| Title of Invention | " A BENZOTRIAZINE COMPOUNDS" |
|---|---|
| Abstract | The invention provides benzotriazine compounds having formula (I). The benzotriazine compounds of the invention are capable of inhibiting kinases, such members of the Src kinase family, and various other specific receptor and non-receptor kinases. |
| Full Text | CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of patent applications U.S. Serial Number 60/561,237 filed April 8,2004, and 60/643,439 filed January 12, 2005, the entire content of which is incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention relates generally to the use of compounds to treat a variety of disorders, diseases and pathologic conditions and more specifically to the use of benzotriazine compounds to treat disorders, BACKGROUND [0003] c-Src plays a major role in the growth, progression and metastasis of a large number of cancers. c-Src can be the transforming element of the oncogenie Rous sarcoma retrovirus. Subsequently, it has been demonstrated that c-Src kinase can have the onco genie potential. Gene knockout experiments suggest that inhibition of some members of the Src family might have potential therapeutic benefit. [0004] Tyrosine kinases (TKs) phosphorylate tyrosine residues in peptides and proteins. These enzym.es are key elements in the regulation of cell signaling including cell proliferation and cell differentiation. Protein TKs comprise the receptor TKs, including the epidermal growth family members (HER1 and HER2 for example), platelet derived growth factor (PDGF) and kinases that play a role in angiogenesis (Tie-2 and KDR for example), and the cellular or non-receptor kinases, which include members of the Src family. [0005] c-Src TK is one of three members of the Src family expressed ubiquitously. c-Src is expressed at low levels in most cell types and, in the absence of the appropriate extracellular stimuli, maintained in an inactive conformation through phosphorylation of a regulatory tyrosine domain at Tyr530. Activation of c-Src occurs through dephosphorylation of the TyrS-SO site and phosphorylation of a second tyrosine, Tyr419, present in the kinase domain of the enzyme. [0006] Src kinase modulates signal transduction through multiple oncogenic pathways, including EGFR, HER2, PDGFR, FGFR and VEGFR. Thus, blocking signaling through the inhibition of the kinase activity of Src can be an effective means of modulating aberrant pathways that drive the oncogenic transformation of cells. [0007] There exists a body of evidence of misregulated increased kinase activity of c-Src in several human tumor types, most notably colon and breast tumors. Misregulated c-Src TK activity has also been associated with adhesion and cytoskeletal changes both in tumor cells and otherwise, ultimately resulting in an invasive phenotype mat may be motile. c-Src TK activity has been shown to be an important component in the epithelial to mesenchymal transition that occurs in the early stages of invasion of carcinoma cells. c-Src activity is also known to be essential in the turnover of local adhesions, a critical cell-motility component. In in vivo models of metastases, c-Src inhibition markedly reduces the rate of lymph and liver metastases. Clinical data supports the link between misregulated Src activity and the increased invasive potential of tumor cells, hi colon tumors, increased c-Src TK activity has been shown to correlate to tumor progression, with the highest activity found in metastatic tissue. Increased Src activity in colon tumors might be an indicator of poor prognosis. In breast and ovarian cancers, enhancement of Src kinase activity has been reported, and in transitional cell carcinoma of the bladder, c-Src activity peaked as superficial tumors became muscle invasive. [0008] Biochemically, cellular stimuli that lead to Src activation result in increased association between Src and the cytoskeleton. As a result, Src mediates the phosphorylation of many intracellular substrates such as EGFR, FAK, PYK2, paxillin, StatS, and cyclin D. The biological effects of these interactions affect cell motility, adhesion, cell cycle progression, and apoptosis and might have some connection to the disease related effects stated above. Thus, Src plays a role in responses to regional hypoxia, limited nutrients, and internal cellular effects to self-destruct. [00091 Increased c-Src TK activity results in breakdown of the E-cadherin-mediated epithelial cell-cell adhesion, which can be restored .by Src inhibition. Intimate connections between increased VEGF activity, Src activity, and cellular barrier function related to vascular leak have been also demonstrated. Inhibition of Src results in decrease in vascular leak when exogenous VEGF is administered in in vivo studies. Examples where excessive vascular permeability leads to particularly deleterious effects include pulmonary edema, cerebral edema, and cardiac edema. [001.0] The cascade of events leading to loss of endothelial barrier function is complex and incompletely understood. Data support some role for kinases in this process. For example, VEGF-mediated edema has been shown to involve intracellular signaling by Src family kinases, protein kinase C, and Akt kinase. Rho-associated kinases have been linked to thrombin-mediated vascular leakage, and protein kinase C to TNF-induced leakage. Kinases are believed to mediate the phosphorylation of junctional proteins such as beta-catenin and vascular endothelial VE-cadherin, leading to the dissolution of adherens junctions and the dissociation of cadherin-catenin complexes from their cytoskeletal anchors. Proteins which regulate the intercellular contractile macllinery such as myosin light chain kinase (MLCK) and myosin light chain (MLC) are also activated, resulting in cellular contraction, and therefore an opening of intercellular junctions. [0011] A general approach to the inhibition of vascular leakage can be to interfere with any of the underlying mechanistic pathways, whether by inhibition of kinase signaling or the intercellular contractile apparatus or other cellular processes. This can then lead to potential treatments for edema and its associated pathologies. For example, inhibiting edema formation should be beneficial to overall patient outcome in situations such as inflammation, allergic diseases, cancer, cerebral stroke, myocardial infarction. pulmonary and cardiac insufficiency, renal failure, and retinopathies, to name a few. Furthermore, as edema is a general consequence of tissue hypoxia, it can. also be concluded that inhibition of vascular leakage represents a potential approach to the treatment of tissue hypoxia. For example, interruption of blood flow by pathologic conditions (such as thrombus formation) or medical intervention (such as cardiopiegia, organ transplantation, and angioplasty) could be treated both acutely and prophylactically using inhibitors of vascular leakage, especially as in the case of Src inhibitors. [0012] Accordingly, a small molecule inhibitor of c-Src can be beneficial for the treatment of several disease states. SUMMARY [0013] The present invention provides methods of use for certain chemical compounds such as kinase inhibitors for treatment of various diseases, disorders, and pathologies, for example, cancer, and vascular disorders, such as myocardial infarction (MI), stroke, orischemia. [0014] The benzotriazine compounds described in this invention may block the enzymatic activity of some or many of the members of the Src family, in addition to blocking the activity of other receptor and non-receptor kinases. Such compounds may be beneficial for treatment of the diseases where disorders affect cell motility, adhesion, and cell cycle progression, and in addition, diseases with related hypoxic conditions, osteoporosis and conditions, which result from or are related to increases in vascular permeability, inflammation or respiratory distress, tumor growth, invasion, angiogenesis, metastases and apoptosis. [0015] According to the embodiments of the invention, some examples of kinase inhibitors that can be used to bring about beneficial therapeutic results include inhibitors of Src kinase. [0016] According to one embodiment of the invention, there are provided compounds having the structure (I), and pharrnaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individuas diastereoners thereof: (I) [0017] wherein each of A can be (CH)o_i, N, NH, 0, S, or a part of a ring fusion to form a second ring, where the second ring can be an aromatic, a heteroaromatic, a bicyclic aromatic, a bicyelic aromatic heterocyclic ring, or a bicyclic with only the first ring being aromatic or heteroaromatic; [0018] each of B can be (CH)o-i, N, NH, 0, S, ora part of a ring fusion to form, a second ring, where the second ring can be an aromatic, a heteroaromatic, a bicyclic aromatic, a bicyclic aromatic heterocyclic ring, or a bicyclic with only the first ring being aromatic or heteroaromatic, with the further proviso that if each B is (CH)o, RS can be any substitutent described below other than hydrogen bonded directly to the position 7 of the adjacent ring; [0019] R0 can be H or lower alkyl; [0020] L can be a bond, or a substituted or unsubsti.tuted alkyl, alkenyl, or alkynyl linking moiety; [0021] R! can be C(R')3, OR1, N(R')2, NR'C(O)R', NR'C(0)0(R'), NR'C(0)N(R')2, SR', C(O)(0)R', C(0), C(0)N(R')2, S03R', OS02R', S02R', SOR1, S(0)N(R')2, OS(0)(0)N(R')2, S(0)(0)N(R')2, S(0)N(R')2, P04R', OP02R', POsR1, P02R', or a 3-6 membered lieterocycle with one or more heterocyclic atoms, with each heteroatom being capable of caiTying any R! group on it, wherein R' can be hydrogen, lower alkyl, allcyl-hydroxyl, thiol-alkyl, alkyl-thiol, arninoalkyl, alkylamino, branched alkyl, branched alkyl hydroxyl, branched thio-alkyl, branched alkyl-thiol, branched arninoalkyl, branched alkylamino, or a closed 3-6 membered carbocycle or heterocycle, with each heteroatom in the 3-6 membered heterocycle being capable of carrying any R' group on it, and wherein each R' can be independent in case there is more than one R'; [0022] R2 is a substitutent situated at position 5,6 or 8 of the ring, wherein R? can be methyl, ethyl, /?.-propyl, wo-propyl, n-butyl, zso-butyl, tot-butyl, zso-pentyl, phenyl, substituted phenyl, halogen, branched or unbranched alkylamino, branched or unbranched aminoalkyl, branched, or unbranched alkyloxo, branched or unbranched oxyalkyl, branched or unbranched thioalkyl, branched or unbranched alkylthiol, CFs, sulfonamido, substituted sulfonamido, sulfonate, sulfonate ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carboxo, amido, ureido, substituted carboxo, substituted amido, substituted ureido, or a 3-6 membered carbocycle or lieterocycle attached to positions 5. 6 or 8 directly or through group L, each heteroatom being capable of carrying any group R2, with the further proviso that either one, two or three substituents R2 can be present in the ring, and each of the substiruents R2 can be the same or different; [0023] Ra can be hydrogen, alkyl, alkoxy, halogen, CFs, cyano, substituted alkyl, or hydroxyl, aryl, substituted aryi, heteroaryl, substituted heteroaryl, heterocycle, C(R")3, OR", N(R")2, NR"C(0)R", NR"C(0)NR", R", C(0)(0)R", OC(0)R", C(0)N(R")2, C(O), OC(0)N(R"}2, S03R", OS02R", S02R", SOR", P04R", OP02R", PO3R", PO2R", wherein R" can be hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, lower alkyl, branched lower alkyl, alkyl-hydroxyl, branched alkyl-hydroxyl, amino-alkyl, branched amino-alkyl, alkyl-amino, branched alkyl-amino, thiol-alkyl, branched thiol-alkyl, alkyl-thiol, branched thiol-alkyl, or may form a closed 3-6 membered heterocycle with one or more heterocyclic atoms, branched alkyl, branched alky] hydroxyl, where each R" can be independent in case there is more than one R"; [0024] n is an integer that can have value between 1 and 5, with the further proviso that if n > 2, then each group R3 is independent of the other groups RS, [0025] with the further proviso that if each A is (CH)o, L is a bond. [0026] In yet. another embodiment, there are provided articles of manufacture including packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material includes a label which indicates that the pharmaceutical composition can be used for treatment of disorders associated with compromised vasculostasis, and wherein the pharmaceutical composition includes at least one compound of structure (I). [0027] In another embodiment, there are provided articles of manufacture including packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material includes a label which indicates that the pharmaceutical composition can be used for treatment of disorders associated with vascular permeability leakage or compromised vasculostasis, such as myocardial infarction, stroke, congestive heart failure, an ischemia or reperfusion injury, cancer, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, autoimmune disease, vascular leakage syndrome, inflammatory disease, edema, transplant rejection, bum, or acute or adult respiratory distress syndrome (ARDS) and wherein, the pharmaceutical composition includes at least one compound of structure (I). [0028] hi another embodiment, there are provided methods of treating a disorder associated with compromised vasculostasis, including the administration of a therapeutically effective amount of at least one compound of structure (I) or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereorners thereof, to a. subject in need of such treatment. [0029] hi yet another embodiment, there are provided methods of treating a disorder associated with compromised vasculostasis including the administration of a therapeutically effective amount of at least one compound of structure (I), or pharmaceuticaily acceptable salts, hydrates, solvates, crystal forms and individual diastereomers (hereof, in combination with an anti-inflammatory, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody or a protein kinase inhibitor, to a subject in need of such treatment, [0030] hi others embodiment, there are provided methods of treating a subject having or at risk of having a disorder selected from myocardial infarction, vascular leakage syndrome (VLS), cancer, stroke, ARDS, bums, arthritis, edema, retinopathy or vitreoretinal disease, ischemic or reperfusion related tissue injury or damage, autoimmune disease, transplant rejection, inflammatory disease, including adniinistering to the subject a therapeutically effective amount of at least one compound of structure (I), thereby treating the subject. [0031] In another embodiment, ther-; are provided processes for making a pharmaceutical composition including ^ombining a combination of at least one compound of structure (I) or its pharmaceuticaily acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof and a pharmaceuticaily acceptable carrier. DETAILED DESCRIPTION A. Terms and Definitions. [0032] The following terminology and definitions apply as used in the present application, generally in conformity with the terminology recommended by the International Union of Pure and Applied Chemistry (IUPAC): [0033] The term "heterocyclic," when used to describe an, aromatic ring, refer to the aromatic .ring containing at least one heteroatom. [0034] The term "heteroatom" refers to any atom other than carbon, for example, N, O, orS, [0035] The term "aromatic" refers to a cyclically conjugated molecular entity with a stability, due to delocalization, significantly greater than that of a hypothetical localized structure, such as the Kekule structure. [0036] The term "heterocyclic," when not used to describe an aromatic ring, refers to cyclic (i.e., ring-containing) groups other than aromatic groups, the cyclic group being formed by between 3 and about 14 carbon atoms and at least one heteroatom described above. [0037] The term, "substituted heterocyclic" refers, for both aromatic and non-aromatic structures, to heterocyclic groups further bearing one or more substituents described above. [0038] The term "alky!" refers to a monovalent straight or branched chain hydrocarbon group having from one to about 12 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, /z-butyl, iso-bntyl, tert-butyl, /7.-pentyl (also known as n-amyl), /7-hexyl, and the like. [0039] The term "substituted alkyl" refers to alkyl groups further bearing one or more substituents such as hydroxy, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocychc, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, sulfuryl, and the like. [0040] The term "lower alkyl" refers to alkyl groups having from 1 to about 6 carbon atoms. [0041] The term "alkenyl" refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon double bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkenyl" refers to alkenyl groups further bearing one or more substituents described above. [0042] The term "alkynyl" refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon triple bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkynyl" refers to alkynyl groups further bearing one or more substituents described above. [0043] The term "aryl" refers to aromatic groups having between about 5 and about 14 carbon atoms and the term "substituted aryl" refers to aryl groups further bearing one or more substituents described above, [0044] The term "heteroaryl" refers to aromatic rings, where the ring structure is formed by between 3 and about 14 carbon atoms and by at least one heteroatom described above, and the term "substituted heteroaryl" refers to heteroaryl groups further bearing one or more substituenfs described above. [0045] The term "alkoxy" refers to the moiety —0—alkyl, wherein alkyl is as defined above, and the term "substituted alkoxy" refers to alkoxy groups further bearing one or more substituents described above. [0046] The term "cycloalkyl" refers to alkyl groups having between 3 and about 8 carbon atoms arranged as a ring, and the term "substituted cycloalkyl" refers to cycloalkyl groups further bearing one or more substituents described above. [0047] The term "alkylaryl" refers to alkyl-substituted aryl groups and the term "substituted alkylaryl" refers to alkylaryl groups further bearing one or more substituents described above. [0048] The term "arylalkyl" refers to aryl-substituted alkyl groups and the term "substituted arylalkyl" refers to arylalkyl groups further bearing one or more substituents described above. [0049] The term "arylalkenyl" refers to aryl-substituted alkenyl groups and the term "substituted arylalkenyl" refers to arylalkenyl groups further bearing one or more substituents described above. [0050] The term "arylalkynyl" refers to aryl-substirated alkynyl groups and. the term "substituted arylalkynyl" refers to arylalkynyl groups further bearing one or more substituents described above. [0051] The term "arylene" refers to divalent aromatic groups having between 5 and about 14 carbon atoms and the term "substituted arylene" refers to arylene groups further bearing one or more substituents described above. [0052] The term "kinase" refers to any enzyme that catalyzes the addition of phosphate groups to a protein residue; for example, serine and threonine kinases catalyze the addition of phosphate groups to serine and threonine residues. [0053] The terms "Src kinase," "Src kinase family," and "Src family" refer to the related homologs or analogs belonging to the mammalian family of Src kinases, including, for example, c-Src, Fyn, Yes and Lyn kinases and the hematopoietic-restricted kiuases Hck, Fgr, Lck and Blk. [0054] The terms "Src kinase signaling pathway," and "Src cascade" refer to both the upstream, and downstream components of the Src signaling cascade. [0055] The term "therapeutically effective amount" refers to the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, e.g., restoration or maintenance of vasculostasis or prevention of the compromise or loss or vasculostasis; reduction of tumor burden; reduction of morbidity and/or mortality. [0056] The term "pharmaceutically acceptable" refers to the fact that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [0057] The terms "administration of a compound" or "administering a compound" refer to the act of providing a compound of the invention or pharmaceutical composition to the subject in need of treatment. [0058] The term "antibody" refers to intact molecules of polyclonal or monoclonal antibodies, as well as fragments thereof, such as Fab and F(ab')2, Fv and SCA fragments which are capable of binding an epitopic determinant. [0059] The term "vasculostasis" refers to the maintenance of the homeostatic vascular functioning leading to the normal physiologic functioning. The term "vasculostatic agents" refers to agents that seek to address conditions in which vasculostasis is compromised by preventing the loss of or restoring or maintaining vasculostasis. B. Embodiments of the Invention. [0060] According to an embodiment of the invention, compounds having the structure (I) are provided for treatment of various diseases, disorders, and pathologies, as well as pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individuals diastereoners of compounds having the structure (I): [0061] wherein each of A can be (CH)o-i, N, NH, 0, S, or a part of a ring fusion to form a second ring, where the second rins can be an aromatic, a heteroaromatic, a bicyclic aromatic, a bicyclic aromatic heterocyclic ring, or a bicyclic with only the first ring being aromatic or heteroaromatic; [0062] each of B can be (CH)o-i, N, NH, 0, S, ora part of a ring fusion to fomi a second ring, where the second ring can be an aromatic, a heteroaromatic, a bicyclic aromatic, a bicyclic aromatic heterocyclic ring, or a bicyclic with only the first ring being aromatic or heteroaromatic, with the further proviso that if each B is (CH)o, RS can be any substitutent described below, other than hydrogen, bonded directly to the position 7 of the adjacent ring; [0063] RQ can be H or lower alkyl; [0064] L can be a bond, or a substituted or unsubstituted alkyl, alkenyl, or alkynyl linking moiety; [0065] R, can be C(R')3, OR', N(R')2, NR'C(0)R, NR'C(O)O(R'), NR'C(O)N(R')2, SR', C(0)(0)R', C(0), C(0)N(R')2, S03R!, OS02R', S02R', SOR', S(O)N(R')2, OS(0)(0)N(R')2, S(0)(0)N(R')2, S(O)N(R')2, P04R', OP02R', PO3R', PO2R', or a 3-6 rnembered heterocycle with one or more heterocyclic atoms, with each heteroatom being capable of carrying any R' group on it, wherein R' can be hydrogen, lower alkyl, alkyl-hydroxyl, thiol-alkyl, alkyl-thiol, aminoalkyl, alkylamino, branched alkyl, branched alkyl hydroxyl, branched thio-alkyl, branched alkyl-thiol, branched aminoalkyl, branched alkylamino, or a closed 3-6 membered carbocycle or heterocycle, with each heteroatom in the 3-6 membered heterocycle being capable of carrying any R' group on it, and wherein each R1 can be independent hi case there is more than one R'; [0066] R2 is a substitutent situated at position 5,6 or 8 of the ring, wherein R2 can be methyl, ethyl, /z-propyl, iso-propyl, /z-butyl, zso-butyl, fert-butyl, zso-pentyl, phenyl, substituted phenyl, halogen, branched or unbranched alkylamino, branched or unbranched aminoalkyl, branched or unbranched alkyloxo, branched or unbranched oxyalkyl, branched or unbranched thioalkyl, branched or unbranched alkylthiol, CFa, sulfonamido, substituted sulfonamido, sulfonate, sulfonate ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carboxo, amido, ureido, substituted, carboxo, substituted amido, substituted ureido, or a 3-6 membered carbocycle or heterocycle attached to positions 5, 6 or 8 directly or through group L, each heteroatom being capable of carrying any group R2, with the further proviso that either one, two or three substituents R2 can be present in the ring, and each of the substituents R2 can be the same or different; [0067] Rs can be hydrogen, alkyl, alkoxy, halogen, CF3, cyano, substituted alkyl, or hydroxyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, C(R")3, OR", N(R")2, NR"C(0)R", NR"C(0)NR", R", C(0)(O)R", OC(O)R", C(0)N(R")2, C(0), OC(0)N(R")2, S03R", OS02R", S02R", SOR", P04R", OP02R", P03R", P02R", wherein R" can be hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, lower alkyl, branched lower alkyl, alkyl-hydroxyl, branched alkyl-hydroxyl, amino-allcyl, branched amino-alkyl, alkyl-amino, branched alkyl-amino, thiol-alkyl, branched thiol-alkyl, alkyl-thiol, branched thiol-alkyl, or may form a closed 3-6 membered heterocycle with one or more heterocyclic atoms, branched alkyl, branched alkyl hydroxyl, where each R" can be independent in case there is more than one R"; [0068] n is an integer that can have value between 1 and 5, with the further proviso that if n > 2, then each group R.3 is independent of the other groups Rj, [0069] with the further proviso that if each A is (CH)o, L is a bond. [0070] Some exemplary compounds described by formula (I) that can be used include the following compounds: REMOVE TEABLE [0071] The compounds and methods of the present invention, either when administered alone or in combination with other agents (e.g., chemotherapeutic agents or protein therapeutic agents described below) are useful in treating a variety of disorders associated with compromised vasculostasis and other disorders, including but not limited to, for example: stroke, cardiovascular disease, myocardial infarction, congestive heart failure, cardiomyopathy, myocarditis, ischemic heart disease, coronary artery disease, cardiogenic shock, vascular shock, pulmonary hypertension, pulmonary edema (including cardiogenic pulmonary edema), cancer, pleural effusions, rheumatoid arthritis, diabetic retinopathy, retinitis pigmentosa, and retinopathi.es, including diabetic retinopathy and retinopathy of prematurity, inflammatory diseases, restenosis, edema, (including edema associated with pathologic situations such as cancers and edema induced by medical interventions such as chemotherapy), asthma, acute or adult respiratory distress syndrome (ARCS), lupus, vascular leakage, transplant (such as organ transplant, acute transplant or heterograft or homo graft (such as is employed in burn treatment)) rejection; protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, transplantation tolerance induction; ischemic or reperfusion injury following angioplasty; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; inflammatory bowel disease, including ulcerative colitis and Crohn's disease; lupus (systemic lupus crythematosis); graft vs. host diseases; T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); Type 1 diabetes; psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome; Autoimmune Hyperthyroidism, such as Graves' disease; Addison's disease (autoimmune disease of the adrenal glands); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; other autoimmune diseases; cancers, including those where kinases such as Src-farnily kinases are activated or overexpressed, such as colon carcinoma and thymoma, or cancers where kinase activity facilitates tumor growth or survival; glornerulonephritis, serum sickness; uticaria; allergic diseases such as respiratory allergies (asthma, hayfever, allergic rhinitis) or skin allergies; mycosis fungoides; acute inflammatory responses (such as acute or adult respiratory distress syndrome and ischemia/repernision injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease; Pustulosis palmoplanteris; Pyoderma gangrenum; Sezary's syndrome; atopic dermatitis; systemic schlerosis; morphea; peripheral limb ischemia and ischemic hmb disease; bone disease such as osteoporosis, osteomalacia, hyperparathyroidism, Paget's disease, and renal osteodystrophy; vascular leak syndromes, including vascular leak syndromes induced by chemotherapies or immunomodulators such as IL-2; spinal cord and brain injury or trauma; glaucoma; retinal diseases, including macular degeneration; vitreoretinal disease; pancreatitis; vasculatides, including vasculitis, Kawasaki disease, thromboangiitis obliterans, Wegener's granulomatosis, and Behcet's disease; scleroderma; preeclampsia; thalassemia; Kaposi's sarcoma; von Hippel Lindau disease; and the like. [0072] Src-family tyrosine kinases other than Lck, such as Hck and Fgr, are important in the Fc gamma receptor induced respiratory burst of neutrophils as well as the Fc gamma receptor responses of monocytes and macrophages. The compositions and methods of the present invention may be useful in inhibiting the Fc gamma induced respiratory burst response in neutrophils, and may also be useful in inhibiting the Fc gamma dependent production of TNF alpha. The ability to inhibit Fc gamma receptor dependent neutrophil, monocyte and macrophage responses would result in. additional anti-inflammatory activity for the compounds employed in invention methods. This activity would be especially of value, for example, in the treatment of inflammatory diseases, such as arthritis or inflammatory bowel disease. The compositions and methods of the present invention may also be useful in the treatment of autoimmune glornerulonephritis and other instances of glornerulonephritis induced by deposition of immune complexes in the kidney that trigger Fc gamma receptor responses and which can lead to kidney damage. [0073] In addition, certain Src-family tyrosine kinases, such as Lyn and Src, may be important in the Fc epsilon receptor induced degranulation of mast cells and basophils that plays an important role in asthma, allergic rhinitis, and other allergic disease. Fc epsilon receptors are stimulated by IgE-antigen complexes. Compounds employed in the methods of the present invention may inhibit the Fc epsilon induced degranulation responses. The ability to inhibit Fc epsilon receptor dependent mast cell and basophil responses may result in additional anti-inflammatory activity for the present compounds beyond their effect on T cells. [0074] The present invention also provides articles of manufacture comprising packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material comprises a label which indicates that the pharmaceutical composition can be used for treatment of disorders and wherein the pharmaceutical composition comprises a compound according to the present invention. Thus, in one aspect, the invention provides a pharmaceutical composition including a therapeutic agent and a compound of the invention, wherein the compound is present in a concentration effective to reduce vascular leakage associated with indications or therapeutic agents which have vascular leak as a side effect. For example, administration of a compound of the invention can be in conjunction with IL-2, immunotoxins, antibodies or chemotherapeutics. In these cases, IL-2, immunotoxin, antibody or chemotherapeutic concentration can be determined by one having ordinary skill in the art according to standard treatment regimen or, for example, as determined by an in vivo animal assay. [0075] The present invention also provides pharmaceutical compositions comprising IL-2, immunotoxin, antibody or chemotherapeutic and at least one invention compound in an amount effective for inhibiting vascular permeability, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or mntment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharma,ceutical compositions comprising the present compounds; or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally. [0078] In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens), ,..,.. . [0079] The pharmaceutical compositions for the administration of the compounds of this embodiment either alone or in combination with IL-2, immunotoxin, antibody or chemotherapeutic may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. cosolvent or complexing agent or dispersing agent or excipi'ent or combination thereof for example 1,3-butanediol, polyethylene glycols, polypropylene glycols, ethanol or other alcohols, povidones, various brands of TWEEN surfactant, sodium dodecyl sulfate, sodium deoxycholate, dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, and excipients such as inorganic salts (e.g., sodium chloride), buffering agents (e.g., sodium citrate, sodium phosphate), and sugars (e.g., saccharose and dextrose). Among the acceptable vehicles and solvents that may be employed are water, dextrose solutions, Ringer's solutions 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 diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0087] Depending on the condition being treated, these pharmaceutical compositions may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences" (Mack Publishing Co, Easton Pa.), Suitable routes may, for example,'include oral or transmucosal administration; as well as parenteral delivery, including intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration. For injection, the pharmaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known, in the art. Pharmaceutical formulations for parenteral administratioii include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol. or dexrran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions, [0088] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. [008.9J For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shah1 include mouthwashes and gargles). [0090] In one aspect, the invention compounds are administered in combination with an anti-inflammatory agent, antihistamines, chemotherapeutic agent, imrmmomodulator, therapeutic antibody or a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor, to a subject in need of such treatment. While not wanting to be limiting, chemotherapeutic agents include antimetabolites, such as methotrexate, DNA cross-unking agents, such as cisplatin/carboplatin; alkylating agents, such as canbusil; topoisomerase I inhibitors such as dactinomicin; microrubule inhibitors such as taxol (paclitaxol), and the like. Other chemotherapeutic agents include, for example, a vinca alkaloid, mitomycin-type antibiotic, bleomycin-ty^" antibiotic, antifolate, colchicine, demecoline, etoposide, taxane, anthracycline ai: jiotic, doxorubicin, daunombicin, carminomycin, epirubicin, idarubicui, mithoxanthrone, 4-dimethoxy-daunomycin, 11-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycia-14-benzoate, adriamycin-14-octanoate, adriamycin-14-naphthaleneacetate, amsacrine, carmustine, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topetecan, oxalaplatin, chlorambucil, methtrexate, lomustine, thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, or mechlorethamine. While not wanting to be limiting, therapeutic antibodies include antibodies directed against the HER2 protein, such as trastuzumab; antibodies directed against growth factors or growth factor receptors, such as bevacizumab, which targets vascular endothelial growth factor, and OSI-774, which targets epidermal growth factor; antibodies targeting integrin receptors, such as Vitaxro (also known as MED 1-522), and the like. Classes of anticancer agents suitable for use in compositions and methods of the present invention include, but are not limited to: 1) alkaloids, including, microtubule inhibitors (e.g., Vincristine, Vinblastine, and Vindesine, etc.), microtubule stabilizers (e.g., Paclitaxel [Taxol], and Docetaxel, Taxotere, etc.), and chromatin function inhibitors, including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide [VP-16], and Teniposide [VM-26], etc,), and agents that target topoisomerase 1 (e.g., Camptothecin and Isirinotecan [CPT-11], etc.); 2) covalent DMA-binding agents [alkylating agents], hicludirig, nitrogen mustards (e.g., Mechlorethamine, Chlorambucil, Cyclophosphamide, Ifosphamide, and Busulfan [Myleran], etc.), nitrosoureas (e.g., Carmustine, Lomustine, and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine, Thiotepa, and Mitocycin, etc.); 3) noncovalent DNA-binding agents [antirumor antibiotics], including, nucleic acid inhibitors (e.g., Dactinomycin [ActinomycinD], etc.), anthracyclines (e.g., Daunorubicin [Daunomycin, and Cerubidine], Doxorubicin [Adriamycin], and Idarubicin [Idamycin], etc.), anthracenediones (e.g., anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicainycin (Mithramycin), etc.; 4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex, and Mexate, etc.), purine antimetabolites (e.g., 6-Mercaptopurine [6-MP, Purinethol], 6-Thioguanine [6-TG], Azathioprine, Acyclovir, Ganciclovir, Chlorodeoxyadenosine, 2-chlorodeoxyadenosine [CdA], and 2'-Deoxycoformycin [Pentostatin], etc.), pyrimidine antagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fiuorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosine arabinosides (e.g., Cytosar [ara-C] and Fludarabine, etc.); 5) enzymes, including, L-asparaginase, and hydroxyurea, etc.; 6) hormones, including, glucocorticoids, such as, antiestrogens (e.g., Tamoxifen, etc.), nonsteroidal antiandrogens (e.g., Flutamide, etc.), and aromatase inhibitors (e.g., anastrozole [Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin and Carboplatin, etc.); 8) monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides, etc.; 9) biological response modifiers (e.g., interferons [e.g., IFN-.alpha., etc.] and interleukins [e.g., DL-2, etc.], etc.); 10) adoptive immunotherapy; 11) hematopoietic growth factors; 12) agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastases (e.g., Batimistat, etc.); and 17) inhibitors of angiogenesis. [0091]' The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Examples of other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp.39 (i.e., GDI54), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inliibitors, of NF-kappaB function, such'as deoxyspergualin (DSG), cholesterol b;e?ynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinilammatory drugs (NSATDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf) "-'vcophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. [0092] Other agents that may be administered in combination with invention compounds include protein therapeutic agents such as cytokines, immunomodulatory agents and antibodies. As used herein the term "cytokine" encompasses chemokines, interleukins, lymphokines, monokines, colony, stimulating factors, and receptor associated prqteins. and functional fragments thereof. As used herein, the term "functional fragment" refers to a polypeptide or peptide which possesses biological function or activity that is identified through a defined functional assay. [0093] The cytokines include endothelial monocyte activating polypeptide E (EMAP-n), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), IL-1, IL-2, EL-3, IL-4, IL-5, IL-6, EL-12, and IL-1.3, interferons, and the like and which is associated with a particular biologic, morphologic, or phenotypic alteration in a cell or cell mechanism. [0094] When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one having ordinal-}' skill in the art. [0095] In the treatment or prevention of conditions which involve compromised vasculostasis an appropriate dosage level can generally be between about 0.01 and about 500 mg per 1 kg of patient body weight per day which can be administered in" single or multiple doses. For example, the dosage level can be between about 0.01 and about 250 mg/kg per day; more narrowly, between about 0.5 and about 100 mg/kgper day. A suitable dosage level can be between about 0.01 and about 250 mg/kg per day, between about 0.05 and about 100 mg/kg per day, or between about 0.1 and about 50 mg/kg per day, or about 1.0 mg/kg per day. For example, within this range the dosage can be between about 0,05 and about 0.5 mg/kg per day, or between about 0.5 and about 5 mg/kg per day, or between about 5 and about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing between about 1.0 and about 1,000 mg of the active ingredient, for example, about 1.0, about 5.0, about 10.0, about 15,0, about'20.0, about 25.0, about 50.0, about 75.0, about lOO'.O, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1,000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, such as once or twice per day. There may be a period of no administration followed by another regimen of administration. Preferably, administration of the compound is closely associated with the schedule of IL- 2 administration. For example, administration can be prior to, simultaneously with or immediately following IL-2 administration. [0096] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [0097] Compounds of the present invention can be used, alone or in combination with an effective amount of a therapeutic antibody (or therapeutic fragment thereof), a chemotherapeutic or an immunotoxic agent, for treatment of tumors. While doxorubicin, docetaxel, or taxol are described in the present application as illustrative examples of chemotherapeutic agents, it should be understood that the invention includes combination therapy including a compound of the invention, including but not limited to vasculostatic agents, such as tyrosine, serine or threonine kinase inhibitors, for example, Src-family inhibitors, and any chemptherapeutic agent or therapeutic antibody. C. Examples [0098] The following examples are provided to further illustrate the advantages and features of the present invention, but are not intended to limit the scope of the invention. 