactants. To the resulting
solution, at ambient temperature, was added aluminum
trichloride (1 equivalent). After 2 hours, the reaction
mixture was applied directly onto a silica gel column.
Gradient elution with 10% ethyl acetate to 50% ethyl
acetate in hexanes provided compound 1 in 60% yield. XH
NMR (CDC13) 6 4.0 (s, 2H), 7.1-7.35 (m, 7H), 9.7 (br s,
NH). HPLC using method B provided Rt of 4.9 minutes.
LC/MS (M+l) 330.2, (M-l) 328.1.
2,2,2-Trichloro-l-(4-(3-Chlorophenyl) acetyl-lH-pyrrol-2-
yl)-ethanone (2J .- In a dry flask, 3-chlorophenylacetyl
chloride (1 equivalent) was combined with 2-
trichloroacetyl pyrrole (1 equivalent) in a minimum
amount of dichloromethane (DCM). To the resulting
solution, at ambient temperature, was added aluminum
trichloride (1 equivalent). After 2 hours, the reaction
mixture was applied directly onto a silica gel column.
Gradient elution with 10% ethyl acetate to 50% ethyl
acetate in hexanes provided compound 2 . HPLC using
method A provided Rt of 15 minutes
1- [5- (2,2,2-Trichloro-acetyl) -lH-pyrrol-3-yl) -propan-1-
one (2> : In a dry flask, 3-proprionyl chloride (1
equivalent) was combined with 2-trichloroacetyl pyrrole
(1 equivalent) in a minimum amount of dichloromethane
(DCM) . To the resulting solution, at ambient
temperature, was added aluminum trichloride (1
equivalent). After 2 hours, the reaction mixture was
applied directly onto a silica gel column. Gradient
elution with 10% ethyl acetate to 50% ethyl acetate in
hexanes provided compound 3
4-Phenylacetyl-lff-pyrrole-2-carboxylic acid benzylamide
(•4) : To a solution of compound 1 (1 equivalent) in DMF,
at ambient temperature, was added benzylamine (1.2
equivalents). After 24 hours, the solvent was evaporated
and the crude product 4 was used without purification.
HPLC using method B provided Rt of 3.8 minutes. FIA/MS
(M+l) 319.3, (M-l) 317.2.
2-(3-Chlorophenyl)l-[5-(morpholine-4-carbonyl)-lH-pyrrol-
3-yl] -ethanone (E) : To a solution of compound 2(1
equivalent) in DMF, at ambient temperature, was added
morpholine (1.2 equivalents). After 24 hours, the
solvent was evaporated and the crude product 5 was used
without purification. FIA/MS (M+l) 333.3, (M-l) 331.2.
1H NMR was consistent with expected structure. .
4-Propionyl-lH-pyrrole-2-carboxylic acid 3,4-difluoro-
benzylamide (_6) : To a solution of compound 3_ U
equivalent) in DMF, at ambient temperature, was added
3,4-difluorobenzyl amine (1.2 equivalents). After 24
hours, the solvent was evaporated and the crude product 6
was used without purification.
4- (3-Dimethylamino-2-phenyl-acryloyl) -lIf-pyrrole-2-
carboxylic acid benzylamide (!) ¦. To a solution of
compound 4_ (1 equivalent) in THF, at ambient temperature,
was added (Me2N) 2CHOt-Bu (3 equivalents). After 24 hours,
the solvent was evaporated and the crude product 1_ was
used without purification. XH NMR (CDC13) 5 4.4 (s, 2H.) ,
4.8 (s, NH), 6.8-7.4 (m, 13H).
2-(3-Chloro-phenyl)-3-dimethylamino-l-[5-(morpholine-4-
carbonyl)-lH-pyrrol-3-yl]-propenone (J3) : To a solution of
compound j> (1 equivalent) in THF, at ambient temperature,
was added (Me2N) 2CHOt-Bu (3 equivalents) . After 24 hours,
the solvent was evaporated and the crude product 8_ was
used without purification. HPLC using method B provided Rt
of 11.2 minutes.
4- (2-Amino-5-inethyl-pyriinidin-4-yl) -Iff-pyrrole-2-
carboxylic acid 3 , 4-difluoro-benzylamide (III-a-74) :
Step 1: To a solution of compound 6_ (1 equivalent) in
THF, at ambient temperature, was added (Me2N) 2CHOt-Bu (3
equivalents). After 24 hours, the solvent was evaporated
and the crude product was utilized without purification.
Step 2: To a solution of the compound formed above at
Step 1 (1 equivalent) in ethanol, at ambient temperature,
was added guanidine (3 equivalents) and the resulting
mixture heated at reflux. After 12 hours, the solvent
was evaporated and the crude product purified by-
preparatory HPLC (reverse phase; 10—>90% MeCN in water; 15
minutes) to afford the desired compound III-a-74. HPLC
using method B provided Rt of 7.9 minutes. 1H NMR was
consistent with expected structure. FIA/MS Obs. M+l /M-
1.
{4- [2-Amino-5- (3-chlorophenyl) -pyrimidine-4-yl] -1H-
pyrrol-2-yl}-morpholin-4-yl-methanone (III-a-72): To a
solution of compound 8_ (1 equivalent) in ethanol, at
ambient temperature, was added guanidine (3 equivalents)
and the resulting mixture heated at reflux. After 12
hours, the solvent was evaporated and the crude product
purified by preparatory HPLC (reverse phase; 10—>90% MeCN
in water; 15 minutes) to afford the desired compound III-
a-72. HPLC using method B, Rt=7.9 minutes. 1H NMR was
consistent with expected structure. FIA/MS Obs. (M+l)
384.4 amu.
N- (2-Hydroxy-l- (3) -phenyl-ethyl) -guanidine»HCl.- (5) -
Phenylglycinol (0.38g, 2.7 mmol) and bis-Boc guanidine
(AT)-triflate (0.9g, 2.3 mmol) were combined in methyle
chloride (anhydrous, 5mL) and stirred at ambient
temperature overnight. Completion of the reaction was
verified by HPLC. The mixture was diluted with ethyl
acetate, washed with 2M sodium bisulfite, brine then
dried over MgSO4, filtered and concentrated in vacuo.
The bis-Boc guanidine intermediate was treated with 4N
HCl/dioxane (5raL) and stirred at room temperature unti]
deprotection was complete (48 h) to afford the title
compound..
4- [2- (2-Hydroxy-l- (S) -phenyl-ethylamino) -5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-
1-(S)-phenyl-ethyl)-amide (III-a-155): 4-(3-
Dimethylamino-2-methyl-acryloyl) - 1H~pyrrole-2-carboxylic
acid (2-hydroxy-l-phenyl-ethyl)-amide {100 mg, 0.29 mmol)
was combined with N-(S)-phenylglycinol guanidine»HCl (126
mg) and potassium carbonate (121 mg) in N,N-
dimethylacetamide (2mL). The resulting suspension was
heated and stirred at 100° C for 24 hours. The crude
material was diluted with ethyl acetate, washed with
saturated NaHC03, brine, dried over MgSO4 and concentrated
in vacuo. Purification by prep HPLC (Gilson: Column =
CombiHT SB-C189 5 [iM 21.2 mm x 100 mm, eluent = 0.1%TFA
MeCN/H2O gradient) followed by preparative TLC (silica,
5% MeOH in CH2C12) afforded compound III-a-155 as a pale
yellow solid (8.0 mg). HPLC Method B, Rc=4.76 minutes; MS
(FIA) 458.2 (M+l), 456.1 (M-l); XH NMR consistent with
structure.
4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -phenyl-ethyl)-
amide (III-a-162): 4-(3-Dimethylamino-2-methyl-acryloyl)-
l#-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-
amide (100 mg, 0.29 mtnol) was combined with cyclopropyl
guanidine»HCl (80 mg) and potassium carbonate (121 mg) in
N,N-dimethylacetamide (2mL). The resulting suspension
was heated and stirred at 100°C for 24 hours. The crude
material was diluted with ethyl acetate, washed with
saturated NaHCO3 and brine, dried over MgSO4 then
concentrated in vacuo. Purification by preparative TLC
(silica, 1:1 EtOAc.-Hexanes) afforded III-a-162 as a
yellow solid (7.8 mg). HPLC Method B, Rt=4.29 minutes;
LC/MS(m/z) 378.2 (M+l), 376.2 (M-l); JH NMR consistent
with structure.
3-Methoxy-l-[5-(2, 2 , 2-trichloro-acetyl)-lH-pyrrol-3-yl]-
propan-1-one: To a solution of 2-trichloroacetyl pyrrole
4- (3-Methoxy-propionyl) -lff-pyrrole-2-carboxylic acid (2-
hydroxy-1- (S) -phenyl-ethyl) -amide: To a solution of 3-
methoxy-1- [5- (2,2, 2-trichloro-acetyl) - 1H-pyrrol-3 -yl] -
propan-1-one (3.0 g, 10 ramol) in acetonitrile (50 mL) ,
cooled to 0°C, was added (S)-( + )-phenyl glycinol (1.2
equivalent, 1.65 g, 12 mmol) and the resulting mixture
stirred for 3 days at room temperature. The solvent was
removed under reduced pressure and the residue purified
by chromatography on silica gel (MeOH 5% in DCM) to
afford 5.3 g of the title compound as a white solid.
HPLC Method B, Rt=4.2 minutes; LC/MS(m/z) 317.03 (M+l),
315.00 (M-l) ; 1H NMR consistent with structure.
(1.0 equivalent, 4.67g, 22 mmol) in methylene chloride (5
mL) was added 3-methoxypropionyl chloride (1.0
equivalent, 22 mmol) then aluminium trichloride (1.0
equivalent, 2.93g, 22 mmol) was added in small portions.
After 2.5 hours, the crude mixture was chromatographed on
silica gel (MeOH 2% in DCM) to afford 3.0 g of the
Friedel-Craft product. 1H NMR consistent with structure.
4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -lff-pyrrole-
2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide:
4-(3-Methoxy-propionyl)-l.H-pyrrole-2-carboxylic acid (2-
hydroxy-1-(S)-phenyl-ethyl)-amide was treated with an
excess of Bredereck's reagent in THF at room temperature
to 50°C for 3 days. The solvent was removed under
reduced pressure and the concentrate was used directly in
the next step. HPLC Method B, Rt=5.0 minutes "broad
peak".
4- (5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-
amide (III-a-164): 4-(3-Dimethylamino-2-methoxymethyl-
acryloyl)-l#-pyrrole-2-carboxylic acid (2-hydroxy-l- (S)-
phenyl-ethyl)-amide (0.27 mmol) was combined with phenyl
guanidine (73 mg) in N,N-dimethylacetamide (2 mL) and the
resulting suspension was heated at 90°C for 35 hours.
The reaction mixture was diluted with ethyl acetate,
washed with saturated NaHCO3 and brine, dried over MgS04
and concentrated in vacuo. The crude product was
purified by prep HPLC (Gilson: Column = CombiHT SB-C189 5
p.M, 21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient)
to afford III-a-164 as a yellow solid (3.2 mg).
LC/MS(m/z) 444.16 (M+l), 442.19 (M-l); HPLC Method B,
Rt=5.16 minutes: 1H NMR consistent with structure.
4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-
amide (III-a-165): To a solution of III-a-164 (15 mg,
0.03 mmol) in dichloromethane (2 mL), cooled to -78°C,
was added BBr3 (135 |IL, 0.13 mmol) . After 15 minutes the
reaction was allowed to warm to room temperature. After
45 minutes, the reaction was quenched with a saturated
solution of sodium carbonate and the resulting mixture
was stirred for an additionnal 3 0 minutes before
extraction with ethyl acetate. The organic layers were
combined and washed with brine then dried over sodium
sulfate. The crude mixture was purified by prep TLC
(silica, 7% MeOH in CH2Cl2) to afford III-a-165 as a beige
solid (1.6 mg) . HPLC Method B, Rt=4.54 minutes; LC/MS
(m/z) 430.15 (M+l), 428.03 (M-l); ^ NMR consistent with
structure.
4- (2-Amino-5-methoxymethyl-pyrimidin-4-yl) -l.ff-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide (Ill-a-
161): The enamine formed above at Example 16 (0.27 mmol)
was combined with guanidine»HCl (51 mg), and K2CO3 (100
mg) in N,N-dimethylacetamide (4 mL). The heterogenous
mixture was heated and stirred at 90° C for 3 5 h. The
crude material was diluted with ethyl acetate, washed
with saturatedd NaHCO3 and brine, dried (MgSO4) and
concentrated in vacuo. Purification by prep HPLC
(Gilson: Column = CombiHT SB-C189 5 fiM, 21.2 mm x 100 mm,
eluent = 0.l%TFA MeCN/H2O gradient) afforded III-a-161 as
a yellow solid (2.0 mg). LC/MS(m/z) 368.12 (M+l), 366.15
(M-l), Rt (HPLC) =-3.77 min, XH NMR consistent with
structure.
4- (2-Mercapto-5-methyl-pyrimidin-4-yl)-Iff-pyrrole-2-
carboxylic acid (2-hydroxy-l-(5)-phenyl-ethyl)-amide:
4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -Iff-pyrrol e-
2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide
(17.6 mmol, 6.0 g) was combined with thiourea (39 mmol,
3.0 g) and potassium carbonate (53 mmol, 7.3 g) in
ethanol (50 mL) and the resulting suspension was heated
at 90° C for 24 hrs. The solvent was removed in vacuo and
the resulting black solid was diluted with water and the
solid was removed by filtration. The solid was washed
with ethyl acetate twice and the aqueous solution was
acidified to pH 5-6 with HC1(2N). The solid formed was
removed by filtration and the aqueous solution was then
extracted twice with ethyl acetate. The combined organic
phases were dried over sodium sulfate. The solvent was
removed under vacuum to afford the title compound as a
brown solid (3.0 g, 48% yield). HPLC Method B, Rt=3 .7
minutes, 1H NMR consistent with structure.
4- (5-Methyl-2-propylsulfanyl-pyrimidin-4-yl) -1H-pyrrole-
2-carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide:
To a solution of 4-(2-mercapto-5-methyl-pyrimidin-4-yl) -
lH-pyrrole-2-carboxylic acid (2-hydroxy-l-(S)-phenyl-
ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueous ammonia
(15%) was added at room temperature n-propyliodide (11.6
mmol, 1.1 mL). The solution was stirred overnight at
room temperature. The resulting solid was collected by
filtration and used directly for the next step. 1H NMR
consistent with the structure.
4- [5-Methyl-2- (propane-1-sulfonyl)-pyrimidin-4-yl]~1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -phenyl-ethyl)-
amide: The thiopropyl compound (7.7 mmol, 3.05g) prepared
at Example 21 above was dissolved in 120 mL of ethanol.
To this solution, maintained at room temperature, was
added m-CPBA (70% w/w%, 23.1 mmol, 4.0 g). The solution
was stirred for an additional 4 hours at room
temperature. The solvent was removed in vacuo and the
residue dissolved in ethyl acetate, then washed 4 times
with a solution of sodium hydroxide (IN) . The organic
phase was dried over sodium sulfate and concentrated in
vacuo to afford the title compound as a white solid
(1.7g, 51% yield for 2 steps). HPLC Method B, Rc=5.4
minutes. 1H NMR consistent with the structure.
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide: To a
solution of 4-[5-methyl-2-(propane-1-sulfonyl)-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-(S) -
phenyl-ethyl)-amide (47 p.mol, 20 mg) in DMSO (1 mL) was
added ethylamine (0.5 mmol, 150 |xL) . The mixture was
heated at 130°C for 24 hours to afford the title
compound. LC/MS(m/z) 366.2 (M+l); HPLC Method B, Rt=4.2
minutes; 1H NMR consistent with the structure.