1. General Methodology [0099] All experiments were performed under anhydrous conditions (i.e. dry solvents) in an atmosphere of argon, except where stated, using oven-dried apparatus and employing standard techniques in handling air-sensitive materials. Aqueous solutions of sodium bicarbonate (NaHCOs) and sodium chloride (brine) were saturated. [00100] Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F254 plates with visualization by ultraviolet and/or anisaldehyde, potassium permanganate or phosphomolybdic acid dips, [0100] Reverse-phase HPLC chromatography was carried out on Gilson 215 liquid handler equipped with Waters SymmetryShield™ RP18 7p,m (40 x 100mm) Prep-Pak cartridge. Mobile phase consisted of standard acetonitrile (ACN) and DI Water, each with 0.1% TFA added. Purification was carried out at a flow rate of 40mL/ min, and a gradient such that the peak of interest was eluted between 12-15 min in a 30 min run. [0101] NMR spectra: 1H Nuclear magnetic resonance spectra were recorded at 500 MHz. Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn - quintet, dd = doublet of doublets, m = multiplet, bs = broad singlet), coupling constant (J/Hz) and integration. Coupling constants were taken directly from the spectra and are uncorrected. [0102] Low resolution mass spectra: Electrospray (ES+) ionization was used. The protonated parent ion (M+H) or fragment of highest mass is quoted. Analytical gradient consisted of 10% ACN in water ramping up-to 100% ACN over 5 minutes unless otherwise stated. 2. General Synthetic Procedures. • [0103] Whereever Suzuki coupling was used, the following general procedure was employed. To a mixture of boronic acid, aryl bromide, and palladium tetrakis(triphenylphosphine)palladium(0) (Pd(Ph3)4) in 4:1 DME/EtOH was added a 2 M aqueous solution of sodium carbonate. The mixture was flushed with argon for 5 min and a condenser was added under argon flow. The reaction was heated to reflux (ca. 100 °C) for 2-18 h. The crude mixture was filtered and the solid filter cake was rinsed thoroughly with MeOH and DCM. The filtrate was concentrated in vacua and purified by column chromatography. [0104] Whereever Buchwald coupling was used, the following general procedure was employed. A mixture of amine, bromi.de, CS2C03, Xantphos, and Pd2(dba)s in dioxane was purged with argon for 5 min after which a condenser was added under argon flow. The reaction was heated to reflux (ca 110 °C) for 4-18h. The crude mixture was filtered and the solid filter cake was rinsed thoroughly with MeOH and DCM. The filtrate was concentrated in vacua and purified by column chrornatography. [0105] Whereever deprotection of aryl methoxy was necessary, the following general procedure was employed. To a solution of the aryl methoxy compound in DCM was added BBrs (either 1 M. in DCM or neat). The reaction was checked for completion and additional BBrs was added if needed. The reaction was quenched with NaHCO.3 and basified to ca. pH 10-11. The biphasic mixture was filtered and the collected solid was rinsed with water. Trace solvents were removed in vacua. [0106] In general, one of three methods A, B, or C, can be used for synthesizing some of the compounds of the present invention. Those having ordinary skill in the art can determine, depending on variety of factors, including the particular compound that is sought to be made, whether to selected the method A, B or C. [0107] The synthetic method A is shown by the reaction scheme (H). About 1 equivalent of compound 1 was mixed with 2 equivalent of cynamide in a vial. The mixture was heated to about 100°C until the mixture was completely melted. The mixture was cooled down to room temperature and concentrated HCI was added. The mixture was then again heated at about 100°C for about 40 minutes and cooled down hi ice water. About 14 moles of NaOH were carefully added to the above reaction mixture followed by heating the mixture at about 1 00°C for about 2 hours, and by cooling down to room temperature. [0108] Compound 2, shown by the reaction scheme (II), was isolated by filtration and washed several times with water, methanol and diethyl ether. About 1 equivalent of compound 2 was dissolved in N, N-dimethylacetamide, and ethanol solution containing about 4 equivalent of boronic acid and the aqueous solution containing about 0.15 equivalent of potassium carbonate were added. About 0. 1 equivalent of triphenylphosphine and about 0.0246 equivalent of tris(dibenzyllideneatone) dipalladium (0) were added to the mixture. The mixture was reflux overnight. The crude product was poured into saturated NaHC03 solution, and CHaCla was used to extract the product. [0109] Compound 3, shown by the reaction scheme (If), was isolated by removing solvent in the organic phase. Compound 3 was dissolved in N, N-dimethylacetamide in a vial with a septum. Catalytic amount of 10% palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for about 2 hours. Celite was used to remove the palladium and carbon. Solvent was removed under vacuum and compound 4, shown by the reaction scheme (IT), was isolated. About 1 equivalent of compound 4 was dissolved in anhydrous toluene solution containing about 1.2 equivalent of bromide RaBr, about 0.025 equivalent of Pd(dba)3, about 0.07 equivalent of BINAP, and about 0.6 equivalent of KOt-Bu.. The mixture was kept at about 1 00°C for 24 hours under argon. Compound 5, shown by the reaction scheme (U), was then isolated by high pressure liquid chromatography (HPLC). [0110] The synthetic method B is shown by the reaction scheme (in). Compounds 1, 2, 3, and 4 were consecutively prepared and isolated as described in Method A. About 1 equivalent of compound 4 was dissolved in. an aniline followed by adding about 2 equivalents of sulfamic acid. The mixture was heated at about 200°C overnight Compound 5 was isolated by HPLC. [0111] The synthetic method C is shown by the reaction scheme (IV). Compounds 1, 2, 3, and 4 were consecutively prepared and isolated as described in Method A. About 1 equivalent of compound 4 was dissolved in substituted phenylamine followed by adding about 2 equivalent of sulfamic acid. The mixture was heated at about 200°C overnight. Compound 5 was isolated by HPLC and was dissolved in dry CH^C^. The mixture was cooled to about -78°C using a dry ice-acetone bath. About 2 equivalents of BBrs (1M solution in CHiCy was added dropwise to the mixture at about -78°C under nitrogen atmosphere. The mixture was then allowed to warm to about 0°C and stirred overnight at about 0°C, followed by adding saturated aqueous solution of NaHCC>3 at about 0°C and by separating the mixture in a separator funnel. The water layer was extracted twice with CH2Ci2, and the combined organic layer was washed with brine and dried over Na2SC»4. Compound 6 was isolated by removing solvent under vacuum. Compound 6 was dissolved in acetone, and about 6 equivalent of K^COs and about 2 equivalent of RsCl were added to the mixture. The mixture was heated to reflux and stirred overnight, cooled and water was added. Compound 7 was isolated by prep HPLC. Example 1 Synthesis of 7-bromo-benzo|1.2,41triazm-3-ylamine-l-oxide [0112] About 2.48 g (11.4 mmol) of 4-bromo-2-ni.tro-phenylamine was mixed with about 1.51 g (about 36 mmol) of cynamide in a 20 ml vial. The mixture was heated to about 100°C till the mixture was totally melted. The mixture was cooled down to room temperature and about 6.5 ml of concentrated HC1 was added. The mixture was heated at about 100°C for about 40 minutes and cooled down in ice water. About 6.5 ml of 14M NaOH was carefully added to the above reaction mixture. The resulted mixture was heated at about 100°C for about 2 hours, then cooled down to room temperature, and filtrated. After filtration, the precipitate was washed several times with water, methanol and diethylether to remove the starting material. About 0.739 g of the product having * formula (V) was obtained. Yield: about 27%, ES1-MS: [M+H]+, 241, 243; 1H NMR (DMSO-d6): 5 7.48 (d, J= 9.0 Hz, 1 H), 7.89 (dd,,// = 9.0 Hz, /, - 2.1 Hz, 1 H), 8.26 (d, J=2.1Hz, 1H). Example 2 Synthesis of 7-bromo-5-methyl-benzo[ 1,2,4]triazni-3-ylamine-l-oxide [0113] About 1 g (4.33 mmol) of 4-bromo-2-metliyl-6-nitro-phenylamine was mixed with about 0.5 g (12 mmol) of cynamide and about 5 g pyridine hydrochloride in a 20 ml vial. The mixture was heated to reflux overnight. The mixture was cooled down to room temperature and 10% NaOH was carefully added. The resulted mixture was heated at about 100°C for about 2 hours, then cooled down, to room temperature, and filtrated. After nitration, the precipitate was washed several times with water, acetone and diethyl ether to remove the starting material. About 0.4 g of the product having the formula (VI) was obtained. Yield: about 36%. ESI-MS: [M+H]4, 255,257; 1H NMR (DMSO-d6): 8 2.45 (s, 3 H), 7.81 (s, 1 H), 8.26 (s, 1 H). Example 3 Synthesis of 7-bromo-5-methyi-benzo[l,2,4]triazin-3-ylam{iie [0114] About 4.26g of 7-bromo-5-methyl-benzo[l,2,4]triazin-3-ylamiQe-l-oxide (VI) prepared as described in Example 2, was dissolved in about 100 ml of acetic acid, and about 1 g of iron powder was added to the solution. The mixture was refluxing for about 10 minutes. The iron was removed by filtration. The solvent in the filtrate was removed under vacuum. Water was added to remove the salt from the product. About 3.9 g of the pure product having formula (VET) was obtained. Example 4 Synthesis of l-Q-chioropropanyDpyrroIidiDe [0115] To the solution of about 186 g (1.18 mol) of l-bromo-3-chloropropane in about 200 ml of'ether was added about 2 equivalent of pyrrolidine at about 0°C. .After addition, the mixture was allowed to warm to room temperature and stirred overnight. The resulting white solid residue was removed and to the clear solution was added ice-cold 10% hydrochloric acid. The ether layer was discarded and the acid layer was basified with ice-cold 20% NaOH, extracted with ether and dried over Na2SC>4. Ether was removed and the residue was distilled under vacuum (95 °C /30 mmHg). About 91 g of product having formula (VIII) was obtained in a form of a pale yellow liquid. The yield was about 53 %. Example 5 Synthesis of |7-(2,6-dimethyl-pheiiyI)-5-methvI-benzori,2,4]triazin-3-yI]-[4-(2-pyrroIidin-l-yI-ethoxy)-pheny{]-amme [0116] About 1 g (3.78 mmol) of 7-bromo-5-methyl-benzo[l,2,4]triazin-3-ylamine and about 2.04 g (7.56 mmol) of l-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine were dissolved in about 500 ml of toluene. About 174 rag (0.19 mmol) of Pd(dba)3, about 340 mg (0.54 mmol) of BINAP, and about 500 mg (4.46 mmol) KOl-Bu were added to the solution. The mixture was kept at about 100°C for about 24 hours under argon. The crude product was purified by preparative HPLC. About 90 mg of [7-(2,6-drmethyl-phenyl)-5-methyl-benzo[l,2,4]triazm-3-yl]-[4-(2-pyrrolidin-l-yl-sthoxy)-phenyl]-amine (product having formula (DC)) was isolated. Yield: about 5.2%. ESI-MS: [M+Hf, 454.6; 1E NMR (DMSO-d6): 5 1.90-2.05 (m, 10 H), 2.64(s, 3H), 3.15 (m, 2 H), 3.59-3.64 (m, 4 H), 4.31 (t, J= 5.2 Hz, 2 H), 7.09(d, J= 9.2 Hz, 2 H), 7.18 (d, J= 7.4 Hz, 2 H), 7.23 (m, 1 H), 7.60 (s, 1 H), 7.91 (s, 1 H), 7.98 (d, J= 9.2 Hz, 2 H). Example 6 Synthesis of l-(4-f7-(2,6-dimethyl-phenyI)-5-methy!-benzofl,2,41triazin-3-ytaminol-phenyIj-cvclQpropanecarboKitrile (X) [0117] About 50 mg (0.2 mmol) of 7-bromo-5-methyl-benzo[l,2,4]triazin-3-ylamine and about 84 mg (0.38 mmol) of l-(4-bromo-phenyl)-cyclopropanecarbonitrile were dissolved in about 10 ml of toluene. About 8 mg (0.009 mmol) of Pd(dba)3, about 17 mg (0.027 mmol) of BINAP, and about 50 mg (0.226 mmol) of KO'-Bu were added to the solution. The mixture was kept at about 100°C for about 24 hours under argon. The crude product was purified by preparative HPLC. About 5 mg of l-{4-[7-(2,6-dimethyl-phenyl)-5-methyl-berizo[l,2,4]triazin-3-ylamino]-phenyl}-cyclopropanecarbonitrile (product having formula (X)) was isolated. ESI-MS: [M+HJ, 406.5; 1R NMR (DMSO-4): 5 1.49 (q, 2 H, J = 5.3 Hz), 1.72 (q, 2 H, J = 5.3 Hz), 2.05 (s, 6 H), 2.67(s, 3H), 7.18 (d, /= 7.4 Hz, 2 H), 7.23 (m, 1 H), 7,38 (d, J= 6,85 Hz, 2 H), 7.63 (s, 1 H), 7.91 (s, 1 H), 8.06 (d, .7= 6.85 Hz, 2 H). Example 7 Synthesis of [7-(2,6-dimethyi-phenvI)-benzo[l,2,4]triazm-3-yI1-[4-(2-pyrrolidin-l-yl-ethory)-phenvn-amine [0118] To a solution of about 1.00 mg (0.42 mmol) of 7-bromo-benzo[l,2,4]triazin-3-ylamine-1-oxide dissolved in about 6 ml of N, N-dimethylacetamide in a 20 ml vial, were added about 240 mg (1.6 mmol) of 2,6-dimethylphenylboronic acid dissolved in about 1 ml of ethanol and about 64 mg (0.6 mmol) of potassium carbonate dissolved in about 1 ml of water. About 9 mg (0.034 mmol) of triphenylphosphine and about 9 mg (9.83 mmol) of tris(dibenzylideneacetone) dipalladium (0) were added to the mixture. The mixture was reflux overnight. The crude product was poured into about 50 ml of saturated aqueous solution of NaHC03, and CH2C12 was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of about 2 ml of N, N-dimethylacetamide and about 1 ml of ethyl alcohol in a 20 ml vial with a septum. Catalytic amount of 10% palladium on carbon was added to the mixture. A balloon filled'with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for about 2 hours. Celite was used to remove the palladium and carbon. The crude product and about 200 mg (0.74 mmol) of l-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine were dissolved in 10 ml of toluene. About 17 mg (0.018 mmol) of Pd(dba)3, about 34 mg (0.054 mmol) of BTNAP, and about 50 mg (0.226 mmol) of KOt-Bu were added to the solution. The mixture was kept at about 100°C for about 24 hours under argon. The crude product was purified by preparative HPLC. About 2 mg of [7-(256-dimethyl-phenyl)-benzo[l,2,4]triazin-3-yl]-[4-(2- pyirolidm-l-yl-ethoxy)-phenyl]-arnine (product having formula (XI)) was isolated. Yield: about 1.6%; ES1-MS: [M+H]+, 440.6; 1HNMR(DMSO-d6): 8 1.90-2.05 (m, 10 H), 3.15 (m, 2 H), 3.59-3,64 (m, 4 H), 4.31 (t, J= 5.15 Hz, 2 H), 7.09(d, J= 9,06 Hz, 2 H), 7.18 (d, /= 7.4 Hz, 2 H), 7.23 (m, 1 H), 7.70 (d, J = 8.7 Hz, 1 H), 7.78 (d, J= 8.7 Hz, 1 H), 7.90 (d, J= 9.06 Hz, 2 H), 8.08 (s, 1 H). Example 8 Synthesis of [7-(2,6-dimethyt-pheDyl)-5-methyI-benzo[l,2,4]triazin-3-yIl- quinoIin-8-yI-amiDe by Method A [0119] About 100 mg (0.4 mmol) of 7-bromo-5-memyl-benzo[l,2,4]1riazin-3-ylamine and about 158 mg (0.8 mrnol) of 8-bromo-quinoline were dissolved in about 10 ml toluene. About 17 mg (0.018 mmol) of Pd(dba)3, about 17 mg (0.027 mmol) of BINAP, and about 50 mg (0.226 mmol) of KOt-Bu were added to the solution. The mixture was kept at about 100°C for about 24 hours under argon. The crude product was purified by preparative HPLC. About 50 mg [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-quinolin-8-yl-amine (product having formula (XTTj) was isolated. Yield: about 33.8%; ESI-MS: [M+H]+, 392; !H NMR (DMSO-ds): 5 2.07 (s, 6 H), 2.79(s, 3H), 7.19 (d, J= 7.4 Hz, 2 H), 7.25 (m, 1 H), 7.71-7.79 (m, 4 H), 8.04 (s, 1 H), 8.50 (d, J= 8.3 Hz, 1 H), 9.05 (m, 2 H). Example 9 Synthesis of [7-(2,6-dimethyI-phenyI)-5-methyI-beazofl,2,4]triazia-3-vn- pyridin-2-yI-amine by Method A [0120] Title product having formula (XIII) was synthesized using Method A described above. ESI-MS: [M+H]+, 342;1HNMR (500 MHz, DMSO-d6): S 2.05 (s, 6H), 2.71 (s, 3H), 7.18-7.26 (m, 4 H), 7.71 (s, 1 H), 8.00 (m, 2 H), 8.44 (m, 2 H), 11.42 (s, IH, NH). Example 10 Synthesis of f7-(2,6-dimethyI-phenyl)-5-methyl-benzo[l,2,4]triaziD-3- yIl-qumoIin-3-vI-amine by Method A (XIV) [0121] Title product having formula (XUT) was synthesized using Method A described above. ESI-MS: [M+H]+, 392; 1E NMR (500 MHz, DMSOd6): 5 2.07 (s, 6H), 2.77 (s, 3H), 7.18 (d, J= 7.4 Hz, 2 H), 7.23 (m, 1 H), 7.62 (m, 2H), 7.70 (s, IH), 7.94 (dd, /, = 8.14Hz, J2= 1.48 Hz, IH), 8.01 (m, 2H), 9.16 (s, IH), 9.30 (s, IH), 11.44 (s, IH, NH). Example 11 Synthesis of f7-f2,6-dimethyl-phenvl)-5-methyi-benzo[l,2.41triazin-3- yl]-m-toly{-amine by Method B N (XV) [0122] Title product having formula (XV) was synthesized using Method B described above. ESI-MS: [M+H]4, 355; JH NMR (CDC13): 5 2.10 (s, 6 H), 2.44 (s, 3 H), 2.74 (s, 3 H), 6.97 (d, J - 7.6 Hz, 1 H), 7.17 (d, J = 7.6 Hz, 2 H), 7.22 (m, 1 H), 7.33 (m, 1 H), 7.49 (s, 1 H), 7.74 (d, J= 7.6 Hz, 1 H), 7.96 (s, 1 H), 7.99 (s, 1 H). Example 12 Synthesis of [7-(2,6-dimethyI-phenvI)-5-methvI-benzofl,2,41triazin-3- yn-p-tolyl-amine by Method B (XVI) [0123] Title product having formula (XVI) was synthesized using Method B described above. ESI-MS: [M+H]"", 355; 'HNMR (CDC13): 6 2.09 (s, 6 H), 2,38 (s, 3 H), 2.72 (s, 3 H), 7.16 (d, J - 7.6 Hz, 2 H), 7.22 (m, 2 H), 7.47 (s, 1 H), 7.80 (d, J- 8.4 Hz, 2 H), 7.96 (s, 1 H). Example 13 Synthesis of (Z^-dimethvI-phenvlVfT-fl^-dimethyl-phenYD-S-methvl-benzQJl,2,41triazin-3-yn-amine by Method B (xvn) [0124] Title product having formula (XVH) was synthesized using Method B described above. ESI-MS: [M+H]+, 369; !H NMR (CDCI3): 5 2.09 (s, 6 H), 2.35 (s, 3 H), 2.40 (s, 3 H), 2.72 (s, 3 H), 7.03 (d, J - 7.6 Hz, 1 H), 7.16 (d, J = 7.2 Hz, 2 H), 7.20-7.24 (m, 2 H), 7.45 (s, 1 H), 7.95 (s, 1 H), 8.20 (d, .7= 7.6 Hz, 1 H). Example 14 Synthesis of (2,4-dimethyI-phenyI)-f7-(2,6-dimethyI-phepyl>-5-methyI-benzo[l,2,41triazip-3-yI]-amine by Method B (XVffl) [0125] Title product having formula (XVTfl) was synthesized using Method B described above. ESI-MS: [M+Hf, 369; :H NMR (CDC13): 8 2.09 (s, 6 H), 2.36 (s, 3 H), 2.44 (s, 3 H), 2.66 (s, 3 H), 7.11-7.20 (m, 5 H), 7.45 (s, 1 H), 7.95 (s, 1 H), 8.20 (d, J= 8.4 Hz, 1H). Example 15 Synthesis of (2,5-dimethyl-phenyl)- f 7-f2,6-dimethyI-phenyI)-5-methyI-beuzo|l,2,41triaziD-3-yI1--amiiie by Method B (XIX) [0126] Title product having formula (XIX) was synthesized using Method B described above. ESI-MS: [M+Hf, 369; 'H NMR (CDC13): 8 2.09 (s, 6 H), 2.42 (s, 3 H), 2.43 (s, 3 H), 2.69 (s, 3 H), 6.90 (d, J - 7.6 Hz, 1 H), 7.16 (d, J - 7.6 Hz, 2 H), 7.26 (m, 2 H), 7.47 (s, 1 H), 7.95 (s, 1 H), 8,40 (s, 1 H). Example 16 Synthesis of (3 (XX) [0127] Title product having formula (XX) was synthesized using Method B described above. ESI-MS: [M+H]+, 369; 'H NMR (CDC13): 5 2.09 (s, 6 H), 2.29 (s, 3 H), 2.34 (s, 3 H), 2.72 (s, 3 H), 7.17-7.23 (m, 4 H), 7.47 (s, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.92 (s, 1 H), 7.95 (s, 1 H). Example 17 Synthesis of (3-chioro-4-fluoro-pheDvl)-[7-(2,6-dimethyl-phenvl)-5-methYl-benzofl,2,41triazm-3-vH-amhie by Method B CH3 (XXI) [0128] Title product having formula (XXI) was synthesized using Method B described above. ESI-MS: [M+H]+, 393; 1HNMR (GDC13): 8 2.09 (s, 6 H), 2.74 (s, 3 H), 7.17 (d, J = 7.6 Hz, 2 H), 7.24 (m, 1 H), 7.54 (s, 1 H), 7.65 (m, 1 H), 8.06 (s, 1 H), 830 (s, 1 H), ; = 6.8Hz,/2 = 3.2Hz, 1 H). Example 18 Synthesis of f7-(2-chloro-phenvl)-5-methyI-benzofl,2,41triazin-3-yI]- phepyl-amine by Method B (xxn) [0129] Title product having formula (XXTT) was synthesized using Method B described above. ESI-MS: [M+Hf, 347; 1HNMR (CDC13): 3 2.75 (s, 3 H), 7.15 (t, J = 7.6 Hz, 1 H), 7.37-7.39 (m, 2 H), 7.44-7.48 (in, 3 H), 7.53 (d, J - 7.6 Hz, 1 H), 7.81 (s, 1 H), 7.92 (d, J - 7.6 Hz, 2 H), 8.24 (s, 1 .H). Example 19 Synthesis of (4-methoxv-phenvi)-[7-(2-methoyv-phenvI)-5-methYJ-benzo[l,2,4]triazin-3-yI]-amine by Method B (xxnn [0130] Title product having formula (XXIII) was synthesized using Method B described above. ESI-MS: [M+H]4, 373; ]H NMR (CDG3): 5 2.70 (s, 3 H), 3.83 (s, 3 H), 3.87 (s, 3 H), 6.99 (d, J= 8.8 Hz, 2 H), 7.05 (d, J= 8 Hz, 1 H), 7.09 (m, 1 H), 7.38 (m, 1 H), 7.45 (d, /= 8 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 2 H), 7.88 (s, 1 H), 8.29 (s, 1 H). Example 20 Synthesis of (4-butyl-phenyl)-r7-(2,6-dimethyI-phenyI)-5-methyI-beDZo[l,2.4]triazin-3-yll-amine by Method B (XXIV) [0131] Title product having formula (XXIV) was synthesized using Method B described above. ESI-MS: [M+H]4,397.3; 1E NMR (CDC13): 5 0.95 (t, J - 7.6 Hz, 3 H), 1.32 (m, 2 H), 1.64 (m, 2 H), 2.10 (s, 6 H), 2.64 (t, J = 7.6 Hz, 2 H), 2.66 (s, 3 H), 7.16 (d, J - 8.4 Hz, 2 H), 7.16 (d, J= 7.6 Hz, 2 H), 7.22 (m, 1 H), 7.47 (s, 1 H), 7.82 (d, J = 8.4 Hz, 2 H), 7.95 (s, 1 H). Example 21 Synthesis of f7-f2.6-dimethyl-phenyI)-5-methyI-benzo[l,2,4]triazin-3-yn-(2-metbory-phenyI)-amine by Method B (XXV) [0132] Title product having formula (XXV) was synthesized using Method B described above. ESI-MS: [M+H]+, 371.2; 1E NMR (CDC13): 5 2.10 (s, 6 H), 2.75 (s, 3 H), 4.01 (s, 3 H), 6.98 (dd, /; = 7.6 Hz, J2 = 2 Hz, 1 H), 7.10 (m, 2 H), 7.16 (d, /= 7.6 Hz, 2 H), 7.22 (m, 1 H), 7,49 (s, 1 H), 7.97 (s, 1 H), 8.84 (dd, Jj = 7.6 Hz, J2-= 2.4 Hz, 1 H). Example 22 Synthesis of [7-(2,6-dimethyl-phenvI)-5-methy!-benzoH,2,41triazin-3-yi1-(3-methoxv-phenyl)-amine by Method B (XXVI) [0133] Title product having formula (XXVI) was synthesized using Method B described above. ESI-MS: [M+H]+, 371.2; JH NMR (CDC13): 5 2.10 (s, 6 H), 2,75 (s, 3 H), 3.92 (s, 3 H), 6,70 (d, /= 7.6 Hz, 1 H), 7,16 (d, 7- 7.6 Hz, 2 H), 7.22 (m, 1 H), 7.26-7.35 (m, 2 H), 7.49 (s, 1 H), 7,88 (s, 1 H), 7.98 (s, 1 H), Example 23 Synthesis of [7-(2,6-dimethyi-pIieaYl)-5-methvi-benzofl,2,41triazia-3-_ vlH4-methoxv-pbenvI)-amine by Method B (product TG100-412-1) (XXVH) [0134] Title product having formula (XXVII) was synthesized using Method B described above. ESI-MS: [M+H]+, 371.2; !H NMR. (CDC13): § 2.10 (s, 6 H), 2.70 (s, 3 H), 3.86 (s, 3 H), 7.0 (d, J= 9.2 Hz, 2 H), 7.16 (d, /= 7.6 Hz, 2 H), 7.22 (m, 1 H), 7.46 (s, 1 H), 7.80 (d, /= 9.2 Hz, 2 H), 7.94 (s, 1 H). Example 24 Synthesis of [7-(2.6-dimethyl-phenyl)-5-metbvl-benzo[l,2,41triazip-3-y{1-(4-ethoxy-phenyI)-amine bv Method B (XXVIH) [0135] Title product having formula (XXVIE) was synthesized using Method B described above. ESI-MS: [M+H]+, 385.3; 1H NMR (CDC13): 5 1.44 (t, /= 7.2 Hz, 3 H), 2.10 (s, 6 H), 2.70 (s, 3 H), 4.08 (q, J= 7.2 Hz, 2 H), 6.98 (d, J= 9.2 Hz, 2 H), 7.16 (d, / - 7.2 Hz, 2 H), 7,22 (m, 1 H), 7.46 (s, 1 H), 7.80 (d, J= 9.2 Hz, 2 H), 7.94 (s, 1 H). Example 25 Synthesis of (3-chloro-phenv})-f7-(2,6-dimethvi-phenyl)-5-methv{-benzofl,2,41triazin-3-yl]-amiiie by Method B (XXIX) [0136] Title product having formula (XXIX) was synthesized using Method B described above. ESI-MS: [M+Hf, 375.3; 'HNMR (CDC13): 8 2.10 (s, 6 H), 2.76 (s, 3 H), 7.LO (d, J= 9.2 Hz, 1 H), 7.17 (d, J= 7.6 Hz, 2 H), 7.22 (m, 1 H), 7.37 (m, 1 H), 7.49 (s, 1 H), 7,64 (d, J= 9.2 Hz, 1 H), 8.00 (s, 1 H), 8.25 (s, 1 H). Example 26 Synthesis of (3,4-dichlorQ-phenyl)-f7-(2.6-dimethyl-phenyl)-5-methvl-benzo[1.2,41triazin-3-yl|-amine by Method B (XXX) [0137] Title product having formula (XXX) was synthesized using Method B described above. ESI-MS: [M+H]+, 409,3; !H NMR (CDC13): 5 2.09 (s, 6 H), 2.75 (s, 3 H), 7.17 (d, J= 7.6 Hz, 2 H), 7,24 (m, 1 H), 7.47 (d, J= 8.8 Hz, 1 H), 7.54(s, 1 H), 7.62 (d,/= 8,8 Hz, 1 H), 8.01 (s, 1 H), 8.38 (s, 1 H). Example 27 Synthesis of r7-(3,5-dimethoxv-phenvI)-5-methvi-benzo[1.2,4]triazin-3- vll-m-tolyl-amine by Method B (XXXI) [0138] Title product having formula (XXXI) was synthesized using Method B described above. ESI-MS: [M+H]+, 387.4; [H NMR (CDC13): § 2.43 (s, 3 H), 2.76 (s, 3 H), 3.89 (s, 6 H), 6.53 (s, 1 H), 6.85 (s, 2 H), 6.96 (d, J= 7.2 Hz, 1 H), 7.33(m, 1 H), 7.72 (m, 2 H), 7.94 (s, 1 H), 8.36 (s, 1 H). Example 28 Synthesis of [7-(3,5-dimethory-phenvI)-5-methvl-benzo[1.2,41triazin-3- yl]-p-tolyl-amine by Method B (xxxn). [0139] Title product having formula (XXXII) was synthesized using Method B described above. ESI-MS: [M+Hf, 387.4; 'H NMR (CDC13): 6 2.38 (s, 3 H), 2.74 (s, 3 H), 3.89 (s, 6 H), 6.53 (s, 1 H), 6.85 (s, 2 H), 7.23 (d, J= 8.0 Hz, 2 H), 7.78(d, /= S.O Hz, 2 H), 7.92 (s, 1 H), 8.35 (s, 1 H). Example 29 Synthesis of f7-(3 (XXXffl) [0140] Title product having formula (XXXIH) was synthesized using Method B described above. ESI-MS: [M+H]+, 401.4; 1HNMR (CDC13): 5 2.36 (s, 3 H), 2.43 (s, 3 H), 2.69 (s, 3 H), 3.89 (s, 6 H), 6.53 (s, 1 H), 6.85 (s, 2 H), 7.11 (s, 1 H), 7.14 (d, /= 8.8 Hz, 1 H), 7.90 (s, 1 H), 8.30 (d, J= 8.8 Hz, 1 H), 8.35 (s, 1 H). Example 30 Synthesis of r7-(3,5-dimethoxy-phenyI)-5-methyl-benzofl,2,41triazin-3-yl]-(2.5-dimethyl-phenyI)-amipe by Method B (XXXIV) [0141] Title product having formula (XXXIV) was synthesized using Method B described above. ESI-MS: [M+H]+, 401.4; !H NMR (CDC13): 5 2.43 (s, 6 H), 2.72 (s, 3 H), 3.89 (s, 6 H), 6.53 (s, 1 H), 6.86 (s, 2 H), 6.91 (d,J= 7.2 Hz, 1 H), 7.1.6 (d, J= 12 Hz, 1 H), 7.93 (s, 1 H), 8.36 (s, 1 H), 8,40 (s, 1 H). Example 31 Synthesis of [7-(3,5-dimethoxy-phemrI)-5-methyl-bepzo|l,2.4]triazin-3-yIH3,4-dimethy{-Dhenyi)-amine bv Method B (XXXV) [0142] Title product having formula (XXXV) was synthesized using Method. B described above. ESI-MS: [M+HJ4, 401.4; 'H NMR (CDC13): 5 2.29 (s, 3 H), 2.34 (s, 3 H), 2.75 (s, 3 H), 3.89 (s, 6 H), 6.53 (s, 1 H), 6.86 (s, 2 H), 7.20 (d, J= 7.6 Hz, 1 H), 7.65 (d, J= 7.6 Hz, 1 H), 7.68 (s, 1 H), 7.92 (s, 1 H), 8.36 (s, 1 H). Example 32 Synthesis of (4-bu^l-phenyl)-[7-(3,5-diniethoxy-plienYl)-5-methvI-benzo[1.2,4]triaziD-3-vI]-amijae by Method B (XXXVI) [0143] Title product having formula (XXXVI) was synthesized using Method B described above. ESI-MS: [M+H]+, 429.4; !H NMR (CDC13): 5 0.95 (t,J= 7.2 Hz, 3 H), 1.40 (m, 2 H), 1.64 (m, 2 H), 2.64 (t, /= S Hz, 2 H), 2.75 (s, 3 H), 3.89 (s, 6 H), 6.53 (s, 1 H), 6.86 (s, 2 H), 7.24 (d, .7= 8.4 Hz, 2 H), 7.80 (d, /= 8.4 Hz, 2 H), 7.92 (s, 1 H), 8.35 (s, 1 H). Example 33 Synthesis of [7-(3,5-dimethoxy-phenyl)-5-methyl-benzo [1,2,4]triazin-3-vri-(4-ethoxv-phenvl)-amme by Method B (XXXVE) [0144] Title product having formula (XXXVII) was synthesized using Method B described above. ESI-MS: [M+H]+, 417.3; !H NMR (CDC13): 5 1.44 (t, J= 6.8 Hz, 3 H), 2.73 (s, 3 H), 3.89 (s, 6 H), 4.07 (q, /- 6.8 Hz, 2 H), 6.53 (s, 1 H), 6.86 (s, 2 H), 6.98 (d, /= 8.8 Hz, 2 H), 7.80 (d, J= 8.8 Hz, 2 H), 7.91 (s, 1 H), 8.34 (s, 1 H). Example 34 Synthesis of [7-(3,5-dimethory-phenyl)-5-metbyI-beuzo[l,2,4]triazin-3- yI]-pyridin-4-yl-amipe by Method B (xxxvm) [0145] Title product having formula (XXXVTH) was synthesized using Method B described above. ESI-MS: [M+H]+, 374.4; 'H NMR (CDC13): 8 2.82 (s, 3 H), 3.89 (s, 6 H), 6.53 (s, 1 H), 6.87 (s, 2 H), 7,87 (d, J= 5.2 Hz, 2 H), 8,02 (s, 1 H), 8.43 (s, 1 H), 8,60 (d,y=5.2Hz,2H). Example 35 Synthesis of r7-(3,5-dimetlioxY-phenvl)-5-tnetIiyl-benzQfl,2,4]triazin-3-yI]-(2,3-dimethyl-phenyI)-amine by Method B O' (XXXIX) [0146] Title product having formula (XXXIX) was synthesized using Method B described above. ESI-MS: [M+Hf, 401.4; 'HNMR (CDC13): 5 2.36 (s, 3 H), 2.39 (s, 3 H), 2.68 (s, 3 H), 3.89 (s, 6 H), 6.53 (s, 1 H), 6.86 (s, 2-H), 7.04 (d, /= 7.6 Hz, 1 H), 7.22 (m, 1 H), 7.90 (s, 1 H), 8.18 (d, J= 7.6 Hz, 1 H), 8.35 (s, 1 H). Example 36.Synthesis of f7-(3,5-dimethoxy-phenyj)-5-methvI-benzo{l,2,4]triazin-3-yl]-(2-methoxy-pheayl)-amine by Method B (XL) [0147] Title product having formula (XL) was synthesized using Method B described above. ESI-MS; [M+H]+, 403.4; !HNMR (CDC13): 5 2.77 (s, 3 H), 3.89 (s, 6 H), 3.99 (s, 3 H), 6.53 (s, 1 H), 6,86 (s, 2 H), 7,00 (d, J= 7.6 Hz, 1 H), 7.08 (m, 2 H), 7,93 (s, 1 H), 8.36 (s, 1 H), 8.80 (d, J= 7.6 Hz, 1 H). Example 41 Synthesis of [7-(2,6-dichioro-phenvi)-5-methyI-benzo[1.2,4]triazia-3- yll-pyridm-4-yj-amine by Method A Cl Ci (XLV) [0152] Title product having formula (XLV) was synthesized using Method A described above. ESI-MS: [M+Hf, 3S2.4; !HNMR. (DM.SO-d6): 5 2.77 (s, 3 H), 7.5 (t, I H), 7.70 (d, 2 H), 7.90 (s, 1 H), 8.30 (s, 1 H), 8.40 (d, 2 H), 8.70 (d, 2 H). Example 42 Synthesis of [7-(216-dichloro-pheHvI)-5-metbvl-benzofl,2,4]triazm-3- yl]-pvridm-3-yl-amme by Method A (XLV3) [0153] Title product having formula (XLVI) was synthesized using Method A described above. ESI-MS: [M+H]4, 382.4; JH NMR. (DMSO-d6): 6 2.68 (s, 3 H), 7.5 (t, 1 H), 7.70 (m, 3 H), 7.80 (s, 1 H), 8.20 (s, 1 H), 8.40 (m, 1 H), 8.60 (d, 1 H), 9.35 (s, 1 H). Example 49 Synthesis of f3-(2-diethyiamino-ethoxy)-phenyI1-f7-(2,6-dimethvI-phenyD-5-methyl-benzo[ 1,2,4] tnazin-3-yl]-amine by Method C (LIV) [0160] Title product having formula (LIV) was synthesized using Method C described above. ESI-MS: [M+H]+, 456.3; !H NMR (DMSO-d6): 5 1.27 (t, J = 7.2 Hz, 6 H), 2.05 (s, 6 H), 2.68 (s, 3 H), 3.25 (br, 4 H), 3.58 (br, 2 H), 4.38 (br, 2 H), 6.72 (d, J = 8.8 Hz, 1 H), 7.19 (d, J- 7.3 Hz, 2 H), 7.24 (m, 1 H), 7.33 (m, 1 H), 7.51 (d, /= 8.8 Hz, 1 H), 7.66 (s, 1 H), 7.96 (s, 1 H), 8.02 (s, 1 H). Example 50 Synthesis of 7-(2-chloro-5-methoxy-phepvI)-5-methyl-benzo 11,2.41 triazin-3-vlamine MeO (LV) [0161] 7-bromo-5-methyl-benzo[l,2,4]triazin-3-ylamine (33.47 mmol, 1.0 equiv), 1-chloro-4-methoxy-2-boronic acid (50.21 mmol, 1.5 equiv), Pd(PPH3)4 (3.347 mmol, 0.1 equiv), and. Na2C03 (133.9 mmol, 4.0 equiv) dissolved in DME/EtOH/water 6:1:1 and refluxed at 100 °C under an argon blanket for 4 h. The reaction was cooled to room temperature and diluted with 100 rnL DCM and filtered. Precipitate recovered was suspended in water, filtered and rinsed with ether. Precipitate afforded product: 7-(2-cWoro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazm-3-ylarrmie, a green solid (8.37 g, 84% yield). R{•= 0.85 (9:1 DCM/MeOH). {R NMR (DMSO-d6): 5 3.35 (s, 6H), 7.01 (dd, [0163] . 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.333 mmol, 1.0 equiv), 3-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (0.499 ramol, 1.5 equiv), Cs2C03 (0,999 mmol, 3.0 equiv), Pd2(dba)3 (0.0333 mmol, 0.1 equiv), and Xantphos (0.0666 ramol, 0.2 equiv) were dissolved in 7 mL dioxane. The reaction was placed under an argon atmosphere and refluxed at 100°C for 18 h. The organics were filtered to remove excess inorganics, dissolved in EtOAc, washed with saturated NaHCOs and brine, dried over NaiSC^ and concentrated under reduced pressure to give 3-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]1riazin-3-ylainino]-N-(2-dimethylamino-ethyl)-benzenesulfonamide, which was precipitated using EtO Ac/hex anes (1:5 v/v) to give a dark orange solid (168.4mg, 96% yield). Rf = 0.50 MS (ES+) m/z = 527. Example 53 Synthesis of 3-[7-(2-chloro-5-hydroxv-phenvl)-5-methyl-benzofl.2^4]triazin-3-yiammo1-N-(2-dimetbyIamino-ethvI)-benzenesulfonamide (LVHJ) [0164] 3 -[7-(2-chloro-5 -mettioxy-phenyl)-5-metiiyl-benzo[ 1,2,4]triazin-3 -ylamino] -N-(2-dimethylamino-ethyl)-benzenesulfonainide (0.32 mmol, 1.0 equiv) was dissolved in 10 mL of anhydrous DCM and placed under an argon atmosphere. 4 mL of BBr3 (0.1 M) added via syringe and the reaction stirred at room temperature for 2 h. BBr3 was quenched with saturated NaHC03 until pH = 7. The mixture was filtered and washed with water and Et20 to give 3-[7-(2-chloro-5~hydroxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yIamino]-N-(2-dimethylamino -ethyl)-benzenesulfonamide, as an orange solid (132.2 mg, 81% yield). 1H NMR (DMSO-d6): 8 2.71 (s, 2H), 3.01 (bs, 2H), 6.87 (dd, J= 8.8 Hz, J= 2.9 Hz, 1H), 6.94 (d, J= 3.0 Hz, 1H), 7.41 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 1.9 Hz, IE), 7.64 (t,J= 8.1 Hz, 2H), 7.90 (s, 1H), 8.06 (d, /= 6.7 Hz, 1H), Example 55 Synthesis of 4-[7-(2-chloro-5-hydroxy-pbeayi)-5-methvl-beDZo|l,2,41triaziu-3-vIamino1-N-methvl-N-(2-pyrrolidiD-l-yl-ethvD- benzenesulfonamide (LX) [0166] 4-[7-(2-cMoro-5-methoxy-phenyl)-5-metiiyl-benzo[l,2,4]triazhi-3-ylamino]-N-methyl-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0,297 mniol, 1.0 equiv) was dissolved in 10 mL anhydrous DCM and placed under an argon atmosphere. 4 ml. of BBra (0.1 M) was added via syringe and the reaction was stirred at room temperature for 2 h, BBr3 was quenched with saturated NaHCOs until pH = 7. The mixture was filtered and washed with water and Et20 to give 4-[7-(2-chloro-5-hydi'oxy-phenyl)-5-methyl-benzo[l,2,4]triaziii-3-ylamino]-N-methyl-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide, as a dark green solid (120.5 mg, 74% yield). Rf = 0.61 1H NMR (DMSO-d6): 5 1.90(m, 2H), 2.01 (m, 2H), 2.72 (s, 6H), 3.06 (m, 2H), 3.30 (t, J= 5.6 Hz, 2H), 3.38 (t, J= 6.0 Hz, 2H), 3.59 (m, 2H), 6.89 (dd, J= 8.8 Hz, J= 2.9 Hz, IH), 6.96 (d, J= 2.9 Hz, IH), 7,40 (d, /= 8.6 Hz, IH), 7.87 (d, /= 8.9Hz, 2H)3 7.92 (d, J= 0.9 Hz, IH), 8.21 (d, /= 1.7Hz, IH), 8.30 (d, J= 9.0 Hz, H), 11.50 (s, IH). MS (ES+) m/z - 553 LC retention time 2.41 min. Elemental for CiTHsoCkNeCbS 5H2O Calculated: C 47.72, H 5.93, N 11.37. Found: C 46.59, H 5.67, N 11.42. 3,46 (m, 2H), 3.78 (m, 2H), 6,88 (dd, J= 8,8Hz, J = 2.9 Hz, IH), 6.95 (d, J = 2.9 Hz, 1H),7.41 (d,/=8.7Hz, IH), 7,45 (dd, J= 7,9 Hz, 7 = 1.7 Hz, IH), 7.72 (t, J= 8.1 Hz, 2H),7.91 (d, .7= 1.7 Hz, IH), 8,12 (del,./- 8,3 Hz,/= 1.7 Hz, IH), 8.21 (d, 7= 1.9 Hz, IH), 8.93 (d, J= 1.9 Hz, IH), 9.99 (s, IH), 11,46 (s, IH). MS(ES+): m/z = 526. Elemental for C^HjeClzNeOgS 5H20 Calculated: C 46.08, H 5.57, N 12.90. Found: C 46.84, H 5.04, N 12.66. Example 62 Synthesis of 7-(2-chloro-5-nitro-phenvI)-5-rnethYl-benzo[l vlamine N NH2 (LXVII) [0173] 7-bromo-5-methyl-benzo[l,2,4]triazin-3-ylamine (3.35 mmol, 1.0 equiv), 2-chloro-5-nitrophenyl-boronic acid (5.02 mmol, 1.5 equiv), Pd(PPhs)4 (0.335 mmol, 0.1 equiv), and IS^COa (13.4 mmol, 4,0 equiv) were dissolved, in a mixture of DME/EtOH/H2O (4:1:1 v/v/v) andrefluxed at 100°C tor 18 h. The reaction was diluted with 50 mL DCM and filtered. The precipitate was suspended in water to remove excess NaaCOs and filtered again with a final EtaO wash to remove water. The crude precipitate gave 7-(2-cMoro-5-rutro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylanaine, as a dark green solid (l.Og, 94% yield). Rf = 0.55 MS (ES+) m/z = 316 LC retention time 2.96 irrm. 3.35 (dt, J= 5,3 Hz, /= 5,4 Hz, 4H), 3.58 (q, J= 5.2 Ez, 2H), 7.52 (t, J= 7.6 Hz, 1H), 7,67 (d, J= 3.2 Hz, 2H), 7.79 (s, 1H), 7.87 (d, .7= 3.2 Hz, 2H),8.18 (s, 1H), 8.31 (s,J= 9.0 Hz, 2H), 10.51 (bs, IH), 11.55 (s, 1H). MS (ES+) m/z = 574, LC retention tune 2.80 minutes. Example 67 Synthesis of f7-(2-chIoro-5-methoxv-phenyi)-5-methvl-b en zo ] 1.2,41triazin-3-vn-[4-(4-methvI-piperaziDe-l-sulfoDyi)-phenvn-amiae (Lxxn) [0179] 7-(2-cMoro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazm-3-ylamine(1.0 equiv., 0.75 mmol), l-(4-bromo-benzenesulfonyl)-4-methyl-piperazine (1.5 equiv., 1.125 ramol), Xaatphos (0.1 equiv.,'0.074 ramol), palladium acetate (0.05 equiv., 0.0375 mmol), and potassium-tert-butoxide (2.0 equiv, 1.5 mmol) were dissolved in 20 rriL of dioxane and bubbled with argon. The reaction was stirred in an oil bath at 100°C for 18 h under an argon blanket. The reaction was cooled to room temperature and filtered to remove inorganics, concentrated under reduced pressure, then brought up in EtOAc and extracted using saturated NaHCOs and brine. The organics were dried over Na2S04 and concentrated under reduced pressure then precipitated using EtOAc/ Hexanes (1:5 v/v) to afford brown solid (182.3 mg, 45% yield). MS (ES+): m/z - 540 LC retention time: 2.67 min. Example 68 Synthesis of 4-chloro-3-{5-methvI-3-[4-(4-methyI-piperazine-l-sulfonyl)-phenylammol-benzo [ 1.2,41 triazin-7-yl}-phenot (LXXffl) [0180] [7-(2-cMoro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-[4-(4-methyl-piperazine-l-sulfonyl)-pheayl]-amine (1.0 equiv., 0.339 mmol) was dissolved in 10 mL anhydrous DCM, purged of air via house vacuum, then blanketed with argon. Neat BBr3 (4.0 equiv., 1.355 mmol) was added via syringe'dropwise and allowed to stir at room temperature for 2 h. The reaction was quenched with saturated NaHCOa; the precipitate was filtered and rinsed with Et20 to afford crude orange solid. The compound was purified by prep. HPLC using 10-50-75 gradient, collecting peaks for 9-14 minutes. A yellow solid was recovered (70.5 nig, 40% yield). *H NMR (DMSO-d6): 8 1.98 (s, 3H), 2.37 (bs, 4H), 2.72 (s, 3H), 2.90 (bs, 4H), 6.88 (dd, J= 2.94 Hz, 8.81 Hz, 1H), 6.95 (d, /= 2.92 Hz, 1H), 7.41 (d, J= 8.79 Hz, 1H), 7.78 (d, /== 8.89 Hz, 2H), 7.92 (m, 1H), 8.21 (d, /= 1.35 Hz, 1H), 8.28 (d, J= 8.88 Hz, 2H), 11.47 (s, 1H). MS (ES+): m/z = 526 LC retention time: 2.30 minutes. Example 69 Synthesis of l-[2-f3-bromo-pheDy!suIfanvl)-ethyn-pyrroIidine [0181] l-(2-chloroethyl)pyrrolidine hydrochloride (1.0 equiv,, 8,82 mmol) and 3-bromothiophenol (1.5 equiv., 13,23 mmol) were dissolved in acetonitrile (100 mL). Potassium carbonate (10.0 equiv., 88.2 mmol) was added to the reaction while stirring. The reaction was kept in oil bath at 80°C to reflux for 18 h. The reaction was then cooled to room temperature and filtered to remove excess inorganics, and the organics were extracted with saturated NaHCO.-) and brine. The organics were dried over NaaSCU then concentrated under reduced pressure. The resulting crude oil was purifbd by flash chromatography using 4:6 EtOAc/hexanes. The fractions were concentrated to afford product as a yellow oil (792,3 mg, 32% yield). Rf = 0.75 MS (ES+): m/z - 287 LC retention time: 1.81 ruin. Example 70 Synthesis of |7-(2-chloro-5-methoxy-phenvI)-5-methvl-benzo[l,2.41triazm-3-vn-[3-(2-pyrroIidm-l-vI-ethy{suIfapvl)-phenyl1-amine (LXXV) [0182] 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazm-3-ylanoine(1.0 equiv., 083 mmol), l-[2-(3-bromo-phenylsulfanyl)-ethyl]-pyrrolidine (1.5 equiv., 1.25 rnmol), Xantphos (0.1 equiv., 0.084 mmol), palladium acetate (0.05 equiv., 0.042 rhmol), and potassium-tert-butoxide (2.0 equiv., 1.66 mmol) were dissolved in 10 mL of dioxane, and argon was bubbled through the solution. The reaction was run under an argon blanket while refluxing at 100°C for 18 h. The reaction was then cooled to room temperature, filtered to remove inorganics, extracted using EtOAc with saturated NaHCOs and brine, dried over NaaSCU, and concentrated under reduced pressure. A crude material was precipitated using 1: 5 (v/v) EtOAc/ hexanes to afford a bright orange solid (311.8 mg, 74% yield). Rf = 0.48. Example 71 Synthesis of 4-chIoro-3-{5-tnethvl-3-|3-(2-pvLTolidiu-l-yl-ethylsulfanv!)-phepyIaminol-benzofl,2,4]triazin-7-yl}-phenoI (LXXVI) [0183]' [7-(2-chloro-5-methoxy-phenyI)-5-methyl-benzo[l,2,4]triazin-3-yl]-[3-(2-pyrrolidin-l-yl-ethylsulfanyl)-phenyl]-amine (1.0 equiv., 0.62 mmol) was dissolved in anhydrous DCM, purged of air using house vacuum, and placed under an argon blanket. Neat BBra (4.0 equiv., 2.5 mmol) was then added via syringe and allowed to stir at room temperature for 2 h. The reaction was quenched using saturated NaHCOs; the precipitate was filtered and washed with water and EtiO to afford a dark orange/brown solid. The compound was purified by flash chromatography using 90:10 DCM/MeOH to recover a burnt orange solid (64.6 rng, 22% yield). Rf = 0.32 JH NMR (DMSO-d6): 8 1.68 (bs, 4H), 2.68 (s, 3H), 2.73 (bs, 2H), 3.14 (t, J= 6.87 Hz, 2H), 6.87 (d, J= 8.10 Hz, 1H), 6.93 (s, 1H), 7.03 (d, J= 7.42 Hz, 1H), 7.34 (t, J= 7.58 Hz, 1H), 7.40 (d, J= 8.65 Hz, 1H), 7.77 (d,/- 7.95 Hz, 1H), 8.16 (s, 2H), 9.93 (s, 1H), 11.01 (s, 1H). MS (ES+): 772/2 = 493 Example 72 Synthesis of 4-f7-(2-chIoro-5-methoxy-phenvI)-6-methyl-benzofl,2,4]triazin-3-yIamino]-N-methyi-N-(2-pyrroIidin-l-vl-ethy{)- benzenesulfonamide ! H (LXXVII) [0184] 7-(2-ch.loro-5-methoxy-pheiiyl)-6-meth.yI-benzo[l,2,4]triazm-3-ylamme(1.0 equiv., 0.28 mmol), 4-bromo-N-methyl-N-(2-pyrrolidin-l-yl-etliyl)-benzenesulfonamide (1.5 equiv., 0,42 mmol), Cs2C03 (3.0 equiv., 0.84 mmol), Pd2(dba)3 (0.1 equiv., 0.028 mmol), and Xantphos (0.2 equiv., 0.056 mmol) were dissolved in 20 mL of dioxane and argon was bubbled through the reaction mixture. The reaction was kept in oil bath to reflux at 100°C for 18 h. The reaction was then cooled to room temperature, filtered to remove inorganics, extracted with EtOAc, saturated NaHCOs and brine, and the orgam'cs were dried over NaiSCU, then concentrated under reduced pressure to give an orange solid (147.2 mg, 93% yield). The resulting crude material was used as is to prepare 4-[7-(2-chloro-5-hydroxy-phenyl)-6-methyl-benzo[l,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide as described hi the next example. Example 73 Synthesis of 4-F7-(2-chloro-5-hvdroxy-phenyI)-6-metbYi-benzo[l,2,4]triazm-3-ylamino1-N-methvl-N-(2-pvrroIidin-l-yl-ethvl)- benzenesulfonamide (Lxxvnr) [0185] 4-[7-(2-cMoro-5-methoxy-phenyl)-6-methyl-benzo[l,2,4]triazrn-3-ylarriino]-N-methyl-N-(2-pyrroHdin-l-yl-ethyl)-benzenesulfonamide (1.0 equiv., 0.26 mmol) obtained as described in Example 72, was dissolved in anhydrous DCM, purged of air using house vacuum, and placed under an argon blanket. Neat BBrs (4.0 equiv., 1.04 mmol) was then added via syringe and allowed to stir at room temperature for 2 h. The reaction was quenched using saturated NaHCOs, and the resulting precipitate was filtered and washed with water and Et^O to afford an olive green solid. The compound was purified by flash chromatography using 90:10 DCM/MeOH to recover a yellow/orange solid (88.2 mg, 62% yield). Rf = 0.19 !H NMR (DMSO-d6): 6 1.19 (t, J = 7.32 Hz, 2H), 1.89 (m, 2H), 2.01 (m, 2H), 2.29 (s, 3H), 2.73 (s, 3H), 3.06 (m, 4H), 6.82 (d, /= 2.85 Hz, IH), 6.91 (dd, J- 2.91 Hz, 8.61 Hz, IH), 7.40 (d, J= 8.81 Hz, IH), 7.79 (s, IH), 7,83 (d, J = 8.95 Hz, 2H), 8.11 (s, IH), 8,26 (d, /= 8.90 Hz, 2H). MS (ES+): m/z = 555 LC retention time: 2.28 min. Example 74 Synthesis of Acetic acid 4-chlQrQ-3-{5-methyI-3-f4-(2-pyrroIidLn-l-yt-ethoxY)-pbenylaminol-benzoll,2^41triazig-7-yU-phenyI ester (LXXK) [0186] To a solution of 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-l-yl-ethoxy)-phenylamino]-beiizo[l,2,4]triazin-7-yl}-phenolhydrochloride (1.0 equiv., 0.978 mmol) in DCM (30 mL) was added neat EtjN (10 equiv., 4.89 mmol) under an argon rich atmosphere and stirred for 10 minutes. Neat Acetyl chloride (1.2 equiv,, 1.17 mmol) was added dropwise via syringe to the reaction mixture and allowed to stir at room temperature for 24 h. The reaction was quenched using saturated NaHCOs; the organics were dried over NaaSC^ and then concentrated down under reduced pressure. The • resulting crude solid was then brought up in DCM and purified by flash chromatography using a solvent system of 85:10:5 (v/v/v) DCM/MeOH/EtsN. The fractions were concentrated under reduced pressure and precipitated out using 1:5 (v/v) DCM/hexanes to afford an orange solid (409.1 mg, 75% yield). 1H NMR (DMSO-d6): 5 1.68 (m, 4H), 2.29 (s, 3H), 2.51 (m, 4H), 2.63 (s, 3H), 2.78 (t, /= 5.94 Hz, 2H), 4.07 (t, J= 5.99 Hz, 2H), 6.99 (dd, /= 7.05 Hz, 12.55 Hz, 2H), 7.27 (dd, .7= 5.90 Hz, 8.75 Hz, 1H), 7.41 (d, J = 2.80 Hz, IH), 7.67 (d, J- 8.75 Hz, 1H), 7.85 (m, 1H), 7.93 (d, J= 9.05 Hz, 2H), 8.17 (m, IH), 10.83 (s, IH). Rf = 0.29 MS (ES+) m/z = 520, LC retention time 2.57 minutes. Example 77 Synthesis of 2,2-dimethyl-propionic acid 4-chloro-3-|5-methyI-3-[4-(2-pyrro{idin-l-vl-ethox^')-phenvlamino1-benzo[l,2,41triazin-7-yi}-phetiyl ester (LXXXE) [0189] The title product was synthesized and had the following characteristics. ]H NMR (DMSO-de) : 6 1.31 (s, 9H), 1.69 (m, 4H), 2.54 (m, 4H), 2.64 (s, 3H), 2.80 (t, J= 5.67 Hz, 2H), 4.07 (t, J= 5.95 Hz, 2H), 7.0 (d, 7 = 2.2 Hz, 2H), 7.25 (dd, J= 2.55 Hz, 8.45 Hz, IH), 7.39 (d, .7 = 2.7 Hz, IH), 7.67 (d, J= 8.75 Hz, IH), 7.85 (d, 7= 0.9 Hz, IH), 7.93 (d, J= 9.15 Hz, 2H), 8.19 (d, 7= 1.65 Hz, IH), 10.84 (s, IH). MS (ES+) m/z =560.4, LC retention time: 2.98 minutes. Example 78 Synthesis of Isobutyric acid 4-chloro-3-(5-methyI-3-[4-(2-pyrrolidin-l-yi-ethoxT)-phenvlamino1-benzo[l,2-,4Hriazm-7-yi|-phenyI ester (Lxxxni) [0190] The title product was synthesized and had the following characteristics. 1H NMR (DMSO-d6): 5 1.23 (s, 3H), 1.25 (s, 3H), 1.69 (m, 4H), 2.53 (m, 4H), 2.64 (s, 3H), 2.79 (t, 7= 5.88 Hz, 2H), 4.07 (t, 7= 5.94 Hz, 2H), 6.99 (d, 7= 7.05 Hz, 2H), 7.25 (dd, 7 - 2.85 Hz, 8.8 Hz, IH), 7.41 (d,7= 2.85 Hz, IH), 7.67 (d, 7= S.SHz, IH), 7.85 (d, 7= 1.1 Hz, IH), 7.93 (d, 7- 9.05 Hz, 2H), 8.18 (d, 7= 1.S5 Hz, IH), 10.84 (s, IH). MS (ES+) ???/z =548.7, LC retention time: 2.80 minutes. Example 79 Synthesis of 7-bromo-l-oxy-benzo[l,2,4|triazin-3-yIamine oe (LXXXTV) [0191] 4-bromo-2-nitro-phenylamine (11 .0 g) and cyanamide (1 1.0 g) were weighed out into a 1000 niL round bottom flask and heated to 100°C until melted. Heating was removed and concentrated HC1 (35 mL) was added slowly in. multiple small portions as this addition was extremely exothermic. Upon complete addition of HCI, reaction heating was resumed at 1 10°C for 4 hours. Reaction heating was then removed and 30% NaOH was added slowly in sufficient quantity so as to bring the reaction pH to about 13-14. This resulted hi copious yellow precipitate. Reaction heating was resumed for 1 hour. The reaction mixture was cooled, diluted with water (400 mL) and filtered. Isolated solids were dried, taken up hi DCM and filtered again to provide the pure material. Yellow solids (9.56 g, 80% yield). MS (ESI+): m/z = 243.0, JH NMR (DMSO-ds): § 7.46(d, 7=9.1 Hz, 1H), 7.88 (dd, J= 9.0 Hz, J= 2.4 Hz, 1H), 8.25 (d, ,7= 2.3 Hz, 1H), Example 80 Synthesis of 7-bromo-5-Ditro-l-oxy-benzofl.2,41triazin-3-vlamine (LXXXV) [0192] In a 1000 mL round bottom flask, 7-bromo-l-oxy-benzof l,2,4]triazin-3-ylamhie (9.5 g, 39.4 mmol, 1 equiv) was dissolved completely in suliunc acid (24 mL) and chilled to 0°C using an ice bath. Fuming nitric acid (24 mL) was added hi 3 portions Example 82 Synthesis of 4-f7-(2,6-dimethvl-pheDyl)-5-nitro-l-gxY-benzofl,2.41triazin-3-vlaminol-N-(2-pyrroIidin-l-v{-ethvl)-benzenesuIfonaniide (Lxxxvn) [0194] In a dry 25 raL round bottom flask, 7-(2,6-dimethyl-phenyl)-5-nJ.; u-l-oxy-benzo[l,2,4]triazin-3-ylamine (0.069 g, 0.22 mmol, 1 equiv), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (O.llg, 0.33 mmol, 1.5 equiv), cesium carbonate (0.22g, 0.67 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dirnethy] xanthene (0.026 g, 0.044 mmol, 0.2 equiv) and tris(dibenzylideneaeetone) dipalladium (0.021 g, 0.022mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (8 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 6 hours, then filtered hot, and the solvents were diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and. dried over sodium sulfate (NaiSO^). Filtration followed by evaporation and silica gel chromatography (6:1 DCM/ MeOH) provided desired product as a yellow powder (0.079 g, 63% yield). MS (ESI+):m/z = 564.4, LC retention time: 2.73 min. (LXXXVIIT) Example 83 Synthesis of 4-f5-amino-7-(2,6-dimethyl-pheDvI)-bep2o[l [0195] 4-[7-(2,6-dimethyI-phenyl)-5-nitro-l-oxy-benzo[l,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonainide (0.079 g, 0.14 mmol, 1 equiv) was combined with 10% palladium on carbon (0.029 g) and flushed with argon. The reactants were then diluted with methanol (5 niL) and the reaction atmosphere was evacuated and replaced with hydrogen. A hydrogen balloon was affixed and the reaction was allowed to stir for 3 hours. Argon was then bubbled through the reaction mixture and contents were filtered though a pad of Celite. Solvents were evaporated to provide a green solid product (0.045 g, 62% yield). MS (ESI+): 518.4 (M+H), r.t.= 2.56 mm. Example 84 Synthesis of N-(7-f2,6-dimethvl-phenvI)-3-f4-(2-pyrrolidin-l-vl-ethvlsuIfanioYD-phenylaminol-benzofl^^ltriazln-S-yll-acetamideTFAsalt (LXXXDQ [0196] A 0°C solution of 4-[5-amino-7-(2}6-drrnethyl-phenyl)-beirzo[ 1,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.045 g, 0.087 mmol, 1 equiv) in DCM (3 mL) was treated with acetyl chloride (0.011 g, 0,14 mmol., 1.6 equiv) and allowed to warm to ambient temperature. After 18 hours, the reaction solvents were evaporated to provide crude residue. HPLC purification provided the TFA salt of desired product as a yellow powder (0.011 g, 23% yield). MS (ESI+): m/z = 560.4, LC retention time: 2.67 min. !H NMR (DMSO-d6): 5 1.85-1.88 (m, 2H), 1.99-2.01 (m, 2H), 2.07 (s, 6H), 2.2S (s, 3H), 3.02-3.08 (m, 4H), 3.23-3.27 (m, 2H), 3.54-3.57 (m, 2H), 7.20 (d, J=7.6 Hz, 2H), 7.24-7.27 (m, 1H), 7.87 (d, J=8.9 Hz, 2H), 7.89 (t, .7=6.1 Hz, 1H), 7.94 (d, Xl.8 Hz, 1H), 8.26 (d, 7=8.9 Hz, 3H), 9.56 (bs, 1.H), 9.84 (s, 1H) 11.48 (s, 1H). Example 85 'Synthesis of N-f3-(4-facetvI-(2-pyrroI{dm-l-v{-ethyI)-suIi'amovI]-DheavIamiDo|-7-r2.6-dimethvi-phenvl)-benzofl,2,41triazin-5-vl1-acetamide (XC) [0197] A 0°C degree solution of 4-[5-amino-7-(2,6-dimethyl-phenyl)-benzo[l,2,4]1riazm-3-ylamino]-N-(2~pyiToIidin-l-yl-ethyl)-benzenesulfonamide (0.045 g, 0.087 mmol, 1 equiv) in DCM (3 ml) was treated with acetyl chloride (0.011 g, 0.14 mmol, 1.6 equiv) and allowed to warm to ambient temperature. After 18 hours, the reaction solvents were evaporated to provide crude residue. HPLC purification provided the TFA salt, of the desired product as a yellow powder (0.004 g, 8% yield). MS (ESI+): m/z - 602.4, LC retention time: 2.83 min. 'H NMR (DMSO-d6): 8 1.87-1.89 (m, 2H), 2.04-2.08 (m, SH), 2.29 (s, 3H), 2.36 (s, 3H), 3.09-3,11 (m, 2H), 3.64-3.66 (m, 2H), 4.08 (t, /=7.0 Hz, 2.H), 7.20 (d, J=7.6 Hz, 2H), 7.24-7.27 (m, IH), 7.96 (d, .7=1.6 Hz, IH), 8.04 (d, J=9.0 Hz, 2H), 8.26-8.30 (m, 3H), 9.73 (bs, IH), 9.85 (s, IH) 11.60 (s, IH). Example 86 Synthesis of 4-[7-(2-ch? ?ro-5-methoxy-pJienyl)-5-methyI-benzo|l,2,41triazin-3-ylamiao]-N-(2-pyrrolidin-l-vI-ethyl)-benzenesu{fonamide (XCI) [0198] In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.157 g, 0.523 mmol, 1 equiv), 4-bromo-N-(2-pyrrolidin- l-yl-ethyl)-benzenesulfonamide (0.261 g, 0.785 mmol, 1.5 equiv), cesium carbonate (0.512 g, 1.57 mmol, 3 equiv), 4,5-bis(diphenylphosphino)~9,9-dimethyl xanthene (0.061 g, 0.10 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.048 g, 0.052mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (5 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot, and the solvents were diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2S04), Filtration followed by evaporation provided slightly impure product. Solids were diluted in minimum amount of DCM and precipitated out using excess hexanes. The resulting solids were filtered off and dried to yield a yellow powder (0.276 g, 95% yield). MS (ESI+): m/z = 553.3, LC retention time: 2.77 xnin. Example 87 Synthesis of 4-{7-(2-chlprQ-5-hydrox>;r-phenv{)-5-methyl-benzojlt2,41triazin-3-yiamiaol-N-(2-pyrrolidm-l-Yl-ethyl)-benzenesuifoiiamideTFA salt (xcn) [0199] 4-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-ylamino]-N-(2-pyrrolidm-l-yl-ethyl)-benzenesulfonamide (0.055 g, 0.099 mmol, 1 equiv) was diluted with 15 mL DCM and chilled to 0°C using an ice bath. A 1.0 M solution of BBrs in DCM (0.25 mL, 0.25 mmol, 2.5 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 15 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 3-5 minutes. Additional DCM was added and this mixture was washed with sodium bicarbonate followed by brine. The organic phase was separated, dried over sodium sulfate (Na2SO4), filtered and evaporated to iryness. HPLC purification provided the TFA salt of desired product as a yellow solid (0.013 g, 25% yield). MS (ESI+): m/z = 539.3 , LC retention time: 2.50 ruin. 1E NMR (DMSO-d6): S 1.86 (bs, 2H), 1.99(bs, 2H), 2.71 (s, 3H), 2.28 (s, 3H), 3.04-3.07 (rn, 4H), 3.23(bs, 2H), 3.55(s, 2H), 6.53 (s, IH), 6.89 (dd, 7=8.7 Hz, 7-2.9 Hz, IH), 6.94 (d, 7=2.9 Hz, IH), 7.41 (d, 7=8.7 Hz, 1HJ, 7.83 (bs, IH), 7.87 (d, 7-8.8 Hz, 2H), 7.92 (s, IH), 8.22 (d, 7=1.7 Hz, IH), 8.26 (d, 7=8.8 Hz, 2H), 9.55 (bs, IH), 9,96 (s, IH) 11.44 (s, IH). Example 88 Synthesis of 3-(3-amino-5-methyl-benzofl,2i41triazin-7-yI)-4-chIoro- phenol N NH2 (XCIH) [0200] 7-(2-chloro-5-metlioxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.158 g, 0.527 mmol, 1 equiv) was diluted with. 10 mL DCM and chilled to 0°C using an ice bath. A 1.0 M solution of Bfta in DCM (3.16 mL, 3.16 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 3.5 hours, then quenched, by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonicatiou for 3-5 minutes. Additional DCM was added and this mixture was washed with sodium bicarbonate followed by brine. The organic phase was separated, dried over sodium sulfate (Na?,SO4), filtered and evaporated to dryness. Solids were then diluted with minimum amount of ethyl acetate and precipitated out with hexanes. Product was filtered off and dried to yield a yellow solid (0.110 g, 73 % yield). MS (ESI+): m/z = 287.1, LC retention time: 2.46 miri. Example 89 Synthesis of N-(5-f7-(2-chIoro-5-hydro^-phenyl)-5-methvI-beiizofl,2.4]triazin-3-YlamiDol-pyridmr2-yl}-acetamideTFAsalt (xcrv) [0201] In a dry 25 mL round bottom flask, 3-(3-amino-5-methyl-benzo[l,2,4]triazin-7-yl)-4-chloro-phenol (0.0641 g, 0.224 mmol, 1 equiv), N-(5-bromo-pyridin-2-yl)-acetaniide (0.0723 g, 0.336 mmol, 1.5 equiv), cesium.carbonate (0.220 g, 0.672 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xarithene (0.026 g, 0.0448 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.0205 g, 0.0224 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (8 mL) and outfitted with reflux condenser. The reaction was heated to reflux for IS hours, then filtered hot and solvents were diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2S04). Filtration followed by evaporation and HPLC purification provided the TFA salt of desired product as a yellow powder (0.004 g, 4% yield). MS (ESI+): m/z = 421.1, LC retention time: 2.44 min. 1HNMR (DMSO-ds): 8 2.09 (s, 3H), 2.65 (s, 3H), 6.87 (dd, J=8.7 Hz, J=2.9 Hz, 1H), 6.93 (d, J=2.9 Hz, 1H), 7.40 (d, J-8.7 Hz, 1H), 7.86 (s, 1H), 8.11 (d, J=8.9 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 8.39 (dd, /-9.0 Hz, J-2.7 Hz, 1H), 8.93 (d, .7=2.5 Hz, 1H), 9.92 (bs, 1H), 10.47 (s, 1H), 11.05 (s, 1H), Example 90 Synthesis of l-f2-(3-bromo-phenQxy)-ethyl1-pyrro{idme Br' (XCV) [0202] 3-bromo-phenol (5,34 g, 30.9 mmol, I equiv), l-(2-chioro-ethyl)-pyrrolidine (5,24 g, 30.9 mmol, 1 equiv) and potassium carbonate (KjCOs) (34 g, 24.7 mmol, 8 equiv) were weighed out into a 500 mL round bottom flask, were diluted with 150 mL DMF and stirred for 2 days. The contents were poured onto ethyl acetate water mixture and extracted once. The organic layer was separated, washed with brine and dried over sodium sulfate (Na^SO^. Filtration followed by concentration provided crude product as a pale yellow oil. Column chromatography (1:9 ethyl acetate/ hexanes) provided desired product as a yellow oil (3.6 g, 43% yield). 1E NMR (DMSO-ds): 5 1.65-1,69 (m, 4H), 2.72 (s, IH), 2.75 (t, /= 5.8 Hz, 2H), 2.88 (s, IH), 4.06 (t, J= 5.8 Hz, 2H), 6.95 (dd, J= 8.35 Hz, IH), 7.11 (d, J=7.7, IE), 7.13-7.14 (m, IH), 7.22 (t, J= 8.1Hz, IH). Example 91 Synthesis, of f7-(2-chloro-5-methory-pheDvI)-5-methyl-benzoJl,2,4]triazin-3-yn-[3-(2-pyrroIidin-l-yI-ethory)-pheiivII-amine (XCVI) [0203] In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-rnethyl-benzo[l,2,4]triazin-3-ylamine (0.113 g, 0.377 mmol, 1 equiv), l-[2-(3-bromo-phenoxy)-ethylj-pyrrolidrne (0.153 g, 0.565 mmol, 1.5 equiv), cesium carbonate (0.368 g, 1.13 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0,044 g, 0.0753 mmol, 0,2 equiv) and tris(dibeazylideneacetoriG) dipalladium (0.034 g, 0.0376 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (8 rnL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot and the solvents were diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2SC>4). Filtration followed by evaporation and column chromatography (1:5 MeOH/ DCM) provided desired product as a. yellow powder (0.12 g, 65% yield). MS (ESI+): m/z = 491.1, LC retention time: 2.94 min. Example 92 Synthesis of 4-chloro-3-{5-methvl-3-[3-(2-pyrrolidin-l-y{-ethoxY)-pheDvlamino1-benzofl.2,41triazin-7-yl}-pheDQ{ TFA salt (xcvri) [0204] [7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-[3-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-amine (0.120 g, 0.245 mmol, 1 equiv) was diluted with 8 mL DCM and chilled to 0°C using an ice bath. A 1.0 M solution of BBr3 in DCM (2 mL, 1.96 mmol, 8.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 3.5 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate, followed by sonication for 5 minutes. Additional DCM was added and this mixture was washed with sodium bicarbonate followed by brine. The organic phase was separated, dried over sodium sulfate (Na2S04), filtered and evaporated to dryness. Solids were then diluted with rninimum. amount of ethyl acetate and precipitated out with hexanes. Product was filtered off and dried. HPLC purification provided TFA salt of desired product as a yellow solid (0.008 g, 7 % yield). MS (ESI+): 'm/z = 476.1, LC retention time: 2.64 min. !H NMR (DMSO-d6): 5 1.88-1.91 (m, 2H), 2.04-2.07 (m, 2H), 2.68 (s, 3H), 3.17-3.20 (m, 2H), 3.64-3.66 (m, 4H), 4.36 (t, .7=4.7 Hz, 2H), 6.74 (dd, 7=8.1 Hz, 7=2.3 Hz, 1H), 6,88 (dd, 7=8.5 Hz, 7=2.8 Hz, 1H), 6.93 (d, 7-2.9 Hz, 1H), 7.35 (t, 7=8.2 Hz,, 1H), 7.41 (d, 7=8.7 Hz, 1H), 7.55 (d, 7=8.7 Hz, 1H), 7.8S.(s, 1H), 7.95-7.96 (m, 1H), 8.17 (d, 7=1.7 Hz, 1H), 9,79 (bs, 1H), 9,95 (s, 1H), 11.04 (s, 1H). Example 93 Synthesis of (4-f7-(2-chlorp-5-methoxy-phenyl)-5-methyI-beDzofl,2,4|triazin.-3-ylamino|-phenyU-(4-methyI-piperazin-l-yl)-methanone H (xcvrn) [0205] In. a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl V5-methyl-benzo[1.2,4]triazin-3-ylamine (0.282 g, 0.94 mmol, 1 equiv), (4-bromo-phenyl)-(4-methyl-piperazin-l-yl)-methanone (0.399 g, 1.41 mmol, 1.5 equiv), cesium carbonate (0.919 g, 2.82 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.109 g, 0.1SS mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.086 g, 0.094 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (12 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot and solvents were evaporated. The residue was diluted with toluene and. water (approx. 2:1), and the mixture was heated to 70°C and stirred for 20 rain. The contents were then poured, into 250 mL separatory funnel and shaken. The resulting precipitate was filtered off, washed with water and dried to yield a yellow powder (0.275 g, 58% yield). MS (ESI+): m/z = 504.1, LC retention time: 1.75 min. Example 94 Synthesis of {4-f7-(2-chioro-5-hydrQxy-phenyI)-5-methvi-benzo|1.2,41triaziu-3-vIamino]-phenvl|-(4-methyi-piperazin-l-yl)-methanoneTFA salt (XCIX) [0206] {4-[7-(2-cliloro-5-methoxy-phenyl)-5-methyl-beiizo[l,2,4]triazia-3-ylamino]-phenyl}-(4-methyl-piperazm-l-yl)-methanone (0.139 g, 0.276 mtnol, 1 equiv) was diluted with 10 mL DCM and chilled to 0°C using an ice bath. A 1.0 M solution of BBrs in DCM (1.66 mL, 1.66 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 1 hour, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 5 minutes. The resulting solids were filtered off and dried. HPLC purification provided desired product as TFA salt to yield a yellow solid (0.024 g, 18 % yield). MS (ESI+): m/z = 489.1, LC retention time: 2.11 min. l'R NMR (DMSO-dg): 5 2.69 (s, 3H), 2.84 (s, 3H), 3.22 (bs, 2H), 6.88 (dd, .7=8.8 Hz, >2.9 Hz, IK), 6.93 (d, J=2.9 Hz, 1H), 7.41 (d, /=8J Hz, 1H), 7.55 (d, /=8.7 Hz, 2H), 7.89 (s, 1H), 8.14 (d, J=8.7 Hz, 2H), 8.19 (d, J=1.3 Hz, 1H), 9.88 (bs, 1H), 9.95 (bs, 1H), 11.24 (s, 1H). Example 95 Synthesis of 5-f7-(2-chIoro-5-methoxy-plienvI)-5-mettivl-benzofl,2,4]triaziii-3-vlamiiio]-pyridine-2-carboxylic acid (2-pyrrolidin-I-vI-ethvl)- araide (C) [0207] In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.090 g, 0.299 mmol, 1 equiv), 5-bromo-pyridine-2-carboxylic acid (2-pyrrolidin-l-yl-ethyl)-aniide (0.134 g, 0.449mmol, 1.5 equiv), cesium carbonate (0.293 g, 0.899 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.035 g, 0.059 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.027 g, 0.0299 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (8 mL) and outfitted with reflux condenser. The reaction was heated, to reflux for 24 hours, then sonicated and slowly diluted with water. The resulting orange precipitate was filtered and dried. Column chromatography (1:5 MeOH/ DCM) provided desired product as a yellow solid (0.085 g, 55% yield). Example 96 Synthesis of 5-f7-(2-chloro-5-hydrQxy-phgnyI)-5-metIiyI-benzo[l,214]triazin-3-yIamiDQl-pvridine-2-carboxylicacid(2-pyrroIidin-l-yl-etbyI)- (CD amide HCI salt [0208] 5-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]- • pyridine-2-carboxylic acid (2-pyrrolidm-l-yl-ethyl)-arnide (0.085 g, 0.164 mmol, 1 equiv) was diluted with 20 mL DCM and chilled, to 0°C using an ice bath. A 1.0 M solution of BBi'3 in DCM (1 mL, 0.984 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient, temperature and stirred, for 6 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 5 minutes. The resulting solids were filtered off, dried, and dissolved in DCM (10 mL) and MeOH (20 mL) mixture and treated with 2.0 M solution of HCI in diethyl ether (0.16 mL, 0.317 mmol, 2 equiv). The solvents were evaporated leaving desired product as HCI salt in. a form of a yellow solid (0.084 g, 95 % yield). MS (ESI+): m/z = 504.1, LC retention time: 2.23 min. 'H NMR (DMSO-d^): 8 1.864.88 (m, 2H), 1.99-2.02 (m, 2H), 2.70 (s, 3H), 3.01-3.05 (m, 2H), 3.33-3.37 (m, 2H), 6.90 (dd, .7=8.7 Hz, J=2.9 Hz, 1H), 6.97 (d, ,7=2.9 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.92-7.93 (m, 1H), S.12 (d, .7=8.7 Hz, 1H), S.22 (d, .7=1.5 Hz, 1H), 8.51 (dd, J=8.6 Hz, J=2.5 Hz, 1H), 9.06 (t, .7=5.9 Hz, 1H), 9.43 (d, J=2.4 Hz, 1H), 10.17 (bs, 1H), 11.50 (s, 1H). Example 97 Synthesis of [7-(2-chloro-5-methoxy-phenyI)-5-methyI-benzoH.2,41triazin-3-yn-F4-(3-pyrroIidm-l-yI-propane-l-su{fonyI)-phenyn-amine (C1T) [0209] In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamme (0.0361 g, 0.1.22 mmol, 1 equiv), l-[3-(4-bromo-benzenesulfonyl)-propyl]-pyrrolidine (0.061 g, 0.184 mmol, 1.5 equiv), cesium carbonate (0.120 g, 0.367 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.014 g, 0.0244 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipaliadium (0.012 g, 0.0122-mmol, 0,1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (6 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, filtered hot, diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (NajSCU). Filtration followed by evaporation provided crude product, whichwas dissolved in minimum amount of DCM and precipitated out with excess hexanes. Solids were filtered off and dried to yield a yellow powder (0.06 g, 91% yield). Example 98 Synthesis of 4-chioro-3-|5-metbyi-3-f4-(3-pyrroIidiD-l-yI-propane-l-suIfonYl)-phenylamino]-benzofl,2,4]triazm-7-yl}-phenQl TFA salt (CHI) [0210] [7-(2-chJoro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-[4-(3-pyrrolidin-l-yl-propane-l-sulfonyl)-phenyl]-amine (0.080 g, 0.1.45 mmol, 1 equiv) was diluted with 10 mL DCM and chilled to 0°C using an ice bath. A 1.0 M solution of BBr3 in DCM (0.87 mL, 0.87 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 6 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 3-5 minutes. The resulting solids were filtered off and dried. HPLC purification provided desired product as TFA salt in a form of a yellow solid (0.013 g, 17 % yield). MS (ESI+): m/z - 538.1, LC retention time: 2.35 min. !HNMR (DMSO-de): 5 1.81-1.84 (m, 2H), 1.93-2.00 (m, 4H), 2.72 (s, 3H), 2.95-2.99 (m, 2H), 3.20-3.24 (m, 2H), 3.53-3.54 (m, 2H), 6.89 (dd, .7=8.7 Hz, ,7=2.9 Hz, 1H), 6.94 (d, /=2.8 Hz, 1H), 7.41 (d, .7=8.7 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 8.23 (d, ,7=1.6 Hz, 1H), 8,31 (d, /=8.9 Hz, 2H), 9.61 (bs, 1H), 9.98 (s, 1H), 11.52 (s, 1H). Example 99 Synthesis of N-[3"(3-amiflo-5-methyI-benzo[1.2,41triazin-7-vt)-pbenvn- methanesulfonamide (CIV) [0211] An oven dried 25 mL round bottom flask was charged with 7-bromo-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.889 g, 3.72 rnmol, 1 equiv), 3-(methylsulfonylamino) phenyl boronic acid (1.12 g, 5,21 mmol, 1.4 equiv), sodium carbonate (1.57 g, 14.9 mmol, 4 equiv) and tetrakis(triphenylphosphine) palladium(O) (0.43 g, 0.372 mmol, 0.1. equiv). The reactants were flushed with argon and diluted with ethylene glycol dimethyl ether (20 niL), ethanol (5 mL) and Dl water (5 mL). The reaction vessel was outfitted with condenser and refluxed for 4 hours. The reaction was filtered hot and diluted with ethyl acetate. The Organic layer was isolated and concentrated to a dark residue. This was dissolved in DMF (6 mL) and slowly diluted with water so as to precipitate out the product. Solids were filtered off and dried to yield an orange solid (1 g, 82% yield). Example 100 Synthesis of 4-f7-(3-methanesuIfony|amiiio-phenyl)-5-niethyI-benzofl.2,41triazin-3-yIamino]-N-(2-pyrroIidin-l-vl-ethyl)-benzenesuifonamideTFA salt (CV) [0212] In a dry 25 mL round bottom flask, N-[3-(3-amino-5-methyl-ben2o[l,2,4]triazin-7-yl)-phenyrj-methanesulfonamide(0.12 g, 0.365 mmol, 1 equiv), 4- Dromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.182 g, 0.55 mrnol, 1.5 equiv), cesium carbonate (0.357 g, 1.09 mrnol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dirnethyl xanthene (0..0422 g, 0.073 mrnol. 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.033 g, 0.036 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (10 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 2 hours, then filtered hot and the solvents were. evaporated. HPLC purification provided desired product as TFA salt, in a form of a yellow powder{0.02 g, 9% yield). MS (ESI+): m/z = 582.1, LC retention time: 2.21 min. ^NMR (DMSO-dg): 5 1.85-1.87 (m, 2H), 1.99-2.01 (m, 2H), 2.74 (s, 3H), 3.04-3.08 (m, 3H), 3.04-3.07 (m, 7H), 3.23-3.25 (m, 2H), 3.56(bs, 2H), 7.29 (dd, .7=8.0 Hz, .7=1.6 Hz, IH), 7.52 (t, J=7.9 Hz, IH), 7.63 (d, J=8.0 Hz, 2H), 7.66 (bs, IH), 7.83-7.88 (m, 3H), 8.18 (bs, IH), 8.25 (d, .7=8.9 Hz, 2H), 8,43 (d, J=1.7 Hz, IH), 9.57 (bs, IH), 9.92 (s, IH) 11.43(s, IH). Example 101 Synthesis of 5-methv!-7-(3-mtro-phenyl)-benzo[1,2,4]triazin-3- vlamine (CVI) [0213] An oven dried 25 mL round bottom flask was charged with 7-bromo-5-methyl-benzo[l,2,4]triazin-3-ylamine (1.05 g, 4.49 mmol, 1 equiv), 3-Nitro phenyl boronic acid (1.05 g, 6.29 mmol, 1.4 equiv), sodium carbonate (1.9 g, 18 mmol, 4 equiv) and tetralds(rriphenylphosphine) palladium(O) (0.519 g, 0.449 mmol, 0.1 equiv). The reactants were flushed with argon and diluted with ethylene glycol dimethyl ether (6 mL), ethanol (1 mL) and DI water (1 mL). The reaction vessel was outfitted with condenser and refluxed for 2.5 hours. The reaction was cooled to ambient temperature and diluted with water. The resulting precipitate was filtered off, washed thoroughly with water and dried . Brown solids (0.9 g, 73% yield). MS (ESI+): m/z = 282.4, LC retention time: 2.77 min. Example 102 Synthesis of 4-r5-methyI-7-(3-nitro-pheuyl)-beuzo[l,2,41triazin-3-vIaminol-N-(2-pyrrolidin-l-yt-ethyl)-benzenesulfonamide (cvn) [0214] In a dry 25 mL round bottom flask, 5-methyl-7-(3-nitro-phenyl)-benzo[l,2,4]triazm-3-ylainine (0.223 g, 0.7935 mmol, 1 equiv), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.396 g, 1.19 mmol, 1.5 equiv), cesium carbonate (0.776 g, 2.38 mmol, 3 equiv), 4,5-bis(diphenylphospMno)-9,9-dimethyl xanthene (0.092 g, 0.159 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.073 g, 0.079 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (10 mL) and outfitted with, a reflux condenser. The reaction was heated to reflux for 5 hours, then filtered hot and the solvents were evaporated. Silica gel column purification provided desired product as a yellow powder (0.16 g, 39% yield). MS (ESI+): m/z = 582.1 Example 103 Synthesis of 4-f5-methvl-7-(3-methylamino-phenyI)-benzofl,2,41triazip-3-ylamino]-N-(2-pyrroIidin-l-vl-'ethvl)-ben2enesjuIfonamideTFA (CVffl) salt [0215] 4-[7-(3-amino-phenyl)-5-methyl-benzo[l52,4]triazin-3-ylamino]-N-(2-pyrro]idm-l-yl-ethyl)-benzenesulfonamide (0.031 g, 0.062 mmol, 1 equiv) and cesium carbonate (0.012 g, 0.037 mmols 0.6 equiv) were combined and diluted with dioxane (5 mL). The mixture was then treated with methyl iodide (0.013 g, 0.092 mmol, 1.5 equiv) and stirred at ambient temperature. After initial 5-10 minutes of stirring, DMF (1 mL) was added to improve solubility, followed by stirring for 16 hours, after which the solvents were evaporated and the resulting residue purified by HPLC chrornatography to yield a yellow solid, the TFA salt (0.07g, 22% yield). MS (ESI+): m/z = 518.7, LC retention time: 1.86 min. 1HNMR(DMSO-d6): 8 2.08 (bs, 4H), 2.74 (s, 3H), 3.02 (s, 3H), 3.24 (m, 2H), 3.46-3.49 (m, 5H), 3.52-3.56(m, 3H), 6.8 (d, ,7=8.2 Hz, IH), 7.19 (m, 2H), 7.26-7.29 (m, IH), 7.88 (d, 7=8.8 Hz, IH), 7.94 (t, /=7.7 Hz, IH), 8.16 (d, /=1.7 Hz, IH), 8.25 (d, .7=8.8 Hz, 2H), 8.36 (d, J=1.7 Hz, IH), 11.44 (s, IH). ' Example 104 Synthesis of 4-[7-f3-amino-phenvl)-5-methyl-benzofl,2,41triazin-3-vIamino|-N-(2-pyrroIidin-l-vl-ethyI)-benzenesuIfonamide (OX) [0216] 4-[5-methyl-7-(3-nitro-phenyl)-benzo[l,2,4]rriazm-3-ylamino]-N-(2-pyrrolidin-l-yl-ethyl)-berizenesulfonamide (0.16 g, 0.3 mmol, 1 equiv) was combined with 10% palladium on carbon (0.135 g) and flushed with argon. The reactants were then diluted with methanol (15 mL), and rthe eaction atmosphere was evacuated and replaced with hydrogen. A hydrogen balloon was affixed and the reaction was allowed to stir for 3 hours. Argon was then bubbled through the reaction mixture and the contents were filtered though a pad of Celite. The solvents were evaporated to provide the product as an orange solid (0.15 g, 98% yield). MS (ESI+): m/z = 504.6, LC retention time: 1.84 min. 