4- [2-{N' ,N' -Dimethyl-hydrazino)-5-methyl-pyrimidin-4-yl]-
lff-pyrrole-2-carboxylic acid (2-hydroxy-l- (5)-phenyl-
ethyl)-amide (III-a-226): To a solution of 4-(3-
dimethylamino-2-methoxymethyl-acryloyl)-ltf-pyrrole-2-
carboxylic acid (2-hydroxy-l-(S)-phenyl-ethyl)-amide
(0.15 mmol, 50 mg) in DMA (2 mL) was added dimethyl-N,N-
aminoguanidine»2HCl (0.17 mmol, 30 mg) and potassium
carbonate (0.36 mmol, 50 mg). The reaction mixture was
stirred for 48 hrs at 100°C. The solvent was removed by
hi-vacuum "GeneVac" and the residue purified by
preparative HPLC (Gilson: Column = CombiHT SB-C189 5 J^M
21.2 mm x 100 mm, eluent = 0.1%TFA MeCN/H2O gradient)
followed by preparative TLC (silica, 5% MeOH in CH2C12)
"double elutions" afforded compound III-a-226 as a pale
yellow solid (1.3 mg). HPLC Method B, Rt=4.03 min.; LC/MS
(m/z) 381.1 (M+l), 379.1 (M-l); 2H NMR consistent with
structure.

Ethanolguanidine: Ethanolamine hydrochloride (2 00 mg, 2
mmol) was added to a mixture of N, N'-di-boc -N'-
triflylguanidine (8 00 mg, 2 mmol) and TEA (0.28 mL, 2
mmol) in dichloromethane (10 mL). The mixture was
stirred overnight then diluted with EtOAc, washed with
sodium bisulfate (2M), saturated sodium bicarbonate,
dried over NaS04 and concentrated in vacuo. The crude
residue was purified by flash column chromatography
eluting with 20% CH2Cl2/hexane to afford a white solid
(0.56 g, 92%). ). 2H NMR (CDC13) : 5 4.18 (q, 2H) , 1.60 (d,
18H), 1.37 (t, 3H). To this bis-Boc guanidine was added
4M HCl/dioxane (5 mL). The mixture was stirred for 24 h
and then concentrated to afford the title compound (0.26
g) . *H NMR (MeOD) : 5 3.92 (q, 2H), 1.27 (t, 3H) . MS (M+l)
104.

4-(2-Ethanolamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-(s)-phenyl-ethyl)-amide
(III-a-195): To a mixture of 4-(3-dimethylamino-2-methyl-
acryloyl)-lH-pyrrole-2-carboxylic acid (2-hydroxymethyl-
1- (S) -phenyl-ethyl) amide (0.1 mmol) and K2CO3 (55 mg, 0.4
mmol) in DMF (1 mL) was added ethanolguanidine hydrogen
chloride (0.2 mmol). The resulting suspension was
stirred for 6 hours at 90 °C. The reaction mixture was
filtered and the filtrate concentrated in vacuo. The
crude residue was purified by preparative HPLC (Gilson:
Column = CombiHT SB-C189 5 JIM 21.2 mm x 100 mm, eluent =
0.1%TFA MeCN/H2O gradient) to afford compound III-a-195
as yellow oil (21 mg). HPLC (method B) Rt = 4.08 min; MS
(M+l) 382.1.