'HNMR (DMSO-de): 8 1.64 (bs, 4H), 2.72 (s, 3H), 2.87 (bs, 2H), 5.26 (s, 2H), 6.65 (d, J=7.8 Hz, 1H), 7.00 (d, 7=8.1 Hz, 1H), 7.05 (m, 1H), 7.18 (t, J=7.8 Hz, 1H), 7.83 (d, . J=8.8 Hz, 2H), 8.12 (s, 1H), 8.21 (d, J=8.8 Hz, 2H), 8.27 (d, J=1.7 Hz, 1H), 11.44 (s, 1H). Example 105 Synthesis of 4-(4-bromo-benzenesulfonyl)-piperazine-l-carboxvlic acid tert-butyl ester • (CX) [0217] To a stirring, 0°C solution of piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 6.29 mmol, 1.05 equiv) and TEA (1.67 mL, 11.98 mmol, 2.0 equiv) in DCM (10 mL) was added 4-bromo-benzenesulfonyl chloride (1.53 g, 5.99 mmol, 1 equiv). The reaction was allowed to warm to ambient temperature and stir for 3 h. The reaction solvents were evaporated and the resulting solids were dried, washed with water and filtered, yielding a white powder (2.24 g, 92% yield). MS (ESI+): m/z = 306.9, LC retention time: 3.17 min. Rf = 0.56 (30% EtOAc/hexanes). Example 106 Synthesis of 4-{4-f7-(2.6-dichloro-phenyl)-5-methyI-benzo[l,2.41triazin-3-ylainino1-beDzenesulfonyU-piperazme-l-carboxylicacidtert- butyl ester [0218] In a dry 25 mL round bottom flask, 7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.205 g, 0.672 mmol, 1 equiv), 4-(4-bromo-benzenesulfonyl)-piperazine-l-carboxylic acid tert-butyl ester (0.408 g, 1.01 rnmol, 1.5 equiv), cesium carbonate (0.657 g, 2.02 rnmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.078 g, 0.134 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.0615 g, 0.067 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (20 mL) and outfitted with a reflux condenser. The reaction was heated to reflux for 2 hours, then filtered hot, and the solvents were evaporated. Purification on silica gel flash column provided desired product as a yellow solid (0.185 g, 44% yield). MS (ESI+): m/z = 529.0 (M -100), LC retention time: 3.51min. 1H NMR (DMSO-d6): 8 1.33 (s, 9H), 2.72 (s, 3H), 2.87 (m, 4 H), 3.4 (m, 4H), 7.5 (m, IH), 7.67 (d, J=8.7 Hz, 2H), 7.78 (m, 3H), 8.18 (d, J=1.7 Hz, IH), 8.30 (d, .7=8.8 Hz,2H), 11.53 (s, IH). Example 107 Synthesis of r7-(2,6-dichloro-phenyl)-5-methyI-benzofl,2,4]triazin-3-vIH4-(piperazine-l-saLfonyr)-phenvI1-am!ne TFA salt Cl (cxn) [0219] 4- {4-[7-(2,6-dicMoro-phenyl)-5-methyi-benzo[l ,2,4]triazin-3-ylamino]-benzenesulfonyl}-piperazine-l-carboxylic acid tert-butyl ester (0.0696 g, 0.11 1 mmol, 1 equiv) was diluted with DCM (5 mL) and treated with TFA (0.051 mL, 0.664 mmol, 6 equiv). The resulting red solution was stirred at ambient temperature for 6 hours. Additional 6 equivalents of TFA were then added and the reaction was stirred for 12 hours. The solvents were then evaporated and the resulting solids collected and dried to yield a yellow powder (0.062 g, 99% yield). MS (ESI+): m/z = 528.9 , LC retention time: 2,70 min. :H NMR (DMSO-d6): 5 2.72 (s, 3H), 3.13 (m, 4 H), 3.22 (m, 4H), 7.53 (m, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.84 (d, J=8.7 Hz, 2 H), 8.20 (d, J=4.7 Hz, 1H), 8.32 (d, J=8.8 Hz, 2H), 8.62 (bs, 2H),11.53 (s, 1H). Example 108 Synthesis of 4-bromQ-N-isopropyl-N-(2-pyrroIidm-l-vl-ethyl)- benzenesulfonamide (cxm) 10220] 4-bromo-N-isopropyl-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (1.03 g, 3.09 mmol, 1 equiv), 2-bromo-propane (3.8 g, 31 mmol, 10 equiv) and cesium carbonate (2 g, 6.2 mmol, 2.0 equiv) were refluxed in acetone for 24h. The solvents were then removed and the resulting residue was dissolved in ethyl acetate and washed with water. The organic phase was then washed again with brine, dried over sodium sulfate, filtered and evaporated to yield the oily residue (0.86 g, 74% yield). MS (ESI+): m/z = 377.5, LC retention time: 2.16 min. Rf = 0.48 (10% MeOH:DCM), Example 109 Synthesis of [7-(2,6-dichloro-phenyl)-5-methyl-benzoH,2,41trlazin-3-vn-f4-fpiperazine-l-sulfonyIVphenyll-aniine HCI salt C! (CXIV) [0221] In a dry 25 nil round bottom flask, 7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.162 g, 0.533 mmol, 1 equiv), 4-bromo-N-isopropyl-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.3 g, 0.8 mmol, 1.5 equiv), cesium carbonate (0.522 g, 1.59 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.062 g, 0.106 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.049 g, 0.0533 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (20 mL), and outfitted with a reflux condenser. The reaction was heated to reflux for 2 hours, then filtered hot and the solvents were evaporated. Purification on silica gel flash column provided desired product, 0.144 g yellow solids, which were taken up in 5 mL DCM and treated with 2 mL 2M HC1 in ether solution. The solvents were then evaporated and the resulting solids were collected and dried to yield a yellow solid (0.16 g, 50% yield). MS (ESI+): m/z = 599.2, LC retention time: 2.99 min. 'HNMR (DMSO-de): S 0.98 (d, 6H), 1.88 (m, 2 H), 2.01 (m, 2H), 2.72 (s, 3H), 3.02-3.08 (m, 2H), 3.37 (m, 2H), 3.46 (m, 2H), 3.62 (m, 2H), 4.02 (m, 1H), 7.53 (m, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.79 (s, 1H), 7.92 (d, ,7=8.7 Hz, 2H), 8.18 (d, J=1.6 Hz, 1H), 8.27 (d, J=8.7 Hz, 2H), 10.7 (m, 1H), 11.51 (s, 1H). Example 110 Synthesis of 4-f7-(2,6-dichloro-phenvl)-5-methyl-benzofl,2,41triazin-3-vIammo1-N-(2-pyrroIidin-l-yl-ethyl)-benzenesuIfonamide HC1 salt (CXV). [0222] In a dry 25 mL round bottom flask, 7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.193 g, 0.633 mmol, 1 equiv), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-b.enzenesulfonamide (0.316 g, 0.95 mmol, 1.5 equiv), cesium carbonate (0.62 g, 1.89 mmol, 3 equiv), 4,5~bis(diphenylphosphino)-9,9-dimethyl xanthene (0.073 g, 0.127 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.058 g, 0.0533 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (20 mL), and outfitted with a reflux condenser. The reaction was heated to reflux for 16 hours, then filtered hot and the solvents were evaporated. HPLC purification provided desired product. Pure HPLC fractions were combined, diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was evaporated to dryness, diluted with DCM (10 mL) and treated with 2 mL 2M HCI in ether solution. The solvents were then evaporated and the resulting solids were collected and dried to yield a yellow solid (0.091 g, 26% yield). MS (ESI+): m/z = 559.6, LC retention time: 2.71 min. 1H NMR (DMSO-d6): 5 1.86 (bs, 2H), 1.98 (bs, 2H), 2.71 (s, 3H), 2.98-3.01 (m, 2H), 3.09-3,13 (m, 2H), 3.21-3.25 (m, 2H), 3.51-3.53 (m, 2H), 7.52 (m, 1H), 7.67 (d, J=8,7 Hz, 2H), 7.79 (m, 1H), 7.89 (dd, J=8.7 Hz, ,>=2.9 Hz, 1H), 7.95 (t, J=6.1 Hz, 1H), 8.18 (d, js=1.7 Hz, 1H), 8.26 (d, J=8.8 Hz, 2H), 10.37 (bs, 1H), 11.44 (s, 1H). Example 111 Synthesis of 7-(2-chIoro-5-methoxy-phenyI)-5-methvl-benzoU ,2,41triazia-3-vIamiae . (CXVI) [0223] In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.214 g, 0.713 mmol, 1 equiv), 4-bromo~N-isopropyl-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.321g, 0.856 mmol, 1.2 equiv), Cesium carbonate (0.698 g, 2.14 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.083 g, 0.143 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.065 g, 0.071 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (20 mL), and outfitted with a reflux condenser. The reaction was heated to reflux for 18 hours, then cooled to,room temperature and. the solvents were removed. The residue was diluted with DCM and purified via ISCO silica gel column chromatography (0% to 6% methanol in chloroform as solvent system), yielding a yellow powder (0.265 g, 62% yield). MS (ESI+): m/z = 597.7, LC retention time: 2.94 min. Rf = 0.45 (10% MeOH: DCM). Example 112 Synthesis of 4-F7-(2-chIoro-5-hydroxy-phenyl)-5-methyl- b enzo [1,2 t41triazip-3-ylamiPo1-N-isopropyl-N-f 2-pyrroIidin-l -yl-ethvD- benzenesulfonamide HC1 salt (cxvn) [0224] 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2)4]triazin-3-ylamine (0.158 g, 0.527 mmol, 1 equiv) was diluted with 10 mL DCM and chilled to 0°C using an ice bath. A 1.0 M solution of BBrs in DCM (3.16 mL, 3.16 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 3.5 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate, followed by sonication for 3-5 minutes. Additional DCM was added and this mixture was washed with sodium bicarbonate followed by brine. The organic phase was separated, dried over sodium sulfate (TSl^SCU), filtered and evaporated to dryness. The resulting solids were then diluted with rrunirnum amount of ethyl acetate and precipitated out with hexanes. The product was filtered off and dried yielding a yellow solid (0.110 g, 73 % yield). MS (ESI+): m/z = 582.0, LC retention time: 2.57 min. 1E NMR (DMSO-d5): 8 0.97 (d, J-6.7 Hz, 6H)51.87 (m, 2H), 2.02 (m, 2H), 2.71 (s, 3H), 3.04' (m, 2H), 3.29-3.37 (m, 2H), 3.49(m, 2H), 3.61 (m, 2H), 4.00 (m, 1H), 6.89 (dd, J=8.7 Hz, J=2.8 Hz, 1H), 6.96 (d, ,7=2.8 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.91-7.94 (m; 3H), 8.21 (d,/=1.5 Hz, 1H), 8.26 (d, J=8.9 Hz, 2H), 10.0 (s, 1H), 11.17(bs, 1H) 11.47 (s, 1H). Example 113 Synthesis of 4-(4-bromo-benzenesuIfonyI>piperidine-l-carboxYlic acid benzyl ester (CXVffl) [0225] 4-(4-bromo-phenylsulfanyl)-piperidine-l-carboxylic acid benzyl ester (1.2 g, 2.96 mmol, 1 equiv) and sodium perborate tetrahydrate (NaB03'4H2O) (1.36 g,.8.87 mm.o'1, 3 equiv) were heated to 55°C in HO Ac and stirred for 18h. The reaction was cooled to room temperature and poured onto water. The aqueous phase was extracted with EtOAc (3 x 100 mL). The organic phases were combined and washed carefully with saturated sodium bicarbonate solution (CAUTION: copious gas evolution), dried over sodium sulfate, filtered and evaporated to yield a white solid (1.2 g, 93% yield). Rf = 0.16 (20% EtOAc/hexanes). Example 114 Synthesis of 4-(4-bromo-phenylsulfanyl)-piperidSne-l-carboxyIic acid benzyl ester (cxrx) [0226] 4-bromo-benzenethiol (0.634 g, 3.36 mmol, 1 equiv), 4-bromo-piperidine-l-carboxylic acid benzyl ester (Ig, 3.36 mmol, 1 equiv) and cesium carbonate (2.18 g, 6.7 mmol, 2 equiv) were refluxed in acetone for 2 h. The reaction solvents were then removed and the resulting white solids were taken up in EtOAc and washed with water, then with brine. The organic phase was then dried over sodium sulfate, filtered and evaporated to yield clear oil (1.2 g, 88 % yield). Rf = 0.45 (20% EtOAc: Hexanes). Example 115 Synthesis of 4-{4-f7-(2-chIoro-5-methoxy-phenylV5-methvi-benzofl,2.41triazin-3-vlamino1-benzenesulfonvl}-piperidine-l-carboxvIic acid benzyl ester (CXX) [0227] In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (0.132 g, 0.44 mmol, 1 equiv), 4-(4-bromo-benzenesulfonyl)-piperidine-l-carboxylic acid benzyl ester (0.232 g, 0.529 mmol, 1.2 equiv), Cesium carbonate (0.432 g, 1.33 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.051 g, 0.088 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.040 g, 0.044 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (12 mL) and outfitted with a reflux condenser. The reaction was heated to reflux for 18 hours, then cooled to room temperature and slowly diluted with water. The resulting precipitate was collected and dried yielding a yellow powder (0.271 g, 93% yield). MS (ESI+): m/z = 658.2, LC retention time: 3.41 min. Example 116 Synthesis of 4-chIoro-3-{5-methyI-3-f4-(piperidme-4-sulfonvlV pheuyIamino1-benzo[l,2,41triazin-7-yI}-phenol HC1 salt (CXXI) [0228] 4- {4-[7-(2-chloro-5-methoxy-phenyl)-5-m.ethyl-benzo[l ,2,4]triazin-3-ylammo]-benzenesulfonyl}-piperidme-l-carboxylic acid benzyl ester (0.165 g, 0.251 mmol, 1 equiv) was diluted with 15 mL DCM and chilled to 0°C using an ice bath. A 1.0 M solution of BBrs in DCM (2.5 mL, 2.5 mmol, 10 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 3.5 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 3-5 minutes. The resulting solids were filtered off and dried. HPLC purification provided desired product as TFA salt in a form of a yellow solid (0.028 g, 22 % yield). MS (ESI+): m/z = 510.0, LC retention time: 2.27 min. !H NMR (DMSO-d6): 8 1.68-1.77 (m, 2H), 2.02-2.07 (m, 2H)5 2.72 (s, 3H), 2.82-2.88 (m, 2H), 3.51-3.58 (m, 1H), 6.89 (dd, J=8.8 Hz, J=2.9 Hz, 1H), 6.95 (d, J=2.9 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.93 (s, 1H)5 8.22 (d, J=1.7 Hz, 1H), 8.33 (d, J=8.8 Hz, 2H), 10.01 (s, 1H), 11.56 (s, 1H). Example 117 Synthesis of l-f2-(4-bromo-phenvIsuIfanyI)-ethyI1-pyrrolidine (CXXH) [0229] 4-bromo-benzenetbiol (7.05 g, 37.3 mmol, 1 equiv), l-(2-chloro-ethyl)-pyrrolidine hydrochloride (8.8 g, 52.2 mmol, 1.4 equiv) and cesium carbonate (26.8 g, 82.06 rnrnol, 2.2 equiv) were refluxed in acetone for 18 h. The reaction solvents were then evaporated, and the resulting residue was diluted with EtOAc and washed with water. The organic phase was then dried over sodium sulfate, filtered and evaporated to yield a pale brown oil (8 g, 75 % yield). Rf = 0.1 (40% EtOAc: Hexanes). Example 118 Synthesis of [7-(2-chIoro-5-methoxy-phenyI)-5-methvl-benzofl.2,41triazin-3-yn-|i4-(2-pvrrolidin-l-yl-ethvIsulfanvlVpheiivn-amine (cxxm) [0230] In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazrn-3-ylamrne (0.625 g, 2.08 mmol, 1 equiv), l-[2-(4-bromo-phenylsulfanyl)-ethyl]-pyrrolidine (0.894 g, 3.12 mmol, 1.5 equiv), cesium carbonate (2.04 g, 6.25 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.24 g, 0.417 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.19 g, 0.208 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (12 mL), outfitted with reflux condenser and heated to reflux for 16 hours. The reaction was then filtered and the solvents were removed. The residue was taken up in minimum amount of DCM (ca. 5 mL) and precipitated out with excess hexanes. The resulting precipitate was collected and dried. 0.5 g of this crude product was taken on and purified by ISCO silica gel chromatography to afford product as an orange solid (0.224 g, 22% yield). MS (ESI+): m/z = 506.1, LC retention time: 2.91 min. xample 119 Synthesis of 4-chloro-3-(5-methyI-3-[4-(2-pyrrolidin-l-yl-ethvlsulfanvIV phenylamino1-benzo[1.2,4]triazin-7-yI]-pheno| TFA salt (CXXIV) [0231] [7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l52,4]triazin-3-yl]-[4-(2-pyrrolidin-l-yl-ethylsulfanyl)-plienyl]-amine (Q.22 g, 0.435 mmol51 equiv) was diluted with 20 mLDCM and chilled to 0°C using an ice bath. A 1.0 M solution of BBrs in DCM (3.4 mL, 3.5 mmol, 10 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 3.5 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 5 minutes. The resulting solids were filtered off and dried. HPLC purification provided desired product as TFA salt in a form of an orange solid (0.088 g, 41 % yield). MS (ESI+): m/z = 492,1, LC retention time: 2.52 min. *H NMR (DMSO-d Example 120 Synthesis of 4-(3-(4-(2-(pyrroIidin-l-yI)etIioxy)phenvlaminoV5-methvlbenzore1fl,2,41triaziD-7-yn-3,5-dimethylphenol (CXXV) [0232] The title compound was synthesized as shown by the reaction scheme (CXXVI). IWeO B{OH)2 Me° Me 2 Pd2(dba)3/Ph3P K2CO3/DMA Me 3 Me H2/10% Pd-C Me° THF-MeOH CF3C02H Br Pd2(dba)3/BINAP/KOBu' (CXXVI) [0233] To a solution of the 7-bromo-5-methylbenzo[l,2,4]triazin-3-yl-amine-l -oxide 1 shown on scheme (CCXXVI) (100 mg, 0.39 mmol) in N,N-dimethylacetamide (6 mL) was added a solution of 4-methoxy-2,6-dimethylphenylboronic acid 2 (210 mg, 1,17 mmol) in EtOH (1 mL), a solution of K2C03 (90 mg, 0.65 mmol) in H2O (1 mL), tris(dibenzylidenacetone)dipalladium [0] (Pd2 (dba)3, 9 mg, 0.01 mmol), and PPh.3 (9 mg, 0.034 mmol). The suspension was heated under reflux for 18 h. The cold reaction mixture was poured into saturated NaHCC-3 and CH2Cl2 was used to extract the product. The crude product was purified by chromatography (SiOa/Hexane : EtOAc = 1: 1) to afford 3 as yellow solid. The 3 was reduced to 4 by hydrogenation, as shown by scheme (CCXXVI). To a solution of 4 in CH2C12 was added 1.0 M BBr3 in CH2C12 (1 mL, 1 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCOa was added and the organic layer was separated. The aqueous layer was extracted with CH2C12 (3x10 mL), The combined organic solution was dried (MgSO4) to afford 5. [0234] As further shown by scheme (CCXXVI), to a suspension of 5 in dry PhMe (1 mL) was added l-(2-(4-bromophenoxy)ethyl)pyrrolidine 6 (44.4 mg, 0,16 mmol), rac-2,2'-bis(diphenyl-phosphino)-l,r-bmaphthyl (BINAP, 8 mg, 0.012 mmol), Pd2 (dba) 3 (4 mg, 0.004 mmol), and KOBut (38 mg, 0.33 mmol). The mixture was heated under reflux for 48 h under argon. The solid was filtered off and washed with PhMe. The product was purified by preparative HPLC (Symmetry Shield-CIS, 200 x 40 mm, 7 jum, starting from 30% solvent A (0.1% TFA in H2O) to 100% solvent B (0.1% TFA in.MeCN), flow rate 40 ml/min, X = 282 nm). Fractions containing the products were combined to yield the title product (CXXV) as its TFA salt (1.3 mg, 3%). 1E NMR (CDC13): 8 2.02-2.04 (m, 2H); 2.12-2.17 (m, 2H); 2.93 (s, 3H); 3.01 (s, 6H); 3.59-3.61 (m, 2H); 3.94-4.00 (m, 4H); 4.40 (t, J= 4.9 Hz, 2H); 6.65 (s, 1H); 7.30 (s, 1H); 7.48 (d, J= 7.9 Hz, 2H); 7.61 (s, 1H); 8.06 (s, 1H); 8.09 (d, J= 7.9 Hz, 1H); 8.92 (br, 1H). MS (ESI+): m/z = 470.3. Example 121 Synthesis of [7-(3n5-dimethYl-isoxazol-4-yll-5-methvl-beHZofl,2,4Ur}azin-3-yn-(4-methoxy-phenyD-amine OMe (cxxvn) [0235] The reaction scheme (CXXVTH) includes an illustration of the synthesis of the title compound. .OMe OWIe BBr3/CH2CI2 H2NS03H/200°C 10 .Me Br- Cs2C03/Dioxane/Reflux (cxxvin) [0236] The mixture of 5-memyl-7-(3s5-dimethyh'soxazol-4-yl)benzo[e][l,2,4]triazin-3-amine (compound 7 on scheme (CXXVITf)) (107 mg, 0.42 mmol), sulfamic acid (81.4 mg, 0.84 mmol), and 4-methoxybenzenamine 8 (774 mg, 6.3 mmol) was heated at 180°C overnight. The product was purified by chromatography (Si.(V CHaCh) and the title product (48.7 mg, 32%) was obtained as a yellow solid. !H NMR (CD2C12): 8 2.34 (s, 3H); 2.49 (s, 3H); 2.70 (s, 3H); 3.84 (s, 3H); 6.99 (d, J= 8.9 Hz, 2H); 7,57 (s, IH); 7.83 (d, J= 8.9 Hz, 2H); 8.03 (s, IH); 8.10 (br, IH). MS (ESI+):m/z = 362.1. Example 122 Synthesis of f7-f3,5-dimethyl-isoxazoI-4-yD-5-methvI-beuzofl.2.4]triazin-3-yll-(4-f2-f4-inethyl-piperazin-l-yl)-ethoxy1-phenyU-aniine -Me CF3CO2H (CXXDC) [0237] The synthesis of the title compound is also illustrated by the reaction scheme (CXXVHI). Compound (CXXVII) obtained as described in Example 121 (48.7mmg, 0.13 mmol) was demethylated by using EEr^f CH2C12 to obtain compound 9 shown by the scheme (CXXVffl) (46 mg, 99%). To a solution of 9 (18.8 mg, 0.054 mmol) in anhydrous 1,4-dioxane (10 mL) was added Cs2C03 (176 mg, 0.54 mmol), and l-(2-bromoethyl)-4-methylpiperazine 10 shown by the scheme (CXXVDT) (40 mg, 0.11 mmol). The mixture was heated under reflux overnight. The product was purified by preparative HPLC (Symmetry Shield-Cl 8, 200 x 40 mm, 7 /an, starting from 30% solvent A (0.1% TFA in H2O) to 100% solvent B (0.1% TFA in MeCN), flow rate 40 ml/min, 1 = 288 nm). Fractions containing the products were combined. The title compound was obtained (0.8 mg, 3%) as its TFA salt. }H NMR (CD2C12):8 2.24 (s, 3H); 2.39 (s, 3H); 2.61 (s, 3H); 2.73 (s, 3H); 317 (t, J= 4.5 Hz, 2H); 3.25-3.40 (m, 8H); 4.20 (t, J= 4.5 Hz, 2H); 6.91 (d, J= 9.0 Hz, 2H); 7.48 (s, 1H); 7.75 (d, J= 9.0 Hz, 2H); 7.94 (s, 1H). MS (ESI+): m/z = 474.2. Example 123 Synthesis of 3-(5-methyl-7-(2,6-dimethylphenyI)benzofe]ri.2.4]triazin- 3-ylamino)bepzene-suIfonamide (CXXX) [0238] The title compound was synthesized as shown by the reaction scheme (CXXXI). SO2NH2 Br SO2NH2 12 Pd2(dba)3/BINAP/KOBi/ (CXXXI) [0239] To a suspension of compound 11 shown on scheme (CXXXI) (200 mg, 0.75 mmol) in dry PhMe (5 mL) was added 3-bromobenzenesulfonamide 12 (268 mg, 1.13 mmol) , rac-2,2'-bis(diphenylphosphino)-l,r-binaphthyl (BINAP, 141 mg, 0.23 mmol), Pd2 (dba)3 (69 mg, 0.075 mmol), and KOBut (170 mg, 1.51 mmol). The mixture was heated under reflux for 20 h. The solid was filtered off and washed with PhMe. The product was purified by preparative HPLC (Symmetry Shield-CIS, 200 x 40 mm, 7 /an, starting from 30% solvent A (0.1% TFA in H2O) to 100% solvent B (0.1% TFA in MeCN), flow rate 40 ml/min, X = 288 nm). Fractions containing the products were combined. The title compound was obtained (10.4 mg, 3%) as its TFA salt. !H NMR (DMSO-/): 8 2.06 (s, 6H); 2.71 (s, 3H); 7.19 (d, /= 7.3 Hz, 2H); 7.24 (m, 1H); 7.35 (br, 2H); 7.53 (d, /= 7.9 Hz, 1H); 7.60 (t, J= 7.9 Hz, 1H); 7.65 (s, 1H); 7.97 (s, 1H); 8.05 (d, J= 7.9 Hz, 1H); 8.85 (s, 1H); 11.24 (s, 1H). MS (ESI+): m/z = 420.1. Example 124 Synthesis of 3-(5-methyl-7-(2,6-dimethylphenyl)bepzofeTfl,2,41triazin-3-vIamino)-N-(2-pyrrolidin-l-yl)ethyl)benzenesulfonamidehvdrochloride Me (CXXXH) [0240] The title compound was synthesized as shown by the reaction scheme (cxxxm). Me Br-^S02C. Et3N/CH2C!2 13 Pdz(dba)3/BINAP/KOBu( Me V-J (cxxxm) [0241] To a solution of 3-bromobenzenesulfonyl chloride 13 shown on scheme (CXXXHI) (930 nag, 3.7 mmol) in anhydrous CH2C12 (10 mL) was added 2-(pyrrolidin-l-yl)ethanamine 14 (840 mg, 7.32 mmol) and Et3N (1.85 g, 18.3 mmol). The mixture was stirred 24 h at room temperature. Saturated NaHCO3 (50 mL) was added and organic layer was separated and washed with brine (3 x 20 mL), dried (NaijSCU). The solvent was removed and product 15 shown on scheme (CXXXIQ) was obtained as a colorless oil. [0242] The title compound was prepared by a method that was analogous to that used to synthesize compound (CXXX) (Example 123) using compounds 15 (780 nig, 2.54 mmol) and 11 (447 mg, 1.69 mmol) to give the title compound (260 mg, 31%) as a norange solid. !H NMR (CD2C12): 5 1.57-163 (m, 4H); 2.10 (s, 6H); 2.29 (br, 4H); 2.50 (t, J= 5.9 Hz, 2H); 2.80 (s, 3H); 3.04 (t, J= 5.6 Hz, 2H); 7.17 (d, J= 7.7 Hz, 2H); 7.21-7.24 (m, IH); 7.57-7.60 (m, 3H); 8.03 (s, 2H); 8.87 (br, IH); 8.97 (s, IH). MS (ESI+): = 517.4. Example 125 Synthesis of 3-r5-methyl-7-f2,6-dimethylphenyI)benzorell:l,2 (CXXXTV) * [0243] The title compound was synthesized as shown by the reaction scheme (CXXXV). Me Br" ^ S02C! 13 H2N 16 Et3N/CH2CI2 1) Pd2(dba)3/BINAP/KOBu( 2)HCI . (CXXXV) [0244] Compound 17 shown on scheme (CXXXV) was prepared by a method that was analogous to that used for preparation of compound 15 shown on scheme (CXXXHT), except compounds 16 (700 mg, 7.9 mmol) and 13 (1.2 g, 3.9 mmol) were used to yield the compound 17 (1.2 g, 99%) as a colorless oil. The title compound (CXXXTV) was prepared by a method that was analogous to that used to synthesize compound (CXXX) (Example 123), except compounds 17 (840 mg, 2.53 mmol) and 11 (450 mg, 1.69 mmol) were used, as shown by scheme (CXXXV), to give title compound (CXXXIV) (260 mg, 31%) as a orange solid. !H NMR (CD2C12): 8 2.11 (s, 6H); 2.84 (a, 9H); 3.30 (br, 2H); 3.59 (br, 2H); 7.15-7.18 (m, 3H); 7.21-7.24 (m, IS); 7.45 (d, /= 7.6 Hz, IH); 7.56 (s, IH); 7.84-7.86 (m, 2H); 7.93 (s, IH); 9.06 (s, IH); 9.37 (s, IH); 11.87 (br, IH). MS (ESI+): m/z = 491.3. Example 126 Synthesis of 2-(5-methvI-7-(2,6-dimetliylphenyI)benzofe1fl,2,41tria2in-3-vlamino)-N-(2-(pyrrolidiD-l-yl)ethyl)thiazoIe-4-carboxamide (CXXXVI) [0245] The title compound was synthesized as shown by the reaction scheme (CXXXVH). -Me -Me ,C02Et Me C02Et 18 Br" DMF/Pd2(dba)3/BINAP/KOBuf LiOH THF/MeOH/H2O -Me ,C02H Me CF3C02H Me O 21 H2N CDMT/NMM/CH2CI2 (cxxxvn) [0246] To a solution of 11 shown by scheme (CXXXVLf) (646 mg, 2.44 mmol) in dry DMF (20 mL) was added ethyl 2-bromothiazole-4-carboxylate 18 (750 mg, 3.1.7 mmol) , rac-232l-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP, 304 mg, 0.48 mmol), Pd2 (dba)3 (223 mg, 0.24 mmol), and Cs2CO3 (1.6 g, 4.88 mmol). The mixture was heated under reflux for 20 h. The solid was filtered off and washed with DMF. The filtrate was concentrated. The residue was dissolved in CH2C12 and washed with brine (3 x 100 mL). The crude product ethyl 2-(5-methyl-7-(2,6-dimethylphenyl)benzo[e][l,2,4]triazin-3-ylamino)thiazole-4-carboxylate 19 was dissolved in MeOH (10 mL) and THF (10 mL), followed by adding solution of LiOH (586 mg, 24.4 mmol) in H20 (10 mL). The mixture was heated at 60°C for 2 h. The solvent was removed in vacuo. The product was purified using chromatograpy (SiO2/CH2Cl2: MeOH: NH3.H20 = 100 : 10: 2.5 and then 100: 100 : 50). 2-(5-methyl-7-(2,6-dimethylphenyl)benzo[e][l,2,4] triazin-3-ylamino)thiazole-4-carboxylic acid (750 mg, 78%) (compound 20 shown by scheme (CXXXVII)) was obtained as an orange solid. [0247] The synthesis was continued by dissolving compound 20 (400 mg, 1.02 mmol) in anhydrous CH2C12 (20 mL), followed by adding 2-chloro-4,6-dimethoxy-l,3,5-trizine (CDMT, 198 mg, 1.12 mmol) and 4-methylmophline (NMM, 0.23 mL, 2.04 mmol). The mixture was stirred at room temperature for 0.5 h, followed by adding 2-(pyrrolidin-l-yl)ethanamine 21 (198 mg, 1.12 mmol). The reaction was stirred at room temperature overnight. The solid was filtered off and washed with GEfeCb. The filtrate was washed with saturated NaHCOs (1x50 mL) and then brine (2 x 50 mL). The organic solution was dried (Na2S04). [0248] The product was purified by preparative HPLC (Symmetry Shield-CIS, 200 x 40 mm, 7 jum, starting from 30% solvent A (0.1% TFA in H2O) to 100% solvent B (0.1% TFA in MeCN), flow rate 40 ml/min, /L = 282 nm). Fractions containing the products were combined. The title product (CXXXVI) was obtained (110 mg, 20%) as its TFA salt. 'H NMR (DMSO-/): 5 1.86-1.89 (m, 2H); 2.02-2.05 (m, 2H); 2.05 (s, 6H); 2.80 (s, 3H); 3.05-3.09 (m, 2H); 3.35-3.38 (m, 2H); 3.64-3.67 (m, 4H); 7.20 (d, /= 7.7 Hz, 2H); 7.24-7.27 (m, 1H); 7.78 (s, 1H); 7.97 (s, 1H); 8.10 (s, 1H); 8.25 (t, /= 6.1 Hz, 1H); 9.42 (br, 1H); 12.56 (s, 1H). MS (ESI+): m/z = 488.2. Example 127 Synthesis of 3-(5-methvl-7-(2,6-dimethyIphenyI)benzofe1ll.2,41triazin-S-vlaminoVN-methyl-N^-fpyrrolidin-l-yBethvnbenzenesulfonamidehydrQchloride H^^ (cxxxvm) [0249] The title compound was synthesized as shown by the reaction scheme (CXXXTX). [0250] To a solution of ethyl formate (10 mL) in anhydrous EtaO was added compound 21 as shown on scheme (CXXXIX) (2 mL). The solution was stirred at room temperature for 2 h. The solvent was removed in vacuo, followed by adding 1.0 M LLAJELt in THF (5 mL). The mixture was heated under reflux overnight and cooled. Water was then added slowly. The solid was filtered off and washed with THF. The filtrate was concentrated and remained aqueous, and was extracted with EtiO (3 x 20 mL) and dried (NaaSO^. The solvent was removed and the residue was dissolved in CHzClz (10 mL), followed by adding 4-bromobenzenesulfonyl chloride 24 (1,2 g, 4.72 mmol) and EtsN (3 mL). The mixture was stirred at room temperature for 3 hours, then saturated NaHCOs (100 mL) was added. The organic layer was separated and the aqueous was extracted with CHiCk (2x10 mL). Combined organic solution was dried . (Na2SO4). The solvent was removed in vacuo and afforded compound 25 shown on scheme (CXXXIX) as a yellow oil. [0251] The title compound (CXXXVTH) was prepared by using a method that was analogous to that used to synthesize compound (CXXX) (Example 123) except compounds 25 (600 mg, 1.72 mmol) and 11 (351 mg, 1.33 minol) were used to give title compound (CXXXVni) (276 mg, 37%) as its HC1 salt. 1HNMR (DMSO-/): 5 1.88-1.91 (m, 2H); 2.02-2.05 (m, 2H); 2.06 (s, 6H); 2.72 (s, 3H); 2.74 (s, 3H); 3.05-3.09 (m, 2H); 3.30-3.38 (m, 4H); 3.58-3.61 (m, 2H); 7.19 (d, J= 7.3 Hz, 2H); 7.23-7.26 (m, 1H); 7.70 (s, 1H); 7.86 (d, «/= 8.9 Hz, 2H); 8.01 (s, 1H); 8.31 (d, J= 8.9 Hz, 2H); 10.18 (br, 1H); 11.47 (s, 1H). MS (ESI+): m/z = 531.3. Example 128 Synthesis of f7-f2,6-dimethyl-phenyI)-5-nitro-l-oxy-beazoH,2,41triazin-3-yn-f4-(2-pyrrolidip-l-yI-ethoxyVphenvn-amine (CXL) [0252] The title compound was synthesized as shown by the reaction scheme (CXLI). The intermediate compounds 27 and 28 shown on scheme (CXLI) had the following spectral characteristics: [0253] Compound 27:1E NMR (DMSO-/): 3 7.30 (d, / = 8.8 Hz, 1H); 7.97 (dd, ,7= 8.8 Hz, J= 2.0 Hz, 1H); 8.25 (d, J= 2.0 Hz, 1H). MS (ESI+): m/z = 241. Compound 28: !H NMR (DMSO-/):5 8.22 (d, /= 2.3 Hz, 1H); 8.27 (d, J= 2.3 Hz, 1H). MS (ESI+): ?«/z = 286. 1)NH2CN/HCI/110°C/2h ~2) 30%NaOH/110°C/0,5 h' 26 27 HNO3/H2SO4 Br VN Me 29 NO2 DME/EtOH/H20 Pd(Ph3P)4/Na2C03 Reflux/18 h H2/Pd-C Me N=N i. te=> p \\ H. \\ /~Me ,Me 0 Br \L3~0 Me 'N"" 6 O. N/^ ^N ~NH2 Dioxane/Pd2(dba)3/Xaht Phos °zN N ~^N__/~^ Cs2C03/Reflux/4 h •Me -N—' CH3COCI ^—^ VN 1)CH2CI2 2)HCI Me NH2 * ^NH N=K Me O(CXLI) [0254] To a solution of compound 28 (500 mg, 1.75 mmol) in 1,2-dimethoxyethane (DME, 20 mL) was added solution of compound 29 (526 mg, 3.5 mmol) in EtOH (2 mL), solution of Na2CO3 (750 mg, 7.0 mmol) in H2O (2mL), and Pd(PPh3)4 (202 mg, 0.2 mmol), as shown by scheme (CXLI). The mixture was heated under reflux overnight. The solid was filtered off and washed with EtOAc. The filtrate was washed with brine (1 x 100 mL). The organic solution was separated and dried (NaaSO^. The product was purified by chromatograph ((SiOa/Hexane : EtOAc =1: 1) to yield compound 30 (450 mg, 82%) as a yellow solid. [0255] To a solution of 30 (450 mg, 1.45 mmol) in 1,4-dioxane (20 mL) were added compound 6 (586 mg, 2,17 mmol), Cs2C03 (1.90 g, 5.8 mmol), Pd2(dba)3 (133 mg, 0.14 rnmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 251 mg, 0.43 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (50 mL) was added, the solid was collected by filtration. The crude product was purified by chromatograph (SiCV CH2Cl2,then CH2C32 : MeOH : NH3.H2O = 100 : 10 : 2.5) and afforded the title compound (CXL) (124 mg, 17%). rHNMR (CD2C12): 8 1.82 (br, 4H); 2.08 (s, 6H); 2.69 (br, 4H); 2.95 (br, 2H); 4.16 (t, J= 5.5 Hz, 2H); 6.99 (d, J= 7.1 Hz, 2H); 7.17 (d, /= 7.5 Hz, 2H); 7.24-7.27 (m, 1H); 7.52 (br, 1H); 7.72 (d, J= 7.1 Hz, 2H); 8.13 (d, J= 1.9 Hz, 1H); 8.35 (d, .7= 1.9 Hz, 1H). MS (ESI+): m/z = 501.3. Example 129 Synthesis of 7-(2,6-dimethyl-phenyI)-N3-|4-(2-pyrrolidip-l-vl-ethoxy)-phenvn-benzofl,2,4]triazine-3,5-diamine [0256] Compound (CXL) synthesized as described in Example 128 was hydrogenated (scheme (CXLI)) to afford the title compound (CXLIT) (yield, 73%). *H NMR (CD2C12): 8 1.84 (br, 4H); 2.10 (s, 6H); 2.75 (br, 4H); 2.99 (br, 2H); 4.16 (t, J=4.25 Hz, 2H); 4.78 (br, 2H); 6.80 (d, J= 1.6 Hz, 1H); 6.99 (d, J= 6.9 Hz, 2H); 7.13 (d, J= 7.6 Hz, 2H); 7.17-7.20 (m, 1H); 7.42 (d, /= 1.6 Hz, 1H); 7.71 (d, /= 6.9 Hz, 2H); 7.96 (br, 1H). MS (ESI+): m/z = 455.4. Example 130 Synthesis of N-f3-(4-f2-(pyrro!idin-l-yl)ethoxy)phenviaminoV7-f2,6-dimethyIpheDvl)ben2o[e1-fl,2,41triazin-5-vl)acetamidehydrochIoride (cxun) [0257] To a solution of compound (CXI.II) obtained as described in Example 129 (122 mg, 0.27 mmol) in anhydrous CHaCla (5 mL) was added acetyl chloride (25 mg, 0.32 mmol). The solution was stirred at RT for 0.5 h and solvent was removed in vacuo. The residue was dissolved in CHaCla (2 mL) and Et2O was added to precipate product. The product was collected by filtration and dried. The title compound (CXLHT) (92 mg, 64%) was obtained as its HC1 salt. 1H NMR (CD2C12): 5 2.06-2.12 (m, 2H); 2.10 (s, 6H); 2.18-2.21 (m, 2H); 2.28 (s, 3H); 2.97-3.02 (m, 2H); 3.48-3.51 (m, 2H); 3.'83-3.85 (m, 2H); 4.57 (t, J= 4.8 Hz, 2H); 7.06 (d, /= 6.8 Hz, 2H); 7.14 (d, /= 7.4 Hz, 2H); 7.19-7.22 (m, IH); 7.73 (d,/= 6.8 Hz, 2H); 7.77 (d, J= 1.8 Hz, IH); 8.48 (s, IH); 8.57 (br, IH); 8.94 (s, IH); 12.4 (br, IH). MS (ESI+): m/z = 497.4. (CXLIV) Example 131 Synthesis of N-(3-(4-(2-(pyrroIidin-l-yl)ethoxy')phenylamiao>-7-r2,6-dimethvIphenvl)benzofe1-fl,2,41triazin-5-vI)methylsulfonvI amide hydrochloride . [0258] The title compound was synthesized as shown by the reaction scheme (CXLV). Me (CXLV) [0259] As shown by scheme (CXLV), to a solution of compound (CXLII) obtained as described in Example 129 (40 mg, 0.09 mmol) in anhydrous PhMe (5 mL) was added methylsulfonyl chloride (13 mg, 0.11 mmol). The solution was heated under reflux for 18 h and solvent was removed in vacuo. The residue was dissolved in CHaCla (2 mL) and EtaO was added to precipate product. The product was purified by HPLC. The title compound (CXLIV) (30 mg, 60%) was obtained as its HCl salt. 'H NMR (CD2C12): 5 2.00-2.02 (m, 2H); 2.12 (s, 6H); 2.08-2.12 (m, 2H); 3.14 (s, 3H); 3.18-3.21 (m, 2H); 3.61-3.64 (m, 2H); 3.73-3.76 (m, 2H); 4.62 (t, J= 5.0 Hz, 2H); 7.13 (d, J= 9.1 Hz, ZH); 7.19 (d, J= 7.1 Hz, ZH); 7.20-7.25 (m, IH); 7.69 (d, J= 1.8 Hz, IH); 7.88 (d, J= 1.8 Hz, IH); 7.95 (d, /= 9.1 Hz, IH); 8.49 (s, IH); 9.92 (s, IH); 12.4 (br, IH). MS (ESI+): m/z = 533.4. Example 132 Synthesis of {4-f7-(2-chloro-5-hydroxy-phenvI)-6-methyl-benzofl,2,41triazin-3-yIaipino1-phenvU-(4-methvI-piperazin-l-yl)-methaiioneHCI (CXLVT) salt [0260] The title compound was synthesized as shown by the reaction scheme (CXLVH). MeQ [0261] To a solution of a methoxylated product in MeSOsH (SO mg, 0.083 mmol) in anhydrous CH2C12 (2 mL) was added 1.0 M BBr3 (0.2 mL, 0.2 mmol) in CH2C12, as shown by scheme (CXLVH). The mixture was stirred at RT overnight. Sat. NaHCOs (10 mL) was added. The solid was collected and washed with HaO and CHCls. The crude product was further purified by HPLC and transferred its HC1 salt. The title product (CXLVI) (30 mg, 69%) was obtained as orange solid. 1K NMR (DMSO-/): 5 2.28 (s, 3H); 2.72 (s, 3H); 2.79 (s, 3H); 2.75-2.80 (m, 4H); 3.06-3.11 (m, 4H); 6.81 (d, J= 2.9 Hz, 1H); 6.81 (dd, J= 8.8 Hz, J= 2.9 Hz, 1H); 7.40 (d, J= 8.9 Hz, 1H); 1.52 (d, J= 6.9 Hz, 1H); 7.76 (s, 1H); 8.07 (s, 1H); 8.09 (d, J= 6.9 Hz, 2H); 9.98 (br, 1H); 10.78 (br, 1H); 11.13 (s, 1H). MS (ESI+): «J/z -489.2. Example 133 Synthesis of 7-f2-chloro-5-methoxv-phenyl)-5-methyl-benzori,2,41triazin-3-yl1-f4-(2-pvrrolidin-l-yl-ethoxy)-phenyl1-amine (CXLVID) [0262] The title compound was synthesized as shown by the reaction scheme (CXLDQ. MeO Dioxane/Pd2(dba)3/Xant Phos Cs2CO3/Reflux/4 h Cl MeO"'^"^B(OH)2 31 Me 32 DME/EtOH/H2O Pd(Ph3P)4/Na2C03 Reflux/18 h MeO' (CXLIX) [0263] Compound 33 shown by scheme (CXLIX) was prepared by a method that was analogous to that used to make compound 30 as shown on scheme (CXLI), except 2-chloro-5-methoxyphenylboronic acid (compound 31) (510 mg, 2.73 mmol) and 7-bromo-5-methylbenzo[e][l,2,4]triazin-3-amine (compound 32) (503 mgs 2.10 mmol) were used to produce compound 33 (500 mg, 80%) as a yellow solid. The title compound (CXLVIII) was then prepared by a method that was analogous to that used to make compound (CXL) as described in Example 128, except compounds 33 (500 mg, 1.66 mmol) and 6 (674 mg, 2.49 mmol) were used as shown by scheme (CXLIX) to afford the title compound (CXLVIII) (440 mg, 54%) as a yellow solid. (CL) Example 134 Synthesis of 3-(3-f4-(2-(pyrroIidin-l-yI)ethoxy)phenyIaniino)-5-methylbenzofel ri,2,41triazin-7-yl)-4-chIorophenoI hydrochloride [0264] The title compound (CL) was prepared by a method that was analogous to that used to make compound (CXLVTj as described in Example 132, except compound (CXLVIH) as described in Example 133 (440 mg, 0.90 mmol) was use to produce the title compound (CL) (387 mg, 84%) as HC1 salt and orange solid. ]H NMR (DMSCW5): 8 1.88-1.92 (m, 2H); 1.97-2.05 (m, 2H); 2.64 (s, 3H); 3.09-3.14 (m, 2H); 3.57-3.61 (m, 4H); 4.36 (t, J= 4.9 Hz, 2H); 6.87 (dd, /= 8.8 Hz, /== 2.9 Hz, IH); 6.94 (d, J= 2.9 Hz, IH); 7.09 (d, J= 9.0 Hz, 2H); 7.39 (d, J== 8.8 Hz, IH); 7.83 (d, J= 1.6 Hz, IH); 7.98 (d, J= 9.0 Hz, 2H); 8.12 (d, J= 1.6 Hz, IH); 9.97 (s, IH); 10.55 (br, IH); 10.87 (s, IH). MS (ESI+): m/z = 476.3. Example 135 Synthesis of 3-(7-(2-chIoro-5-hydroxyphenylV5-methvlbenzo[eiriT2,41triazin-3-ylamino)-N-(2-(pvrroIidin-l-yl)ethyl)benzamide (CL1) [0265] The title compound was synthesized as shown, by the reaction scheme (CLII). hydrochloride -Cl Cl MeO MeO 33 Br CO2Et 34 N Dioxane/Pd2(dba)3/Xant Phos Cs2C03/Reflux/4 h Nri2 MeO CO2H LiOH THF/MeOH/H2O/RT Me / ,N Me H2N' 37 1) CDMT/NMM/CH2CI2 2) BBr3/CH2CI2 2) HCI (CUT) [0266] Compound 36 shown on scheme (CL'H) was prepared by a method that was analogous to that used to make compound 20 shown on scheme (CXXXVTI), except using compounds 34 (ethyl 3-bromobenzoate) (84 mg, 0.37 mmol) and 33 (74 mg, 0.24 mmol) were used to afford compound 36 (72 mg, 71%) as a yellow solid. The title compound (CLI) was prepared by a method that was analogous to that used to make compound (CXXXVI) as described in Example 126, except using compounds 36 (35 mg, 0.083 mmol) and 37 (N\N1-dimethylemane4,2-diamine) (15 mg, 0.17 mmol) were used to afford the title compound (CLI) (6.3 mg, 15%) as its HCI solid and yellow solid. 