Ethyl carbamate guanidine: Ethylcarbazate (208 mg, 2
mmol) was added to a solution of N'N'-di-boc N'-
triflylguanidine (800 mg, 2 mmol) in dichloromethane (10
mL). The mixture was stirred for overnight then diluted
with EtOAc, washed with sodium bisulfat (2M), saturated
sodium bicarbonate, dried over anhydrous NaSO4 and
concentrated in vacuo. The crude residue was purified by
flash column chromatography eluting with 3 0% EtOAc/hexane
to afford a white solid (0.55g). To this bis-boc
guanidine was added 4M HCl/Dioxane (5 mL). The mixture
was stirred for 24 hours and then concentrated to afford
the title compound. 1H NMR (MeOD) : 5 3.4.18 (d, 2H) , 3.26
(s, 1H), 1.28 (t, 3H). MS (M+l) 134.

III-a-218
4-(2-Ethyl carbamate-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-(s)-phenyl-ethyl)-amide
(III-a-218): To a mixture of 4-(3-dimethylamino-2-methyl-
acryloyl)-lH-pyrrole-2-carboxylic acid (2-hydroxymethyl-
1-(S)-phenyl-ethyl) amide (0.1 mmol) and K2CO3 (55 mg, 0.4
mmol) in DMF (1 mL) was added ethyl carbamate guanidine
hydrogen chloride (0.2 mmol). The resulting suspension
was stirred for 6 hours at 90 °C. The reaction mixture
was filtered and the filtrate was concentrated in vacuo.
The crude residue was purified by preparative HPLC
(Gilson: Column = CombiHT SB-C189 5 |iM 21.2 mm x 100 mm,
eluent = 0.1%TFA MeCN/H2O gradient) to afford compound
III-a-218 as a yellow oil (10 mg). HPLC (method B) Rt =
4.03/ MS (M+l) 425.1. ^NMR (MeOD) 8.08 (s, 1H); 7.87 (s,
1H) ; 7.7 (s, 1H) , 7.24-7.5 (m, 5H) ; 5.15 (t, 1H) , 4.2 (m,
2H), 3.85 (m, 2H); 2.5 (s, 3H).
Example 2 9
We have prepared other compounds of formula
III-a by methods substantially similar to those described
in the above Examples 1-28 and those illustrated in
Schemes I-XII. The characterization data for these
compounds is summarized in Table 3 below and includes
LC/MS, HPLC, and 1H NMR data.
Where applicable, 1H NMR data is summarized in
Table 3 below wherein "Y" designates 1H NMR data is
5 available and was found to be consistant with structure.
Compound numbers correspond to the compound numbers
listed in Table 1.
BIOLOGICAL TESTING
The activity of the present compounds as
protein kinase inhibitors may be assayed in vitro, in
vivo or in a cell line. In vitro assays include assays
that determine inhibition of either the phosphorylatiori
activity or ATPase activity of the activated protein
kinase. Alternate in vitro assays guantitate the ability
of the inhibitor to bind to the protein kinase.
Inhibitor binding may be measured by radiolabelling the
inhibitor prior to binding, isolating the
inhibitor/protein kinase complex and determining the
amount of radiolabel bound. Alternatively, inhibitor
binding may be determined by running a competition
experiment where new inhibitors are incubated with the
protein kinase bound to known radioligands. The details
of the conditions used for performing these assays are
set forth in Examples 3 0 through 37.
Example 3 0
ERK INHIBITION ASSAY
Compounds were assayed for the inhibition of
ERK2 by a spectrophotometric coupled-enzyme assay (Fox et
al (1998) Protein Sci 7, 2249). In this assay, a fixed
concentration of activated ERK2 (10 nM) was incubated
with various concentrations of the compound in DMSO (2.5
%) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.5,
containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200
uM NADH, 150 ug/mL pyruvate kinase, 50 ug/mL lactate
dehydrogenase, and 200 uM erktide peptide. The reaction
was initiated by the addition of 65 uM ATP. The rate of
decrease of absorbance at 34 0 nM was monitored. The IC50
was evaluated from the rate data as a function of
inhibitor concentration.
Table 4 shows the results of the activity of
selected compounds of this invention in the ERK2
inhibition assay. The compound numbers correspond to the
compound numbers in Table 1. Compounds having an
activity designated as "A" provided a percent inhibition
less than or equal to 33%; compounds having an activity
designated as "B" provided a percent inhibition of
between 24% and 66%; and compounds having an activity
designated as "C" provided a provided a percent
inhibition of between 67% and 100%. Compounds having an
activity designated as "D" provided a Xi of less than 0.1
micromolar; compounds having an activity designated as
"E" provided a Kj. of between 0.1 and 1.0 micromolar; and
compounds having an activity designated as "F" provided a
Ki of greater than 1.0 micromolar.
Example 31
ERK2 INHIBITION: Cell Proliferation Assay
Compounds may be assayed for the inhibition of
ERK2 by a cell proliferation assay. In this assay, a
complete media is prepared by adding 10% fetal bovine
serum and penicillin/streptomycin solution to RPMI 1640
medium (JRH Biosciences). Colon cancer cells (HT-29 cell
line) are added to each of 84 wells of a 96 well plate at
a seeding density of 10,000 cells/well/150 µL- The cells
are allowed to attach to the plate by incubating at 37°C
for 2 hours. A solution of test compound is prepared in
complete media by serial dilution to obtain the following
concentrations: 20 (µM, 6.7 |J.M, 2.2 (µM, 0.74 (J.M, 0.25 µM,
and 0.08 µM. The test compound solution (50 |iL) is added
to each of 72 cell-containing wells. To the 12 remaining
cell-containing wells, only complete media (200 µL.) is
added to form a control group in order to measure maximal
proliferation. To the remaining 12 empty wells, complete
media is added to form a vehicle control group in order
to measure background. The plates are incubated at 3 7°C
for 3 days. A stock solution of 3H-thymidine (1 mCi/mL,
New England Nuclear, Boston, MA) is diluted to 20 µCi/mL
in RPMI medium then 20 µL of this solution is added to
each well. The plates are further incubated at 37°C for 8
hours then harvested and analyzed for 3H-thyraidine uptake
using a liquid scintillation counter.
Compounds III-a-116, III-a-139, and III-a-136
were each shown to have an IC50 of less than 0.1 µM.
Example 32
ERK1 INHIBITION ASSAY
Compounds were assayed for the inhibition of
ERK1 by a spectrophotometric coupled-enzyme assay (Fox et
al (1998) Protein Sci 7, 2249). In this assay, a fixed
concentration of activated ERK1 (20 nM) was incubated
with various concentrations of the compound in DMSO (2.0
%) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.6,
containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200
uM NADH, 30 ug/mL pyruvate kinase, 10 µg/mL lactate
dehydrogenase, and 150 uM erktide peptide. The reaction
was initiated by the addition of 140 uM ATP (20 uL) . The
rate of decrease of absorbance at 34 0 nM was monitored.
The Kj was evaluated from the rate data as a function of
inhibitor concentration.
Examples of compounds that were found to
inhibit ERK1 with an activity of less than 0.1 uM include
III-a-202, III-a-204, and III-a-205.
Example 33
GSK-3 INHIBITION ASSAY
Compounds were screened for their ability to
inhibit GSK-3[3 (AA 1-420) activity using a standard
coupled enzyme system (Fox et al. (1998) Protein Sci. 7,
2249). Reactions were carried out in a solution
containing 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl,
3 00 uM NADH, 1 mM DTT and 1.5% DMSO. Final substrate
concentrations in the assay were 2 0 uM ATP (Sigma
Chemicals, St Louis, MO) and 300 uM peptide
(HSSPHQS(PO3H2)EDEEE, American Peptide, Sunnyvale, CA) .
Reactions were carried out at 3 0 °C and 2 0 nM GSK-3J3.
Final concentrations of the components of the coupled
enzyme system were 2.5 mM phosphoenolpyruvate, 3 00 µM
NADH, 3 0 ug/ml pyruvate kinase and 10 ug/ml lactate
dehydrogenase.
An assay stock buffer solution was prepared
containing all of the reagents listed above with the
exception of ATP and the test compound of interest. The
assay stock buffer solution (175 µi) was incubated in a
96 well plate with 5 ul of the test compound of interest
at final concentrations spanning 0.002 uM to 30 uM at 30
°C for 10 min. Typically, a 12 point titration was
conducted by preparing serial dilutions (from 10 mM
compound stocks) with DMSO of the test compounds in
daughter plates. The reaction was initiated by the
addition of 20 ul of ATP (final concentration 20 uM).
Rates of reaction were obtained using a Molecular Devices
Spectramax plate reader (Sunnyvale, CA) over 10 min at