1E NMR (DMSO-/): 8 2.71 (s, 3H); 2.85 (s, 6H); 3.28 (t, /= 5.3 Hz, 2H); 3.55-3.76 (m, 2H); 6.88 (dd, J= 8.7 Hz, /= 2.9 Hz, IH); 6.95 (d, J= 2.9 Hz, IH); 7.40 (d, /= 8.8 Hz, IH); 7.52 (t, .7= 7.9 Hz, IH); 7.61 (d, J= 7.9 Hz, IH); 7.87 (d, J= 1.7 Hz, IH); 8.10 (dd, J= 8.1 Hz, J= 1.8 Hz, IH); 8.17 (d, J= 1.8 Hz, IH); 8.74 (s, IH); 8.77 (t, J= 5.6 Hz, 1H);9.30 (br, IH); 9.97 (s, IH); 11.14 (s, IH). MS (ESI+): m/z = 477.1. Example 136 Synthesis of 3-(3-(3-(dimethylamino)phenyIamino)-5-methylbenzo[el[l,2,41triazin-7-yl)-4-chlorophenolhydrochIoride (CLEDO [0267] The title compound was synthesized as shown by the reaction scheme (CLIV). MeO' MeO' NMe2 Br NMe2 38 Dioxane/Pda(dba)3/Xant Phos Cs2C03/Reflux/4 h 1)BBr3/CH2CI2 2)HCI (CLIV) [0268] As shown by scheme (CLTV), to a solution of compound 33 (520 mg, 1.73 mmol) in anhydrous dioxane (20 mL) were added 3-bromo-N,N-dimethylbenzenamine (compound 38) (692 mg, 3.46 mmol), Cs2CO3 (2.3 g, 6.92 mmol), Pd2 (dba) 3 (158 mg, 0.17 mmol), and xantphos (300 mg, 0.52 mmol). The resulted mixture was heated under reflux for 2 h. The solid was filtered off and washed with EtOAc. The filtrate was washed with brine (1 x 100 mL). The organic layer was separated and dried (Na2SO4). The crude product was purified by chromatography (SiO2/ CH2Cl2,then 5% MeOH in CH2C12) and afforded compound 39 as shown by scheme (CLIV). Compound 39 was then demethylated by using BBr3/CH2Cl2 to afford the title product (CLITT) (80 mg, 10%) as its HC1 salt and yellow solid. !H NMR (DMSO-d*): 8 2.70 (s, 3H); 3.07 (s, 6H); 6.88 ' (dd, J= 8.7 Hz, J= 2.9 Hz, IH); 6.94 (d, J- 2.9 Hz, IH); 7.36 (br, 2H); 7.40 (d, J= 8.8 Hz, IH); 7.48 (br, IH); 7.86 (s, IH); 8.10 (br, IH); 8.16 (d, J Example 137 Synthesis of 3-(3-(6-methoxypyridin-3-yIamino)-5" methyIbenzofe1ll,2,4Hriazin-7-yI)-4-chlorophenol hvdrochloride (CLV) [0269] The title compound was synthesized as shown by the reaction scheme (CLVI). MeO Me 40 Br Dioxane/Pd2(dba)3/Xant Phos Cs2CO3/Reflux/4 h HCI 1)BBr3/CH2Cl2 2) HC! (CLVI) [0270] The title compound was prepared by a method that was analogous to that used to make compound (GLUT), as described in Example 136, except using compounds 33 (37 mg, 0.13 mmol) and 40 (5-bromo-2-methoxypyridine) (36.4 mg, 0.20 mmol) shown, on scheme (CLVI) were used to afford the title compound (CLV) (13 mg, 23%) as its HCI salt in a form of a red solid. !H NMR (DMSO-/): 8 64 (s, 3H); 3.87 (s, 3H); 6.88 (dd, J= 8.7 Hz, J= 2.9 Hz, IH); 6.92 (d, J= 8.9 Hz, IH); 6.95 (d, J= 2.9 Hz, IH); 7.39 (d; /= 8.8 Hz, IH); 7.84 (dd, J= 1.9 Hz5 J= 1.0 Hz, IH); 8.14 (d, J= 1.7 Hz, IH); 8.24 (dd, J= 8.9 Hz, J= 2.9 Hz, IH); 8.88 (d, J= 2.6 Hz, IH); 10.00 (br, IH); 10.92 (s, IH). MS (ESI+): w/z = 394.0. Example 138 Synthesis of 3-(3-(2-(pyrrolidin-l-YnethyIamino)-5-methvlbenzofe] [l,2,41triazin-7-yl)-4-chlorophenol hydrochloride [0271] The title compound was synthesized as shown by the reaction scheme (CLVEI). 42 MeO 1) DMF/K2C03/80°C/72 h HO' 2) BBr3,CH2C12 3) HCI cr [0272] As shown by scheme (CLVHT), to a solution of compound 33 (320 mg, 1.06 mmol) in anhydrous DMF (20 mL) were added K2C03 (1.2 g, 8.51 mmol), and l-(2-chloroethyl)pyrrolidine 42 (217 mg, 1.27 mmol). The mixture was heated at 150 °C for 72 h. The solid was filtered off and washed with OE^C^. The filtrate was concentrated in vacuo. The residue was dissolved in CHsC^ and washed with brine (2 x 50 mL). The organic layer was separated and dried (NaiSCU). The solvent was removed and the residue was demethylated by using BBr3/CH2Cl2. The product was purified by preparative HPLC. The title compound (CLVIT) (90 mg, 21%) was obtained as HCI salt in a form of a yellow solid. !HNMR (DMSO-/): 5 1.88-1.90 (m, 2H); 1.97-2.02 (m, 2H); 2.58 (s, 3H); 3.05-3.10 (m, 2H); 3.44-3.48 (m, 4H); 6.86 (dd, J= 8.7 Hz, /= 2.9 Hz, IH); 6.94 (d, J= 2.9 Hz, IH); 7.37 (d, /= 8.6 Hz, IH); 7.76 (dd, /= 1.8 Hz, .7= 1.0 Hz, IH); 8.05 (d, J= 1.8 Hz, IH); 10.05 (br, IH); 10.78 (br, IH). MS (ESI+): m/z = 384.1. Example 139 Synthesis of 3-f5-(2-(pyrrolidin-l-yI)ethoxv)-3-(pyridin-3-vlamino)benzo[e1fl,2,41triazm-7-yl)-4-chlorophenoidihydrochIoride (CLK) [0273] The title compound was synthesized as shown by the reaction scheme (CLX). OH NH2 44 Br2/Dioxane Br NO 2 Br- 1)NH2CN/HCI/110aC MH2 - OH 2)30%NaOH/110°C 45 OH 46 Raney Ni/H2 MeO MeO' 48 DMBEtOH/H2O Pd(Ph3P)4/Na2C03 Reflux/18 h MeO' D Cs2CO3/Me2GO/Reflux 50 Br Dioxane/Pd2(dba)3/Xant Phos Cs2C03/Reflux/4 h MeO S1 2HC1 1)BBr3/CH2CI2 2)HCI (CLX) [0274] As shown by scheme (CLX), to a solution of 2-amino-3-nitrophenol 44 (10 g, 65 mmol) in anhydrous 1,4-dioxane (1 L) was added bromine (12.5 g, 78 mmol). The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with dioxane and dried. 2-amiao-5-bromo-3-nitrophenol 45 (18 g, 90%) was obtained as its HBr salt in a form of a yellow solid. 'H NMR (DMSO-/): 6 6.28 (br, 2H); 6.99 (d, J= 2.2 Hz, 1H); 7.57 (d, /= 2.1 Hz51H). MS (ESI+): m/z = 234. Compound 45 (6 g, 19.1 mmol) was converted into compound 46 by using a method that was analogous to that used to synthesize compound 27, as shown on scheme (CXLI). Hydrogenation of compound 46 affords compound 47 (3.1 g, 67%) as a red solid. [0275] Compound 48 was then prepared by using a method that was analogous to that used to synthesize compound 33, as described in Example 133 (scheme (CXLDC)) except compounds 47 (870 mg, 3.6 mmol) and 31 (740 mg, 4.0 mmol) were used to afford compound 48 (108 mg, 10%) as yellow solid. :H NMR (DMSO-/): 8 7.02 (dd, J= 8.9 Hz, J= 3.1 Hz, 1H); 7.07 (d, J= 3.1 Hz, 1H); 7.16 (d, J= 1.9 Hz, 1H); 7.49 (d, J= 8.9 Hz, 1H); 7.60 (br, 2H); 7.69 (d, J= 1.9 Hz, 1H). MS (ESI+): m/z = 303.7. [0276] To a solution of compound 48 (47 mg, 0.15) in Me2CO (20 mL) were then added Cs2CO3 (202 mg, 0.62 mmol), l-(2-chloroethyl)pyrroUdine 43 (26.4 mg, 0.15 mmol), and Nal (15 mg, 0.1 mmol). The mixture was heated under reflux overnight. The solid was filtered off and washed with Me2CO. The filtrate was concentrated in vacuo. The residue was dissolved in CHiC^ and washed with brine (2 x 50 mL). The organic layer was separated and dried (Na2SO4). The solvent was removed in vacuo and compound 49 was obtained as a yellow solid. Compound 51 was then prepared by using a method that was analogous to that used to synthesize compound 39 (scheme (CLIV), Example 136), except compound s 49 (62 mg, 0.15 mmol) and 50 (3-bromopyridine) (36.7 mg, 0.23 mmol) were used to afford compound 51 as a yellow solid. [0277] Compound 51 was demetbylated as shown by scheme (CLX)., by using BBr3/CH2Cl2 to afford the title compound (CLIX) (60 mg, 56%) as its HC1 salt in a form of a yellow solid. !H NMR (DMSO-/): 5 1.82-1.84 (m, 2H); 1.99-2.01 (m, 2H); 3.36-3.40 (m, 2H); 3.69-3.70 (m, 2H); 3.90-3.92 (m, 2H); 4.68(t, J=4.2 Hz, 2H); 6.92 (dd, J= 8.6 Hz, J= 2.9 Hz, 1H); 7.00 (d, J= 2.9 Hz, 1H); 7.43 (d, /= 8.8 Hz, 2H); 7.58 (d, /= 1.5 Hz, 1H); 8.01 (br, 1H); 8.06 (d, J= 1.5 Hz, 1H); .8.62 (d, J= 4.9 Hz, 1H); 8.69 (d, /= 8.8 Hz, 1H); 9.77 (s, 1H); 10.06 (br, 1H); 10.79 (br, 1H); 11.90 (s, 1H). MS (ESI+): m/z = 463.1. Example 140 Synthesis of 7-(lH-indoI-4-vl)-5-methyl-bepzo[l,2.41triazin-3-vl-amine (CLXI) [0278] The title compound was synthesized as shown by the reaction scheme (CLXH). Br 1)NaH 2) B(OMe)3 3) H3*0 B(OH)2 53 'N N NH2 Me 32 DME/EtOH/H2O Pd(Ph3P)4/Na2C03 Reflux/18 h HNV^. Dioxane/Pd2(dba)a/Xant Phos Cs2C03/Reflux/4 h HC! H HCI [0279] As shown by scheme (CLXII)., the solution of 4-bromo-lH-indole 52 (1.56 g, 7.96 mmol) in anhydrous Et20 (20 mL) was cooled in ice-B^O, Followed by adding NaH (0.22 g, 9.6 mmol). The suspension was stirred at OoC for 30 min. The flask was further cooled in dry ice-acetone and 2.5 M BuLi in hexane (8 mL, 20 mmol) was dropped. After stirring for 30 min, the neat B(OMe)3 was dropped and the mixture was stirred at room temperature overnight. The mixture was put into 1 M EbPCU in portions and stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with EtaO (2 x 20 ml). The combined organic layer was washed with 1 M NaOH (3 x 50 mL). The combined aqueous was aerified with 1 M H3PC>4 (pH [0280] The title compound (CLXI) was prepared by using a method that was analogous to that used to synthesize compound 33, as described in Example 133 (scheme (CXLIX)), except compounds 53 (1.16 g, 7.2 mmol) and 31 (also described in Example 133 (scheme (CXLIX)) (1.15 g, 4.8 mmol) were used to afford the title compound (CLXI) (220 mg, 17%) as a yellow solid. JHNMR (DMSO-/): 8 2.59 (s, 3H); 6.64 (t, / - 1.1 Hz, IH); 7.22-7.25 (m, 2H); 7.46-7.48 (m, 2H); 7.64 (br, 2H); 8.02 (d, /= 1.9 Hz, IH); 8.24 (d, J= 1.9 Hz, IH); 11.35 (s, IH). MS (ESI+): m/z = 276.2. Example 141 Synthesis of 4-f7-(m-indoI-4-vI)-5-methvIbenzore1fl,2,4Uriazin-3-vlamiao>-]N-f2-(pyrrolidin-l-vl)ethvI)benzenesulfoKamidehydrochIoride (CLXin) [0281] The title compound was prepared was prepared by using a method that was analogous to that used to synthesize compound (CXL), as described in Example 128, except compound (CLXI) (described in Example 140) (37 mg, 0.13 mmol) and compound 54 (shown on scheme (CLXII)) (53 mg, 0.16 mmol) were used to afford the title compound (CLXIH) (5.7 mg, 8%) as its HC1 salt and orange solid. !H NMR (DMSO-d6): § 1.85-1.88 (m, 2H); 1.98-2.01 (m, 2H); 2.78 (s, 3H); 2.98-3.04 (m, 2H); 3.08-3.12 (m, 2H); 3.22-3.26 (m, 2H); 3.53-3.56 (m, 2H); 6.69 (t, J== 1.9 Hz, IH); 7.25-7.31 (m, 2H); 7.51-7.52 (m, 2H); 7.88 (d, /= 9.0 Hz, 2H); 8.23 (s, IH); 8.27 (d, J= 9.0 Hz, 1H); 8.43 (d, J= 1.8 Hz, 1H); 10.04 (br, 1H); 11.40 (s, 1H); 11.42 (s, 1H). MS (ESI+): m/z = 528.4. . Example 142 Synthesis of 4-(7-(2-bromo-5-hydroxyplieiiyl)-5- methylbenzofeUl^^ltriazin-S-vIammo^-N-fZ-fpyrrolidin-l-yDethyl) benzenesulfonamide hydrochloride (CLX3Y) [0282] The title compound was synthesized as shown by the reaction scheme (CLXV). MeO N NH2 ,Br MeO" ^ ~B(OH)2 56 Me 32 DME/BOH/H2O Pd(Ph3PVNa2C03 Reflux/18 h MeO Br .OH 54 Dioxane/Pd2(dba)3/Xant Phos Cs2C03/Reflux/4 h 1)BBr3/CH2CI2 2)HCI (CLXV) [0283] The intermediate'compounds 57 and 58 shown on scheme (CLXV) were prepared as follows. Compound 57 was prepared by using a method that was analogous to that used to synthesize compound 30 shown, on scheme (CXLI) and described in Example 128, except 2-bromo-5-methoxyphenylboronic acid (compound 56) (233 mg, 1.1 mmol) and 7-bromo-5-methylbenzo[e][l,2,4]triazin-3-amine (compound 32) (240 mg, 1.0 mmol) were used to afford compound 57 (300 mg, 87%) as a yellow solid. Compound 58 was prepared by using a method that was analogous to that used to synthesize compound (CXL), as described in Example 128, except compounds 57 (150 mg, 0.43 mmol) and 54 (174 mg, 0.52 mmol) were used, as shown on scheme (CLXV) to afford compound 58 as a yellow solid. [0284] The title compound was prepared by using a method that was analogous to that used to synthesize compound (CXLVT), as described in Example 132, except compound 58 (0.90 mmol) was used to afford the title compound (CLXTV) (51 mg, 20% in two steps) as HC1 salt and orange solid. 'HNMR (DMSO-/): 8 1.83-1.86 (m, 2H); 1.95-2.05 (m, 2H); 2.71 (s, 3H); 2.95-3.01 (m, 2H); 3.12-3.16 (m, 2H); 3.21-3.24 (m, 2H); 3.48- 3.53 (m, 2H); 6.84 (dd, J= 8.8 Hz, J= 2.9 Hz, IH); 6.97 (d, J= 2.9 Hz, IH); 7.55 (d, J= 8.8 Hz, IH); 7.88 (d, J= 8.8 Hz, 2H); 7.87 (d, J= 1.8 Hz, IH); 8.04 (t, /= 6.0 Hz, IH); 8.17 (d, J= 1.8 Hz, IH); 8.25 (d, J= 8.8 Hz, 2H); 10,12 (s, IH); 10,85 (br, IH); 11.44 (s, IH). MS (ES1+): m/z = 583.0. . . . Example 143 Synthesis of 4-(7-(2-chloro-6-hydroxyphenyl)-5- methvlbenzQfe]H,2,4Uriazin-3-ylaminoVN-(2-(pYrrolidin-l- (CLXVT) yI)ethyl)beDzensuli'onamidehydrochIoride [0285] The title compound was synthesized as shown by the reaction scheme (CLXvn). Br Cl OMe 59 N^NH2 DME/EtOH/H2O Pd(Ph3P)4/Na2CO3/Reflux/18 h OMe H Br 54 Dioxane/Pd2(dba)3/Xant Phos Cs2CO3/Reflux/4 h I 95% I HCI OH 1)BBr3/CH2CI2 2)HCI [75%! (CLxvn) [0286] As shown by scheme (CLXVII), compound 60 was prepared by using a method that was analogous to that used to synthesize compound 30 shown, on scheme (CXLI) and described in Example 128, except 2-chloro-6-methoxyphenylboronic acid 59 (1 g, 4.18 mmol) and 7-bromo-5-methylbenzo[e][l,2,4]triazin-3-amine 32 (1.2 g, 6.28 mmol) were used to give compound 60 (7-(2-chloro-6-methoxyphenyl)-5-methylbenzo[e][l,2,4]triazin-3-amine) (1.12 g, 90%) as a yellow solid. Compound 61 was prepared was prepared by using a method that was analogous to that used to synthesize compound (CXL), as described in Example 128, except compounds 60 (390 mg, 1.30 mmol) and 54 (518 mg, 1.56 mmol) were used to afford compound 61 (4-(7-(2-chloro-6-methoxyphenyl)-5-methylbenzo[e][l,2,4]triazm-3-ylamino)-N-(2-(pyrrolidin-l-yl)ethyl)benzensulfonamide) (680 mg, 95%) as a yellow solid. [0287] The title compound was prepared by using a method that was analogous to that used to synthesize compound (CXLVI), as described in Example 132. except compound 61 (680 mg, 1.23 mmol) was used to afford the title compound 4-(7-(2-chloro-6-hydroxyphenyl)-5-methylbenzo[e][l,2,4]triazin-3-ylamino)-N-(2-(pyrrolidin-l-yl)ethyl)benzensulfonamide (CLXVT) (529 mg, 75%) as HC1 salt and yellow solid. !H NMR (DMSO-/): 8 1.83-1.87 (m, 2H); 1.95-2.01 (m, 2H); 2.70 (s, 3H); 2.97-3.04 (m, 2H); 3.09-3.13 (m, 2H); 3.21-3.25 (m, 2H); 3.51-3.56 (m, 2H); 7.01 (d, J= 8.3 Hz 1H); 7.06 (d, J= 7.9 Hz, 1H); 7.27 (t, /= 8.0 Hz, 1H); 7.77 (s, 1H); 7.88 (d, J= 8,9 Hz, 2H); 7.92 (t, J= 6.0 Hz, 1H); 8.09 (s, 1H); 8.26 (d, J= 8.9 Hz, 2H); 10.09 (s, 1H); 10.22 (br, 1H); 11.40 (s, 1H)." MS (ESI+): m/z = 540.5. Example 144 Synthesis of 3-{6-methvl-3-[4-(2-pyrroIidm-l-yl-ethylsulfamoyI)-phenvlaminol"benzori,2,4UriaziH-7-vl}-beiizamide 0 ii OH ^^ H (CLxvm) [0288] Compound 52 (scheme (CLXH), Example 140) (0.11 g, 0.22 mmol), 3-carbamoylphenylboronic acid (45 mg, 0.27 mmol), Pd(PPh3)4 (25 mg, 0.022 mmol), and 2 M Na2CC>3 (0.5 mL, 1.0 mmol) were suspended in a mixture of DME/ethanol (4:1, 10 mL). The resulting mixture was heated at reflux for 6 h. The mixture was allowed to cool to room temperature, filtered and washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were poured into saturated NaHCOs and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaaSCU, and filtered. The filtrate was concentrated to afford the free base compound, which was converted to HC1 salt according to method C and furnished the title compound as a yellow solid (40 mg, 32% overall). ]H NMR (DMSO-d6): 6 1.78-1.90 (m, 2H), 1.90-2.03 (m, 2H), 2.45 (s, 3H), 2.95-3.10 (m, 2H), 3.12 (q, J = 6.2 Hz, 2H), 3.23 (q, J= 6.1 Hz, 2H), 3.48-3.55 (m, 2H), 7.47 (s, IH), 7.61 (t, J= 7.8 Hz, IH), 7.68 (d, /= 7.8 Hz, IH), 7,83 (s, IH), 7.86 (d, J= 8.9 Hz, IH), 7.95-8.05 (m, 3H), 8.12 (s, IH), 8.20-8.24 (m, 3H), 10.55 (br s, IH), 11.33 (s, IH). MS (ESI+): m/z 533. Example 145 Synthesis of 2-f4-{6-f7-(2,6-dichloro-pfaenyI)-5-methyl-benzo|l,2,41triazin-3-ylammo1-2-methyl-pyrimidin-4-yl}-piperaziu-l-yI)-ethanoi Cl (CLxrx) [0289] To synthesize the title compound (CLXIX), two intermediate compounds 62 (2-[4-(6-cMoro-2-methyl-pyrimidin-4-yl)-piperazin-l-yl]-ethaaol) and 63 (7-(2,6- dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine) shown below were used. OH 62 Cl N NH2 [0290] To synthesize compound 62, 'to a solution of 4,6-dicmorp-2~methyl-pyrimidine (5.0 g, 31 mmol) and 2-piperazin-l-yl-ethanol (2.7 g, 21 mmol) in dioxane (25 mL) was added DEPEA (3.0 mL, 17 mmol). The mixture was heated at reflux for 16 h. The mixture was allowed to- cool to room temperature and poured into water. The reaulting aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over NaaSCU and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to afford compound 62 as a brown liquid (2.1 g, 39%). MS (ESI+): m/z 257. [0291] To synthesize the title compound (CLXTX), a suspension of compound 62 (0.15 g, 0.49 mmol), compound (LXTfl) (0.16 g, 0.62 mmol), Pd(OAc)2 (7 mg, 0.031 mmol), Xantphos (36 mg, 0.062 mmol) and potassium fert-butoxide (0.11 g, 0.98 mmol) in dioxane/DMF (4 mL, 3/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160 °C for 20 min. After cooling down to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to afford the free base compound. The free base compound was converted to HC1 salt according to method C and furnished the title compound as a yellow solid (0.18 g, 65% overall). 1E NMR (DMSO-d6): 5 2.54 (s, 3H), 2.75 (s, 3H), 3.15-3.25 (m, 4H), 3.59-3.72 (m, 6H), 3.82 (t, J= 4.6 Hz, 2H), 4.56 (br s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.67 (d, J= 8.2 Hz, 2H), 7.91-7.93 (m, 1H), 8.31 (d, J= 1.5 Hz, IE), 10.93 (br s, IE), 11.83 (br s, 1H). MS (ESI+): m/z 525. (CLXX) Example 146 Synthesis of 4-chIoro-3-(3-{6-[4-(2-hvdroxy-ethvl)-piperazin-l-vIl-2-methyl-pyrimidin-4-yIamiDo}-5-methyl-benzori,2,4]triazin-7-vl)-pheiioI [0292] To synthesize the title compound (CLXX), an intermediate compound 64 (2-(4- {6-[7-(2-chloro-5-methoxy-phen.yl)-5-methyl-benzo[ 1,2,4]triazin-3-ylainino]-2-methyl-pyrimidin-4-yl}-piperazin-l-yl)-ethanol) shown below was used. MeO 64 [0293] To synthesize compound 64, a suspension of compound 16 (scheme (CXXXV), Example 124) (0.10 g, 0.33 mmol), compound 53 (Example 145) (0.10 g, 0.39 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and potassium fert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (2.5 mL, 4/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160°C for 20 min. After cooling down to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to yield compound 64 as a yellow solid (43 mg, 25%). MS (ESI+): m/z 521. [0294] The title compound (CLXX) in the free base form was prepared from compound 64 according to method B and without further purification. The free base compound was then converted to HC1 salt according to method C as a yellow solid (25 mg, 60% overall). JH NMR (DMSO-d6): 8 2.74 (s, 3H), 3.15-3.25 (m, 4H), 3.55-3.75 (m, 6H), 3.82 (t, J= 5.1 Hz, 2H), 4.54 (br s, 1H), 6.91 (dd, /= 8.8 Hz, .7= 2.9 Hz, 1H), 6.98 (d, J=2.9 Hz, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.75 (s, 1H), 8.03 (dd, ./= 1.8 Hz, J = 0.9 Hz, 1H), 8.30 (d, J= 1.8 Hz, 1H), 10.05 (br s, 1H), 10.78 (br s, 1H), 11.73 (br s, 1H). Example 147 Synthesis of 4-[7-f2-chlorg-5-hydroxv-phenyl)-5-methvI- [ benzorLZ^ltriazm-S-vIamiDol-N-ethvl-N-fZ-pyrrolidm-l-yl-ethyl)-benzenesulfonamide r~~ (CLXXT) [0295] To synthesize the title compound (CLXXI), intermediate compounds 65 (4-bromo-ALethyl-JV-(2-pynroUdin-l-yl-ethyl)-benzenesulfonarnide) and 66 (4-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylarruno]-A^emyl-Ar-(2-pyrroUdin-l-yl-ethyl)-benzenesulfonamide) shown below were used. 65 MeO 66 [0296] To synthesize compound 65, a solution of compound 38 (scheme (CLTV), Example 135) (1.0 g, 3.0 mmol), iodoethane (0.25 mL, 3.1 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in acetonitrile (25 mL) was stirred at room temperature for 16 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (8% MeOH/DCM) to afford compound 65 as a white solid (0.80 g, 74%). !H NMR (DMSO-d^): 5 1.03 (t, J= 7.1 Hz, 3H), 1.55-1.75 (m, 4H), 2.35-2.75 (m, 4H), 3.15-3.25 (m, 4H), 3.32 (br s, 2H), 7.76 (d, J= 8.8 Hz, 2H), 7,81 (d, J= 8.6 Hz, 2H). MS (ESI+): mlz 363 . [0297] To synthesize compound 66, a suspension of compound 16 (scheme (CXXXV), Example 124) (0.10 gyO.33 mmol), compound 65 (0.15 g, 0.42 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3 mL, 2/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160°C for 20 min. After cooling down to room temperature, the cap was removed, the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue titrated in MeOH. Compound 66 was obtained as a yellow solid (0.17 g, 89%) after filtration and washed with MeOH. MS (ESH-): m/z 581. [0298] The title compound (CLXXI) in the free base form was prepared from compound 66 according to method B and the crude product purified by flash chromatography on silica gel (10% MeOH/DCM). The free base compound was then converted to HC1 salt according to .method C to yield a yellow solid (0.13 g, 77% overall). 'HNMR (DMSO-d6): 5 1.04 (t, /= 7.1 Hz, 3H), 1.80-L92 (m, 2H), 1.95-2.10 (m, 2H), 2.72 (s, 3H), 3.00-3.15 (m, 2H), 3.23 (q, J= 7.1 Hz, 2H), 3.28-3.38 (m, 2H), 3.40-(m, 2H), 3.53-3.63 (m, 2H), 6.89 (dd, J= 8.7 Hz, J= 2.8 Hz, 1H), 6.95 (d, J= 2.9 Hz, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.90 (d, J= 8.8 Hz, 2H), 7.93 (dd, J= L8 Hz, 7= 0.9 Hz, 1H), 8.23 (d, J= 1.8 Hz, 1H), 8.28 (d, J= 8.8 Hz, 2H), 9.97 (s, 1H), 10.01 (br s, 1H), 11.48 (s, 1H). MS (ESI+): m/z 567. Example 148 Synthesis of 4-r7-f2-chIoro-5-hydroxy-phenyI)-5-methvl-benzofl,2,41triazin-3-vlamino1-Ar-methyI-JV-f2-morpholia-4-yl-ethyl')- benzenesulfonamide (CLXXD) [0299] To synthesize the title compound (CLXXII), intermediate compounds 67 (4-bromo-ALmethyl-benzenesulfonamide)J 68 (4-bromo-JV-methyl-^V-(2-moipholin-4-yl-ethyl)-benzenesulfonamide) and 69 (4-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-berizo[l,2,4]1riazin-3-ylainino]-JV:-methyl-7V-(2-morpholin-4-yl-ethyl)-benzenesulfonamide) shown below were used. 67 ii N O I Br MeO [0300] To synthesize compound 67, to a solution of 4-bromosulfonyl chloride (5.0 g, 20 mmol) in DCM (30 mL) was added methylamirie (2 M in THF, 20 mL, 40 mmol). The mixture was stirred at room temperature for 1 h and then the solvent was removed. A saturated NaHCOs solution was added to the residue and then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2S04 and filtered. The filtrate was concentrated and the residue triturated in hexane. Compound 67 was obtained as a white solid after filtration (4.0 g, 82%). 1J3. NMR (DMSO-d6): 8 2.41 (d, J= 5.0 Hz, 3H), 7.56 (q, J= 4.9 Hz, IH), 7.70 (d, J= 8.7 Hz, 2H),7.83(d,Jr=8.7Hz,2H). [0301] To synthesize compound 68, a solution of compound 67 (1.0 g, 4.0 mmol), 4- (2-chloro-ethyl)-morpholine (0.85 g, 4.6 mmol) and cesium carbonate (3.3 g, 1.0 mmol) . in acetonittile (30 mL) was heated at reflux for 15 h. The mixture was cooled and poured into water. The aqueous layer was extracted with EtOAc and the combined organic • layers washed with brine, dried over NaaSC^ and filtered. The filtrate was concentrated and the residue triturated in Et2Q/hexane (1/1) to afford compound 68 as an off-white solid (1.2 g, 83%) after filtration. MS (ESI+): m/z 363. [0302] To synthesize compound 69 a suspension of compound 16 (scheme (CXXXV), Example 124) (0.10 g, 0.33 mmol), compound 68 (0.15 g, 0.41 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and potassium tot-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3 mL, 2/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160 °C for 20 min. After cooling down to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue triturated in DCM/hexane (1/5). Compound 69 was obtained as a green solid (0.18 g, 93%) after filtration and washed with hexane. 1E NMR (DMSO-dg): 8 2.35-2.42 (m, 4H), 2.46 (t, J = 6.7 Hz, 2H), 2.72 (s, 3H), 2.73 (s, 3H), 3.10 (t, J= 6.7 Hz, 2H), 3.55 (t, ./= 4.5 Hz, 2H), 3.84 (s, 3H), 7.07 (dd, J= 8.9 Hz, J= 3.0 Hz, IH), 7.16 (d, .7=3.1 Hz, IH), 7.54 (d, J= 8.9 Hz, IH), 7.84 (d, J= 8.9 Hz, 2H), 7.92 (s, IH), 8.26 (d, J= 8.9 Hz, 2H), 8.28 (d, J = 1.8 Hz, IH), 11.45 (s, IH). MS (ESI+): m/z 583. [0303] The title compound (CLXXII) in the free base form was prepared from compound 69 according to method B and the crude product purified by flash chromatography on silica gel (10% MeOH/DCM). The free base compound was then converted to HC1 salt according to method C as a brown solid (0.10 g, 57% overall). 1H NMR (DMSO-dg): 5 3.10-3.20 (m, 2H), 3.30-3.40 (m, 4H), 3.50 (br d, J= 11.9 Hz, 2H), 3.78 (br t, ./= 11.8 Hz, 2H), 3.99 (br d, J= 11.9 Hz, 2H), 6.89 (dd, J= 8.8 Hz, /= 2.9 Hz, 1'H), 6.96 (d, J = 2.9 Hz, IH), 7.41 (d, /= 8.8 Hz, IH), 7.88 (d, J= 8.9 Hz, 2H), 7.91-7.93 (m, IH), 8.22 (d, J= 1.8 Hz, IH), 8.31 (d, J= 8.9 Hz, 2H), 10.00 (s, IH), 10.56 (br s, IH), 11.50 (s, IH). MS (ESI+): m/z 569 (M+H)+, Example 149 Synthesis of 4-chloro-3-f3-f4-{K2-diethyIamino-ethyI)-methyI-amino1-metfavI|-phenyIamiao)-5-methyI-benzofl,2,41tria2;in-7-yn-phenol (CLXXJH) [0304] To synthesize the title compound (CLXXTIT), intermediate compounds 70 (4-bromo-benzyl)-A/"'^'-diethyl-A/-methyl-ethane-l,2-diamine) and 71 (7V-{4-[7-(2-chloro-5-methoxy-phenyl)-5-memyl-benzo[l,2,4]triazin-3-ylarmno]-benzyl}-7V'rAr-diethyl-A^-methyl-ethane-l^-diamine) shown below were used. Br MeO 71 [0305] To synthesize compound 70, a solution of JV^-diethyl-Af -methyl-ethane-1,2-diamine (3.4 g, 26 mmol), 4-bromobenzyl bromide (5.0 g, 20 mmol) and cesium carbonate (13 g, 40 mmol) in acetonitrile (60 mL) was heated at reflux for 18 h. The mixture was cooled and poured into water. The aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over NaaSCU, and filtered. The. filtrate was concentrated and the crude compound 70 was used in the next step without purification. [0306] To synthesize compound 71 a suspension of compound 16 (scheme (CXXXV), Example 124) (0.10 g, 0.33 mmol), compound 70 (0.15 g, •O.iOmmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and potassium i^rt-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3 mL, 2/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160°C for 20 min. After cooling down to room temperature, the cap was removed, the resulting mixture was filtered, and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (10% MeOH/DCM to 20% MeOH, 2% TEA in DCM) to afford compound 71 as an orange solid (0.10 g, 59%). ]H NMR (DMSO-d6): 5 0.93 (t, /= 7.1 Hz, 6H), 2.15 (s, 3H), 2.35-2.46 (m, 8H), 2.66 (s, 3H), 3.47 (s, 2H), 3.83 (s, 3H), 7.05 (dd, /= 8.9 Hz, /= 3.1 Hz, 1H), 7.14 (d, J= 3.2 Hz, 1H), 7.32 (d, ./= 8.5 Hz, 1H), 7.53 (d, J= 8.9 Hz, 2H), 7.87-7.89 (m, 1H), 7.98 (d, J= 8.6 Hz, 2H), 8.21 (d, J= 1.8 Hz, 1H), 10.95 (s, 1H). MS (ESI-f): m/z 519 . [0307] The title compound (CLXXlTf) in the free base form was prepared from compound 71 according to method B and the crude product purified by HPLC. The corrected fractions were poured into saturated NaHCOa and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaaSO^ and filtered. The filtrate was concentrated to afford the free base compound, which was converted to HC1 salt according to method C and furnished the title compound as an orange solid (40 mg, 19% overall). 'H NMR (DMSO-ds): 6 1.26 (t, J= 7.2 Hz, 6H), 2.69 (s, 3H), 2.71 (br s, 3H), 3.10-3.25 (m, 4H), 3.45-3.62 (m, 4H), 4.20-4.30 (m, IH), 4.51 (br d, J= 11.3 Hz, IH), 6.89 (dd, J= 8.7 Hz,,/ = 2.9 Hz, .IH), 6.95 (d, /= 2.9 Hz, IH), 7.4.1 (d, /= 8.7 Hz, IH), 7.67 (d, J== 8.0 Hz, 2H), 7.89 (s, IH), 8.13 (d, /= 8.4 Hz, 2H), 8.18 (d, /= 1.7 Hz, IH), 10.00(s, IH), 10.81 (brs, !H),11.19(s,lH), 11.23 (brs, IH). MS (ESI+): nth505. Example 150 Synthesis of 4-f7-(2-fluoro-3-hvdroxy-phenvl)-5-methyl-benzofl,2,4]triazin-3-yIamino]-A;r-(2-pyrrolidin-l-yl-ethyr)-benzeiiesulfonamide (CLXXTV) [0308] To synthesize the title compound (CLXXIV), intermediate compounds 72 (7-(2-fiuoro-3-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamme) and 73 (4-[7-(2-fluoro-3-methoxy-phenyl)-5-methyl-benzo[ 1,2,4]tri.azin-3-ylamino]-yV-(2-pyrrolidia-1 -yl-ethyl)-benzenesulfonamide) shown below were used. OMe OMe 73 [0309] To synthesize compound 72, compound 2 (scheme (CXXVI), Example 120) (1.0 g, 4.2 mmol), 2-fiuoro,3-methoxybenzene boronic acid (0.87 g, 5.1 mmol), Pd(PPh3)4 (0.40 g, 0.35 mmol), 2 M Na2C03 (5 mL, 10 mmol) were suspended in a mixture of DME/ethanol (4:1, 25 mL). The resulting mixture was heated at reflux for 1 h. The mixture was allowed to cool to room temperature, filtered and washed with DCM. The filtrate was concentrated and the residue triturated in MeOH. The resulting green solid was filtered and washed with MeOH. The resulting crude compound 72 was used in the next step without further purification. MS (ESI+): m/z 285. [0310] To synthesize compound 73, a suspension of compound 72 (0.10 g, 0.35 mmol), compound 38 (scheme (CLIV), Example 135) (0.14 g, 0.42 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 rng, 0.045 mmol) and potassium fert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3 mL, 2/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160 °C for 20 min. After cooling down to RT, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (10-20% MeOH/DCM) to afford compound 73 as a yellow solid (80 mg, 43%). 1H NMR (DMSO-d6): 5 1.55-1.65 (m, 4H), 2.30-2.40 (m, 4H), 2.44 (t, /= 7.0 Hz, 2H), 2.72 (s, 3H), 2.80-2.90 (m, 2H), 3.92 (s, 3H), 7.20-7.35 (m, 3H), 7.80 (d, /= 8.5 Hz, 1H), 7.84 (d, /= 8.9 Hz, 2H), 8.04 (s, 1H), 8.21 (d, J= 8.9 Hz, 2H), 8.35 (s, 1H), 1 1.40 (s, ). MS(ESI+):ni/z537. [0311] The title compound (CLXXIV) in the free base form was prepared from compound 73 (71 mg, 0. 13 mmol) according to method B. The free base compound was then converted to HC1 salt according to method C as an orange solid (48 rug, 66% overall). !H NMR (DMSO-d6): 8 1.80-1.90 (m, 2H), 1.95-2.03 (m, 2H), 2.73 (s, 3H), 2.95-3.05 (m, 2H), 3.10 (q, J= 6.2 Hz, 2H), 3.24 (q, J= 6.1 Hz, 2H), 3.48-3.58 (m, 2H), 7.00-7.20 (m, 3H)S 7.88 (d, /= 9.0 Hz, 2H), 7.91 (t, J= 6.1 Hz, 1H), 8.05 (s, 1H), 8.25 (d, /== 9.0 Hz, 2H>, 8.34 (s, 1H), 10.05 (br s, 1H), 10.10 (s, 1H), 11.45 (s, 1H). MS (ESI+): m/z 523. Example 151 Synthesis of 4-r7-(2-fluoro-6-hydroxy-phenyl)-5-methyl-benzofl,2,41triazig-3-yIamino|-7V-(2-pyrroIidin-l-yl-ethyl)-benzenesulfonamide (CLXXV) [0312] To synthesize the title compound (CLXXV), intermediate compounds 74 (7-(2-fluoro-6-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine) and 75 (4-[7-(2-fluoro-6-methoxy-phenyl)-5-meliiyl-benzo[l,2J4]1riazm-3-ylammo]-^-(2-pynroHdin-l-ethyl)-benzenestilfonamide) shown below were used. OMe 74 [0313] To synthesize compound 74, compound 2 (scheme (CXXVI), Example 120) (1.0 g, 4.2 mmol), 2-fiuoro,6-methoxybenzene boronic acid (0.87 g, 5,1 mmol), Pd(PPh3)4 (0.40 g, 0.35 mmol), 2 MNa2CO3 (5 mL, 10 mmol) were suspended in a mixture of DME/ethanol (4:1, 25 mL). The resulting mixture was heated at reflux for 1 h. The mixture was allowed to cool to room temperature, filtered and washed with DCM. The filtrate was concentrated and the residue triturated in MeOH. The resulting green solid was filtered and washed with MeOH. The resulting crude compound 74 was used in the next step without further purification. MS (ESI+): m/z 285. [0314] To synthesize compound 75, a suspension of compound 74 (0.10 g, 0.35 mmol), compound 38 (scheme (CUV), Example 135) (0.14 g, 0.42 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3 mL, 2/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160 °C for 20 min. After cooling down to room temperature, the cap was removed, the resulting.mixture was filtered, and the. filtered solid was washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (10-20% MeOH/DCM) to afford compound 75 as a yellow solid (0.14 g, 74%). 'H NMR (DMSO-d 15.3 Hz, J= 8.4 Hz, 1H), 7.83 (s, 1H), 7.84 (d, J= 9.0 Hz, 2H), 8.18 (s, 1H), 8.22 (d, J = 8.9 Hz, 2H), 11.37 (s, 1H). MS (ESI+): m/z 537. [0315] The title compound (CLXXV) in the free base form was prepared from compound 75 (0.14 g, 0.26 mmol) according to method B. The free base compound was then converted to HC1 salt according to method C as an orange solid (0.10 g, 69% overall). 1HNMR(DMSO-d6): 5 1.80-1.90 (m, 2H), 1.95-2.03 (m, 2H), 2.70 (s, 3H), 2,97-3.05 (m, 2H), 3.10 (q, J= 6.3 Hz, 2H), 3.24 (q, J= 6.1 Hz, 2H), 3.50-3.60 (m, 2H), 6.81 (t, J= 9.1 Hz, 1H), 6.89 (d, J= 8.3 Hz, 2H), 7.28 (dd, J= 15.2 Hz, J= 8.3 Hz, 1H), 7.88 (dd, J= 8.8 Hz, 2H), 7.89 (s, 1H), 7.90 (t, /- 6.1 Hz, 1H), 8.21 (s, 1H), 8.26 (d, /= 9.0 Hz, 2H), 10.04 (br s, 1H), 10.20 (s, 1H), 11.40 (s, 1H). MS (ESI+): m/z 523 . Example 152 Synthesis of benzoic acid 4-chloro-3-(5-methyl-3-f4-f2-pvrrolidin-l-Yl-ethoxy)-phenyIamino1-benzofl.2,41triazin-7-yU-phenyl ester (CLXXVI) [0316] The title compound was synthesizrd and had the following characteristics. !H NMR (DMSO-d6): 5 1.65-1.72 (m, 4H), 2.50-2.56 (m, 4H), 2.63 (s, 3H)5 2.79 (t, J= 5.9 Hz, 2H), 4.07 (t, /= 6.0 Hz, 2H), 7.00 (d, /= 9.1 Hz, 2H), 7.46 (dd, J= 8.7 Hz, J= 2.8 Hz, IH), 7.60-7.65 (m, 3H), 7.75 (d, /= 8.6 Hz, IH), 7.76 (t, J= 7.4 Hz, IH), 7.90 (dd, J = 1.8 Hz, J= 1.0 Hz, IH), 7.93 (d, /- 9.1 Hz, 2H), 8.16 (d, J= 8.4 Hz, 2H), 8.22 (d, J= 1.8 Hz, IH), 10.84 (br s, IE). MS (ESI+): m/z 581. [0317] For all the Examples 153-159 that follow, the synthetic procedures that were used corresponded to the general synthetic scheme (CLXXVII). R2 Rs "NH, DME/EtOH(4:1) Pd(PPh3)4 2M Na2CO3,100 "C Br 3, Xantphos, Cs2CO3, dioxane Ar, 100°C (CLXXVIT) Example 153 Synthesis^of N-("4-(2-rpyrroIidin-l-yl)ethoxy)pheDvI)-6-methvI-7-(4-methyIpyridin-3-yl)benzoIeUl,2,41triazin-3-amine (CLXxvm) [0318] The synthesis of the title compound (CLXXVTDT) can be generally described by the reaction scheme (CLXXIX). 76 77 Title Compound (CLXXIX) [0319] To synthesize the title compound, the general Buchwald procedure was employed using compounds 76 (124 mg, 0,5 mmol), 77 (171 mg, 0.6 mmol), C (660 mg, 2.0 mmol), Xantphos (58 mg, 0.1 mmol), Pd2(dba)3 (47 mg, 0.05 mmol), 3A mol sieves (ca. 500 mg), and 10 mL dioxane for 18 h. The reaction mixture was concentrated in vacua and purified using column chromatography (1:9 MeOH/CHCla) to afford the title compound as a red-orange solid (128 mg, 49%). Rf = 0.24 (1:9 MeOH/CHCl3); 1HNMRDMSO-d61.87-1.94 (m, 2H), 2.02-2.11 (m, 2H), 2.12 (s, 3H), 2.19 (s, 3H), 2.30 (s, 1.7H), 3.12-3.20 (m, 2H), 3.60-3.66 (m, 4H), 4.31 (t, /== 5.0 Hz, 2H), 7.07 (d, J= 9.1 Hz, 2H), 7.45 (d, J= 5.0 Hz, IH), 7.69 (s, IH), 7.91 (d, J= 9.0 Hz, 2H), 8.07 (s, IH), 8.41 (s, IH), 8.54 (d,/= 5.1 Hz, IH), 9.72 (br.s, IH), 10.75 (s, IH). Example 154 Synthesis of 5-r5-methyl-7-(2,6-dimethvlphenyI)benzofe1fl,2,41triazin-3-yIamino)-l-r3-(pyrrolidig4-yI)propyI)pyridm-2(lH)-one [0321] First, 2-(3-bromopropoxy)-5-nitropyridine (compound 80 on scheme (CLXXXT)) was synthesized. To synthesize, to a mixture of compounds 78 (5,0 g, 32 mmol) and 7.9 (4.1 mL, 47 mmol) in toluene (160 mL) was added 50% aqueous NaOH (1.9 mL, 49 mmol) followed by Adogen 464 (0.6 g,-1.6 mmol). The biphasic reaction mixture was stirred for 5 h. at 60 °C, cooled, and concentrated in vacua. The crude mixture was purified by column chromatography (3:7-4:7 EtoAc/hexanes) to afford compound 80 as an impure pale-yellow oil (3.7 g, 45%). Rf = 0.5 (3:7 EtOAc/hexanes 1H NMR CDC13: 5 2.35 (quintet, J= 6.4 Hz, 2H), 3.56 (t, J- 6.7 Hz, 2H), 4.57 (t, J= 5.9 Hz, 2H), 6.82 (d, J=> 9.6 Hz, IH), 8.36 (dd, J= 9.5, 3.0 Hz, IH), 9,07 (d, J= 2.6 Hz, IH). [0322] Next, compound 81 (l-(3-bromopropyl)-5-nitropyridin-2(lH)-one) was synthesized by refluxing bromide 80 (3.7 g, 14 mmol) in acetonitrile (70 mL) for 5 h.} cooling, and concentrating in vacua. The crude mixture was purified by column chromatography (1:1 EtOAc/hexanes) to afford compound 81 as a pale-yellow oil (2.5 g, 68%, 90% yield corrected for starting impurity). Rf = 0.2(3:7 EtOAc/hexanes); 1H NMR CDC13: 5 2.38 (quintet, J= 6.4 Hz, 2H), 3.43 (d, /= 6.1 Hz, 2H), 4.20 (t, J= 6.9 Hz, 2H), 6.57 (d, J= 10.1 Hz, IH), 8.11 (dd, /= 10.1, 3.1 Hz, IH), 8.67 (d, /= 3.0 Hz, IH). [0323] Next, compound 83 (5-nitro-l-(3-(pyrrolidin-l-yl)propyl)pyridin-2(lH)-one) was synthesized by adding pyrrolidine (14 niL, 169 mmol) to compound 81 (2.5 g, 9.5 mmol) in acetonitrile (50 mL); solution immediately became yellow. The reaction sat for 14 h. to ensure completion, was concentrated in vacua, and purified by column chromatography (1:10:189 NH^HMeOH/CHiCl) to afford compound .83 as a pale-yellow oil (2.3 g, 95%). LC retention time: 1.09 min. MS (ESI+) m/z= 252.1 !H NMR CDC13 :5 1.73-1.75 (m, 4H), 1.92 (quintet, J= 6.5 Hz, 2H), 2.38-2.46 (m, 6H), 4.10 (t, / = 6.5 Hz, 2H), 6.48 (d, ./= 10.0 Hz, IH), 8.03 (dd, J= 10.1, 3.1 Hz, IH), 8.84 (d, J= 3.0 Hz, IH); 13C NMR CDC13:5 23.7, 26.7, 49.2, 51.8, 53.8,119.3,130.2, 133.1, 141.2, 161.7. [0324] To compound 83 (2.1 g, 8.3 mmol) in MeOH (65 mL) was added palladium acetate (178.4 mg, 0.8 mmol), and the suspension was bubbled with Ha until the palladium turned black (ca. 10 min). The suspension was stirred under Efc for 3h., purged with argon, and filtered through celite using methanol to thoroughly wash the filter cake. The organic solution was concentrated in vacua to afford compound 84 (5-amino-l-(3-(pyrrolidin-l-yl)propyl)pyridin-2(lH)-one) as a black oil (1.8 g, quant.). LC retention time - 0.5 min MS (ESI+) m/z = 222.2 !H NMR CDC13:5 1.91-2.00 (m, 4H), 2.15 (quintet, /= 7.3 Hz, 2H), 2.82 (t, J= 7.5 Hz, 2H), 2.88-2.95 (m, 4H), 3.63 (br s, 2H), 3.99 (t, J= 7.0 Hz, 2H), 6.49 (d, J= 9.5 Hz, 1H) 6.91 (d, J = 3.0 Hz, 1H), 7.04 (dd, J= 9.5, 3.0 Hz, 1H). [0325] To copper (I) bromide (5 81 mg, 4.1 mmol) in CH3CN (25 mL) was added 90 % isoamyl nitrite (0.5 mL, 3.4 mmol) and the solution warmed to 65 °C. A suspension of amine 85 in CHjCN (10 mL) was added and the reaction was refluxed for 90 min. The black solution was filtered, diluted with, 20% HCL (80 mL) and extracted with ether (2x80 mL). The combined organic layers were washed with 20% HC1 (2x40 mL),. dried (MgSC>4), filtered, and concentrated in vacua to afford compound 86 (3-bromo-5-methyl-7-(2,6-dimethylphenyl)benzo[e][l,2,4]triazine) as an oily solid which was used immediately in the next reaction (717 rng, 54%). Rf = 0.58 (3:7 EtOAc/hexanes). [0326] To compound 86 (167 mg, 0.5 mmol) in THF (2 mL) was added a solution of 0.1 M (1:1:2:6 THF/dioxane/DMF/water) compound 84 (5.0 mL, 0.5 mmol) obtained as described above. After 22 h. under reflux with only minimal forward reaction, TEA (140 1-iL, 1.0 mmol) was added and continued reflux for 42 h. The reaction was diluted with water (10 mL) and extracted with EtOAc (3x15 .mL). The organic layers were combined, dried (MgSC^), filtered, and concentrated in vacua. The crude mixture was purified by HPLC to afford the title product as an orange solid (3.7 mg, 1.3%). LC retention time = 2.54 min,MS (ESI+) m/z = 469.4 JH NMRDMSO-d6: 5 1.81-1.88 (m, 2H), 1.97-2.02 (m, 2H), 2.05 (s, 6H), 2.08-2.16 (m, 2H), 2.65 (s, 3H), 2.95-3.05 (m, 2H), 3.15-3.24 (m, 2H), 4.05 (t, J= 6.8 Hz, 2H), 6.58 (d, J= 9.7 Hz, 1H), 7.15-7.28 (m, 3H), 7.63 (s, IK), 7.79 (dd, /= 9.8,2.9 Hz, 1H), 7.94 (d, J= 1.6 Hz, 1H), 8.62 (br s, 1H), 9.51 (br s, 1H), 10.71 (brs, 1H). Example 155 Synthesis of 2-r7-(2-cfalQro-5-hydroxyphenvl)-5-methyIbenzore1[l,2,4]triazin-3-ylanuuQ)-N-(2-rpyrrolidm-l-vl)ethvI)thiazoIe-4- carboxamide (CLXXXD) [0327] The synthesis of the title compound (CLXXXII) can be generally described by the reaction scheme (CLXXXHT), 85 86 87 BBr3 DCM Title Compound (CLXXXffl) [0328] The general Buchwald procedure was employed using compounds 85 (254 mg, 0.84 mmol), 86 (214 mg, 0.70 mmol), Cs2CO3 (937 mg, 2.88 mmol), Xantphos (83 mg, 0.14 mmol), Pd2(dba)3 (66 mg, 0.07 mmol), and 15 mL dioxane for 22 h. The crude reaction mixture was diluted with 50 mL water and extracted with DCM (4x75 mL). The combined organic layers were concentrated in vacua and purified using column chromatography (1:5:94 NH4OH/MeOH/DCM) to afford compound 87 as a yellow solid (188 mg, 51%). Rf = 0.06 (1:20:179 % m4OH/MeOH/CHCl3); LC retention time: 2.67 min, MS (ESI+) m/z = 524.2/526.4, [0329] The general aryl methoxy deprotection procedure was then employed using aryl methoxy compound 87 (188 mg, 0.36 mmol) and 1M BBr3 in DCM (2.1 mL, 2.1 mmol). in 12 mL DCM for 1 h. The reaction was quenched and filtered to afford the title compound (CLXXXII) as a brown solid (132 mgs 72%). LC retention time: 2.20 min, MS (ESI+) m/z = 510.5/512.3 !H NMR DMSO-d6: 5 1.72(s, 4H), 2.52(shoulder under DMSO), 2.62 (t, J= 6.4 Hz, 2H), 2.76 (s, 3H), 3.43 (q, /= 6.1 Hz, 2H), 6,88 (dd, J= 8.8, 2.9 Hz, 1H), 6.95 (d, /= 2.9 Hz, 1H), 7.41 (d, J= 8.7 Hz, 1H), 7.83 (s, 1H), 7.86 (t, J= 5.8 Hz, 1H), 7.94 (s, 1H), 8.23 (s, 1H), 9.94 (br s, 1H). Calcd for C24H24CIN7O2S.2.5H20.0..1Br: C 51.14, H 5.36, N 17.39. Found C 50.74, H 4.79, N 17.03. Example 15.6 Synthesis of 3-(3-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)-6-methyIbenzo[eiri^,4]triazin-7-yl)-4-fluQrophenoI (CLXXXTV) [0330] The synthesis of the title compound (CLXXXIV) can be generally described by the reaction scheme (CLXXXV). 