3 0°C. The Ki values were determined from the rate data as
a function of inhibitor concentration.
Table 5 shows the results of the activity of
selected compounds of this invention in the GSK3
inhibition assay. The compound numbers correspond to the
compound numbers in Table 1. Compounds having an
activity designated as "A" provided a Ki of less than 0.1
micromolar; compounds having an activity designated as
"B" provided a Ki of between 0.1 and 1.0 micromolar; and
compounds having an activity designated as "C" provided a
Ki of greater than 1.0 micromolar.
Example 3 4
AURORA-2 INHIBITION ASSAY
Compounds were screened in the following manner
for their ability to inhibit Aurora-2 using a standard
coupled enzyme assay (Fox et al (1998) Protein Sci 7,
2249).
To an assay stock buffer solution containing
0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM
phosphoenolpyruvate, 300 mM NADH, 3 0 mg/ml pyruvate
kinase, 10 mg/ml lactate dehydrogenase, 4 0 mM ATP, and
800 uM peptide (LRRASLG, American Peptide, Sunnyvale, CA)
was added a DMSO solution of a compound of the present
invention to a final concentration of 30 uM. The
resulting mixture was incubated at 3 0 °C for 10 min. The
reaction was initiated by the addition of 10 uL of
Aurora-2 stock solution to give a final concentration of
70 nM in the assay. The rates of reaction were obtained
by monitoring absorbance at 34 0 ran over a 5 minute read
time at 3 0 °C using a BioRad Ultramark plate reader
(Hercules, CA) . The Ki values were determined from the
rate data as a function of inhibitor concentration.
Examples of compounds that were found to inhibit Aurora-2
include III-a-116,- III-a-117, III-a-136, III-a-138, III-
a-139, IIl-a-140, and III-a-141.
Example 3 5
CDK-2 INHIBITION ASSAY
Compounds were screened in the following manner
for their ability to inhibit CDK-2 using a standard
coupled enzyme assay (Fox et al (1998) Protein Sci 1,
2249) .
To an assay stock buffer solution containing
0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM
phosphoenolpyruvate, 3 00 mM NADH, 3 0 mg/ml pyruvate
kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and
100 uM peptide (MAHHHRSPRKRAKKK, American Peptide,
Sunnyvale, CA) was added a DMSO solution of a compound of
the present invention to a final concentration of 3 0 uM.
The resulting mixture was incubated at 3 0 °C for 10 min.
The reaction was initiated by the addition of
10 uL of CDK-2/Cyclin A stock solution to give a final
concentration of 25 nM in the assay. The rates of
reaction were obtained by monitoring absorbance at 340 nm
over a 5-minute read time at 30 °C using a BioRad
Ultramark plate reader (Hercules, CA) . The Ki values were
determined from the rate data as a function of inhibitor
concentration.
The following compounds were shown to have Ki
values than 0.1 µM for CDK-2: III-a-116, III-a-142, III-
a-149, and III-a-152.
The following compounds were shown to have Ki
values between 0.1 µM and 1 µM for CDK-2: III-a-146, III-
a-148, III-a-150, III-a-155, III-a-162, and III-a-174.
The following compounds were shown to have Ki
values between 1.0 and 20.0 µM for CDK-2: III-a-117, III-
a-156, and III-a-159.
Example 3 6
LCK INHIBITION ASSAY
The compounds were evaluated as inhibitors of
human Lck kinase using either a radioactivity-based assay
or spectrophotometric assay.
Lck Inhibition Assay A: Radioactivity-based Assay
The compounds were assayed as inhibitors of
full length bovine thymus Lck kinase (from Upstate
Biotechnology, cat. no. 14-106) expressed and purified
from baculo viral cells. Lck kinase activity was
monitored by following the incorporation of 33P from ATP
into the tyrosine of a random poly Glu-Tyr polymer
substrate of composition, Glu.-Tyr = 4:1 (Sigma, cat. no.
ß0275). The following were the final concentrations of
the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2,
2 mM DTT, 0.25 mg/ml BSA, 10 uM ATP (1-2 uCi 33P-ATP per
reaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of
recombinant human Src kinase. In a typical assay, all
the reaction components with the exception of ATP were
pre-mixed and aliquoted into assay plate wells.
Inhibitors dissolved in DMSO were added to the wells to
give a final DMSO concentration of 2.5%. The assay plate
was incubated at 30 C for 10 min before initiating the
reaction with 33P-ATP. After 20 min of reaction, the
reactions were quenched with 150 ul of 10%
trichloroacetic acid (TCA) containing 20 mM Na3PO4. The
quenched samples were then transferred to a 96-well
filter plate (Whatman, UNI-Filter GF/F Glass Fiber
Filter, cat no. 7700-3310) installed on a filter plate
vacuum manifold. Filter plates were washed four times
with 10% TCA containing 20 mM Na3PO4 and then 4 times with
methanol. 200ul of scintillation fluid was then added to
each well. The plates were sealed and the amount of
radioactivity associated with the filters was quantified
on a TopCount scintillation counter. The radioactivity
incorporated was plotted as a function of the inhibitor
concentration. The data was fitted to a competitive
inhibition kinetics model to get the Ki for the compound.
Lck Inhibition Assay B: Spectrophotometric Assay
The ADP produced from ATP by the human
recombinant Lck kinase-catalyzed phosphorylation of poly
Glu-Tyr substrate was quanitified using a coupled enzyme
assay (Fox et al (1998)' Protein Sci 7, 2249) . In this
assay one molecule of NADH is oxidised to NAD for every
molecule of ADP produced in the kinase reaction. The
disappearance of NADH can be conveniently followed at 340
nm.
The following were the final concentrations of
the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2,
2 mM DTT, 5 mg/ml poly Glu-Tyr, and 5 0 nM of recombinant
human Lck kinase. Final concentrations of the components
of the coupled enzyme system were 2.5 mM
phosphoenolpyruvate, 2 00 uM NADH, 3 0 ug/ml pyruvate
kinase and 10 ug/ml lactate dehydrogenase.
In a typical assay, all the reaction components
with the exception of ATP were pre-mixed and aliquoted
into assay plate wells. Inhibitors dissolved in DMSO
were added to the wells to give a final DMSO
concentration of 2.5%. The assay plate was incubated at
30 °C for 10 min before initiating the reaction with 150
uM ATP. The absorbance change at 34 0 nm with time, the
rate of the reaction, was monitored on a molecular
devices plate reader. The data of rate as a function of
the inhibitor concentration was fitted to competitive
inhibition kinetics model to get the Ki for the compound.
The following compounds were shown to have Ki
values than 1 µM for Lck: III-a-170, III-a-171, Ill-a-
172, III-a-173, III-a-181, and III-a-203.
The following compounds were shown to have Ki
values between l.o and 20.0 µM for Lck: III-a-204, Ill-a-
205, III-a-206, and III-a-207.
Example 3 7
AKT3 INHIBITION ASSAY
Compounds were screened for their ability to
inhibit AKT3 using a standard coupled enzyme assay (Fox
et al., Protein Sci., (1998) 7, 224 9). Assays were
carried out in a mixture of 100 mM HEPES 7.5, 10 mM
MgCl2, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final
substrate concentrations in the assay were 170 uM ATP
(Sigma Chemicals) and 200 uM peptide (RPRAATF, American
Peptide, Sunnyvale, CA). Assays were carried out at 30
"C and 45 nM AKT3. Final concentrations of the
components of the coupled enzyme system were 2.5 mM
phosphoenolpyruvate, 3 00 uM NADH, 3 0 ug/ML pyruvate
kinase and 10 ug/ml lactate dehydrogenase.
An assay stock buffer solution was prepared
containing all of the reagents listed above, with the
exception of AKT3, DTT, and the test compound of
interest. 56 ul of the stock solution was placed in a
384 well plate followed by addition of 1 ul of 2 mM DMSO
stock containing the test compound (final compound
concentration 30 uM). The plate was preincubated for
about 10 minutes at 30°C and the reaction initiated by
addition of 10 µl of enzyme (final concentration 45 nM)
and 1 mM DTT. Rates of reaction were obtained using a
BioRad Ultramark plate reader (Hercules, CA) over a 5
minute read time at 30 0C. Compounds showing greater than
50% inhibition versus standard wells containing the assay
mixture and DMSO without test compound were titrated to
determine IC50 values.