88 77 89 Title Compound (CLXXXV) [0331] The general Buchwald procedure was employed using compounds 88 (2-(7-(2-chloro-5-methoxyphenyl)-5-methylbenzo[e][l,2,4]triazin-3-ylarnino)-N-(2-(pyrrolidin-l-yl)ethyl)thiazole-4-carboxamide) (254 mg, 0.94 mmol), 77 (described above) (177 pJL, 0.85 mmol), Cs2C03 (1.1 g, 3.42 mmol), Xantphos (102 mg, 0.18 mmol), Pd2(dba)3 (78 mg, 0.09 mmol), and 17 mL dioxane for 18 h, to obtain compound 89 (N~(4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)-7-(2-fluoro-5-methoxyphenyl)-6-methylbenzo[e][l,2,4]triazin-3-amine). Chromatography was run at 1:10:189 NH40H/MeOH/CHCl3 to afford the title compound as a red solid (181 mg, 45%). Rf = 0.06 (1:20:179 % NELtOHMeOH/GHCk); LC retention time: 2.65 min, MS (ESI+) m/z = 474.2. [0332] The general aryl methoxy deprotection procedure was then employed using aryl methoxy compound 89 (181 mg, 0.3 8 mmol) and 1M BBr3 in, DCM (2.3 mL, 2.3 mmol), in 10 mL DCM for 90 min. The reaction was, quenched and filtered. The water soluble product was recovered by extraction with EtOAc (50 mL). The organic layer was combined, with the filtered solid, concentrated in vacuo, and purified using HPLC to afford the title compound (CLXXXV) as a red solid (30 mg, 14%). LC retention time: 2.26 min, MS (ESI+) m/z = 460.2 !HNMR.DMSO-d6: 8 L864.94 (m, 2H)5 2.02-2.08 . (m, 2H), 2.32 (s, 3H), 3.11-3.20 (m, 2H), 3.58-3.66 (m, 4H), 4.30 (t, J= 5..0 Hz, 2H), 6.76 (dd, J= 6.2, 3.1 Hz, 1H), 6.86 (dt, J= 8.9, 3.6 Hz, 1H), 7.07 (d, J= 9.1 Hz, 2H)5 7.16 (t, J= 9.2 Hz, 1H), 7.64 (s, 1H), 7.91 (d, J= 9.1 Hz, 2H), 8.09 (s, 1H), 9.63 (s, 1H), 9.71 (br s, 1H), 10.75 (s, 1H), Example 157 Synthesis of 447-(2-fl^oro-5-hvdroxy-phenvI)-6-methyI-^ (CLXXXVI) [0333] The synthesis of the title compound (CLXXXVI) can be generally described by the reaction scheme (CLXXXVE). 90 91 92 Title Compound (CLXXXVII) [0334] The general Suzuki procedure was employed using compounds 90 (79 nag, 0.47 mmol), 91 (157 mg, 0.32 mmol), Pd(Ph3)4 (39 mg, 0.03 mmol), and 2M aqueous Na2C03 (0.6 mL, 1.2 mmol) for 2.5 h to afford, after chromatography (1:10:189 NHtOH/MeOH/CHCls), compound 92 (4-[7-(2-fluoro-5-methoxy-phenyl)-6-methyl~ beiizo[l,2,4]triazin-3-ylamiiio]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesu]fonamide), as an orange solid (89 mg, 52%). LC retention time: 2.66 min, MS (ESI+) m/z = 537.2. [0335] The general aryl rnethoxy deprotection procedure was then employed using aryl methoxy compound 92 (89 mg, 0.17 mmol) and 1M BBr3 in DCM (1 mL, 1.0' mmol), in 20 rnL DCM for 90 min. The reaction was quenched, filtered, and purified using HPLC to afford the title compound (CLXXXVI), as an orange solid (19 mg, 22%). LC retention time: 2.24 min, MS (ESI+) m/z = 523.2 !H NMR DMSO-d6: 8 1.83-1.91 (m, 2H), 1.96-2.04 (m, 2H), 2.36 (s, 3H), 2.99-3.08 (m, 4H), 3.21-3.27 (m, 2H), 3.52-3.60 (m, 2H), 6.78 (dd, J= 6.2, 3.1 Hz, 1H), 6.88 (dt, .7= 9.2 Hz, IE), 7.79 (s, 1H), 7.84 (d, J= 8.9 Hz, 2H), 8.86 (t, /= 6.2 Hz, 1H), 8.19 (s, 1H), 8.22 (d,J.= 8,9 Hz, 2H), 9.52 (br s, 1H), 9.66 (s, 1H). . Example 158 Synthesis of 4-[6-methyl-7-(lH-pyrazol-4-yI)-benzofl,2,41triazin-3-vIamino|-N-f2-pyrroIidin-l-yl-ethyl)-benzenesuIfonamide (CLxxxvni) [0336] The synthesis of the title compound (CLXXXVin) can be generally described by the reaction scheme (CLXXXDC). Br- HN N' ° HN— 93 91 Title Compound (CLXXXK) [0337] The general Suzuki procedure was employed using compounds 93 (117 mg, 2.2 .mmol), 91 (206 mg, 0.42 mmol), Pd(Ph3)4 (53 mg, 0.05 mmol), and CsF (128 mg, 0.84 mmol) in 4:1 DME/MEOH (4 mL) and 2M aqueous Na2CO3 (0.8 ml, 1.2 mmol) for 16 h. Additional amounts of compound 93 (308 mg, 1.6 mmol), Pd(Ph3)4 (53 mg, 0.05 mmol), and CsF (178 mg, 1.2 mmol) were added and the reaction was refluxed for 7 h. to afford, after .HPLC purification, the title compound (CLXXXVm), as a yellow solid (62 mg, 31%). LC retention time: 1.94 min, MS (ESI+) m/z = 479.2 !H NMR DMSO-d6: 5 1.82-1.91 (m, 2H), 7.97-2.04 (m, 2H), 2.64 (s, 3H), 2.99-3.08 (m, 4H), 3,22-3.27 (m, 2H), 3.53-3.59 (m, 2H), 7.76 (s, 1H), 7.84 (d, /= 7.1 Hz, 2H), 7.86 (t, J= 6.2 Hz, 1H), 8.11 (br s, 1H), 8.20 (d, /- 7.1 Hz, 2H), 8.35 (s, 1H), 9.57 (br s, 1H), 11.24 (s, 1H). Example 159 Synthesis of 4-f7-(2-chIoro-5-hydroxy-phenyI)-6-methyI-benzofl,2,41triazin-3-ylaminol-N-(2-pyrrolidin-l-yI-ethyI)-benzenesuIfonami(ie (CXC) [0338] The synthesis of the title compound (CXC) can be generally described by the reaction scheme (CXCI), Title Compound (CXC1) [0339] The general Suzuki procedure was employed using compounds 94 (194 mg, 1.0 mmol), 91 (252 mg, 0.5 mmol), Pd(Ph3)4 (59 mg, 0.05 mmol), and 2M aqueous Na2CO3 (1.0 mL, 2.0 mmol) for 15 h. The reaction was diluted with DCM (10 mL) and water (10 mL) and the biphasic mixture was filtered to afford compound 95 (4-[7-(2-chloro-5-memoxy-phenyl)-6-methyl-berEo[lJ2,4]triazm-3-ylammo]-N-(2-pyrrondiii-l-yl-ethyl)-benzenesulfonamide), as an orange solid (85 mg, 15%). LC retention time: 2.75 min, MS (ESI+) m/z = 553.2/555.4. [0340] The general aryl methoxy deprotection procedure was then employed using aryl methoxy compound 95 (86 mg, 0.16 mmol) and 1M BBr3 in. DCM (0.93 mL, 0.93 mmol), in 5 mL DCM for 3 h. The reaction was quenched, filtered, and purified using HPLC to afford the title compound (CXC), as an orange solid (19 mg, 23%). LC retention time: 2.42 min, MS (ESI+) m/z = 539.1/541.4 'HNMR DMSO-d6: 8 1.83-1.89 (rn, 2H), 1.94-2.03 (m, 2H), 2.29(s, 3H), 2.98-3.05 (m, 2H), 3.09 (q, J=6.2 Hz, 2H), 3.22-3.25 (m, 2H), 3.50-3.57 (m, 2H), 6,81 (d, /= 2.9 Hz, IH), 6.91 (dd, J= 8.8,2.9 Hz, IH), 7.41 (d, J= 8.8Hz, IH), 7.80 (s, IH), 7.85 (d, J= 8.9 Hz, 2H), 7.92 (t, J= 4.5 Hz, IH), 8.11 (s, IH), 8.21 (d, /= 8.9 Hz, 2H), 9.98 (s, 2H), 11.33 (s, IH). Example 160 Synthesis of 4-[7-(3-hydroxvmethyl-phenyI)-6-methyI-benzofl,2,4|triazin-3-vIamino1-N-(2-pyrrolidin-l-vI-ethvl)-ben2eiiesulfonamide (cxcn) [0341] The synthesis of the title compound (CXCH) can be generally described by the reaction schemes (CXCffl) and (CXCIV). HO NH2 OH OH DME/EtOH/H2O Na2CO3 Pd (PPh3)4, reflux (cxcm) [0342] The mixture of 7-bromo-6-mefhylbenzo[e][l,2j4]tria2m-3-amine (240 mg, 1.0 mmol), 3-(hydroxymethyl)phenylboronic acid (310 mg, 2.0 mmol), ethylene glycol dimethyl ether (10 mL), EtOH (1 ml,), H20 (1 mL), Pd(PPh3)4 (120 mg, 0.1 mmol) and Na2CO3 (1,1 g, 10 mmol) was degassed.with argon for 5 minutes and refluxed for overnight under argon. The reaction mixture was brought to room temperature, and the solid was removed by filtration. After evaporation of the volatiles, the crude product was purified by silica gel column (3.5 x 16 cm) chrornatography with 10% CHsOH/CHCls as an eluent to give a yellow solid product (200 mg5 75%). [0343] The product of reaction shown by scheme (CXCITf) was further reacted as shown by scheme (CXCIV). Pd2 (dba)3 Xantphos Cs2CO3 Dioxane, reflux (CXCIV) [0344] A mixture of (3-(3-amino-6-methylbenzo[e][l,2,4]triazin-7-yl)phenyl)rnethanol (200 mg, 0.75 mmol), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (380mg, 1.13 mmol), cesium carbonate (730 mg, 2.25 mmol), Xantphos (90 mg, 0,15 mmol), Pd2(dba)3 (70 mg, 0.075 mrnrnol) in 15 mL of anhydrous dioxane was degassed with argon for 5 minutes and was refluxed for 4 h. The reaction mixture was brought to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography using 30% CHsOH in CHCb as an eluent. The solid was washed with acetone to afford the title compound (CXCH), as a bright yellow solid (200 mg, 52%). !H NMR DMSO-d6: 5 1.67 (br s, 4H), 2.44 (s; 3H), 2.50 (br s, 4H), 2.88 (br s, 2H), 4.60 (d, J = 3.6 Hz, 2H), 5.28 (br s, IH), 7.43 (m, 5H), 7.80 (m, 3H), 8.12 (s, IH), 8.18 (d, J- 8.7 Hz, 2H), 11.25 (s, IH). MS (ESI+) mk = 519. Example 161 Synthesis of 4-f7-(5-chloro-thiophen-2-yl)-6-methyl-benzo[l,2,41triazin-3-yIammo1-N-(2-pyrrolidin-l-yI-ethyl)-benzenesulfonamide (CXCV) [0345] The synthesis of the title compound (CXCV) can be generally described by the reaction schemes (CXCVT) and (CXCVH). OH DME / EtOH / H20 Na2CO3 Pd (PPh3)4i reflux (CXCVI) [0346] The mixture of 74>romo-6-memylberizo[e][l,2J4]triazm-3~amine (310 mg, 1.3 mmol), 5-chloro-2-tbiopheneboronic acid (320 mg, 2,0 mmol), ethylene glycol dimethyl ether (10 mL), EtOH (1 mL), H20 (1 mL), Pd(PPh3)4 (150 mg, 0.13 mmol) and Na2CO3 (1.38 g, 13 mmol) was degassed with argon for 5 minutes and refluxed for 16 h under argon. The reaction mixture was brought to room temperature, and the solid was removed by filtration. After evaporation of the volatiles, the crude product was purified by silica gel column (3.5 x 16 cm) chromatography using 10% CHsOH/CHCla as an eluent to give a yellow solid (220 mg, 61 %). [0347] The product of reaction shown by scheme (CXCVI) was further reacted as shown by scheme (CXCVIT). (dba)3 Xantphos Cs2CO3 Dioxane, reflux (CXCVE) [0348] A mixture of 7-(5-chlorothiophen-2-yl)-6-methylbenzo[e][l52,4]triazin-3-amine (110 mg, 0.4 mmol), 4-bromo-N-(2-pyrrolid:n-l-yl-ethyl)benzenesulfonamide (260 mg, 0.78 mmol), cesium carbonate (390 mg, 1.2 mmol), Xantphos(46 mg, 0.08 mmol), Pd2(dba)3(36 mg, 0.04 mmmol) in anhydrous dioxane (15 mL) was degassed with argon for 5 minutes and the reaction mixture was refluxed for 16 h. The solvent was removed under reduced pressure and the crude product was purified by silica gel column (3.5 x 16 cm) chromatography using 30% CH3OH in. CHC13 as an eluent, to afford the title product (CXCV), as an orange solid (110 mg, 52%).1H NMR DMSO-d6: 5 1.65 (br s, 4H), 2.43 (br s, 4H), 2.60 (s, 3H), 2.86 (t, J= 6.5 Hz, 2H), 7.26 (d, /= 3.9 Hz, 1H), 7.31 (d, J= 3.9 Hz, 1H), 7.45 (br s, 1H), 7.81 (m, 3H), 8.16 (d, /= 9.3 Hz, 2), 8.32 (s, 1H), 11.33 (s, 1H). MS (ESI+) 7«/z - 529. Example 162 Synthesis of 4-(6-methoa:y-7-o-toIvl-benzofl,2,4|triazin-3-vlammo)-N-(2-pyrrolidin-l-vI-ethyI)-benzenesulfonamide (CXCVffl) [0349] The synthesis of the title compound (CXCVUI) can be generally described by the sequence of reaction schemes (CXCTX), (CC), (CCI), (CCII), (CCm), and (CCIV). CH3OH Na (2.6 eq.) CH3ON.a / CH3OH reflux in a sealed tube NH2 (CXCK) [0350] To freshly prepared sodium methoxide using sodium (900 mg, 39 mmol) and anhydrous methanol (20 mL) was added 3-chloro-6-nitroaniUne (2.55 g, 15 mmol). The reaction mixture was heated in a sealed tube at 120°C for 4 hours. The solvent was removed under reduced pressure and the crude solid was dissolved in water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate layer was dried over sodium sulfate. The sodium sulfate was removed by filtration and the solvent was removed. The crude was dried to yield a yellow solid (1.75 g, 69%). [0351] The product of reaction shown by scheme (CXCIX) was further reacted as shown by scheme (CC). fl o N, NBS(1eq.)/AcOH ... " "0 ref|ux BIX ^ ^N, NH2 "- (CC) [0352] A mixture of 3-methoxy-6-nitroaniline (940 mg, 5.6 mmol) and NBS (1.1 g, 6.2 mmol) in glacial acetic acid (25 mL) was heated to reflux under argon for 3 h. The reaction mixture was brought to room temperature and the mixture was diluted with water (100 mL). The yellow precipitate was collected by filtration, washed with water to yield a yellow solid (1 g, 72%). [0353] The product of reaction shown by scheme (CC) was .further reacted as shown by scheme (CCI). O . 1)HCI Q. CN 2)NaOH I NH2 ~ " , (CCD [0354] 4-bromo-3-methoxy-6-rjitroaniline (Ig, 4.05 mmol) was mixed with cyanarnide (1.7 g, 40 mmol) and heated to melt at 90°C. Concentrated HC1 (10 mL) was cautiously added dropwise within 20 minutes. The reaction mixture was heated to reflux until all starting material reacted (about 2 h). Another batch, of cyanamide (1.7 g, 40 mmol) and hydrochloric acid (10 mL) was added and the reaction continued for another hour. The ice cooled reaction mixture was brought to pH 13 with 30% sodium hydroxide. The mixture was heated to reflux for 3 h. The precipitate was collected by filtration and washed with water to give a yellow solid (900 trig, 82%). [0355] The product of reaction shown by scheme (CCI) was further reacted as shown by scheme (CCH). QH DME/EtOH/H20 (CCT) [0356] A mixture of 7-bromo-6-methoxybenzo[e][l,2,4]triazin-3-amme-l-N-oxide (350 mg, 1.3 mmol), 2-methyl phenylboronic acid (350 mg, 2.6 mmol), ethylene glycol dimethyl ether (30 mL), EtOH (3 ml), H2O (3 ml), Pd(PP.h3)4 (150 mg, 0.13 mmol) and Na2C03 (1.38 g, 13 mmol) was degassed with argon for 5 minutes and refluxed for 16 h under argon. The reaction mixture was cooled to room temperature, and the solid was removed by filtration. After evaporation of the volatiles, the crude product was purified by silica gel column (3.5 x 16 cm) chromatography using 5% CHsOH/CHCls as an eluent to give a solid. The solid was washed with dichloromethane/hexanes (1:1) to give a yellow solid (220 mg, 61%). {0357] The product of reaction shown by scheme (CCH) was further reacted as shown by scheme (CCHI). Pd2 (dba)3 Xantphos Cs2CO3 Dioxane, reflux (CCHI) [0358] A mixture of 6-methoxy-7-o-tolylbenzo[e][l,2,4]triazin-3-amme-l-N-oxide (230 mg, 0.82 mmol), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (540 mg, 1.64 mmol), cesium carbonate (800 mg, 2.45 mmol), Xantphos (94 mg, 0.16 mmol), Pda(dba)3(75 mg, 0.08 mmmol) in 15 mL of anhydrous dioxane was degassed with argon for 5 minutes and was refluxed for 4 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography using 20% CHsOH in as an eluent. The solid was washed with minimum amount of methanol ( about 5 mL) to give a orange solid (340 mg, 66%). . [0359] The product of reaction shown by scheme (CCDT) was further reacted as shown by scheme (CCTV). H2, Raney Ni (ccrv) [0360] 4-(6-mefeoxy-l-oxy-7-o-tolyl-benzo[l,2,4]triazm~3-ylamino)-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (140 mg, 0.26 mmol) was reduced in methanol (25 mL) and ethyl acetate (25 mL) mixture with catalytic amount of Raney Ni, and hydrogen for 4 h. The catalyst was removed by filtration and the solvent was removed under reduced pressure to afford the title product (CXCVnT), as a yellow solid (60 mg, 44%).'H NMR DMSO-d6: 6 L63 (br s, 4H), 2.11 (s, 3H), 2.37 (br s, 4H), 2.44 (br s, 2H), 2.85 (t, /= 6.8 Hz, 2H), 3.97 (s, 3H), 7.27 (m, 5H),7.42 (br s, IH), 7.79 (d,/= 8.8 Hz, 2H), 8.02 (s, IH), 8.18 (d, J= 8.9 Hz, 2H), 11.12 (s, IH). MS (ESI+) m/z =519. (CCV) Example 163 Synthesis of 4-(6-hydroxy-7-o-toIyI-benzo[l,2,41triazin-3-yIamino)-N-(2-pyrrolidin-l-yl-ethyl)-benzenesuIfonaniide [0361] The synthesis of the title compound (CCV) can be generally described by the of reaction scheme (CCVI).. • pyridine HCI 160°C in a sealed tube (CCVI) [0362] 4-(6-methoxy-7-o-tolyl-benzo [ 1,2,4]triazm-3-ylamrno)-N-(2-pyrroh'din-1 -yl-ethyl)4>enzenesulfonamide (70 mg, 0.14 mmol) and pyridine hydrochloride (1.0 g, 8.6 mmol) was heated at 160°C in a seal tube for 4 h. The crude was suspended in diluted HCI (30 mL), and the crude product was purified by silica gel column with 20% CHaOH in CHCla as an eluent to afford the title compound (CCVT), as a yellow solid (15 mg, 22%). 'H NMR DMSO-dg: S 1.65 Example 164 Synthesis of 4-(6-ethoxy-7-o-toIvI-benzori,2,41triazia-3-vlamino)-N-(2-pvrrolidin-l-yl-ethyl)-benzenesulfonaniide (CCVII) [0363] The synthesis of the title compound (CCVTI) can be generally described by the sequence of reaction schemes (CCVTfl), (CCIX), (CCX), and (CCXT). pyridineHCI, 175°C in a sealed tube N NH2 (ccvni) [0364] The mixture of 7-bromo-6-methoxybenzo[e][l,2,4]triazm-3-arniae-l-N-oxide (170 mg, 0.6 mmol) and pyridine hydrochlonde (1.0 g, 8.6 mmol) was heated at 170°C in a seal rube for 2 h. The crude was triturated with dilute HC1 (30 mL). The resulting yellow precipitate (100 mg, 62%) was isolated by filtration. [0365] The product of reaction shown by scheme (CCVTH) was further reacted as shown by scheme (CCDC). H2, Raney Ni (ccrx) [0366] 3-amino-7-o-tolylbenzo[e][l,2;4]triazin-6-ol-l-N-oxide (60 mg, 0.2mmol) was reduced in methanol (10 mL) and ethyl acetate (10 mL) with catalytic amount of Raney Ni and hydrogen at room temperature for 4 hours. The catalyst was removed by filtration and the solvent was removed. The solid was washed with acetone to give a yellow solid (50 mg, 89%). [0367] The product of reaction shown by scheme (CCTX) was further reacted as shown by scheme (CCX). N NH2 Cs2CO3 / Kl Acetone / CH3OH reflux (CCX) [0368] A mixture of 3-amino-7-o-tolylbenzo[e][l,2,4]triazin-6-ol (0.06 g, 0.22 mmol), ethyl bromide (0.24 g, 2.2 mmol), cesium, carbonate (0.3 g, 0,92mmol) and KI (0.1 g, 0.6 mmol) in acetone/methanol (5:1, 20 mL) was refluxed for 3 hours. After removing the solvent, the crude product was purified by silica gel column with 5% methanol/ chloroform as an eluent as an orange solid (0.046 g, 73%). f0369] The product of reaction shown by scheme (CCX) was further reacted as shown by scheme (CCXI), Br Pd2 (dba)3 Xantphos Cs2C03 Dioxane, reflux (CCXT) [0370] A mixture of 6-ethoxy-7-o-tolylbenzo[e][l,234]triazin-3-amine (0.046 g, 0.21 mmol), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.14 g, 0.43 mmol), cesium carbonate (0.21 g, 0.63 mmol), Xantphos (25 mg, 0.15 mmol), Pd2(dba)3(20 nig, 0.021 mmol) in 10 mL of anhydrous dioxane was degassed with argon for 5 minutes and was refluxed for 16 h. The solvent was removed and the crude product was purified by silica gel column (3.5 x 16 cm) chromatography using 20% CHsOH in CHCla as an eluent to afford the title compound (CCVH), as a yellow solid (61 mg, 52%). 1H NMR. DMSO-de: S 1.27 (t, J= 7Hz, 3 H), 1.62 (m, 4H), 2.13 (s, 3H), 2.35 (br s, 4H), 2.43 (t, J = 7.3 Hz, 2H), 2.85 (t, J=> 6.9 Hz, 2H), 4.29 (m, 2H), 7.30 (m, 5H), 7.42 (br s, 1H), 7.79 (d, J= 8.9 Hz), 8.02 (s, 1H), 8.18 (d, J= 8.9 Hz, 2H). 11.09 (s, 1H). MS (ESI+) m/z = 533. Example 165 Synthesis of 4-f7-(3-hydroxy-pfaeDvn-6-methoxy-benzofl,2,41triazin-3-y!amiao1-N-(2-pyrroIidin-l-yI-ethyI)-benzenesulfonaniide -N W I* in v H V (CCXII) [0371] The synthesis of the title compound (CCXTf) can be generally described by the sequence of reaction schemes (CCXHI), (CCXTV), (CCXV), and (CCXVI). O- OBn DME/EtOH/H2O ^ " Pd (PPh3)4, reflux (ccxm) [0372] The mixture of 7-bromo-6-methoxybenzo[e][l,2J4]triazin-3-amine-l-N-oxide (0.14 g, 0.52 mrnol), 3-benzyloxyphenylboronic acid (0.24 g, O.lOmmol), ethylene glycol dimethyl ether (15 mL), EtOH (1.5 mL), H2O (1.5 mL), Pd(PPh3)4 (60 mg, 0.05 mmol) and Na2CC>3 (0.55 g, 5.2 mmol) was degassed with argon for 5 minutes and refluxed for 16 h under argon. The solid was filtered off, and the volatiles were evaporated. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography using 10% CH3OH/CHC13 as an eluent to give a yellow solid (0,14 g, 72%). [0373] The product of reaction shown by scheme (CCXHI) was further reacted as shown by scheme (CCXIV). OBn Pd2 (dba)3 /=v O Xantphos / \ if ri fs_ j-**/~Br~\\ /A~s~N^x^M^v Cs2C03 \\ // n ^ N \ __ Dioxane. reflux (CCXIV) [0374] A mixture of 7-(3-(benzyloxy)phenyl)-6-methoxybenzo[e] f 1,2,4]triazia-3-amine-1-N-oxide (0.11 g, 0.29 mmol), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.20 g, 0.6 mmol), cesium carbonate (0.29 g, 0.89 mmol), Xantphos (34 mg, 0.06 mmol), Pd2(dba)3(27 mg, 0.029 mmol) in 15 ml, of anhydrous dioxane was degassed with argon for 5 minutes and was refluxed overnight. The reaction mixture was brought to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography using 30% CHaOH in CHCla as an eluent. The solid was washed with acetone to give a yellow solid (0.1 g, 54%). [0375] The product of reaction shown by scheme (CCXIV) was further reacted as shown by scheme (CCXV). OBn HZ, Raney Ni (CCXV) [0376] 4-[7-(3-benzyloxy-phenyl)-6-methoxy-l-oxy-benzo[l,2,4]triazm-3-ylarnino]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.1 g, 0.16mmol) was dissolved in methanol (10 mL) and ethyl acetate (10 mL) with catalytic amount of Raney Ni and atmosphere hydrogen at room temperature for 4 hours. The catalyst was removed by filtration. The solvent was removed by reduced pressure. The solid was used for the next reaction without further purification, [0377] The product of reaction shown by scheme (CCXV) was further reacted as shown by scheme (CCXVI). OBn BBr3 CHC!3 / EtOAc room temp. (CCXVT) [0378] The above 4-[7-(3-benzyloxy-phenyl)-6-methoxy-benzo[l,2,4]triazin-3-ylarnino]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonarnide in chloroform (10 mL) and ethyl acetate (10 mL) was stirred with IMBBrs in dichloromethane (10 mL, 10 mmol) at room temperature for 5 h. The reaction was quenched by methanol (1 mL). After removing the solvent, the crude product was purified by silica gel column chromatography with 20% % CH-jOH/CHCla as an eluent to give a solid. The solid was washed with acetone to afford the title compound (CCXII), as a yellow solid (0.03g, 36% in 2-steps).IHNMRDMSO-d6: 8 1.62 (br s, 4H), 2.36 (br s, 4H), 2.43 (t, J= 1 Hz, 2H), 2.85 (t,/= 6.9 Hz, 2H), 4.02 (s, 3H),6.83 .(d, J= 8 Hz, 1H), 6.99 (m, 2H), 7.27 (t, /= 8.7 Hz), 7.42 (br s, 1H), 7.80 (d, J= 8.8 Hz, 2H), 8.12 (s, 1H)S 8.17 (d, .7= 8.8 Hz, 2H), 9.55 (s, 1H), 11.10 (s, 1H). MS (ESI+) m/z = 521. Example 166 Synthesis of 4-f6-f2-hydroxy-ethoxy)-7-o-tolyI-ben2ofl,2,41triggin-3-ylamino1-N-(2-pyrroIidin-l-yl-ethyI)-benzepesuIfonamide HO^-x (ccxvn) [0379] The synthesis of the title compound (CCXVH) can be generally described by the sequence of reaction schemes (CCXVTfl) and (CCXTX). H°x/^, Cs2C03 / Kl Acetone / CH3OH refhjx (CCXVTII) [0380] 3-amino-7-o-tolylbenzo[e][l,2,4]triazin-6-ol (0.1 g, 0.4 mmol), 2-bromoethanol (0.5 g, 4 mmol), cesium carbonate (0.3 g, 0.92mmol) and KI (0.1 g, 0.6 mmol) was stirred in acetone/methanol (5: 1, 20 mL) at room temperature for overnight. After cooling down, the solvent was removed by reduced pressure. The crude was purified by silica gel column with 20% methanol/chloroform. as an eluent to give an orange solid (0.04g, 34%). [0381] The product of reaction shown by scheme (CCXVTfT) was further reacted as shown by scheme (CCXIX). Pd2 (dba)3 Xantphos Cs2CO3 Dioxane, reflux (CCXTX) [0382] A mixture of 2-(3-arniao-7-o-tolylbenzo[e][l:i2!4]triazm-6-yloxy)ethanol (0.04g, 0.13 mmol), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (0.09 g, 0.27 mmol), cesium carbonate (0.13 g, 0.4 mmol), Xantphos (20 mg, 0.03 mmol), Pd2(dba)3(10 mg, 0.01 mmol) in 10 mL of anhydrous dioxane was degassed with argon for 5 minutes and was refluxed for overnight. The reaction mixture was brought to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 10 cm) chromatography using 30% CH3OH in CHCla as an eluent to afford the title compound (CCXVTJ), as an orange solid (0,01 g, 14%).!H NMRDMSO-d6: 8 1.65 (br s, 4H), 2.10 (s, 3H), 2.41 (br s, 4H), 2.87 (t, J= 6.9Hz5 2H), 3.87 (t, /= 5.0Hz, 2H), 4.42 (t, J= 4.9 Hz, 2H), 5.92 (s, 1H)3 7.10 (d, /= 7.3 Hz, IS), 7.24 (m, 4H), 7.48 (br s, 1H), 7.76 (m, 4H). MS (ESI+) m/z = 549. Example 167 Synthesis of f7-(2,6-dichloro-phepyl)-5-methyI-benzQfl,2,4]triaziii-3-vn-f2-methyl-6-(2-pyrroIidin-l-yl-ethoxy)-pvrimidin-4-yn-amme Cl (CCXX) [0383] The synthesis of the title compound (CCXX) can be generally described by the sequence of reaction schemes (CCXXI) and (CCXXTT). THF. reflux excess (CCXXI) [0384] 4,6-dichloro-2-methylpyrimidine (1 g, 6.1 mmol) was added into a freshly prepared sodium 2-(pyrrolidin-l-yI)ethoxide from 2-(pyrrolidin-l-yl)ethanol (0.35g, 3.1mmol) and sodium (O.OSg, 3.5mmol) in anhydrous THF (10 mL) with stirring under argon. The mixture was refluxed under argon for 2h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography with CHCls as an eluent to give a pale yellow oil (540 mg, 73%). 1H NMR. CDC13: 8 1.78 (m, 4H), 2.56 (s, 3H), 2.58 (m, 4H), 2.84 (t, J= 5.8 Hz, 2H), 4.48 (t, J= 5.8 Hz, 2H), 6.59 (s, 1H). [0385] The product of reaction shown by scheme (CCXXI) was further reacted as shown by scheme (CCXXTf). (ccxxn) [0386] A mixture of 7-(2,6-dichlorophenyl)-5-methylberizo[e][l,2,4]triazm-3-amme (170 mg, 0.56 mmol), 4-(2-(pyrrolidm-l-yl)ethoxy)-6-chloro-2-methylpvrimidine (270 mg, 1.12 mmol), cesium carbonate (550 mg, 1.7 mmol), Xantphos (65 rng, 0.11 mmol), Pd2(dba)a (51 mg, 0.056 mmol) in anhydrous dioxane (25 mL) was degassed with argon for 5 minutes and was refluxed for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography with 10% CH/jOH in CHCls as an eluent to give the title compound (CCXX), as a yellow solid. (100 mg, 35%). 1R NMR DMSO-d6: 5 1.72 (br s, 4H), 2.6 (m, 7H), 2.92 (br s, 2H), 4.49(br s, 2H), 7.53 (t, J = 8.2 Hz, IB), 7.67 (s, 1H), 7.69 (s, 1H), 7.79 (s, IB), 7.83 (d, J= 1.9 Hz, IB), 8.23 8.23 (d, J= 1.8 Hz, IB), 11.59 (s, IB). MS(ESI+) m/z = 510. Example 168 Synthesis of 4-chloro-3-(5-methyI-3-|2-methyI-6-(2-pyrrolidin-l-vl-ethoxy)-pyrimidia-4-ylamino1-benzo[l,2,4]triazin-7-yI|-phenol (ccxxni) [0387] The synthesis of the title compound (CCXXJCH) can be generally described by the sequence of reaction schemes (CCXXTV) and (CCXXV). N NH2 cr Pd2 (dba)3 Xantphos Cs2C03 Dioxane, reflux (ccxxrv) [0388] A mixture of 7-(2-chloro-5-methoxyphenyl)-5-methylbenzo[e][l,2,4]triazin-3-amine (340 mg, 1.3 mmol), 4-(2-(pyrrolidin-l-yl)ethoxy)-6-chloro-2-methylpyrimidine (270 mg, 1.12 mmol), cesium carbonate (l.lg, 3.37 mmol), Xantphos (130 rng, 0.22 mmol), Pda(dba)3 (100 mg, 0.11 mmol) in anhydrous dioxane (25mL) was degassed with argon for 5 minutes and was refluxed for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 1-6 cm) chrornatography with 10% CHjOH in CHC^. The solid was washed with acetone/hexanes (1:5) to yield a yellow solid (300 mg, 53%). [0389] The product of reaction shown by scheme (CCXXTV) was further reacted as shown by scheme (CCXXV). BBr3 (CCXXV) [0390] The N-(6-(2-(pyrrolidin-1 -yl)ethoxy)-2-methylpyrimidin-4-yl)-7-(2-chloro-5-methoxyphenyl)-5-methylbenzo[e][l,2,4]triazin-3-amine (270 mg, 0.53 mmol) in chloroform (10 ml) was stirred with 1M BBr3 in dichloromethane (5 mL, 5 mmol) at room temperature for 3 h. The reaction was quenched by methanol (1 mL). After removing the solvent, the crude product was neutralized with saturated sodium bicarbonate (1 x 25 mL). The crude product was extracted by ethyl acetate (2 x 50 mL). The combined ethyl acetate was dried over sodium sulfate. The salt was removed by filtration and the solvent was removed by vacuum. The crude product was purified by silica gel column chromatography with 20% CHsOH/CHCL) as an eluent to afford the title compound (CCXXni), as a yellow solid (100 mg, 38%). 'H NMR DMSO-d6: 5 1.68 (m, 4H), 2.48 (s, 3H), 2.53 (m, 4H), 2.65 (s, 3H), 2.81 (t, J= 6.0 Hz, 2H), 4.44 (t, J= 5.8 Hz, 2H), 6.88 (dd, J= 8.8 Hz, /= 2.9 Hz, IH), 6.94 (d, J= 2.9 Hz, 1H), 7.40 (d, J= 8.8 Hz, IH), 7.73 (s, IH), 7.93 (s, IH), 8.24 (d, J= 1.6 Hz, IH), 9.95 (s, IH), 11.55 (s, IH). MS(ESI+) m/z = 492. Example 169 Synthesis of 4-f7-(6-chIoro-2-fluoro-3-hydrQxy-phenvl)-5-methvl-benzori,2,4]triazin-3-vlamino1-N-(2-pvrroIidin-l-yI-ethyI)-benzenesulfonamide (CCXXVI) [0391] The synthesis of the title compound (CCXXVT) can be generally described by the sequence of reaction schemes (CCXXVII), (CCXXVIH), (CCXXTX), and (CCXXX). 1)nBuLi 2) B(OMe)3 (CCXXVIT) [0392] 2.5M nBuLi (14.9mL, 37.4 mmol) was added dropwise over 5 minutes into a mixture of 4-chloro-2-fluoro-l-methoxybenzene (5g, 31.1 mmol) in anhydrous THF (30 mL) at -78°C. After the mixture was stirred at -78°C for 20 minutes, anhydrous trimethyl borate (4.9g, 46.6 mmol) was added into the solution at -78°C. The reaction mixture was brought to room temperature for over period of 2 h. The reaction was quenched by 2N HCI (1 mL). THF was removed by vacuum. The crude product was diluted with 2N HCI (100 mL). The acidic solution was extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate fraction was dried over sodium sulfate. The sodium sulfate was removed by filtration and the solvent was removed by vacuum. The oil was titrated with hexanes/chloroform (1:1) to yield a solid. The precipitate was collected by filtration and washed with hexanes to yield a white solid (2.5g, 39%). :H NMR DMSO-d6: § 3.81 (s, 3H), 7.12 (m,2H), 8.66 (s,2H). [0393] The product of reaction shown by scheme (CCXXVTI) was further reacted as shown by scheme (CCXXVm). DME / EtOH / H20 Na2CO3 Pd(PPh3)4, reflux. (CCXXV1H) [0394] A mixture of 7-bromo-5-methylbenzo[e][l,2,4]triazin-3-amine (420 mg, 1.8 mmol), 6-chloro-2-fluoro-3-methoxyphenylboronic acid (350 mg, 5.4 mmol), ethylene glycol dimethyl ether (20 mL), EtOH (2 mL), H2O (2 mL), Pd(PPh3)4 (200 mg, 0.17 mmol) and Na2C03 (1.87 g, 18 mmol) was degassed with argon for 5 minutes and refluxed for 16 h under argon. The reaction mixture was cooled to room temperature, and the solid was removed by filtration. After evaporation of the volatiles, the crude product was purified by silica gel column (3.5 x 16 cm) chromatography with 5% CHaOH/CHCla as an eluent to give a solid. The solid was washed with chloroform to give a yellow solid (220 mg, 39%). JH NMR DMSO-d6: 8 2.52 (s, 3H), 3.90 (s, 3H), 7.29 (t, J= 9 Hz, IH), 7.43 (dd, J= 9 Hz, 7= 1.7 Hz, IH), 7.62 (s, IH), 7.78 (br s, 2H)S 8.02 (d, /= 1.6 Hz, IH). MS(ESI+)m/z= 319. [0395] The product of reaction shown by scheme (CCXXVIH) was Anther reacted as shown by scheme (CCXXTX). Pd2 (dba)3 Xantphos Cs2CO3 Dioxane, reflux (CCXXIX) [0396] A mixture of 7-(6-chloro-2-fluoro-3-methoxyphenyl)-5-methylbenzo[e][l,2,4]triazin-3-amine (240 mg, 0.75 mmol), 4-bromo-N-(2-pyrrolidin-l- yl-ethyl)benzenesulfonamide (330 mg, 0.99 mmol), cesium carbonate (740 mg, 2.27 mmol), Xantphos (90 mg, 0.16 mmol), Pd2(dba)3 (70 mg, 0.08 mmol) in anhydrous dioxane (30mL) was degassed with argon for 5 minutes and was refluxed for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography with 10% CH3OH in CHC13. The solid was washed with acetone/hexanes (2:1) to yield a yellow solid. (250 mg, 58%). ]H NMR DMSO~dfi: 8 1.62 (m, 4H), 2.36 (br s, 4H), 2.43 (t, J = 7 Hz, 3H), 2.70 (s, 3H), 2.86 (t, /= 7 Hz, 2H), 3.92 (s, 3H), 7.32 (t, /= 9 Hz, 1H), 7.42 (br s, 1H), 7.46 (dd, J= 9 Hz, /= 1.8 Hz, 1H), 7.84 (m, 3H), 8.21 (m, 3H), 11.43 (s, 1H). MS(ESI+) m/z = 571. [0397] The product of reaction shown by scheme (CCXXDC) was further reacted as shown by scheme (CCXXX). BBr-t (CCXXX) [0398] A mixture of 4-[7-(6-chlord-2-fluoro-3-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (170 rng, 0.53 mmol) in chloroform (5 mL) was stirred with IM BBr3 in dichloromethane (5 mL, 5 mmol) at room temperature for overnight. The reaction was quenched by methanol (1 mL). After removing the solvent, the crude product was neutralized with saturated sodium bicarbonate (1 x 25 mL). The crude product was extracted by ethyl acetate (2 x 50 mL). The combined ethyl acetate fraction was dried over sodium sulfate. The salt was removed by filtration and the solvent was removed by vacuum. The crude product was purified by silica gel column chromatography with 20% CHsOH/CHCls as an eluent to afford the title compound ((CCXXVI), as a yellow solid (lOmg, 6%). :H NMR DMSO-d6: § 1.62 (m, 4H), 2.36 (br s, 4H), 2.44 (t, J= 7 Hz, 3H), 2.70 (s, 3H), 2.86 (t, /= 7 Hz, 2H), 7.08 (t, J= 9 Hz, 1H), 7.29 (dd, /= 9 Hz, J= 1.6 Hz, IE), 7.42 (br s, 1H), 7.85 (m, 3H), 8.22 (m, 3H), 10.4 (br s, 1H), 11.42 (s, 1H). MS(ESI+) m/z - 557. Example 170 Synthesis of 4-r7-(5-hydroxy-2-methyl-pheiiyI)-5-methvl-b enzo[l,2,4]triaziii-3-yIamiiio1-N-f2-PvrroIidin-l-yI-ethyI)-benzenesuIfonamide (CCXXXI) [0399] The synthesis of the title compound (CCXXXI) can be generally described by the sequence of reaction schemes (CCXXX1T), (CCXXXHI); (CCXXXIV), (CCXXXV), and (CCXXXV1). 1)NaN02/HBr 2) CuBr (CCXXXD) [0400] A solution of 5-methoxy-2-methylbenzenamine (1.3g, 9.48 mmol) in 48% HBr (13 mL) and EtOH (10 mL) was cooled to 0°C and NaNO2 (0.78g, 11.30 mmol) in water (5 mL) was added dropwise over 15 minutes while keeping the temperature of the reaction between 0-5°C. After the clear pale brown solution was kept at 0°C with stirring for Ih, this solution was transferred into the boiling solution of CuBr (6.8g, 47.4 mmol) in 48% HBr (25 mL). The solution was refluxed for overnight. The reaction mixture was cooled to room temperature and the reaction was diluted with water (50 mL), The acidic solution was extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate was washed by saturated NaCl (1 x 50 mL) and was dried over sodium sulfate. The sodium sulfate was removed by filtration and the solvent was removed by vacuum. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography with hexanes as an eluent to yield colorless oil (750 mg, 39%). [0401] The product of reaction shown by scheme (CCXXXTT) was further reacted as shown by scheme (CCXXXHT), R 1)nBuLi 2)B(OMe)3 (ccxxxnri [0402] 2.5M nBuLi (1.8 mL, 4.5 mmol) was added dropwise over 5 minutes into a mixture of 2-bromo-4-methoxy-l-methylbenzene (750mg, 3.73 mmol) in anhydrous THF (30 mL) at -78°C. After the mixture was stirred at -78°C for 20 minutes, anhydrous trimethyl borate (0.62g, 6 mmol) was added into the solution at -78°C. The reaction mixture was brought to room temperature for over period of 2 h. The reaction was quenched by 2N HC1 (1 mL). The THF was removed by vacuum. The crude product was diluted with 2N HC1 (100 mL). The acidic solution was extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate fraction was dried over sodium sulfate. The sodium sulfate was removed by filtration and the solvent was removed by vacuum to yield a pale yellow solid (0.43g, 69%). [0403] The product of reaction shown by scheme (CCXXXEH) was further reacted as shown by scheme (CCXXXJV). - Y« ,B(OH)2 Pd(PPh3)4, Na2C03 "^"V^y -SN DME/EtOH/H2O (ccxxxrv) [0404] A mixture of 7-bromo-5-methylbenzo[e][l,234]ttiazin-3-amine (500 mg, 2.1 mmol), 5-methoxy-2-methylphenylboronic acid (430 mg, 2.6 mmol), ethylene glycol dimethyl ether (10 mL), EtOH (1 mL), H20 (1 mL), Pd(PPh3)4 (240 mg, 0.21 mmol) and Na2COs (2.2 g, 21 mmol) was degassed with argon for 5 minutes and refluxed for 16 h under argon. The reaction mixture was cooled to room temperature, and the solid was removed by filtration. After evaporation of the volatiles, the crude product was purified by silica gel column (3.5x16 cm) chromatography with 5% CHsOH/CHCls as an eluent to give a solid. The solid was washed with chloroform to give a dark yellow solid (220 mg, 38%). 1ENMR DMSO-dg: 5 2.22 (s, 3H)5 2.54 (s, 3H), 3.77 (s, 3H), 6.89 (s, 1H), 6.90 (d, «/= 3 Hz, 1H), 7.24 (d, J= 8 Hz, 1H), 7.66 (br s, 1H), 7.68 (s, 1H), 7.95 (d, /= 1.6Hz, 1H). MS(ESI+) m/z =281. [0405] The product of reaction shown by scheme (CCXXTV) was further reacted as shown by scheme (CCXXXV). Pd2(dba)3 , . .. Xantphos Dioxane, reflux (CCXXXV) [0406] A mixture of 7-(5-methoxy-2-methylphenyl)-5-methylbenzo[e][l52,4]triazm-3-amine (220 mg, 0.79 mmol)., 4-bromo-N-(2-pyrrolidui-l-yl-ethyl)benzenesulfonamide (340 mg, 1.0 mmol), cesium carbonate (770 mg, 2.36 mmol), Xantphos (90 mg, 0.16 mmol), Pda(dba)3 (70 mg, 0.08 mmol) in anhydrous dioxane (30mL) was degassed with argon for 5 minutes and was refluxed for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (3.5 x 16 cm) chromatography with 10% CHaOH in CHCls. The solid was washed with acetone/hexanes (2:1) to yield a yellow solid. (150 mg, 36%).!H NMR DMSO-d6: 8. 1.62 (m, 4H), 2.25(ss 3H), 2.36 (br s, 4H)3 2.43 (t, J= 7 Hz, Example 171 Synthesis of F7-(2'-hvdroxyethyI-isopropylamino)-6-methvl-benzo[l,2,41triazin-3-yIamino]-N-f2-pyrrolidm-l-yi-ethyI)-benzene-4-sulfonamide H (ccxxxvn) [0409] To a solution of 2-(isopropylamirio)ethanol 48 uL, 0.416 mmol), 4-(7-bromo- 6-memyl-berizo[l,2,4]triazu>3-ylamino)~N-(2-pvrrolidin-l-yl-ethyl)- benzenesulfonamide (245 mg, 0.5 mmol) in dioxane was added xantphos (13 mg, 0.02 mmol) and cesium carbonate (202 mg, 0.62 mmol). The solution was degassed using argon, and Pdz(dba)3 a(l 1 mg, 0.012 mmol) was added. The reaction was refluxed overnight under argon, and quenched with 2 mL of water. The crude reaction mixture was evaporated on a rotoevaporator, diluted with water (15 mL) and extracted with > chloroform (2X50 mL). The chloroform extract was dried over sodium sulfate, and the chloroform was evaporated. The residue was purified using prep HPLC products were isolated to afford the title product (CCXXXVIT) as a yellow solid (3 mg, % yield). !H NMR DMSO-d6: 5 1.05 (d, J = 6.2 Hz, 6H), 1.6-1.7 (m, 4H), 2.3-2.4 (m, 4H), 2.42 (s, 3H), 2.4-2.5 (m, 2H), 2.8-2.95 (m, 3H), 3.0-3.1 (m, 2H), 4.23-4.35 (m, 2H), 7.35-7.45 (br s, 1H), 7.67 (s, 1H), 7.7 (d, J = 0.9 Hz), 7.76 (d, J =8.95 Hz, 2H), 8.1 (d, J = 7 Hz, 2H), 10.94 (s, 1H). MS (ESI+) m/z = 514.2. Example 172 Synthesis of 4-(7-([2-(2-hydroxv-ethoxy)-ethyn-isopropyI-amino>-6-methyl-benzofl,2,41triazin-3-yIamino)-N-(2-pyrroIidin-l-yl-ethyI)-beiizepesuIfonamide N OH H (CCXXXVIH) 2H), 2.71 (s, 3H), 2.86 (t, .7=7 Hz, 2H), 3.79 (s, 3H), 6.93 (m, 2H), 7.28 (d, /= 9 Hz, 1H), 7.40 (br s, 1H), 7.83 (d, J= 9Hz, 2H), 7.89 (d, J= 1.6Hz, 1H), 8.15 (d, J= 9Hz, 2H), 11.35 (brs, 1H). [0407] The product of reaction shown by scheme (CCXXV) was .further reacted as shown by scheme (CCXXXVI). BBr3 (CCXXXVI) [0408] A mixture of 4-[7-(5-methoxy-2-methyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylammo]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (80 mg, 0.15 mmol) in, chloroform (10 mL) was stirred with 1M BBrs in, dichloromethane (10 mL, 10 mmol) at room temperature for overnight. The reaction was quenched by methanol (1 mL). After removing the solvent, the crude product was neutralized with saturated sodium bicarbonate (1 x 25 mL). The crude product was extracted by ethyl acetate (2 x 50 mL). The combined ethyl acetate was dried over sodium sulfate. The salt was removed by filtration and the solvent was removed by vacuum. The crude product was purified by silica gel column chromatography with 20% CHaOH/CHQs as an eluent to afford the title product (CCXXXI), as a yellow solid (20mg, 26%). l'H NMR DMSO-d6: 6 1.62 (m, 4H), 2.20 (s, 3H), 2.35 (br s, 4H), 2.43 (t, J= 7 Hz, 2H), 2.71 (s, 3H), 2.85 (t, J= 6.6 Hz, 2H), 6.75 (m, 2H), 7.15 (d, J= 9 Hz, J= 1.6 Hz, 1H), 7.40 (br s, 1H), 7.84 (m, 3H), 8.09 (d, /= 1.4Hz, 1H), 8.21 (d, J= 9Hz, 2H), 9.38 (br s, 1H), 11.34 (br s, 1H), MS (ESI+) m/z= 519. [0410] The title product was synthesized and had the following characteristics. }H NMR DMSO-d6: 6 1,0 (d, J - 6.6 Hz, 6H), 1.53-1.65 (m, 4H), 2.33-2,39 (m, 4 H), 2.35 (s, 3H), 2.42-2.47 (m, 2H), 2.58 (t, J = 6.7 Hz, 2H), 2.83 (t, J = 6.7 Hz, 2H), 2.90 (t, J - 5.6 Hz, 2H), 2.95-3.05 (m, 1H), 3.42 (t, J = 6.6 Hz, 2H), 4.03 (br s, 2H), 4.19 (t, J = 5.6 Hz, 2H), 7.35-7.45 (br s, 1H), 7.69 (s, 1H), 7.7 (d, J = 0.9 Hz), 7.76 (d, J =8.95 Hz, 2H), 8.1 (d, J = 7.05 Hz, 2H), 10.93 (s, 1H). MS (ESI+) m/z = 558.3. Example 173 Synthesis of 4-(74>romo-6-methyl-benzofl,2,41triazm-3-ylainino>IN-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide O H (ccxxxrx) [0411] A mixture of amine 1 (2.5 g, 10.45 mmol), bromide 2 (4.18 g, 12.54 mmol), Cs2CO3 (5.1 g, 15.67 mmol), Xantphos (363 mg, 0.627 mmol), Pd2(dba)3 (286 mg, 0.31 mmol), and 3 A mol sieves in dioxane (70 mL) was purged with argon for 5 mix, and was heated to reflux for 16 h under argon. Dioxane was removed in vacua and the resulting mixture was partitioned between CHC13 and water (200 mL each). The layers were separated and the aqueous layer was extracted twice more with CHC13 (200 mL). The organic layers were combined and concentrated in vacua. The crude product was purified by flash column chromatography (0.5 % NH4OH /10 % MeOH/89.5% dichloromethane).Orange-yellow solid (1.5 g, 30%). 'HNMRDMSO-de: 5 1.82-1.92 (m, 2H), 1.95-2.05 (m, 2H), 2.59 (s, 3H), 2.96-3.08 (m, 4H), 3.2-3.28 (m, 2H), 3.53-3.61 (m, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.85 (s, 1H), 7.87 (t, J = 6.1 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.68 (s, IE), 9.46-9.57 (br s, 1H), 11.4 (s, 1H). MS (ESI+) m/z - 493. Example 174 Synthesis of f6-methvl-7-r3-methyI-thiophea-2-vI)-beazon,2.41triazin-3-vIl-[4-(2-pyrroIidiD-l-yI-ethQrv)-phenyl1-amine (CCXL) [0412] To a mixture of 3-methylthiophen-2-yl-2-boronic acid (252 mg, 2 mmol), 3-amino-7-bromo-6-methyl benzo-l,2,3-triazine (239 mg, 1 mmol) and Pd(Ph3)4) (58 mg, 0.05 mmol) in 4:1 DME/EtOH was added a 2M aqueous solution of sodium carbonate (4 mL), The mixture was flushed with argon for 5 rnin and was heated under reflux (ca. 100 * °C) for 16 h. The volatiles were evaporated and the residue was triturated with chloroform-water (1:1,200 mL). The chloroform layer was separated and filtered, through a small silica plug. The silica plug was washed with 200 mL of 10% methanol in chloroform. On evaporation the crude product was obtained as a brown solid (255 mg). [0413] A mixture of the crude above amine product (125 mg, 0.5 mmol), l-(2-(4-bromophenoxy)ethyl)pyrrolidine (121 uL, 0.58 mmol), CsaCOs (638 mg, 1.96 nimol), Xantphos (28 mg, 0.049 mmol), Pd2(dba)3 (22 mg, 0.02 mmol), and 3 A mol sieves in dioxane (5 mL) was purged with argon for 5 min, and was heated to reflux for 16 h under argon. The volatiles were evaporated and the residue was triturated with chloroform-water (1:1,200 mL). The chloroform layer was separated and filtered through a small silica plug. The silica plug was washed with 200 mL of 10% methanol in chloroform. The solvent was evaporated and the crude product was purified using HPLC to afford the title product (CCXL), as a red solid (29 mg, 13 %). !H NMR DMSO-d6: § 1.67-1.76 (m, 4H), 2.06 (s, 3H), 2.31 (s, 3H), 2.54-2.6 (m, 4H), 2.81 (t, J = 5.57 Hz, 2H),-4.07 (t, J = 5.9 Hz, 2H), 6.95 (d, J = 6.95 Hz, 2H), 7.07 (d, J = 5.1 Hz; 1H), 7.58 (d, J = 5.2 Hz, 1H), 7.66 (s, 1H), 7.85 (d, J = 6.95 Hz, 2H), 8.09 (s, 1H), 10.71 (s, 1H). MS (ESI+) m/z = 446.1. Example 175 Synthesis of (4-f6-methyl-7-r4-methvI-pyridin-3-vl)-benzofl.2,41triazin-3-ylaminol-pheny][}-(4-mettiyl-piperazin-l-vI)-methanone mesylate (CCXLI) [0414] To a mixture of 4-methylpyridin-3-yl-3~boronic acid (272 mg, 2 mmol), 3-amino-7-bromo-6-methyl benzo-l,2,3-triazine (239 mg, 1 mmol) and Pd(Ph04) (58 mg, 0.05 mmol) in 4:1 DME/EtOH was added a 2M aqueous solution of sodium carbonate (4 ml). The mixture was flushed with argon for 5 min and was heated under reflux (ca. 100 °C) for 16 h. The volatiles were evaporated and the residue was triturated with chloroform-water (1:1,200 ml). The chloroform layer was separated and filtered through a small silica plug. The silica plug was washed with 200 mL of 10% methanol in chloroform. On evaporation the crude product was obtained as a brown solid (260 mg). [0415] A mixture of the above crude amine product (125 mg, 0.5 mmol), l-(2-(4-bromophenoxy)ethyl)pyrrolidine (170 mg, 0.6 mmol), Cs2CO3 (651 mg, 2.0 mmol), Xantphos (58 mg, 0.1 mmol), Pd2(dba)3 (45 mg, 0.05 mmol), and 3 A mol sieves in dioxane (5 mL) was purged with argon for 5 min, and was heated to reflux for 16 h under argon. The volatiles were evaporated and the residue was triturated with chloroform-water (1:1, 200 mL). The chloroform layer was separated and filtered through a small silica plug. The silica plug was washed with 200 mL of 10% methanol in chloroform. The solvent was evaporated and the crude product was purified using HPLC, to afford the title product (CCXXLI), as an orange solid (91 mg, 40.2 %). !H NMR DMSO-d6: 6 2.16,2.22, 2.31, 2.84 (4s, 3H each), 3.05-3.18 (m, 4H), 3.45-3.55 (m, 4H), 7.53 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 4.95 Hz, 1H), 7.81 (s, 3H), 8.10 (d, J = 8.6 Hz, 2H), 8.17 (s, 1H), 8.5 (s, 1H), 8.62 (d, J = 4.5 Hz, 1H), 9.67-9.76 (br s, 1H), 11.15 (s, 3H). MS (ESI+) /«/z = 454.3. Example 176 Synthesis of (4-f7-(4-chloro-pyridin-3-yI)-6-methYl-benzofl,2,41triazin-3-yIamino1-phenyI}-(4-methyI-piperazin-l-yI)-methanone mesylate (ccxm) [0416] To a mixture of 4-chloropyridin-3-yl-3-boronic acid (314 mg, 2 mmol), 3- amino-7-bromo-6-methyl benzo-l,2,3-triazine (239 mg, 1 mmol) and Pd(Ph3)4) (58 mg, 0.05 mmol) in 4:1 DME/EtOH was added a 2M aqueous solution of sodium carbonate (4 mL). The mixture was flushed with argon for 5 min and was heated under reflux (ca. 100 °C) for 16 h. The volatiles were evaporated and the residue was triturated with chloroform-water (1:1,200 mL). The chloroform layer was separated and filtered through a small silica plug. The silica plug was washed with 200 mL of 10% methanol in chloroform. On evaporation the crude product was obtained as a brown solid (260 mg). [0417] A mixture of above crude amine product (125 mg, 0.46 mmol), l-(2-(4-bromophenoxy)ethyl) pyrrolidine (156 mg? 0.55 mmol), Cs2C03 (600 mg, 1.84 mmol), Xantphos (53 mg, 0.1 mmol), Pd2(dba)3 (45 mg, 0.05 mmol), and 3 A mol sieves in dioxane (10 mL) was purged with argon for 5 min, and was heated to reflux for 16 h under argon. The volatiles were evaporated and the residue was triturated with chloroform-water (1:1, 200 mL). The chloroform layer was separated and filtered through a small silica plug. The silica plug was washed with 200 mL of 10% methanol in chloroform. The solvent was evaporated and the crude product was purified using HPLC. The purified product was converted to mesylate salt using methane sulfonic acid, in a form of a yellow solid (51 mg, 18 % yield). 1E NMR DMSO~d6: 8 2.30,2.44, 2.80 (3s, 3H each), 3.05-3.17 (m, 2H), 3.3-3.52 (m, 4H), 7.53 (d, J = 6.9 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.78 (s, 3H), 8.07 (d, J = 2.65 Hz, 2H), 8.09 (d, J - 8.65, 1H), 8.27 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 9.67-9.76 (br s, 1H), 11.17 (s, 1H). MS (BSD-) m/z = 474.2. Example 177 Synthesis of (4-F7-(2,6-dimethyl-phenvI)-5-methyI-benzori.2,41triazin-3-yIamino?-phepyI}-piperazin-l-yI-methanone (CCXLIH) [0418] A mixture of 7-(2,6-dimethylphenyl)-3-amino-5-methyl-l,2,3-triazine (1.66, 6.29 mmol), 4-(4-bromo-benzoyl)-piperazine-l-carboxylic acid tert-butyl ester (2.79 g, 7.55 mmol), potassium t-butoxide (1.05 g, 9.43 mmol), BINAP (235 mg, 0.377 mmol), Pd2(dba)3 (172 mg, 0.18 mmol), and 3 A mol sieves in toluene (120 mL) was purged with argon for 5 min, and was heated to reflux for 16 h under argon. The volatiles were evaporated and the residue was triturated with chloroform-water (1:1, 500 mL). The chloroform layer was separated and filtered through a small silica plug. The silica plug was washed with 400 mL of 10% methanol in chloroform. The solvent was evaporated and the crude product was treated with trifluoroacetic acid (25 mL) in dichloromethane (25 mL) for 1.5 h. The solvent was evaporated and the crude product was purified by column chromatography using chloroform, methanol, ammonia (85:10:5). Some amout was converted to mesylate salt, in a form of a rusty red solid (1.51 g, 54 % yield). *H NMRDMSO-dg: 6 2.05 (s, 6H), 2.69 (s, 3H), 2.69-2.75 (m, 4H), 3.37-3.57 (m, 4H), 7.19 (d, J = 7.6 Hz, 2H), 7.25 (dd, J = 6.2 and 8.6 Hz, 1H), 7.45 (dd, J - 1.75 and 6.85 Hz, 2H), 7.64 (dd, J = 1 and 1.85 Hz, 1H), 7.95 (d, J = 1.85 Hz, 1H), 8.09 (dd, J = 1.7 and 6.85 Hz, 2H), 11.12 (s, 1H). MS (ESI+) m/z = 453.3. Example 178 Synthesis of f7-f2,6-dimethyl-phenyl)-5-methyI-benzofl.2,41triazin-3-yI]-r2-(2-pyrrolidin-l-yl-ethoxv)-pvridia-4-yn-ammemesyIate (CCXLIV) [0419] The title product wa synthesized,,having the following characteristics. 'H NMRDMSO-d Example 179 Synthesis of 7-f2,6-dichloro-3-methoxyphenyI)-5-methylb enzo f elf 1,2,4]triazin-3-amine (CCXLV) 96 [0420] To prepare the title compound (CCXLV), an intermediate compound 96 (2,6-dichloro-3-rnethoxyphenylboronic acid) was synthesized first. [0421] To synthesize compound 96, to 2,4-dichloroanisole (5 mL, 36 mmol) in THF (22 mL) at -78 °C was added 2.5 M wBuLi (17 mLs 43 mmol) keeping the temperature below -65 °C. After 30 min, the reaction was poured into frozen (-78 °C) trimethylborate (14 mL, 215 mmol) followed by another portion of trimethylborate (10 mL, 90 mmol) and allowed to warm to room temperature over 16 h. The solid suspension was poured into a 1 N HC1 aqueous solution and stirred for Ih. The suspension was filtered to give 3.6 g (46%) of a white solid contaminated most likely with B(OH)4. A second batch of crystals formed which were collected as an off-white solid that was compound 96 (5.8 g, 74%). 'H NMR DMSO-ds: 5 8.53 (s, 2H), 7.29 (d, J= 8.8 Hz, IH), 7.06 (d, J= 8.8 Hz, IH), 3.83 (s, 3H). [0422] The general Suzuki procedure was then employed using compound 32 (Example 140) (794 mg, 3.32 mmol), compound 96 (816 mg, 3.70 mmol), Pd(Ph3)4 (386 mg, 0.33 mmol), and 2M aqueous Na2CO3 (7 mL, 14.0 mmol) in 4:1 DME/EtOH (34 mL) for 16 h to afford, after filtration, the title compound (CCXLV), as a crude pale-orange solid (922 mg, 83%) which was used as is with no further purification. LC retention time: 2.98 min, MS (ESI+) m/z = 334.9. Example 180 Synthesis of 4-r7-f2,6-dichloro-3-methoxy-phenyl)-5-methyl-benzofl.2.41triazin-3-ylammol-N-(2-pyrrolidin-l-yI-ethyl)-benzenesulfonamide (CCXLVI) [0423] The general Buchwald procedure was employed using crude compound (CCXLV) (Example 179) (305 mg, 0.91 mmol), compound 54 (Example 140) (304 mg, 0.91 mmol), Cs2CO3 (1.2 g, 3.62 mmol), Xantphos (104 mg, 0.1S mmol), Pd2(dba)3 (82 mg, 0.09 mmol), and 18 mL dioxane for 3 h. Chromatography was run at 0-10% gradient MeOH in CHCl3(with 0.1% NILtOH) to afford the title compound (CCXLVI), as a yellow-brown solid (373 mg, 63%). LC retention time: 2,69 min, MS (ESI-f) m/z = 587.1. Example 181 Synthesis of 4-f7-(2,6-dichloro-3-hydroxv-phenyI)-5-methvl-benzo[l,2,41triazin-3-ylamino1-N-(2-pyrroIidin-l-yl-ethvI)-benzenesulfonamide (ccxLvn) [0424] The general aryl methoxy deprotection procedure was employed using aryl methoxy compound (CCXLVI) (Example 180) (337 mg, 0.57 mmol) and BBr3 (271 j_iL, 2.9 mmol), in 15 mL DCM for Ih. The reaction was quenched and the solids filtered and purified using HPLC. The aqueous HPLC fractions (100 mL) were neutralized with sat. aq. NaHCOs and extracted with EtOAc (2x 150 mL). The combined organic layers Were dried, filtered through celite and concentrated in vacua. The HC1 salt of the product was formed using MeOH and 4M HC1 in dioxane, crashed out using Et2O, and collected by filtration as a yellow solid (204 mg, 58%). LC retention time: 2.34 min, MS (ESI+) m/z = 573.1 'HNMRDMSO-de :5 1.80-1.87 (m, 2H), 1.92-1,99 (m, 2H), 2.71 (s, 3H), 2.93-3.02 (m, 2H), 3.14 (q, J= 6.3 Hz, 2H), 3.18-3.24 (m, 2H)5 3.47-3.55 (m, 2H), 7.17 (d, ./-8.9, Hz, IH), 7.43 (d, J= 8.9, Hz, IH), 7.75 (dd, J= 1.8, 1.0 Hz, IH), 7.89 (d, J= 8.9 Hz, 2H)5 8.02 (t, /= 5.8 Hz IH), 8.11 (d, J= 1.7 Hz, IH), 8.26 (d, J= 8.9 Hz, 2H), 10.78 (br s, IH), 10.85 (s,lH), 11.47 (s,lH).' Example 182 Synthesis of 4-chIoro-3-r3-(4-(r(2-hvdroxv-ethvl)-isopropyI-amiaol-methyI}-phenvIamino)-5-methyI-benzori.2.41triazm-7-vn-phenoI (ccxLvm) 97 [0425] To synthesize the title product, intermediate compounds 97 and 98 shown below were used. 98 [0426] The general Buchwald procedure was employed using compounds 97 (142 mg, 0.50 mmol), 98 (104 mg, 0.38 mmol), Cs2CO3 (473 mg, 1.45 mmol), Xantphos (44 mg, 0.08 mmol), Pd9(dba)3 (34 mg, 0.04 mmol), and 7 mL dioxane for 2 h. The product was purified using HPLC to afford the TFA salt of the title compound (CCXLVITI), as a yellow-brown solid (45 mg, 21%). LC retention time: 2.32 min, MS (ESI+) m/z = 478.0 ^NMR.DMSO-dg: 5 1.31 (d, .7= 6.6, Hz, 3H), 1.37 (d, ./= 6.6, Hz, IH), 2.69 (s, 3H), 3.01-3.11 (m, IH), 3.22-3.28 (m, IH), 3.47-3.54 (m, IH), 3.62-3.72 (m, 2H), 4.29 (dd, J = 13.2, 6.4, Hz, IH), 4.36 (dd, J= 13.2, 4.1, Hz, IH), 5.31 (br s, IH), 6.88 (dd, J= 8.7, 2.9, Hz, IH), 6.93 (d, J- 2.9 Hz, IH), 7.41 (d, J= 8.7, Hz, IH), 7.61 (d, J= 8.6 Hz, IH), 7.89 (dd, J= 1.8,1.0 Hz, 1H), 8.13 (d,J= 8.7 Hz, 1H)S 8.19 (d, J= 1.7 Hz, 1H)3 8.94 (br s, 1H), 9.95 (s, 1H), 11.17(s, 1H). Example 183 Synthesis of N-(4-(2-(pyrroIidin-l-vnethoxy)phenyl)-7-f2,6-dichloro-3-methoxyphenyl)-5-methyIbenzo f el 11.2,4] triazin-3-amine CI (CCXLIX) [0427] The general Buchwald procedure was employed using crude compound (CCXLV) (Example 179) (159 rag, 0.47 mrnol), compound 6 (Example 120) (134 mg, 0.50 mmol), Cs2CO3 (628 mg, 1.93 mmol), Xantphos (56 mg, 0.10 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), and 10 mL dioxane for 16 h. Chromatography was run at 0-10% gradient MeOH in CHCl3(with 0.1% NHjOH) followed by HPLC and NaHCO3 extraction to afford the title compound (CCXLIX), as a red solid (110 mg, 44%). LC retention time: 2.74 min, MS(ESI+)m/z = 524.1. Example 184 Synthesis of 3-(3-(4-(2-(pyrroIidm-l-yl)ethoxy)phenyIamino)-5-methvIbenzofe1fl,2,41triazin-7-yl)-2,4-d{chlorophenol (CCL) [0428] The general aryl methoxy deprotection procedure was employed using aryl methoxy compound (CCXLIX) (Example 183) (110 mg, 0.21 mmol) and BBr3 (120 jjL, 1.27 mmol), in 4 mL DCM for 20 min. The reaction was quenched and the solids filtered and purified using HPLC, The aqueous HPLC fractions (100 mL) were neutralized with sat. aq. NaHCCb and extracted with EtOAc (2x 150 mL). The combined organic layers were dried, filtered through celite and concentrated in vacua. The HCI salt of the product was formed using MeOH and 4M HCI in dioxane, crashed out using Et20, and collected the title compound (CCL) by filtration, as an orange solid (28 mg, 24%). LC retention time: 2.34 min, MS(ESI+) m/z = 510.0 [H NMR DMSO-d6: 5 1.90 (br s, 2H), 2.03 (br s5 2H), 2.64 (s, 3H), 3.12-3,16 (m, 2H), 3.59 (br s, 4H), 4.34 (t, J= 5.0, Hz, 2H), 7.10 (d, J = 9.1, Hz, 2H), 7.10 (d, J= 8.9, Hz, 1H), 7.42 (d, J= 8.9, Hz, 1H), 7.65 (dd, /= 1.8,1.0 Hz, 1H), 7.99 (d,/= 9.1 Hz, 2H), 8.02 (d, /= 1.7 Hz, 1H), 10.18 (br s, 1H), 10.71 (s, 1H), 10.90 (s, 1H). Example 185 Synthesis of benzyl 4-(4-f7-(2,6-dichloro-3-methoxyphenyl)-5-methvIbenzofe]fl (CCLI) [0429] To synthesize the title product, intermediate compound 99 shown below was used. 99 [0430] The general Buchwald procedure was employed using crude compound (CCLV) (example 179) (114 mg, 0.34 mmol), intermediate compound 99 (100 mg, 0.23 mmol), Cs2C03 (312 mg, 0.96 mmol), Xantphos (28 mg, 0.05 mmol), Pd2(dba)3 (21 mg, 0.02 mmol), and 5 mL dioxane for 3 h. Chromatography was run at 0-50% gradient EtOAc in hexanes to afford the title compound (CCLT), as a crude yellow solid (104 mg, 65%). LC retention time: 3.37 min, MS(ESI+) «/z = 692.2. Example 186 Synthesis of S-p-^piperidiD 0N, ,0 sx^- (CCLD) [0431] The general aryl methoxy deprotection procedure was employed using aryl methoxy compound (CCLI) (Example 185) (104 mg, 0.15 mmol) and BBr3 (85 pJL, 0.90 mmol), in 3 mL DCM for 5 min. The reaction was quenched and the solids filtered and purified using HPLC. The aqueous HPLC fractions (100 mL) were neutralized with sat. aq. NaHCOs and extracted with EtOAc (2x 150 mL). The combined organic layers were dried, filtered through celite and concentrated in vacua. The HC1 salt of the title product was formed using MeOH and 4M HC1 in dioxane, crashed out using Et2O, and collected by filtration as a yellow solid (34 nig, 41%). LC retention time: 2.23 min, MS (ESI+) m/z = 544.0 'HNMRDMSO-ds: 8 1.674.78 (m, 2H), 2.03-2.09 (m, 2H), 2.72 (s, 3H), 2.83-2.91 (m, 2H), 3.36 (m against H20 peak), 3.55 (tt, J= 11.9, 0.8, Hz, 1H), 7.13 (d, J= 8.9, Hz, 1H), 7.44 (d, /- 8.8, Hz, 1H), 7.77 (s, 1H), 7.89 (d, J=9.0 Hz, 2H), 8.14 (d, J= 1.3 Hz, 1H), 8.34 (d, J= 8.9 Hz, 2H), 8.43 '(br s, 1H), 8.96 (br s, 1H), 10.75 (s, 1H), 11.59 (s, 1H). Example 187 Synthesis of (4-f7-(3.5-dimethvl-isoxazol-4-yI)-5-methvI-benzori^^ltriazin-a-ylaminol-phenvlT-^-methyl-piperazin-l-yn-methanone (ccLm) [0432] A mixture of above amine (compound (CCLII), Example 186) (125 mg, 0.46 mmol), l-(2-(4-bromophenoxy)ethyl) pyrrolidine (156 mg, 0.55 mmol), Cs2CO3 (600 mg, 1.84 mmol), Xantphos (53 mg, 0.1 mmol), Pd2(dba)3 (45 mg, 0.05 mmol), and 3 A mol sieves in dioxane (10 mL) was purged with argon for 5 min, and was heated to reflux for 16 h under argon. The volatiles were evaporated and the residue was triturated with chloroform-water (1:1,200 mL). The chloroform layer was separated and filtered through a small silica plug. The silica plug was washed with 200 mL of 10% methanol in chloroform. The solvent was evaporated and the crude product was purified using HPLC. The purified product was converted to mesylate salt using methane sulfonic acid, to afford the title product (CCLEI), as an orange solid (54 mg, % yield). 'H NMR DMSO-de: 8 2.16,2.22, 2.31,2.84 (4s, 3H each), 3.05-3.18, 3.24-3.36, 3.43-3.55 (3m, 8 H), 7.55 (d, J = 7 Hz, 2H), 7.89 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 7.0 Hz, 2H), 8.22 (d, J = 1.7 Hz, 1H), 9.86-9.97 (br s, IB), 11.25 (s, 1H). MS (ESI+) m/z = 458,2 [0433] The following Examples 188-192 describe the synthesis of some of the intermediate compounds 100 (7-bromo-5-methyl-benzo[l!2,4]triazin-3-ylamine), 101 (7-bromo-6-methyl-benzo[l,2,4Jtriazin-3-ylamine), 102 ((4-bromo-phenyl)-(4-methyl-piperazin-l-yl)-methanone), 103 (4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzamide), 104 (4-bromo-N- (2-dimethylamino-ethyl)-benzamide), 105 (3 -bromo-N-(2-pyrrolidin-1 -yl-ethyl)-benzamide), 106 (3R-(3-bromo-benzoylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester), 107 (l-[3-(3-bromo-benzenesulfonyl)-propyl]-pyrroh'dine), and 108 (7-(2,6- dimethyl-phenyD-S-methyl-benzotU^Jtria^S-ylaxnine) that were used to synthesize the title compounds of Examples 188-190, 193-205,208, 209, and 213 that follow. Example 188 Synthesis of (4-bromo-phenyl)-f4-methYl-piperazin-l-yI)-methanone (intermediate compound 102) [0434] To a solution of 4-bromo-benzoic acid (1.0 g, 5.0 mmol) in 50 mL acetonitrile and 5 mL DMF were added N-methylpiperazine (566 pi, 5.1 mmol) and EDC (980 mg, 5.1 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed and the residue was dissolved in 60 mL CHjCh and successively washed with water (50 mL) and aqueous saturated NaHCOs solution. The organic phase was dried (MgSCH) and the solvent was removed. The crude product was purified by flash column chromatography (Rf = 0.54, CH2Cl2/MeOH, 90:10) to yield the intermediate compound 102.1E NMR CDC13: 6 2.32 (s, 3H), 2.33 (m, 2H), 2.49 (m, 2H), 3.41 (m, 2H)5 3.78 (m, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.53 (d, /= 8.3 Hz, 2H). MS (ESI+) m/z = 283/285. Example 189 Synthesis of 4-bromo-N-f2-dimethylamino-ethvI)-beazamide (intermediate compound 104) [0435] To a solution of 4-bromo-benzoic acid (5.02 g, 25 mtnol) in 200 mL acetonitrile were added V^-dimethylethylenediamine (2.8 mL, 25 mmol) and EDC (4.9 g, 25.5 mmol). The mixture was stirred at room temperature for 2 h. The white precipitate was removed by filtration and the solvent was evaporated. The residue was dissolved in 150 mL CHaCk, and was washed successively with water (150 mL) and aqueous saturated NaHCOs (150 mL). The organic phase was dried (MgS04) and the solvent was evaporated. The crude product was purified by flash column chromatography Rf = 0.2, (CH2Cl2/MeOH, 90:10) to afford the title intermediate compound 104 (3.68 g, 54%). MS (ESI+) m/z = 271/273. Example 190 Synthesis of 3-bromo-N-(2-pyrroIidin-l-yI-ethyl)-benzamide (intermediate compound 105) [0436] The title compound was prepared according to the procedure described for the intermediate compound 104 (Example 189). The crude product was used without further purification (3.7 g, 50%). MS (ESI+) m/z = 297/299. Example 191 Synthesis of 3R-f3-bromo-benzoyIamino)-pvrrolidine-l-carboxyIic acid tert-butyl ester (intermediate compound 106) [0437] A solution of 3-bromobenzoic acid (4.0 g, 20 mmol) and EDC (3.83 g, 20 mmol) in 50 mL acetonitrile was added dropwise to a solution of (3R)-(+)-3-aminopyrrolidine (1.72 g, 20 mmol) in 100 mL acetonitrile. The reaction mixture was stirred at room temperature for 2 h and the solvent was removed. The residue was dissolved in 50 mL CEzCk and washed with brine (50 mL). The organic phase was dried (MgSO4) and the solvent was removed. The crude product was purified by silica gel column chromatography (Rf = 0.22, CH2Cl2/MeOH, 75:15) to give 3-bromo-N-pyrroh'din~3-yl-benzamide as a colorless solid (2.0 g, 37 %). To a solution of the above precursor (1.14 g, 4.24 mmol) in. 30 mL CH^Ck were added di-tert-butyldicarbonate (925 mg, 4.24 mmol) and triemylamine (596 jil, 4.24 mmol). The reaction mixture was stirred at room temperature for Ih. The solvent was removed and the crude product was purified by silica gel column chromatography (Rf = 0.66, CH2Cl2/MeOH, 90:10) to afford the title intermediate compound 106, as a viscous, colorless oil (1.1 g, 70%). MS (ESI+) m/z = 369/371. Example 192 Synthesis of l-r3-(3-bromo-benzenesulfonvl)-propyl]-pyrroIidme .(intermediate compound 107) [0438] To a solution of 3-bromothiophenol (4.0 g, 21.2 mmol) in 50 mL methanol was added NaOMe (2.28 g, 42 mmol). The mixture was stirred at room temperature for Ih and was added dropwise to 22 mL of 1,3-dibromopropane (42.5 g, 210 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and quenched with water (50 mL). The crude product was extracted with CH2C12 (100 mL) and the combined organic phase was dried (MgSC>4). The volatiles were removed under reduced pressure. The crude product in 150 mL CH2C12 was treated with 3-chloroperoxybenzoic acid (4.9 g, 20 mmol) at 0 °C for 1 h. Another batch of mCPBA (4.9 g, 20 mrnol) was added and the stirring was continued for another 30 min at 0 °C before the mixture was allowed to warm to room temperature. The reaction mixture was diluted with CH^Ck and EtOAc (20 mL each) and washed twice with saturated aqueous NaHCOs solution. The organic phase was dried (MgSO^ and the product was purified by silica gel column chromatography (Rf = 0.53, EtOAc/hexanes 50:50) to give l-bromo-3-(3-bromo-propane-l-sulfonyl)benzene as a colorless solid (5.47 g, 76 %). [0439] A mixture of l-bromo-3-(3-bromo-propane-l-sulfonyl)benzene (5.47 g, 16.4 mmol Cs2CO3 (10.7 g, 32.8 mmol) and pyrrolidine (2.71 mL, 32.8 mmol)) in 100 mL anhydrous 1.4-dioxane was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and was extracted with CH2Cl2 (140 mL). The combined organic phase was dried (MgSC^), and the solvent was removed. The product was dried in vacua to afford the title intermediate compound 107, as a brown oil (4.95 g, 91 %). Example 193 Synthesis of f7-(5-chIoro-2-methoxy-phenyI)-5-methvI-benzo fl ,2,4] triazin-3-yIl- f 4-(2-pvrroIidin-l-vl-ethoxy)-rphen vU-amin e trifluoroacetate (CCLTV) . [0440] To a solution of intermediate compound 100 (24 mg, 0.1 mmol) in 2 mL DMA were added 5-chloro-2-methoxyphenylboronic acid (75 mg, 0.4 mmol) in ethanol (500 pi), K2CO3 (2.8 mg, 0.02 mmol) in water (200 p.1), PPh3 (3 mg, 0.01 mmol) and Pd2(dba)s (9 mg, 0.01 mmol). The reaction mixture was stirred at 80 °C for 16 h under argon, cooled to room temperature and poured into aqueous saturated NaHCOa (50 mL). The product was extracted with CH2Cl2 (100 mL) and purified by reverse phase preparative HPLC using a gradient of acetonitrile/water containing 0.1 % TFA as the eluent. The combined product fractions were washed with aqueous saturated NaHCOs solution. The product was extracted with CH2Cl2, the combined organic phase was dried (MgSO/O and the solvent was evaporated to give a precursor 7-(5-chloro-2-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (25.1 mg, 83 %). To a solution of the purified precursor in 4 mL anhydrous toluene were added l-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (41 pi, 0.2 mmol), BINAP (3.7 mg, 6 jimol), Pd2(dba)3 (2.3 mg, 2.5 (Limol) and KO-'Bu (9.3 mg, 0.083 mmol). Under argon, the reaction mixture was stirred at 100°C for 18 h. It was cooled to room temperature and poured into aqueous saturated NaCl solution. The product was extracted with CH2Cl2 and purified by reverse phase preparative HPLC to afford the title copound(CCLIV) as trifluoroacetate salt, in a form of a red solid (5 mg, 10 %). 'H NMR DMSO-d6: 8 1.90 (m, 2H), 2.05 (m, 2H), 2.64 (s, 3H)3 3.15 (in, 2H), 3.61 (t, J= 5.0 Hz, 2H), 3.63 (m, 2H), 4.31 (t, J= 5.0 Hz, 2H), 7.09 (d, /= 9.0 Hz, 2H), 7.22 (d, J= 8.9 Hz, 2H), 7.47 (dd, J= 8.9 Hz, /= 2.6 Hz, 1H), 7.52 (d, J= 2.6 HzylH), 7.93 (br s, 1H), 7.99 (d, /= 9.0 Hz, 2H), 8.25 (br s, 1H), 11.x (s, 1HJ. MS (ESI+) m/z = 490. Example 194 Synthesis of |4-f7-f2,6-dimethvi-pheayI)-5-niethyI-benzoflv2,41tria2m-3-vIamino1-phenvl}-r4-methyl-piperazin-l-vI)-inethanone trifluoroacetate (CCLV) [0441] The compound was prepared from intermediate compounds 108 and 102, following the coupling procedure described above. The product was purified by reverse phase preparative HPLC to afford the title product in a form of trifluoroacetate, salt as a yellow-orange solid (yield, 56 %). ^NMRmethanol-cU: 8 2.09 (s, 6H), 2.76 (s, 3H), 2.98 (s, 3H), 3.30-3.50 (m, 8H), 7.16 (br d,/= 6.9 Hz, 2H), 7.21 (dd, /= 6.2 Hz, J= 8.7, 1H), 7.59 (d, J= 8.7 Hz, 2H), 7.60 (br s, 1H), 7.91 (br s, 1H), 8.18 (d, J= 8.7 Hz), 11.12 (s, 1H). MS (BSI+) m/z = 467. (CCLVI) Example 195 Synthesis of [7-(3,5-dimethyl-isoxazol-4-yI)-5-methyI-benzori,2,41triazin-3-yn-[4-(2-pyrrolidin-l-yI-ethoxy)-phenyl1-amine [0442] The synthesis of the title product followed the reaction scheme (CCLVH). BBr3 (ccLvn) [0443] 7-(3,5-dimethyl-isoxazol-4-yl)-5-methyl-benzo[l.,2.,4]triazin-3-ylamine (designated as compound 10 on scheme (CCLVTf)) was prepared from the above described intermediate compound 100 and 3,5-dimethylisoxazole-4-boronic acid following the coupling procedure outlined above. A solution of the intermediate (160 mg, 0.627 mmol) and sulfamic acid (122 mg, 1.25 mmol) in methoxyaniline (1.2 g, 9.4 rnmol) was stirred at 135 °C for 6 h to form [7-(3,5-dimethyl-isoxazol-4-yl)-5-methyl-benzo[lJ2,4]triazm-3-yl]-(4-methoxy-phenyl)-amine (designated as compound 11 on scheme (CCLVn)), which was purified by silica gel column chromatography (Rf = 0,24, hexanes/EtOAc, 70:30) (24.2 mg, 11%). The purified precursor, dissolved in 4 rnL CEfeCU, was treated with BBr3 (32 p.1, 0.34 mmol) at room temperature for 2 h. The reaction mixture was diluted with CH^Ck (20 mL) and washed with aqueous saturated sodium thiosulphate. [0444] The organic phase was dried (TS^SCU) and the solvent evaporated to yield 4-[7-(3,5-dimethyl-isoxazol-4-yl)-5-methyl-benzo [ 1,254]triazin-3-ylamino]-phenol (designated as compound 12 on scheme (CCLVH)) (15 mg, 65%), to a solution of which (4.5 mg, 0,013 mmol) in 3 mL 1,4-dioxane were added Cs2CO3 (21 mg, 0.065 mmol) and l-(2-chloro-ethyl)-pyrrolidme (4.4 mg, 0.026 mmol). The mixture was heated under reflux for 2h and the solvent was removed. The crude product was purified by silica gel column chromatography using C^Ck/methanol/NEta (90:10:0.1) as the mobile phase to afford the title product (CCLVI), as a red solid (2.6 mg, 45%).1H NMR methanol-d4: 8 1.89 (m, 4H)S 2.34 (s, 3H), 2.50 (s, 1H), 2.70 (s, 3H), 2.79 (m, 4H), 3.02 (t, /= 5.6 Hz, 2H), 4.18 (t, J= 5.6 Hz, 2H), 7.01 (d, J= 9.0 Hz, 2H), 7.69 (s, 1H), 7.89 (d, /- 9.0 Hz, 2H), 8.02 (brs, 1H), MS (ESI+) m/z = 445. Example 196 Synthesis of 4-f7-(2,6-dimethyI-phenyI)-5-methvl-beDZo[l,2,41triazin-3-ylamino1-N-(2-pyrrolidin-l-yI-etbyQ-benzamide [0445] The compound was prepared from the intermediate compounds 108 and 103 following the above-described coupling procedure. The crude product was purified by reverse phase preparative HPLC to afford the title product (CCLVTfl), as a yellow-orange solid. !H NMR methanokU: 5 2.06 (m, 2H), 2.09 (s, 6H), 2.20 (m, 2H), 2.77 (s, 3H), 3.18 (m, 2H), 3.46 (t, J= 5.8 Hz, 2H), 3.78 (t, J= 5.8 Hz, 2H), 3.82 (m, 2H), 7.16 (br d, J = 6.9 Hz, 2H), 7.21 (dd, /= 6.2 Hz, J= 8.7, 1H), 7.60 (br s, 1H), 7.91 (br s, 1H), 7.96 (d, /= 8.9 Hz), 8.16 (d, /= 8.9 Hz, 2H). MS (ESl+) m/z = 481. Example 197 Synthesis of f7-f2-chloro-5-methoxy-phenyI)-5-methvI-benzQfl,2,41triaziii-3-yll-f4-f2-pyrroIidin-l-yl-ethoxy)-phenyl]-amine trifluoroacetate MeO (CCLK) [0446] The product was prepared from the intermediate compound 100, 2-chloro-5-methoxyphenylboronic acid, and l-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine following the above-described coupling procedures. The crude product was purified by reverse phase preparative HPLC to afford the title product (CCLDC) in a form of trifluoroacetate salt, as an orange solid (100 mg, 10 %),1E NMR methanol-d4: 8 2.08 (m, 2H), 2.22 (m, 2H), 2.70 (s, 3H), 3.27 (m, 2H), 3.68 (t, J= 5.0 Hz, 2H), 3.75 (m, 2H), 4.37 (t, /= 5.0 Hz, 2H), 7.00 (dd, J= 8.8 Hz, /= 3.0,1H), 7.05 (d, /= 3.0, 1H), 7.10 (d, /= 9.0 Hz, 2H), 7.46 (d, J= 8.8 Hz, 1H), 7.81 (br s,lH), 7.96 (d, J= 9.0 Hz, 1H), 8.11 (br s, 1H). MS (ESI+) mfz = 490. Example 198 Synthesis of N-(2-dimethyIamino-etfayI)-4-f7-f2,6-dimethyl-phenyl)-5-methyI-benzofl,2,41triazin-3-ylamino1-benzamidedihydratemesyIate (CCLX) [0447] The compound was prepared from the intermediate compounds 108 and 104 following the above-described coupling procedure. The crude product was purified by silica gel column chromatography using methanol/CHaCla/NEts (50:50:0.1) as the mobile phase and was re-crystallized from CHjCk to give N-(2-dimethylarruno-ethyl)-4-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-benzarnide, to a solution of 80 mg of which in 1.5 ml methanol was added methanesulfonic acid (9.5 jil, 0.146 mmol) and the mixture was stirred for 5 min until clear. The clear solution was added dropwise to 20 mL Et2O. The yellow precipitate was isolated by filtration and dried in vacua to afford the title product (CCLX), as a yellow solid (71 mg, 80%).^ NMR Methanol-d4: 8 2.09 (s, 6H), 2.70 (s, 3H), 2.77 (s, 3H), 3.00 (s, 6H), 3.39 (t, J= 5.9 Hz, 2H), 3.78 (t, J= 5.9 Hz, 2H), 7.16 (br d, J= 7.9 Hz, 2H), 7.21 (dd, J= 6.2 Hz, J= 8.8, 1H), 7.60 (br s, 1H), 7.91 (br s, 1H), 7.97 (d, J= 8.8 Hz), 8.17 (d, J= 8.8 Hz, 2H). Analyzed: (CagHagNgOeS), calculated: C, 57.32, H, 6.53, N, 14.32, found C, 57.00, H5 6.55, N, 14.30. MS (ESI+) m/z = 455. Example 199 Synthesis of 3-f7-f2,6-dimethyl-phenyl)-5-methyI-beazori,2,41triazin-3-yIamino1-N-(2-pyrroIidin-l-yI-ethyI)-benzamidetrifluoroacetate (CCLXTj [0448] The compound was prepared from the intermediate compounds 108 and 104 following the above-described coupling procedure. The crude product was purified by reverse phase preparative HPLC to afford the title product (CCLXI), as a yellow solid (140 mg, 31 %). :H NMRmethanol-d4: 8 2.05 (m, 2H), 2.09 (s, 6H), 2.21 (m, 2H), 2.78 (s, 3H), 3.18 (m, 2H), 3.47 (t, /= 5.9 Hz, 2H), 3.80 (t, J- 5.9 Hz, 2H), 3.83 (m, 2H), 7.16 (br d, J= 7.5 Hz, 2H), 7.21 (dd, /= 6.2 Hz, J= 8,7,1H), 7.53 (t, /= 7.8 Hz, 1H), 7.56 (d, J= 7.8, 1H), 7.58 (br s, 1H), 7.89 (br s, 1H), 815 (d, J= 7.8 Hz, 1H), 8.70 (br s, 1H). MS (ESI+) 772/z = 481. Example 200 Synthesis of 3-f7-f2.6-dimethyI-phenvI)~5-methyI-beazofl.2,41triazin-3-yIamino]-N-pvrrolidin-3-yI-benzamide trifluoroacetate [0449] To a solution of intermediate compound 108 (66 mg, 0.25 mniol) in 4 mL anhydrous toluene were added 7 (92 mg, 0.25 mmol), BINAP (16 mg, 25 f,imol), Pd?,(dba)3 (12 mg, 12.5 umol) and Cs2C03 (122 mg, 0.375 mmol). The reaction mixture was stirred at 90 °C for 18 h under argon. The mixture was heated .in the microwave at 170 "C for 10 min and poured into aqueous saturated NaCl solution. The product was extracted with CHaCk and purified by reverse phase preparative HPLC to afford the title product (CCLXII), as a yellow solid (45 mg, 32%). 