Selected compounds of this invention that
inhibit AKT3 include: III-a-238.
While we have presented a number of embodiments
of this invention, it is apparent that our basic
construction can be altered to provide other embodiments
which utilize the compounds and methods of this
invention. Therefore, it will be appreciated that the
scope of this invention is to be defined by the appended
claims rather than by the specific embodiments which have
been represented by way of example.
Appendix A: Names of Table 1 Compound Numbers III-a-
1: 4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid dimethylamide;
2: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-pyrrolidin-l-yl-methanone;
3 •• {4- [2-Amino-5- (3-chloro-2-fluoro-phenyl) -pyrimidin-4-
yl]-lH-pyrrol-2-yl}-pyrrolidin-l-yl-methanone;
4: 4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
5: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -
morpholin-4-yl-methanone;
6: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
[1,4' ]bipiperidinyl-l' -yl-methanone;
7: {4- [2-Amino-5- (3, 4-dimethoxy-phenyl) -pyrimidin-4-yl] -
lH-pyrrol-2-yl}-(3-hydroxy-piperidin-1-yl) -
methanone;
8: {4- [2-Amino-5- (3, 4-dimethoxy-phenyl) --pyrimidin-4-yl] -
lH-pyrrol-2-yl}-[1,4']bipiperidinyl-1'-yl-methanone;
9 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -
[1,4']bipiperidinyl-1'-yl-methanone;
10: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-[1,4']bipiperidinyl-1'-yl-
methanone;
11: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]- (4-hydroxy-piperidin-1-yl)-methanone;
12 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
[4- (2-fluoro-phenyl)-piperazin-1-yl]-methanone;
13 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
(4-phenyl-piperazin-l-yl)-methanone;
14 .- [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -
[4- (4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-l-yl]-
methanone;
15 : [4- (2-Arnino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -
(4-pyridin-2-yl-piperazin-1-yl)-methanone;
16 : (4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrol-2-yl}-morpholin-4-yl-methanone;
17: 4-[2-Amino-5- (3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)-
amide;
1_8 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-
yl]-morpholin-4-yl-methanone;
19: 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
20: 4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)-
amide;
21: {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-yl]-
methanone;
22 : (4- [2-Amino-5- (3 -chloro-phenyl) -pyrimidin-4-yl] -1H--
pyrrol-2-yl}-(4-phenyl-piperazin-1-yl)-methanone;
23: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-
pyridin-1-yl] -methanone;
24: {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-(3 , 4-dihydro-lH-isoquinolin-2-yl)-
methanone;
25: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)-
methanone,-
26: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-morpholin-4-yl-methanone;
27: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-(4-hydroxy-piperidin-l-yl)-methanone;
28 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[1,4']bipiperidinyl-1'-y1-methanone;
29 : 4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid benzyl-methyl-amide;
30 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
[4- (4-methoxy-phenyl)-piperazin-1-yl]-methanone;
31: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] -
(2-hydroxymethyl-piperidin-1-yl)-methanone;
32 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
(3,4-dihydro-lH-isoquinolin-2-yl)-methanone;
33 : 4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid benzyl-methyl-amide;
34 : (4- [2-Amino-5-(3 t4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-
pyridin-1-yl] -methanone;
35: {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl] -
lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinolin-2-yl)-
methanone;
36 : 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid benzyl-methyl-amide ,-
37: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl] - (4-phenyl-piperazin-l-yl)-methanone;
38 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-IH-pyrrol-2-
yl]- (4-methyl-[1,4]diazepan-1-yl)-methanone;
39 : [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]- (3,4-dihydro-lH-isoquinolin-2-yl)-methanone;
40: 4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl] -1H-
pyrrole-2-carboxylic acid benzyl-methyl-amide;
41: (4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-
methanone;
42 ¦• 4- [2-Amino-5- (3-chloro-2-f luoro-phenyl) -pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid benzyl-methyl-
amide;
43: {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-
methanone;
44: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4 -
yl]-lH-pyrrol-2-yl}-(4-phenyl-piperazin-l-yl)-
methanone;
45: [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]- [4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;
4 6: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]-(3-hydroxy-piperidin-1-yl)-methanone;
47: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl)-lH-pyrrol-2-
yl]- [4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;
4 8 .- [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-
yl]- [4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-l-
yl]-methanone;
49: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-
1-yl] -methanone;
50: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-[4-(4-methoxy-phenyl)-piperazin-
1-yl] -methanone;
51: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-
methanone;
52 : l-(4-(4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-
pyrimidin-4-yl]-lH-pyrrole-2-carbonyl}-piperazin-1-
yl)-ethanone;
53 .- {4- [2-Amino-5- (3-chloro-2-f luoro-phenyl) -pyrimidin-4-
yl]-lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinolin-2-
yl)-methanone;
54 : {4~ [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl)-(3-hydroxy-piperidin-l-yl)-methanone;
55 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] -
(4-methyl-[1,4]diazepan-1-yl)-methanone;
56 : l-(4-{4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-
4-yl]-lH-pyrrole-2-carbonyl}-piperazin-1-yl)-
ethanone;
57 : {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl] -
lH-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-
methanone;
58: [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
(3-hydroxy-piperidin-l-yl)-methanone;
59: 4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H--
pyrrole-2-carboxylic acid methyl-(2-pyridin-2-yl-
ethyl)-amide;
60 : [4- (2-Am'ino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-
yl]-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone;
61: {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin-
1-yl] -methanone;
62: 4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
methyl-2-phenyl-ethyl)-methyl-amide;
63: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)-
methanone;
64: [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl]-
(4-hydroxy-piperidin-1-yl)-methanone;
65: {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
1H-pyrrol-2-yl}-(4-hydroxy-piperidin-1-yl)-
methanone;
66: {4- [2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-
yl]-lH-pyrrol-2-yl}-(4-hydroxy-piperidin-l-yl)-
methanone;
67 : (4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-l-yl)-
methanone;
68 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-
methanone;
69: 1-{4-[4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-
pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone;
70 : {4- [2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-
lH-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-
yl]-methanone;
71 : [4- (2-Amino-5-phenyl-pyrimidin-4-yl)-lH-pyrrol-2-yl] -
pyrrolidin-1-yl-methanone;
72 : {4- [2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-
pyrrol-2-yl}-morpholin-4-yl-methanone;
73 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid benzylamide;
74: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 3,4-difluoro-benzylamide;
75 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
76 : 4 - (2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2 -
carboxylic acid 4-fluoro-benzylamide;
77 : 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 3-chloro-benzylamide;
78 : 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 4-methoxy-benzylamide;
79: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 3-chloro-4-f luoro-benzylamide ,-
80: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide
81: 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide
82: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide;
83: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid . (3-hydroxy-l-phenyl-propyl)-amide;
84: 4- (2,5-Diamino-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid 3-chloro-4-fluoro-benzylamide;
85: 4- (2-Amino-5-methylamino-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
86: 4- (5-Acetylamino-2-amino-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
87 : 4- [2-Amino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1H-
pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
88 : 4- (2-Amino-5-hydroxy-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid 3-chloro-4-fluoro-benzylamide;
89 : 4- (2-Amino-5-methylaminomethyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
90 : 4- (2-Amino-5-hydroxymethyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
91: 4- [2-Cyclohexylamino-5-(3-methyl-ureido)-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
92: 4- [2-Acetylamino-5-(3-methyl-ureido)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide ;
93 : 4- (5-Hydroxy-2-methanesulfonylamino-pyrimidin-4-yl) -
lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide;
94 : 4- (2-Amino-5-methanesulfonyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3-chloro-4-fluoro-
benzylamide;
95 : 4- (2-Amino-5-hydroxymethyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3 , 4-dif luoro-benzylamide ;
96 : 4- (2-Cyclohexylamino-5-methyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide;
97 . 4- [2-Amino-5- (3 , 5-dichloro-phenyl) -pyrimidin-4-yl] -
lH-pyrrole-2-carboxylic acid (pyridin-4-ylmethyl)-
amide;
18: 4- [5- (3 , 5-Dichloro-phenyl) -2 -phenylamino-pyrimidin-4 -
yl]-lH-pyrrole-2-carboxylic acid 3-trifluoromethyl-
benzylamide;
99 : 4- [2-Amino-5-(3, 5-dichloro-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid .(2-hydroxy-l-phenyl-
ethyl)-amide;
100: 4- [2-Amino-5-(3 , 5-dichloro-phenyl)-pyrimidin-4-yl] -
lH-pyrrole-2-carboxylic acid (benzo [1,3]dioxol-5-
ylmethyl)-amide;
101: 4- [2-Amino-5-(3 , 5-dichloro-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid (2-dimethylamino-2-
pyridin-3-yl-ethyl)-amide;
102 : 4- [2-Amino-5-(3, 5-dichloro-phenyl)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid 4-methanesulfonyl-
benzylamide;
103 : 4- [5- (3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid
(benzo [1,3] dioxol-5-ylmethyl) -amide;
104 : 4- [5- (3 , 5-Dichloro-phenyl)-2-phenylamino-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-morpholin-4-
yl-2-pyridin-3-yl-ethyl) -amide;
105 : 4- [2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl) -amide;
106 : 4- (2-Amino-5-propyl-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
107 : 4- (2-Amino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
108 : 4- (5-Methyl-2-methylamino-pyrimidin-4 -yl) -1H-
pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl)-
amide;
109 : 4- (2-Methylamino-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (2-pyridin-3-yl-ethyl)-amide;
110 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (2-dimethylamino-ethyl) -amide,-
111: 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid propylamide;
112 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (3-phenyl-propyl)-amide;
113 .- 4- (2-Ethylamino-5-methyl -pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (naphthalen-1-ylmethyl)-amide,-
114 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid cyclopropylamide;
115 : 4- (2-Ethylamino-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid 2-trifluoromethyl-benzylamide;
116 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
117: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
118 : 4- (2-Ethylamino-pyrimidin-4-yl) -lH-pyrrole-2-
carboxylic acid (4-methyl-cyclohexyl)-amide;
119 : 4-(5-Ethyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid isopropylamide;
120 : 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-amino-ethyl)-amide;
121: 4- (2-Amino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic
acid benzyl-methyl-amide;
122 : 4- (2-Amino-pyrimidiri-4-yl)-lH-pyrrole-2-carboxylic
acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl-
amide;
123 : 1-{4- [4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone;
124 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (3-phenyl-propyl)-amide;
125 : 4- (2-Amino-5-ethyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid [2-(6-methoxy-lH-indol-3-yl)-ethyl]-
amide;
126 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-phenoxy-ethyl)-amide;
127 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (1-methyl-3-phenyl-
propyl)-amide;
128 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (lH-benzoimidazol-2-
ylmethyl)-amide;
129 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (1-hydroxymethyl-3-methyl-
butyl)-amide;
130 .- 4- (5-Methyl-2-phenylamino-pyrimidin-4 -yl) -1H-
pyrrole-2-carboxylic acid [l-hydroxymethyl-2-(1H-
imidazol-4-yl)-ethyl]-amide;
131: 4- (2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-
carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide;
132 : 4- [2-(2-Diethylamino-ethylamino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid 3,4-difluoro-
benzylamide;
133 : 4- [5-Methyl-2-(2-piperidin-l-yl-quinazolin-4-
ylamino)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid benzylamide;
134 : 4- (5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-chloro-4-fluoro-
phenyl)-2-hydroxy-ethyl]-amide;
135 : 4- (5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-chloro-4-fluoro-
phenyl)-2-hydroxy-ethyl]-amide;
136 : 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
137: 4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
138: 4-[2-(3-Hydroxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
139: 4-[2-(Benzo[1,3]dioxol-5-ylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
140: 4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
141: 4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
142: 4- [2- (4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
143: 4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
144: 4- (5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
145: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-fluoro-4-methyl-
phenyl)-2-hydroxy-ethyl]-amide;
146: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [2-hydroxy-l-(3-
trifluoromethyl-phenyl)-ethyl]-amide;
147: 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid [1-(3-fluoro-4-
methyl-phenyl)-2-hydroxy-ethyl]-amide;
148: 4- [2- (3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-
trifluoromethyl-phenyl)-ethyl]-amide;
149: 4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
150: 4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
151: 4- [2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
152 : 4- [2- (4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
153: 4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
154: 4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
155: 4- [2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
156: 4- [2- (2-Methoxy-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl) - amide ,-
157: 4- [5-Methyl-2-(4-trifluoromethoxy-phenylamino)-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
15 8 .- 4- (2-Isobutylamino-5-methyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
159: 4- [2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
160 .- 4- (5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
161: 4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
162 : 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
163: 4- (5-Methyl-2-propylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
164: 4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
165: 4- (5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl) -amide ,•
166 : 4- {2- (2-Hydroxy-l-phenyl-ethylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
167: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-
ethyl)-amide;
168 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-
ethyl)-amide;
169: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-2-phenyl-ethyl)-amide;
170: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2-
phenyl-ethyl)-amide;
171: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-IH-pyrrole-
2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2-
phenyl-ethyl)-amide;
172 : 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide;
173 .- 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (3-hydroxy-l-phenyl-propyl)-amide;
174: 4- [2-(1-Hydroxymethyl-cyclopropylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
175 : 4- [2- (2-Hydroxy-ethylamino) -5-methyl-pyrimidin-4 -
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
176 : 4- [2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
177 : 4- [2- (2-Hydroxy-propylamino) -5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
178 : 4- [2- (2-Hydroxy-propylamino) -5-tnethyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
179 : 4- [2- (2-Hydroxy-cyclohexylamino) -5-methyl-pyrimid.in-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-1-
phenyl-ethyl)-amide;
121: 4- [2- (2-Hydroxy-l-methyl-ethylamino)-5-methyl-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
121: 4- [2- (3 -Dimethylamino-phenylamino) -5-methyl-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
180: 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic
acid (2-hydroxy-l-methyl-2-phenyl-ethyl) -methyl-
amide;
181 : 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -methyl-2-phenyl-ethyl) -methyl-
amide;
183 : 4- (2-Amino-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic
acid (2-hydroxy-2-phenyl-ethyl) -methyl-amide;
184 : { [4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -1H-
pyrrole-2-carbonyl] -amino} -phenyl-acetic acid methyl
ester;
186: 4- (2-Amino-pyrimidin-4-yl)-lH-pyrrole-2-carboxyIic
acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl-
amide;
187: 4- (2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-
ethyl)-amide;
188: 4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-pyridin-3-yl-ethyl)-
amide;
189 : 4- (2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
190 : 4- (2-Ethylamino-5-methyl-pyritnidin-4-yl) -lH-pyrrole-
2-carboxylic acid [1-(3-fluoro-5-trifluoromethyl-
phenyl)-2-hydroxy-ethyl]-amide;
191: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid [1-(3-fluoro-phenyl)-2-hydroxy-
ethyl] -amide;
192 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid [1-(2-fluoro-phenyl)-2-hydroxy-
ethyl] -amide;
193 : 4- [2-(2-Cyclopropyl-l-hydroxymethyl-ethylamino)-5-
methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid
(2-hydroxy-1-phenyl-ethyl)-amide;
194 : 4 - [2- (2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-
4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl -ethyl) -amide;
195 : 4- (2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-
ethyl)-amide;
196: 4- [2-(1-Hydroxymethyl-2-methyl-propylamino)-5-
methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid
(2-hydroxy-l-phenyl-ethyl)-amide;
197: 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-
2-carboxylic acid (2-oxo-1-phenyl-propyl)-amide;
198 : 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl)-IH-pyrrole-
2-carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-
phenyl)-ethyl]-amide;
199: 4- [2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-
trifluoromethyl-phenyl)-ethyl]-amide;
200: 4- [2- (2-Chloro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid [2-hydroxy-l-(3-
trifluoromethyl-phenyl)-ethyl]-amide;
2 01.- 4- [2- (2-Hydroxy-l-phenyl-ethylamino) -5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2-
hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;
200: 4- [2-(3-Dimethylamino-phenylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [2-
hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;
202: 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [2-hydroxy-l-(3 -
trifluoromethyl-phenyl)-ethyl]-amide;
203: 4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [2-hydroxy-l-(2-methoxy-
phenyl) -ethyl] -amide;
2 04: 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1K-
pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2-
hydroxy-ethyl]-amide;
2 05 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-
ethyl)-amide;
206: 4- (2-Methoxyamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
207: 4- (2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
208: 4- [2- (3-Dimethylamino-phenylamino)-5-methyl-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
209: 4- [2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m-
tolyl-ethyl)-amide;
210: 4- [2- (2-Hydroxy-l-phenyl-ethylamino)-5-methyl-
pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
211: 4- [2- (2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m-
tolyl-ethyl)-amide;
212: 4- [2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m-
tolyl-ethyl)-amide;
213: 4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
214: 4- (5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
215: 4- [5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl] -
lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-
ethyl)-amide;
216: 4-(5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-
pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl) -amide;
217: 4-{5-Methyl-2- [ (tetrahydro-furan-2-ylmethyl)-amino]-
pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-pheny1-e thy1)-ami de;
218: N' -{4-[5-(2-Hydroxy-1-phenyl-ethylcarbamoyl) -1H-
pyrrol-3-yl]-5-methyl-pyrimidin-2-yl}-
hydrazinecarboxylic acid ethyl ester;
219: 4-(5-Methyl-2- [(pyridin-3-ylmethyl)-amino]-
pyrimidin-4-yl}-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
220: 4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4-
yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
221: 4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-
ethyl)-amide;
222: 4-[2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
22 3 .- 4- (5-Methyl-2-o-tolylamino-pyrimidin-4-yl) -1H-
pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-
ethyl)-amide;
224: 4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-chloro-phenyl)-2-
hydroxy-ethyl]-amide;
225: 4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4-
yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
226: 4-[2-(N',N'-Dimethyl-hydrazino)-5-methyl-pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl)-amide;
227: 4-[5-Methyl-2-(2-trifluoromethyl-phenylamino) -
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
228: 4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]-
lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-
ethyl)-amide;
229: 4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
230: 4-{2-[1-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-
ethylamino]- 5-methyl-pyrimidin-4-yl}-lH-pyrrole-2 -
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
231: 4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-
pyrrole-2-carboxylic acid [1-(3-fluoro-phenyl)-2-
hydroxy-ethyl]-amide;
232: 4 - [2 -(1-Hydroxymethyl-propylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid [l-(3-
chloro-phenyl)-2-hydroxy-ethyl]-amide;
233: 4- [2-(2-Hydroxy-l-hydroxymethyl-ethylamino)-5-
methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid
[1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;
234: 4- [2-(1-Hydroxymethyl-propylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
235: 4- [2-(2-Hydroxy-1-hydroxymethyl-ethylamino)-5-
methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid
(2-hydroxy-l-phenyl-ethyl)-amide;
236: 4-[2-(1-Hydroxymethyl-propylamino)-5-methyl-
pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
237 : 4- [5-Methyl-2- (2-methyl-cyclopropylamino) -pyrimidin-
4-yl]-lH-pyrrole-2-carboxylic acid (2-hydroxy-l-
phenyl-ethyl) -amide; and
238 : 4- (2-Cyanoamino-5-methyl-pyrimidin-4-yl) -lH-pyrrole-
2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide.
or a pharmaceutically acceptable salt thereof, wherein:
Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring
A and Q'R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to
two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not
simultaneously substituted by R6;
Z1 is N and Z2 is CH;
T is a linker group selected from -NH-, -CH2- , -CO-, or a saturated or unsaturated
C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated
carbons of the chain are optionally replaced by -CO-, -C(O)C(O)-, -C(O)NR7-,
-C(O)NR7NR7-, -CO2,-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-,
-NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-;
Q' is selected from -CO2-, -C(O)NR7- or -SO2NR7-;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-,
-CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
R2' is selected from -(CH2)yCH(R5)2 or -(CH2)yCH(R8)CH(R5)2;
y is 0-6;
R3 is selected from R7, R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2,or -(CH2)y
CH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from
C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl
ring having 3-10 ring atoms;
WE CLAIM:
1. A compound of formula I':
each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -
(CH2)yR5, or-(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7,
SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N
(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7,
NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6;
aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen
to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and
each w is independently selected from 0-4.
2. The compound as claimed in claim 1, wherein Sp is selected from one of the
following:
or a pharmaceutically acceptable salt thereof.
3. The compound as claimed in claim 2, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-
membered aryl or heteroaryl ring.
4. The compound as claimed in claim 3, wherein:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1' is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-
membered aryl or heteroaryl ring.
5. The compound as claimed in claim 3, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl..
isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH)
isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl,
or isoxazolyl group;
(b) TmR1 is selected from an optionally substituted phenyl, methyl, ethyl, propyl.
cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)
NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl
ring, and Q' is -C(O)NH-.
6. The compound as claimed in claim 5, wherein:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH)
isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl,
or isoxazolyl group;
(b) TmR1 is selected from an optionally substituted phenyl, methyl, ethyl, propyl,
cyclopropyl, cyclohexyh CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)
NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl
ring, and Q' is -C(O)NH-.
7. The compound as claimed in claim 2, wherein said compound is of formula I":
or a pharmaceutically acceptable salt thereof.
8. The compound as claimed in claim 7, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1 is hydrogen, N(R4)2:, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
9. The compound as claimed in claim 8, wherein:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is a an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
10. The compound as claimed in claim 2, wherein said compound is of formula I°:
or a pharmaceutically acceptable salt thereof.
11. The compound as claimed in claim 10, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-
membered aryl or heteroaryl ring.
12. The compound as claimed in claim 11, wherein:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group selected
from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-
membered aryl or heteroaryl ring.
13. A compound of formula III-a':
or a pharmaceutically acceptable salt thereof, wherein:
T is a linker group selected from -NH-, -CH2-, -CO-, or a saturated or unsaturated C1.6
alkylidene chain, which is optionally substituted, and wherein up to two saturated.
carbons of the chain are optionally replaced by -C(O)-, -C(O)C(O)-, -CONR7-,
-CONR7NR7-, -CO2-, -OC(O)-, -NR7CO2-, -O-, -NR7CONR\ -OC(O)NR7-:
-NR7NR7-, -NR7CO-, -S-, -SO-, -S(O)2-, -NR7-, -SO2NR7-, or -NR7SO2-;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-,
-CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
R3 is selected from R\ R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2, or -(CH2)
yCH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from
C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl
ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -
(CH2)yR5, or -(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7,
SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N
(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7,
NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted Ci.6
aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen
to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2)wN(R4)2, or (CH2)«SR7; and
each w is independently selected from 0-4.
14. The compound as claimed in claim 13, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or an optionally substituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroary]
ring; and
(c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
15. The compound as claimed in claim 14, wherein:
fa) R3 is hydrogen, carbocyclyl. -CH(R8)R. or an optionally substituted group selected
from Ci-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl
ring;
(b) TmR' is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from Ci-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
16. The compound as claimed in claim 14, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
isopropyl, -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH)
isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or
benzyl group;
(b) TmR' is selected from an optionally substituted phenyl, methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)
NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring.
17. The compound as claimed in claim 16, wherein:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
isopropyl. -CH(CH2OH)phenyl, -CH(CH2OH)ethyl, -CH(CH2OH)2, -CH(CH2OH)
isopropyl, -CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or
benzyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)
NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or a substituted or unsubstituted phenyl or pyridyl ring.
18. A compound of formula III-a°:
or a pharmaceutically acceptable salt thereof, wherein:
T is a linker group selected from -NH-,-CH2-, -CO-, or a saturated or unsaturated C1-6
alkylidene chain, which is optionally substituted, and wherein up to two saturated
carbons of the chain are optionally replaced by -CO-, -C(O)(CO)-, -CONR7-,
-CONR7NR7-, -CO2-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-,
-NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-,
-CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
y is 0-6;
R3 is selected from R\ R, -(CH2)yCH(R8)R, CN, -(CH2))CH(R8)CH(R5)2, or -(CH2)
yCH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from
C1-.6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl
ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -
(CH2)yR\ or -(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7,
SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N
(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7,
NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6;
aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen
to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and
each w is independently selected from 0-4.
19. The compound as claimed in claim 18, wherein said compound has one or more
features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or a substituted or unsubstituted group
selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or
heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or a substituted or
unsubstituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, and R8 is R7 or OR7.
20. The compound as claimed in claim 19, wherein:
a) R3 is hydrogen, carbocyclyl, -CH(R8)R, or a substituted or unsubstituted group
selected from C1-4 aliphatic,3-6 membered heterocyclic,or a 5-6 membered aryl or
heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or a substituted or
unsubstituted group selected from C1-.6 aliphatic or a 5-6 membered aryl or heteroaryl
ring; and
(c) R5 is R or OR7, and R8 is R7 or OR7.
21. The compound as claimed in claim 1, selected from the group consisting of:
4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-methyl-amide;
4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-hydroxy-l -
phenyl-ethyl)-amide;
4-(2-Amino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (3-hydroxy-l -
phenyl-propyl)-amide;
4-(2-Amino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (3-hydroxy-l»
phenyl-propyl)-amide;
4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid
(2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid
(2-dimethylamino-2-pyridin-3-yl-ethyl)-amide;
4-[5-(3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-amide;
4-[2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-
carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrroIe-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-
1 -phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-methyl -amide;
4-(5-Methyl-2-methylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (1 -
hydroxymethy 1-3 -methyl -butyl)-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -
hydroxymethyl-2-(lH-imidazol-4-yl)-ethyl]-amide;
4-(5-Methyl-2-methylamino-pyrirnidin-4-yl)-l H-pyrrole-2-carboxylic acid [l-(3-
chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid [l-(3-
chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid
(2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4- [2-(3 -Hydroxy-phenylamino)-5 -methyl-pyrimidin-4-yl] -1H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(Benzo[l,3]dioxol-5-ylamino)-5-methyl-pyrimidin-4-yl]-lH-p>Trole-2-
carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide;
4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -(3-
fluoro-4-methyl-phenyl)-2-hydroxy-ethyl]-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2-
hydroxy-1 -(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid
[ 1 -(3 -fluoro-4-methy l-phenyl)-2-hydroxy-ethyl] -amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid
[2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide;
4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[5-Methyl-2-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-(2-Isobutylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid
(2-hydroxy- l-phenyl-ethyl)-amide;
4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Methyl-2-propylamino-pyTimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenyl-
ethyl)-methyl-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-
1-methyl-2-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-
1 -methyl-2-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-
2-phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-
phenyl-ethyl)-methyl-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-hydroxy-
l-hydroxymethyl-2-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-
l-hydroxymethyl-2-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (3-hydroxy-
1 -phenyl-propyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (3-hydroxy-
1 -phenyl-propyl)-amide;
4-[2-( 1 -Hydroxymethyl-cyclopropylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid
(2-hydroxy-1-phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-1 -methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid
(2-hydroxy-1 -phenyl-ethyl)-amide;
{[4-(2-Ethylamino-5-methyl-p>Timidin-4-yl)-lH-pyrrole-2-carbonyl]-amino}-phenyl-
acetic acid methyl ester;
4-[2-(2-Hydroxy-1 -methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-methyl-amide;
4-(2-Amino-pyrimidin-4-yl)-1 H-p>Trole-2-carboxylic acid (2-hydroxy-1 -methyl-2-
phenyl-ethyl)-methyl-amide;
4-(2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-
1 -pyridin-3-yl-ethyl)-amide;
4-(2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [1 -(3-
fluoro-5-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [1-(3-
fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid [1 -(2-
fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(2-Cyclopropyl-l-hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-
pyrrole-2-carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxyIic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(l -Hydroxymethyl-2-methyl-propylamino)-5-methyl-pyrimidin-4-yl]-1H-
pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-oxo-1-
phenyl-propyl)-amide;
4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2-hydroxy-
l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pryimidin-4-yl]-1H-pyrrole-2-carboxylic acid
[2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid
[2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(2-Hydroxy-1 -phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-
carboxylic acid [2-hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid [2-
hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [2-
hydroxy-1-(2-methoxy-phenyl)-ethyl] -amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid [1-
(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;
4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1-m-tolyl-ethyl)-amide;
4-(2-Methoxyamino-5-methyl-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-l-phenyl-ethyl)-amide;
4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide;
4-f2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yll-l H-pyrrole-2-carboxylic acid
(2-hydroxy-l-m-tolyl-ethyl)-amide;
4-[2-(2-Hydroxy-l-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide;
4-[2-(2,3-Dirnethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic
acid (2-hydroxy-l-m-tolyl-ethyl)-amide;
4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid
(2-hydroxy-1 -m-tolyl-ethyl)-amide;
4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1-phenyl-ethyl)-amide;
4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl]-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyrrole-2-
carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide;
4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyrrole-2-
carboxylic acid (2-hydroxy- l-phenyl-ethyl)-amide;
N'-{4-[5-(2-Hydroxy-l-phenyl-ethylcarbamoyl)-lH-pyrrol-3-yl]-5-methyl-pyrimidin-
2-yl}-hydrazinecarboxylic acid ethyl ester;
4-{5-Methyl-2-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-lH-pyiTole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic
acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-(2-Cyanoamino-5-methyl-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -phenyl-ethyl)-amide;
4-[2-(2-Hydroxy-l-methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-m-tolyl-ethyl)-amide;
4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-l H-pyrrole-2-carboxylic acid (2-
hydroxy-1 -m-tolyl-ethyl)-amide;
4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1 H-pyrrole-2-carboxylic acid [ 1 -(3 -
chloro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic
acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[2-(N',N'-Dimethyl-hydrazino)-5-methyl-pyrimidin-4-ylJ-l H-pyrrole-2-carboxylic
acid (2-hydroxy-1-pheny l-ethyl)-amide;
4-[5-Methyl-2-(2-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]-l H-pyrrole-2-carboxylic acid
(2-hydroxy-1 -phenyl-ethyl)-amide;
4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide;
4-{2-[l-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-methyl-pyrimidin-4-
yl} -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1 -phenyl-ethyl)-amide;
4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-lH-pyrrole-2-carboxylic acid [l-(3-
fluoro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-( 1 -Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid [l-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(2-Hydroxy-1 -hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-
pyrrole-2-carboxylic acid [l-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;
4-[2-(l -Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1 H-pyrrole-2-
carboxylic acid (2-hydroxy-1-m-tolyl-ethyl)-amide;
4-[2-(2-Hydroxy-1 -hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-l H-
pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
4-[2-(l-Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide; and
4-[5-Methyl-2-(2-methyl-cyclopropylamino)-pyrimidin-4-yl]-lH-pyrrole-2-
carboxylic acid (2-hydroxy-l-phenyl-ethyl)-amide.
22. A composition comprising a compound as claimed in any one of claims 1-21 and
a pharmaceutically acceptable carrier.
23. The composition as claimed in claim 22, comprising an additional therapeutic
agent selected from a chemotherapeutic agent or anti-proliferative agent, or an agents
for treating diabetes, an anti-inflammatory agent, an immunomodulatory or
immunosuppressive agent, an agent for treating neurlogical disorders, an agent for
treating cardiovascular disease, an agent for treating liver disease, cholestyramine, an
interferon, an anti-viral agents, an agents for treating blood disorders, or an agent for
treating immunodeficiency disorders.
24. The composition as claimed in claim 22, wherein said composition is capable of
being used for inhibiting ERK2, GSK-3, Aurora, CDK.2, or Lck activity in a patient.
25. The composition as claimed in claim 24, wherein said composition is used to
inhibit ERK2 activity in a patient.
26. The composition as claimed in claim 25, wherein said ERK2 activity is
associated with a disease selected from cancer, stroke, diabetes, hepatomegaly,
cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease,
autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders,
inflammation, neurological disorders, a hormone-related disease, conditions
associated with organ transplantation, immunodeficiency disorders, destructive bone
disorders, proliferative disorders, infectious diseases, conditions associated with cell
death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML),
liver disease, pathologic immune conditions involving T cell activation, or CNS
disorders.
27. The composition as claimed in claim 26, wherein the disease is cancer.
28. The composition as claimed in claim 27, wherein the disease is a cancer selected
from breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx,
glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid
carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone;
colon, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma,
undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma;
bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid
disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx
(oral), lip, tongue, mouth, pharynx; small intestine: colon-rectum, large intestine,
rectum; brain and central nervous system; or leukemia.
29. The composition as claimed in claim 25, wherein the disease is cardiovascular
disease.
30. The composition as claimed in claim 29, wherein the disease is a cardiovascular
disease selected from restenosis, cardiomegaly, artherosclerosis, myocardial
infarction, or congestive heart failure.
31. The composition as claimed in claim 24, wherein said composition is useful for
treating a GSK-3 -mediated disease in a patient in need thereof.
32. The composition as claimed in claim 31, wherein said disease is diabetes.
33. The composition as claimed in claim 31, wherein said disease is Alzheimer's
disease.
34. The composition as claimed in claim 31, wherein said disease is schizophrenia.
35. The composition as claimed in claim 22, wherein said composition is useful for
enhancing glycogen synthesis in a patient in need thereof.
36. The composition as claimed in claim 22, wherein said composition is useful for
lowering blood levels of glucose in a patient in need thereof.
37. The composition as claimed in claim 22, wherein said composition is useful for
inhibiting the production of hyperphosphorylated Tau protein in a patient in need
thereof.
38. The composition as claimed in claim 22, wherein said composition is useful for
inhibiting the phosphorylation of |3-catenin in a patient in need thereof.
39. The composition as claimed in claim 24, wherein said composition is useful for
treating an Aurora-2-mediated disease in a patient in need thereof.
40. The composition as claimed in claim 39, wherein said disease is selected from
colon, breast, stomach, or ovarian cancer.
41. The composition as claimed in claim 24, wherein said composition is useful for
treating CDK-2-mediated disease in a patient in need thereof.
42. The composition aas claimed in claim 41, wherein said disease is selected from
cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,
cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, or an autoimmune
disease.
43. The composition as claimed in claim 24, wherein said composition is useful for
treating a Lck-mediated disease in a patient in need thereof.
44. The composition as claimed in claim 43, wherein said disease is selected from an
autoimmune disease or transplant rejection.
45. A method for screening ERK2, Aurora-2, GSK-3, CDK-2, AKT3, or Lck activity
in a biological sample in vitro, wherein said biological sample is selected from the
group consisting of a cell culture, an enzyme preparation, a mammalian biopsy,
blood, saliva, urine, feces, semen, tears, and any extract thereof, said method
comprising the step of contacting said biological sample with a compound as claimed
in any one of claims 1-21.
46. A composition for coating an implantable device comprising a compound as
claimed in claim 1 and a carrier suitable for coating said implantable device.
47. An implantable device coated with a composition as claimed in claim 46.

1. A compound of formula I':

or a pharmaceutically acceptable salt thereof, wherein:
Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring
A and Q'R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to
two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not
simultaneously substituted by R6;
Z1 is N and Z2 is CH;
T is a linker group selected from -NH-, -CH2- , -CO-, or a saturated or unsaturated
C1-6 alkylidene chain, which is optionally substituted, and wherein up to two saturated
carbons of the chain are optionally replaced by -CO-, -C(O)C(O)-, -C(O)NR7-,
-C(O)NR7NR7-, -CO2,-, -OC(O)-, -NR7CO2-, -O-, -NR7C(O)NR7-, -OC(O)NR7-,
-NR7NR7-, -NR7CO-, -S-, -SO-, -SO2-, -NR7-, -SO2NR7-, or -NR7SO2-;
Q' is selected from -CO2-, -C(O)NR7- or -SO2NR7-;
U is selected from -NR7-, -NR7CO-, -NR7CONR7-, -NR7CO2-, -O-, -CONR7-, -CO-,
-CO2-, -OC(O)-, -NR7SO2-, -SO2NR7-, -NR7SO2NR7-, or -SO2-;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
R2' is selected from -(CH2)yCH(R5)2 or -(CH2)yCH(R8)CH(R5)2;
y is 0-6;
R3 is selected from R7, R, -(CH2)yCH(R8)R, CN, -(CH2)yCH(R8)CH(R5)2,or -(CH2)y
CH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from
C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl
ring having 3-10 ring atoms;

each R4 is independently selected from R, R7, -COR7, -CO2R, -CON(R7)2, -SO2R7, -
(CH2)yR5, or-(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7,
SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N
(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7,
NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6;
aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen
to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)WOR7, (CH2)WN(R4)2, or (CH2)WSR7; and
each w is independently selected from 0-4.

Documents:

964-kolnp-2003-granted-abstract.pdf

964-kolnp-2003-granted-assignment.pdf

964-kolnp-2003-granted-claims.pdf

964-kolnp-2003-granted-correspondence.pdf

964-kolnp-2003-granted-description (complete).pdf

964-kolnp-2003-granted-form 1.pdf

964-kolnp-2003-granted-form 13.pdf

964-kolnp-2003-granted-form 18.pdf

964-kolnp-2003-granted-form 3.pdf

964-kolnp-2003-granted-form 5.pdf

964-kolnp-2003-granted-gpa.pdf

964-kolnp-2003-granted-reply to examination report.pdf

964-kolnp-2003-granted-specification.pdf

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Patent Number

233884

Indian Patent Application Number

964/KOLNP/2003

PG Journal Number

16/2009

Publication Date

17-Apr-2009

Grant Date

16-Apr-2009

Date of Filing

29-Jul-2003

Name of Patentee

VERTEX PHARMACEUTICALS INCORPORATED

Applicant Address

130 WAVERLY STREET, CAMBRIDGE, MA

Inventors:

#	Inventor's Name	Inventor's Address
1	GREEN JEREMY	21 GREYSTONVE COURT, BURLINGTON, MA 01803
2	STRAUB JUDY	70 KINNAIRD STREET, CAMBRIDGE, MA 02135
3	CAO JINGRONG	15 MADISON AVENUE, NEWTON, MA 02460
4	HALE MICHAEL	42 SUNSET ROAD, BEDFORD MA 01730
5	MALTAIS FRANCOIS	24 RANDOLPH DRIVE TEWKSBURY MA 10876
6	TANG QING	2377 MASSACHUSETTS AVENUE, CAMBRIDGE, MA 02140
7	ARONOV ALEX	13 CIRCUIT LANE, WATERTOWN, MA 02472

PCT International Classification Number

C07D 403/04, 401/14

PCT International Application Number

PCT/US2002/03791

PCT International Filing date

2002-02-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/267,818	2001-02-09	U.S.A.
2	60/328,768	2001-10-12	U.S.A.