'H NMR DMSO-d6: 8 2.01 (m, IH), 2.06 (s, 6H), 2.24 (m, IH), 2.67 (s, 3H), 3.53-3.95 (m, 5H), 7.19 (br d, /- 7.6 Hz, 2H), 7.24 (dd, /== 6.2 Hz, J= 8.7, IH), 7.50 (br t, /= 7.8 Hz, IH), 7.65 (br s, IH), 7.96 (br s, IH), 8.07 (br s, IH), 8.17 (d, J= 8.7 Hz, 2H), 11.07 (s, IH). MS (ESI+) m/z = 453. ' Example 201 Synthesis of f7-(2,6-dimethvl-phenyl)-5-metfayI-benzofl,2,41triazip-3-yll- f3-(3-pyrrolidin-l-yI-propane-l-sulfonyl)-phenvI]-amine monohydrate mesylate (CCLxm) [0450] The compound was prepared from the intermediate compounds 108 and 107 following the above-described coupling procedures. The crude product was purified by reverse phase preparative HPLC to give [7-(2,6-dimethyl-phenyl)-5-methyl-benzo [ 1,2,4] triazin-3 -yl]-[3 -(3 -pyrrolidin-1 -yl-propane-1 -sulfonyl)-phenyl] -amine trifluoroacetate salt, which, was converted to the free amine by washing with saturated aqueous NaHC02 solution and extraction with CHaCb. The combined organic phases were dried (MgS04) and the solvent was removed to yield [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-yl]-[3 -(3 -pyrrolidin-1 -yl-propane-1 -sulfonyl)-phenyl]-amine as a yellow solid, which (132 mg, 0.256 mmol) was combined with methanesulfonic acid (15.78 ul, 0.24 mmol) in 3 mL CH2C12 and with Et20 (80 mL). The yellow precipitate was isolated by filtration and dried in vacua to afford the title product (CCLXm), as a yellow solid (145 mg, 93%).^ NMR DMSO-d6: 5 1.82 (m, 2H), 1.98 (m, 4H), 2.06 (s, 6H), 2.30 (s, 3H), 2.72 (s, 3.H), 2.97 (m, 2H), 3.23 (m, 2H), 3.45 (t, /-7.8 Hz, 2H), 3.51 (m, 2H), 7.19 (d, J= 7.0 Hz, 2H), 7.24 (dd, /= 6.3 Hz, J= 8.6, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.68 (s, 1H), 7.72 (t, J= 8.0 Hz, 1H), 8.00 (s, 1H), 8.13 (d, 8.0 Hz, 1H), 9.04 (s, 1H), 9.38 (br s, 1H), 11.40 (s, 1H). Analyzed: (CsoHasNsOgSa), calculated C, 57.21, H, 6.24, N, 11.12, found C, 56.56, H, 5.79, N, 11.04 MS (ESI+) m/z = 516. Example 202 Synthesis of {4-f7-(2-chloro-5-methoxy-phenyI)-6-methyI-ben2ofl,2,41triazin-3-vlamino]-phenyl|-(4-methyI-piperazin-l-yI>methanone monohydrate mesylate MeO (CCLXTV) [0451] The title product was synthesized from the intermediate compounds 101,102, and 2-chloro-5-methoxyphenylboronic acid, following the above-described coupling procedures. The crude product was purified by reverse phase preparative HPLC and the resulting trifluoroacetate salt was converted to the free amine by washing with saturated aqueous NaHCCb solution and extraction with CHbCb to give {4-[7-(2-chloro-5-methoxy-phenyl)-6-methyl-benzo[l,2,4]1riazin-3-yiamino]-phenyl}-(4-methyl-piperazin-l~yl)-methanone as a yellow solid (49.5%). The free base was converted to the title product (CCLXIV) (189 mg, 96 %). JHNMRDMSO-d6: 8 2.29 (s, 3H), 2.31 (s, 3H, mesylate), 2.85 (br s, 3H), 3.11 (m, 2H), 3.30-3.50 (m, 6H), 3.85 (s, 3H), 7.03 (d, J= 3.0 Hz, 1H), 7.09 (dd, J= 8.9, J= 3.0 Hz, 1H), 7.52-7.55 (m, 3H), 7.76 (s, 1H), 8.09 (d, /= 8.9 Hz, 2H), 8.10 (s, IB), 9.72 (br s, 1H), 11.13 (s, 1H). Anal. (C28H33CIN606S), Calcd C, 54.50, H, 5.39, N, 13.62, found 54.31, H, 5.64, N, 13.38 MS(ESI+) m/z = 503. Example 203 Synthesis of (4-[7-(5-chloro-2- (CCLXV) [0452] The title product was synthesized and purified as described hi Example 202 for compound (CCLXIV), except 5-chloro-2-methylphenylboronic acid was used instead of 2-chloro-5-methoxyphenylboronic acid. JH NMR DMSO-d6: 5 2.04 (s, 3H), 2.21 (s, 3H), 2.32 (s, 3H, mesylate), 2.84 (br s, 3H), 3.11 (m, 2H)S 3.30-3.50 (m, 6H), 7.31 (d, J= 2.0 Hz, 1H), 7.41-7.45 (m, 2H), 7.52 (d, J= 8.6 Hz, 2H), 7.78 (s, 1H), 8.08 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 9.75 (br s, 1H), 11.12 (s, 1H). Analyzed; (CzgHssClNeOsS), calculated: C, 55.95, H, 5.53, N, 13.98, found: C, 55.59, H, 5.57, N, 13.78. MS (ESI+) m/z = 487. Example 204 Synthesis of r7-(5-fluoro-2-methvl-0heuvl)-6-methyI-benzQfl,2,4]tria2lii-3-vn-r4-(2-pyrroIidin-l-vI-ethoxv)-phenvl]-amine trifluoroacetate (CCLXVI) [0453] A precursor, 7-(5-fluoro-2-methyl-phenyl)-6-methyl-benzo[l,2,4]triazin-3-ylamine, was prepared using the above-described coupling procedure. A mixture of the precursor (113 mg, 0.42 mmol), l-[2-(4-bromo-pheaoxy)-ethyl]-pyrrolidine (174 pj 0.84 mmol), Xantphos (49 mg, 0.084 mmol), Pd2(dba)3 (39 m.g, 0.042 mmol) and Cs2CO3 (274 mg, 0.84 mmol) in anhydrous dioxane (4 mL) was heated under reflux for 2 h under argon. The reaction mixture was cooled to room temperature and quenched with brine, The product was extracted with CHzCla and purified by reverse phase preparative HPLC to afford the title product (CCXVI), as an orange solid (10.3 mg, 4.3%). 'H NMR DMSO-d6: 8 1.90 (m, 2H), 2.02 (s, 3H), 2.03 (m, 2H), 2.19 (s, 3H)5 3.15 (m, 2H)S 3.61 (m, 4H), 4.31 (t, .7= 5.0, 2H), 7.07 (d, /== 9.0 Hz, 1H), 7.10 (dd, J = 9 Hz, /= 2.8 Hz, 1H), 7.21 (ddd, J= 8.7 Hz, /= 8.7 Hz, /= 2.8 Hz, 1H), 7.41 (dd, J= 6 Hz, J~ 8.7, 1H), 7.67 (s, 1H), 7.91 (d, /= 9.0 Hz, 2H), 8,00 (s, 1H), 9.77 (br s, IK), 10.73 (s, 1H). MS (ESI+) m/z = 458. (CCLXVII) Example 205 Synthesis of 3-{6-methvl-3-f4-(2-pyrroIidin-l-vI-ethQxy)-phenvIamino]-benzofl,2,41triazin-7-yI}-phenolhydrQch]oride IU454J A precursor, 3-(3-amino-6-methyl-benzo[l,2,4]triazin-7-yl)-phenol, was prepared from the intermediate compound 101 and 3-hydroxyphenylboronic acid using the above-described coupling. The final product was synthesized from the above precursor (0.73 mmol, 185 mg) and l-[2-(4-bromo~phenoxy)-ethyl]-pyrrolidine (303 ul, 1.46 mmol) according to the procedure described above. The product was purified by reverse phase preparative HPLC and was converted to the free amine by washing with saturated aqueous NaHCOs solution and. extraction with CHjCk (94.6 mg, 29 %). The free amine was converted to the title copound (CCLXVII), a red-orange solid (81.3 mg, 80 %). !HNMR DMSO-dg: 5 1.90 (m, 2H); 2.04 (m, 2H), 2.40 (s, 3H), 3.13 (m, 2H), 3.59 (m, 4H), 4.34 (t, /= 5.0 Hz, 2H), 6.84 (s, 1H), 6.84-6.88 (m, 2H), 7.06 (d, /= 9.0 Hz, 2H), 7.30 (dd, J= 7.8 Hz, J= 7.8 Hz, 1H), 7.63 (s, 1H), 7.90 (d, J= 9.0 Hz, 2H), 9.64 (s, OH), 10.39 (br s, 1H), 10.70 (s, 1H). MS(ESI+) m/z = 442. Example 206 Synthesis of N-|3-f4-(2-pyrrolidin-l-yl-ethylsulfamoyI)-phenyIamino1-7-o-tolyl-beHzofl,2,41triazin-6-yI}-acetamide trifluoroacetate (ccLxvm) [0455] As a preliminary step, the synthesis of the title product included a process shown by the reaction scheme (CCLXTX). [0456] The reaction scheme (CCLXIX) illustrates a synthetic process rthat included dropwise adding of 6.4 g bromine (40 mmol) to a solution of 4-m'trobenzene-l,3-diamine (5.56 g, 36.3 mmol), in 50 mL 1,4-dioxane, followed by stirring the solution was room temperature for 16 h. The yellow precipitate was isolated by filtration, washed with 1,4-dioxane (30 mL) and dried in vacuo to give 4-bromo-6-nitro-benzene-l,3--diamine dihydrobromide salt designated on the reaction scheme (CCLXIX) as compound 13 (8 g, 95%). [0457] A mixture of compound 13 (6.0 g, 15.3 mmol) and cyanamide (3.9 g, 92 mmol) was heated to a melt at 90 °C. To the melt was cautiously added concentrated HCI (45 mL) and the reaction mixture was stirred at 95 °C for 2h. It was cooled to room temperature and the reaction mixture was brought to pH 12 with 30% sodium hydroxide (about 65 mL). The mixture was heated to 90 °C for 2h, cooled to room temperature and poured into water (1L). The yellow precipitate was isolated by filtration, washed with water (100 mL) and acetone (20 mL) and was dried to give 7-bromo-.l-oxy-benzo[l,2,4]triazine-3,6-diamine designated on the reaction scheme (CCLXIX) as compound 14 (1.3 g, 33 %). To a suspension of the crude product in 140 mL MeOH were added Raney Ni and the mixture was hydrogenated for 2h. Solids were removed by filtration through a short silica gel column. The solvent was evaporated to give 7-bromo-benzo[l,2,4]triazine-3,6-diamine designated on the reaction scheme (CCLXIX) as compound 15 (1.0 g, 82%). To a solution of compound 15 (1.0 g, 4 mmol) in 60 mL DMA were added 2-methylphenylboronic acid (884 mg, 6.5 mmol) in 16 mL ethanol, K2CO3 (332 mg, 2.4 mmol) in 6 mL water, PPh3 (262 mg, 1 mmol) and Pd2(dba)3 (184 mg, 0.2 mmol). The reaction mixture was stirred for 4 h at 100 °C under argon, cooled to room temperature and poured into aqueous saturated NaHCOs solution (100 mL). The product was extracted with CH2C12 (150 mL) and purified by reverse phase preparative HPLC, The product was washed with saturated aqueous NaHCOs solution and extracted with EtOAc (100 mL). The combined organic phases were dried (Na2$O4) and the solvent removed. The crude product was re-crystallized from MeOH to give 7-o-tolyl-benzo[l,2,4]triazine-3,6-diamine designated on the reaction scheme (CCLXIX) as compound 16 (133.7 mg, 13 %). [0458] To a solution of compound 16 (80 mg, 0.32 mmol) in 10 mL 1,4-dioxane was added potassium bis(trimethylsilyl)amide (127 mg, 0.64 mmol) and the mixture was stirred at room temperature under argon for Ih. To the dark red solution was added acetylchloride (45 J4.1, 0.64 mmol) and stirring was continued for 30 min at room temperature. The product was poured into saturated aqueous NaHCOs solution (40 mL) and was extracted with EtOAc (100 mL). The combined organic phases were dried (Na2SO4) and the solvent was evaporated. The crude product was purified by reverse phase preparative HPLC to give a precursor, N-(3-amino-7-o-tolyl-benzo[l,2,4]triazin-6-yl)-acetamide, as trifluoroacetate salt, which was converted to the free base (53.1 mg, 57 %) by washing with saturated aqueous NaHCOa solution. The final product was synthesized from the purified precursor and 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)~ benzenesulfonamide following the above-described coupling procedure. The purification using reverse phase HPLC afforded the title product (CCLXVHI), as a yellow solid (81.7 mg, 68 %). ]H NMR DMSO-d6: 5 1.87 (m, 2H); 2.01 (m, 2H), 2.02 (s, 3H), 2.11 (s, 3H), 3.04 (m, 2H), 3.07 (td, /= 6.1 Hz, J= 6.1 Hz, 2H), 3.25 (td, J= 6.1 Hz, /= 6.1 Hz, 2H), 3.57 (m, 2H), 7.30 (d, J= 7,8 Hz, IH), 7.36-7.44 (m, 3H), 7.85 (m, IH), 7.86 (d, J= 9.0 Hz, 2H), 8.06 (s, IH), 8.20 (d, J= 9.0 Hz, 2H), 8.41 (s, IH), 8.91 (s, IH), 9.59 (br s, IH), 11.27 (s, IH). MS (ESI+) m/z = 546. EmmBle_207 Synthesis of 4^643-te^ vlamino1-N-(2^pYrrolidip-l-yl-ethyl)-benzenesuIfonamide trifluorQacetate (CCLXX) [Q459] To a solution of 7-o-tolyl-benzo[l ,2,4]triazine~3,6-&arnine (compound 16 on scheme (CCLXIX)) (0.12 mmol, 30 mg) in 5 mL anhydrous 1,4-dioxane was added potassium bis(trimethylsilyl)amide (53 mg, 0.26 nunol) and the mixture was stirred at room temperature under argon for 1.5 h. To the red solution was added ten- . butylisocyanate (28.5 jil, 0.36 mmol) and stirring was continued for 2 h at room temperature. The product was poured into saturated aqueous NaHCOs solution (40 mL) and was extracted with EtOAc (100 mL). The combined organic phases were dried (NaiSCU) and the solvent was evaporated to give l-(3-amino-7~o-tolyl-benzo[l,2,4] triazin-6-yl)-3-tert-butyl-urea (28 mg, 67%). The title product was prepared as a red solid (27.8 mg, 48 %) from the above intermediate and 4-bromo~N-(2-pyrrolidin-l~yl~ ethyl)-benzenesulfonamide following the above-described coupling procedure and was purified by reverse phase preparative HPLC. 'HNMRDMSO-de: 8 1.37 (s, 9H), 1.87 (m, 2H); 2.01 (m, 2H), 2.16 (s, 3H), 3.04 (m, 4H), 3.24 (td, /= 6.1 Hz, /= 6.1 Hz, 2H), 3.56 (m, 2H), 7.21 (s, 1H), 7.33-7.40 (m, 4H), 7.50 (d, J= 9.0 Hz? 2H)5 7.75 (d, J= 9.0 Hz, 2H), 7.88 (t, J= 6.1 Hz, 1H), 7.99 (s, 1H), 8.34 (s, IH), 8.83 (s, 1H), 9.53 (br s, 1H), 10.21 (s, IH). MS (ESI+) »j/z =603. Example 208 Synthesis of 4-f7-f5-hydroxyinethvl-thiophen-2-yl)-6-methvl-benzofl,2.41triazin-3-vlaminol-N-(2-pyrrolidin-l-yl-ethyl)-benzenesuIfonamide trifluoroacetate (CCLXXI) [0460] A precursor, [5-(3-amino-6-methyl-beiizo[l,2,4]triazin-7-yl)-thiophen-2-yl]-methanol, was prepared from the intermediate compound 101 and 5-hydroxymethylthiophene-2-boronic acid according to the above-described coupling procedure. The final compound was synthesized from the precursor and 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide according according to the above-described coupling procedure. The product was purified by reverse phase preparative HPLC to afford the title product (CCLXXI), as an orange solid. 1H NMR DMSO-d6: 8 1.86 (m, 2H); 2.00 (m, 2H), 2.63 (s, 3H), 3.00-3.07 (m, 4H), 3.24 (m, 2H), 3.56 (m, 2H), 4.71 (br s, 2H), 5.60 (m, IH), 7.07 (d, J= 3.5 Hz, IH), 7.27 (d, 3.5 Hz, IH), 7.80 (s, IH), 7.84 (d, /= 9.0 Hz, 2H), 7.88 (t, 6.1 Hz, IH), 8.20 (d, J= 9.0 Hz, 2H), 8.30 (s, IH), 9.60 (br s, IH), 11.35 (s, IH). MS (ESI+) m/z = 525. Example 209 Synthesis of 4-f7-(5-cyano-2-methyi-phenyl)-6-methyl-benzofl,2,41triazin-3-ylamino1-N-(2-pyrroIidin-l-yl-ethvl)-benzenesuIfopamide (ccLxxn) trifluoroacetate [0461] A precursor, 3-(3-amino-6-methyl-benzo[l,2,4]triazin-7-yl)-4-methyl-benzonitrile, was prepared from the intermediate compound 101 and 2-methyl-5- • cyanoboronic acid according to the above-described coupling procedure. The crude product was purified by silica gel column chromatography (Rf = 0.2, EtOAc/hexanes/NEta, 60:40:0.5). The product was synthesized from the precursor and 4-brorno-N-(2-pyn'olidin-l-yl-ethyl)~benzenesulfonamide according to the above-described coupling procedure. The product was purified by reverse phase preparative HPLC to afford the title product (CCLXXII), as an orange solid (42 mg, 50 %). JH NMR DMSO-d6: 8 1.87 (m, 2H); 2.01 (m, 2H), 2.15 (a, 3H), 2.21 (s, 3H), 3.00-3.08 (m, 4H), 3.25 (td, J = 6.1 Hz, J= 6.1 Hz, 2H), 3.57 (m, 2H), 7.62 (d, ,7= 8.0 Hz, 1H), 7.75 (s, 1H), 7.82-7.88 (m, 4H), 8.15 (s, 1H), 8.21 (d, J= 9.0 Hz, 2H), 9.54 (br s, 1H), 11.34 (s, 1H). MS (ESI-f) m/z= 528 Example 210 Sygthesis of 4-chloro-3-r5-methyl-3-f4-pYrroIidin-l-yI-butyIamino)-benzofl,2,41triazin-7-yn-phenol trifluoroacetate salt (ccLxxm) [0462] A suspension of 7-(2-chloro-5-metlioxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine (80 mg, 0.27 mmol) and sulfamic acid (66 mg, 0.68 mmol) in 3 ml 4-pyrrolidinobutyl amine was stirred at 200 °C for 16 h. The mixture was diluted with EtOAc (5 mL) and purified by silica gel column chromatography (Rf = 0.22, CH2Cl2/MeOH/NEt3j 90:10:0.1) (40 mg, 35%). The purified intermediate (40 mg, 0.094 mmol) was treated with BBra (80,3 pi, 0.47 mmol) at room temperature for 2h and was poured into saturated aqueous sodium thiosulphate. The product was extracted with 20 mL CH2Cl2/methanol (90:10). The combined organic phases were dried (Na2SC>4), and the solvent was evaporated. The crude product was purified by reverse phase preparative HPLC to afford the title product (CCLXXIH), as a red solid (43 mg, 87%). 1R NMR DMSO-d6: 8 1.68-1.79 (m, 4H), 1.87 (m, 2H); 2.00 (m, IE), 2.09 (m, 1H), 2.56 (s, 3H), 2.97-3.03 (m, 2H), 3.18 (m, 2H), 3.40-3.55 (m, 4H), 6.85 (dd, J= 8.6 Hz, J= 2.9 Hz, 1H), 6.89 (d, /= 2.9 Hz, 1H), 7.38 (d, /= 8.6 Hz, 1H), 7.73 (s, 1H), 8.02 (s, 1H), 8.60 (br s, 1H), 9.50 (br s, 1H), 9.92 (br s, 1H). MS(BSI-f) TK/Z = 412. Example 2.11 Synthesis of 4-f7-(3-hvdroxv-piper{dip-l-v!)-6-methyI-benzofl,2,4]triazin-3-ylamiBo]-N-(2-pyrrolidin-l-yl-ethyI)-beiizenesulfouamide trifluoroacetate (CCLXXIV) [0463] To a solution of 4-(7-bromo-6-methyl-benzo[l,2,4]triazin-3-ylamino)-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (71 mg, 0.145 mmol) in 2 mL anhydrous xylene were added piperidin-3-ol hydrochloride (80 mg, 0.58 mmol), xantphos (34 mg, 0.058 mmol), Pd(OAc)2 (7 mg, 0.029 mmol) and KOtBu (98 mg, 0.87 mmol). The reaction mixture was heated in a microwave at 150°C for 20 min and poured into aqueous saturated NaHC03 solution. The product was extracted with CH2C12 (50 mL) and purified by reverse phase preparative HPLC to afford the title product (CCLXIV), as a brown solid (7.5 mg, 8.3%). 1E NMR DMSO-d6; 8 1.86 (m, 4H); 2.00 (m, 4H), 2.50 (s, 3H), 3.00-3.08 (m, 4H), 3.20-3.30 (m, 4H), 3.55 (m, 4H), 4.90 (m, 1H), 7.67 (s, IB), 7.73 (s, 1H), 7.80 (d, J= 8.9 Hz, 2H), 8.15 (d, J= 8.9 Hz, 2H), 9.50 (br s, 2H), 11.06 (s, 1H). MS(ESI+) m/z = 512. Example 212 Synthesis of 4-chIoro-3-|6-chloro-3-f4-(2-pyrrolidin-l-yl-ethoxvV phenylamino1-benzo[1.2,41triazin-7-yI}-phenoI (CCLXXV) [0464] As a preliminary step, the synthesis of the title product included a process shown by the reaction scheme (CCLXXVI). mmol) and cyanamide (9.8 gs 231 mmol) at 100°C was cautiously added concentrated HCI (50 mL) and the mixture was stirred at 100°C for 2.5 h. The reaction mixture was cooled to room temperature and the pH was adjusted to pH 11 using 30 % aqueous NaOH. The reaction mixture was stirred at 100 °C for 2 h, cooled to room temperature and poured into water (200 mL), The yellow precipitate was isolated by filtration, washed with CHaCla (20 mL) and dried to give 6-chloro-l-oxy-benzo[l,2,4]triazm-3-ylamine, designated on the reaction scheme (CCLXXVI) as compound 17 (3.42 g, 60%). To a solution of compound 17 (983 mg, 5 mmol) in 30 mL glacial acetic acid was added NBS (1.78 g, 10 mmol) and the mixture was heated to reflux for 4 h. It was cooled to room temperature and poured into water (700 mL). The yellow precipitate was isolated by filtration and was hydrogenated in MeOH (100 mL) for 2 h using Raney Ni (1.0 g). Solids were removed by filtration and the solvent was evaporated. The crude product was purified by silica gel column chromatography using EtOAc as the mobile phase to give 7-bromo-6-chloro-benzo[l,2;4]triazin-3-ylamine, designated on the reaction scheme (CCLXXVT) as compound 18 (95.6 mg, 7.4%). [0466] 6-chloro-7-(2-chloro-5-merhoxy-phenyl)-benzo[l,2,4]triazin-3-ylamine designated on the reaction scheme (CCXXXVT) as compound 19 (54 mg, 68%) was prepared from compound 18 and 2-chloro-5-methoxyphenylboronic acid according to the above-described coupling procedure. The crude product was purified by silica gel column chromatography (Rf = 0.41, EtOAc/hexanes 50:50). The title compound (CCLXXV) was prepared from compound 19 and l-[2-(4-bromo-pheuoxy)-ethyl]-pyrrolidine following the above-described coupling procedure, followed by demethylation. The coupling product was purified by reverse phase preparative HPLC to give [6-chloro-7-(2-chloro-5-memoxy-phenyl)-beiizo[l5254]1riazin-3-yIJ-[4-(2-pyn-olidin-l-yl-ethoxy)-phenyl]-amine (28.7 mg, 27%). Deprotection of the methoxy group with BBr3 (22 jj,l, 0.23 mmol) in 2 mL CHaCli at room temperature yielded 4-chloro-3-{6-chloro-3-[4-(2-pyrrolidin-l-yl-ethoxy)-phenylamino]-benzo[l,2,4]triazin-7-yl}-phenol, which was purified by reverse phase preparative HPLC and converted to the free amine to give a brown solid (13 mg, 57%). 5H NMR DMSO-d6: 6 1.68 (m, 4H), 2.50-2.55 (m, 4H), 2.79 (t, J- 5.9 Hz, 2H), 4.07 (t, J= 5.9, 2H), 7.07 (d, /= 9.0 Hz, 1H), 6.77 (d, J= 2.8,1H), 6.84 (dd, /= 8.8 Hz, J= 2.8 Hz, 1H), 6.98 (d, /= 9.0 Hz, 2H), 7.32 (d, J= 8.8,1H), 7.85 (d, /= 9.0 Hz, 2H), 7.90 (s, 1H), 8.22 (s, 1H), 10.90 (br s, 1H). MS(ESI+) m/z = 496. Example 213 Synthesis of 4-f7-(5-cyano-2-methyI-phenyl)-5--methvI-benzoIl,2,41triazin-3-vIamino1-N-(2-pyrrolidin~l-yI-ethyI)-benzenesuIfonamide trifluoroacetate (CCLXXVH) [0467] 3-(3-amino-5-methyl-benzo[l,2,4]triazin-7-yl)-4-inethyl-beiizonitrile was prepared from the intermediate compound 100 and 2-methyl-3-cyanophenylborordc acid according to the above-described coupling procedure. The crude product was purified by silica gel column chromatography (Rf = 0.35, EtOAc/hexanes, 50:50) (72.4 mg, 77%). The product was purified and reacted with 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide following the above-described coupling procedure. The crude product was purified by reverse phase preparative HPLC to afford the title product (CCLXXVTI), as a yellow solid (30 mg, 18%). *H NMR DMSO-d6: 5 1.87 (m, 2H); 2.01 (m, 2H), 2.41 (s, 3H), 2.72 (s, 3H), 3.04 (m, 2H), 3.07 (td, J= 6.2 Hz, J- 6.2 Hz, 2H), 3.25 (td, J= 6.2 Hz, J= 6.2 Hz, 2H), 3.57 (m, 2H), 7.61 (d, J= 8.2 Hz, 1H), 7.81-7.87 (m, 2H), 7.88 (d, J= 8.9 Hz, 2H), 7.94 (br s, IE), 8.26 (d, J== 8.9 Hz5 2H)5 8.27 (br s, 1H), 9.63 (br s, 1H), 11.46 (s, 1H). MS (ESI+) m/z = 528. Example 214 Synthesis of (4-f7-(2-chIoro-5-hydroxy-phenyI)-5-niethyI-benzofl.2,41triazm-3-vlamino1-phenyI}-(l,l-dioxo-116-thiomorphoIin-4-yl)- (ccLxxvm) metfaanone [0468] To prepare the title compound, the intermediate compound 109 ((4-bromo-pheiiyl)-(l,l-dioxo-116-thiomorpholin-4-yl)-methanone) shown below was synthesized first. o N' 109 [0469] To prepare the intermediate compound 109, a solution of 4-bromo-benzoic acid (2.0 g, 10.0 mmol) in 20 mL acetonitrile were added thiomorpholine (950 p.1, 10 mmol) and EDC (1.92 g, 10 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed and the residue was dissolved in 60 mL CH2C12 and washed with aqueous saturated NaHCOs solution (100 mL). The organic phase was dried (NazSC^) and the solvent was removed. The crude product was purified by flash column chromatography (Rf= 0.45, EtOAc/hexanes, 50:50). To a solution of the above intermediate (100 mg, 0.35 mmol) in CHaCk (30 mL) were added mCPBA (79 mg, 0.35 mmol) at 0° C. The mixture was stirred for 2 h before another batch of mCPBA (79 mg, 0.35 mmol) was added. The mixture was stirred at RT for 16 h and was then quenched with aqueous saturated NaHCOa solution (100 mL). The intermediate compound 109 was extracted with CH^Ck (100 mL) and used without farther purification (105 mg, 94 %). 'HNMRDMSO-d6: § 3.24 (m, 4H), 3.67 (m, 2H), 3.99 (m, 2H), 7.46 (d, /= 8.2 Hz, 2H), 7.68 (d, J= 8.2 Hz, 2H). MS(ESI+) m/z = 182/184. [0470] A mixture of 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-ylamine (50 mg, 0.17 mmol), intermediate compound 109 (80 mg, 0.25 mmol), Xantphos (20 mg, 0.0334 mmol), Pd2(dba)3 (16 mg, 0.0167 mmol) and Cs2CO3 (109 mg, 0.334 mmol) in anhydrous dioxane (4 mL) was refluxed for 4 h under argon. The reaction mixture was cooled to room temperature, diluted, with CHaCk (20 mL) and filtered. The crude product was purified by flash column chromatography to give {4-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-ylamino]-phenyl} -(1,1 -dioxo-116- thiomorpholin-4-yl)-methanone, an amount of which (54 mg, 0.1 mmol) in CH2C12 (8 mL) was treated with a 1.0 M solution of BBr3 in CH2Ck (500 |ul, 0.5 mmol) at 0° C to give {4-[7-(2-chloro-5-hydroxy-phenyl)-5-methyl-benzo[l,2,4]triazin.-3-ylaminoj-phenyl}-(l,l-dioxo-116-thiomorphoUn-4-yl)-methanone. The crude product was purified by reverse phase preparative HPLC to afford the title compound (CCLXXVID), as a yellow powder (15.7 mg, 30 %). 1H NMR DMSO-d6: 5 2.70 (s, 3H), 3.26-3.30 (m, 4H), 3.90 (m, 4H), 6.88 (dd, J= 8.7 Hz, J= 2.9 Hz, IH), 6.93 (d, J=2.9 Hz, IH), 7.41 (d, /= 8.7 Hz, IH), 7.58 (d, /= 8.7 Hz, 2H), 7.89 (br s, IH), 8.12 (d, J= 8.7 Hz, 2H), 8.19 (br s, IH), 9.93 (s, IH), 11.22 (s, IH). MS(ESI+) m/z Example 215 Synthesis of [7-(2,6-dichlorQ-phenyI)-5-metiivI-benzofl,2,41triazin-3-vll-r4-(3-pyrrQlidin-l-yI-propane-l-sulfonyI)-phenyI]-amine (ccLxxrx) [0471] The title compound was prepared from 7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamine and the mtermediate compound 109 following the above-described coupling procedure, followed by purification by reverse phase preparative HPLC, to afford a yellow solid (62 mg, 31 %). !H NMR DMSO-d6: 5 1.84 (m, 2H), 1.99 (m, 4H), 2.72 (s, 3H), 2.95 (m, 2H), 3.20 (m, 2H), 3.40-3.53 (m, 4H), 7.53 (t, J= 8.2 Hz, IH), 7.68 (d, J= 8.2 Hz, IH), 7.80 (br s, IH), 7.95 (d, J= 8.9 Hz, 2H), 8.20 (br s, IH), 8.31 (d, /= 8.9 Hz, 2H), 10.25 (br s, IH), 11.57 (s, IH). MS(ESI+) m/z = 556. Example 216 Synthesis of 4-f7-(2-chloro-6-fluoro-5-hvdroxYphenyl)-5-methvl- ben2o[l,2,4Uria2in-3-ylamino1-N-methyl-N-(2-pyrroIidine-l-yl- ethyDbenzenesulfonamide (CCLXXX) [0472] Standard Buchwald conditions were used, followed by demethylation using BBr3. Yellow solid (17 mg, 18 %). 'HNMR (DMSO-d6): 5 1.85-1,95 (m, 2H), 1.97-2.09 (m, 2H), 2.72, 2.73 (2s, 3H each), 3.05-3.15 (m, 2H), 3.25-3.3, 3.37-3.45, 3.6-3.68 (3m, 2H each), 7.08 (t, J= 8.97 Hz, 1H), 7.29 (dd, J= 1.5 and 9.0 Hz, 1H), 7.85 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 8.24 (d, 7= 1.5 Hz, 1H), 8.31 (d, J= 9.0 Hz, 2H), 9.55 (br s, 1H), 10.40 (s, 1H), 11.5 (s, 1H). MS (ESI+): m/z = 446.1. Example 217 Testing of Inhibition of Kinases/« Vitro [0473] The ability of compounds of the present invention to inhibit the activity of three groups of kinases was tested, Kanases tested included the src family (primarily src and yes), some angiogenic growth factor receptors (Fgfrl, Vegfr, and Pdgfrp) and the ephrin, EphB4, All kinase reactions were conducted in 96-well plates with a final reaction volume of 50 ul. Src Family [0474] Recombinant human c-Src or Yes (28 ng/well, Panvera/Invitrogen, Madison WI), ATP (3 uM), a tyrosine kinase substrate (PTK2, 250 jjM, Promega Corp., Madison WI), and test agents (at concentrations ranging from about 1 nM/1 to about 100 uM/1), in the presence of Src kinase reaction buffer (Upstate USA, Lake Placid NY). After reacting for about 90 minutes at room temperature, residual ATP was determined using a luciferase-based assay (KinaseGlo, Promega Corp.) as a measure of kinase activity. Data from four wells were then averaged and used to determine ICso values for the test compounds (Prism software package, GraphPad Software, San Diego CA). Growth Factor Receptors [0475] Pdgfif (0.1 dug/well, Panvera/Invitrogen) 500 nM ATP and the PTK2 peptide (700uM) were combined with compound and reaction buffer as noted above for src. The reaction was incubated for 60 minutes at 37C, and the residual ATP concentration was determined using the luciferase-based technique also noted above. [0476] FGFR1 and VEGFR2 kinase assays were similarly performed. FGFR1 (76ng/well, Panvera/Invitrogen) was combined with 12.5mg/ml poly(glu.4tyr) (Sigma) and 2.5uM ATP. VEGFR2 (14.1U/well, Cell Signaling/ProQinase) was used with 0.3mg/ml poly(glu4tyr) and 1.5uM ATP. Both were incubated for 60 minutes at 37C, and the residual ATP was measured via luminescence, per the procedure described above. EphB4 [0477] EphB4 kinase activity was similarly measured, using the luciferase-based technique described above. 28.9mU/well EphB4 (Upstate) was reacted with Img/ml poly(glu4tyr), 6uM ATP and test reagents. The reaction was incubated for 60 minutes at 37C and the residual ATP concentration was measured.' [0478] The test results for inhibition of Src kinase are presented in Table 1, and the test results for inhibition of some other kinases (i.e., Yes, EphB4, and Pdgfif) are presented in Table 2. The abbreviation "ICso" means that a particular compound of the invention, when present at the specified concentration, inhibited the kinase by 50%. Table 1. Tests Results of Inhibition of Src Kinase by Some Compounds of the Invention -" Name SrcICSO Structure (nM) [7-(2,6-dimethyl-phenyl)- 1520 benzo[l,2,4]triazin-3-yl]-phenyl- amine [7-(2,6-dimethyl-phenyl)-benzo[ 1,2,4]triazin-3-yl]-j>(4-methyl-piperazin-1 -yi)-propyl]- 5800 amrne [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l ,2,4]triazin-3-yl] -phenyl-amine 294 [5-methyl-7-(2,4,6-trimethyl-phenyl)-benzo[ 1,254]triazin-3-yl]-phenyl-amine >10000 [7-(2-fluoro-6-methoxy-phenyl)- >10000 5-methyl-benzo[ 1,2,4]triazin.-3-yl]-phenyl-amine [7-(2,6-dimethoxy-phenyl)-5-methyl-benzof 1,2,4]triazin-3-yl]-phenyl-amine >10000 [7-(2,6-dimethyl-phenyl)-556- dimethyl-benzo[l,2,4]triazin-3- yl]-phenyl-amine 130 [7-(2,6~dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin.-3-yl]-[3-(4-methyl-piperazin-l-yl)-propyl]-amine 9000 [7-(2,6-dimethyl-phenyl)-5--methyl-benzo[l52,4]triazm-3-yl]-[4-(2-pyrroUdin-l-yl-etho7ty)-phenyl] -amine 6.8 [7-(2,6-dimeihyl-phenyl)- benzo[l,2,4]triazin-3-yI3-[4»(2- pyrrolidin-l-yl-ethoxy)-phenyl]- 15.0 amne l-{4-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylaminoj-phenyl}-cyciopropanecarbonitrile 72 [7-(2,6-dichloro-phenyl)-benzo[l,2,4]triazin-3-yl]-[4-(2- pyrroUdin-l-yl-ethoxy)-phenyl]~ 121 amne [4-(l-aminomethyl-cyclopropyl)-phenyl]-[7-(2,6-dimethyl-pb.enyl)-5-methyi-benzo[l ,2,4]triazin-3-yl]-atnine 76.4 N-[7-(2)6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-yl]-acetamide >10000 N-[7-(2,6-dimethyl-phenyl)-5-methyl-benzof 1,2,4]triazin-3-yl]-benzamide 1800 [7-(2,6-dimethyl-phenyl)-5- methyl-benzo[l 32,4]triazin-3 -yl]-quinolin-8-yl-amiiie >10000 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-yl]-pyridin-2-yl-amine >10000 [7-(256-dimethyl-phenyl)-5- methyl-benzo[l,2,4]triazin-3- yl]-quinolin-3-yl-amine >10000 [7-(2,6-dimethyl-phenyl)-5-methyl-beraofl ,2,4]triazin-3-yl]-m-tolyl-amine 178 [7-(2,6-dimethy]-phenyl)-5- >10000 methyl-benzo [ 1,2,4]triazin-3 -yl]-p-tolyl-amine (2,3-dimethyl-phenyl)-[7-(2,6- >10000 dimethyl-phenyl)-5-methyl- benzo[l,2,4]triazin~3-yl]-arnine (2,4-dimethyl-phenyl)-[7-(2,6- >10000 dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-amine (2,5-dimethyl-phenyl)-[7-(2,6- >10000 dimethyl-phenyl)-5-methyl- benzo [ 1,2,4]triazin-3 -yl] -amine (3,4-dimethyl-phenyl)-[7-(256- 957 dimethyl-phenyl)-5-methyl- benzo [ 1,254]triazin-3-yl]-amine (3-chloro-4-fluoro-phenyl)-[7- >10000 (256-dimethyl-phenyl)-5-rnethyl-benzo [ 1,2,4]triazin-3-yl] - amine [7-(2-chloro-phenyl)-5-methyl- >100000 benzo [ 1,2,4]triazin-3 -yl] -phenyl- amine (4-methoxy-phenyl)-[7-(2- methoxy-phenyl)-5-methyl- benzo[l,2;4]triazin-3-yl]-amine >100000 (4-butyl-phenyl)-[7-(2,6~ dimethyl-phenyl)-5-methyl-benzo[l,234]triazin-3-yl]- amine >100000 (2-methoxy-phenyl)-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]- amine >100000 (3-methoxy-phenyl)-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]- amine >100000 (4-methoxy-phenyl)-[7-(2,6-dirnethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]- amine 140 (4-ethoxy-phenyl)-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,254]triazin-3-yl]- amine 108 (3-chloro-phenyl)-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]- amine 134 (3,4-dichloro-phenyl)-[7-(2,6-dirnethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]- amine >100000 [7-(3,5 -dimethoxy-ph.enyl)-5-methyl-benzof 1,2,4]triazin-3 -yl]-m-tolyl-amine >100000 [7-(3,5-dimethoxy-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3 -yl]~p-tolyl-amine >100000 [7-(3,5-dimethoxy-phenyl)-5- >100000 methyl~benzo[ 1,2,4]triazin-3-yl]-(2,4-diinethyl-pheiiyl)-araine [7-(3,5-dimethoxy-phenyl)-5- >100000 methyl-benzo[l ,2,4]triazin-3-yl] -(2,5-dim ethyl-phenyl)-amine [7-(3,5-dimethoxy-phenyl)-5~ >100000 methyl-benzo[ 1,2,4]triazin-3-yl]-(3,4 -dimethyl-phenyl)- amine (4-butyl-phenyl)-[7-(3,5-dimethoxy-phenyl)-5-methyl-benzo[l,2,4]triazm-3-yl]~ amine >100000 (4-ethoxy-phenyl)-[7-(3,5-dimethoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]- amine >}00000 [7-(3,5-dimethoxy-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-yl]-pyridin-4-yl-amine >100000 [7-(3,5-dimethoxy-phenyl)-5- >100000 methyl-benzo[l,2!4]triazin-3- yl]-(2,3-dimethyl-phenyl)-amine [7-(3,5-dimethoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-(2-methoxy-phenyl)-amine >100000 [7-(3,5-dimethoxy-phenyl)-5-methyl-benzo[l,2,4]tria2iii-3-yl]-(4-methoxy-phenyl)-amine >100000 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-yl]-pyridine-4-yl-amine 36 [7-(2,6-dichloro-phenyl)-5- methyl-benzo[l,2,4]triazin-3- yl]-(3-methoxy-phenyl)~amine 189 [7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl] -(4-methoxy-phenyl)-amine 137 [7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,254]triazin-3-yl] -pyridin-4-yl-amine 42 [7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3- yl] -pyridin-3 -yl-amine 27 [4-(2-diethylamino-eth.oxy)-phenyl]-[7-(2,6-dimethyl-phenyl)-5-methyl-benzofl ,2,4]triazin-3-yl]-pyridin-3-yl-amine 9.67 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]- {4-(2-morpb.olin-4-yl~ etb,oxy)-phenyl]-ainine 32.9 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-{4-(3-pyrrolidin-l-yl-propoxy)-phenyl]-amine 12.6 [7-(2,6-dichloro-ph.enyl)-5- methyl-benzo[ 1,2,4]triazin-3- yl]-[4-(2-pyrrolidin-l-yl- etb.oxy)-phenyl]-amine 9.4 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l ,2,4]triazin-3 -yl]- (4-[2-(4-methyl-piperazin-1 -yl)-ethoxy]-phenyl} -amine 21 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l ,2,4]triazin-3-yl] -[3-(2-pyrrolidin-1 -yl-ethoxyj-phenyl}-amine 6.4 [3~(2-diethylammo-ethoxy)-phenyl]-[7-(2,6-dimethyl-phenyl)-5-meth.yl~ benzo[l,2,4]triazin-3-yl]-ainine 10.2 [7-(2-chloro-6-methoxy-phenyl)- 505 5-methyl-benz»[l,2,4]triazin-3-yl]-[4-(2-pyrrolidin~ 1 -yl-etb_oxy)-phenyl]-amine [7~(2,6-difiuoro-phenyl)-5-methyl-benzo[l,2,4]triazia-3-yl] -[4-(2-pyrrolidin-1 -yl-ethoxy)-plienyl]-amine 208 (5-methyl-7-pyri.din-2-yl-benzo[ 1,2,4]triazin-3-yl)-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- 1800 amine (5-methyl-7-pyrimidin-5-yl-benzo[l,2,4]tria2m-3-yl)-[4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl] - 1500 amine [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-yl]-4-N,N-dimethylanilinyl- 244 amine [7-(2,6-dimethyl-phenyl)-5-. methyl-benzo[l ,2,4]triazin-3-yl]-(6-methoxy-pyridin-3 -yl)- 341 amine [7-(5-chIoro-2-methoxy-phenyl)- 1200 5-methyl-benzo[l ,2,4]triazin-3-yl]- [4-(2-pytrolidin-1 -yl-ethoxy)-phenyl]-amine [7-(2,6-dimethyl-4-hydroxyphenyl)-5-methylbenzo[ 1,2,4]trazin-3 -yl] -[4-(2-pyrrolidine~ 1 -yl-ethoxy)-phenyl]-amine 75 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazm-3-ylj- (3 - [2-(4-methyl-piperazin-1 -yl)-ethoxy]-phenyl} -amine 39.5 [7-(2,6-dimethyl-p1iettyl)-5-methyl-benzo[l,2,4]triazm-3-yl]- {3-[3-(4-methyl-piperazin-l-yl)-propoxy]-phenyl} -amme 38.9 [7-(2,6-dimethyl-phenyl)~5-metliyl-benzo[ 1,2,4]triazin-3-yl]-.{4-[3-(4-methyl-piperazin-l-yl)-propoxy]-phenyl}-amine 35.8 [7-(3,5-dimethyl-isoxazol-4-yl)-5-methyl-benzo[ 1,2,4]triazm-3-yl]-(4-methoxy-phenyl)-amine 11700 {4-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-phenyl}-(4-methyl-piperazin- 1 -yl)-methanone 8.9 {4-[7-(3,5-dimethyl-isoxazol-4- 552 yl)-5-methyl- benzo[l ,2,4]triazin-3-ylamtn.o] - phenyl} -(4-methyl-piperazin-1 - yl)-methanone [7-(3,5-dimethyl-isoxazol-4-yl)- 207 5-methyl-benzo[l,2.,4]triazin-3-yl]-[4-(2-pyrrolidin-l-yi-ethoxy)-phenyl]-amine [7-(3,5-dimethyl-isoxazol-4~yl)- 610 5-methyl-benzo[l ,2,4]triazin-3-yl]- {4-[2-(4-methyl-piperazra-l -yl)-ethoxy]-phenyl} -amine Trifluoro-acetatel-(2-{4-[7-(3,5- 75000 dimethyl~isoxazol-4-yl)-5-methyl-benzo[ 1,2,4]triazin-3-ylamino] -phenoxy) -ethyl)-1,4-dimethyl-piperazin-1 -ium; [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3- 11 /s j.1 -j- ^ iyl]-(6-methoxy-pyndin-3-yl)- amine 5.6 [7-(2,6-dicbloro-phenyl)-5-methyl-benzof 1,2,4]triazin-3-yl]-{3-[2-(4-methyi-piperazin-l-yl)-ethoxy]-phenyl} -amine 27.4 [7-(2,6-dichloro-phenyl)-5-methyl-benzo[ 132?4]triazin-3-ylj- {4-[2-(4-methy]-piperazin-l -yl)-ethoxy]-phenyl} -amine 23.2 [7-(2,6-dicMoro-phenyl)-5-methyl-benzo [ 1,2,4]triazin-3-yl]- {4-[3 -(4-methyl-piperazin-1 -yl)-propoxy]-phenyl} -amine 25.2 [7-(2,6-dicMoro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl] - {3-[3-(4-methyl-piperazin-l -yl)-propoxy]-pb.enyl} -amine 28.8 {4-[7-(2,6-dimethyl-phenyl)-5- methyl-1-oxy- benzo [ 1 ^,4]triazin-3-ylamino] - phenyl) -(4-methyl-piperazin- i - yl)-methanone' 4-[7-(2,6-dimemyl-phenyl)-5-methyl-benzo[l,2,4]triazirL-3-ylamino]-N-(2-pyrrolidin~l -yl-ethyl)-benzamide 96.1 16.1 5-[7-(2,6-dunethyl-phenyl)-5-methyl-benzof 1,2,4]triazin.-3-ylamino] -fturan-2-carboxylic acid methyl ester 1000 [7-(2-chloro-5-methoxy-phenyl)- 788 5-methyl-b enzo [ 1,2,4]triazin~3 -yl]-[4-(2-pyrrolidin-l-yl~ eth.oxy)-plienyl]-amine 3-[7-(2,6-dimethyl-phenyl)-5-methyl~benzo[l,2,4]triazin-3~ ylaminoj-benzenesulfonamide 143 N-(2-dimethylamino-ethyl)-4-[7- 4.6 (2,6-dimeth.yl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-benzamide 3-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazia-3-ylamino]-N-(2-pyrrolidin-l-yl-ethyl)-benzamide 17.6 5-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-ylajaaino]-furan-2-carboxylic acid 1500 4-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino] -2-(2-pyrrolidin-1 -yl-ethoxy)-benzonitril e 21 [7-(2,6-dimethylphenyl)-5-methylbenzo[l,2,4]trazin-3-yl]-3 -(2-pyrrolidine-1 -yl-ethsufomide)-phenyl]-amine 26.4 {5-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l52,4]triazin-3-ylamino]-&ran-2-yl}-(4~methyl-piperazin-l-yl)-methanbne 94 4-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo [ 132,4]triazin~3-ylamino]-N-(2-pyrrolidin-1 ~yl-ethyl)-benzenesulfonamide 9.1 (2-chloro-pyridin-4-yl)-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazm-3-yl]-amine 118 (6-chloro-pyridm-3-yl)-[7-(2,6-dimetliyl-phenyl)-5-methyl~ benzo[l ,2,4]triazin-3-yl]-amiae 232 5-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l ,2,4]triazin-3-ylamino] -furan-2-carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide 17.5 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l ,2,4]triazin-3- yl]-[3-(4-methyl-piperazine-1» sulfonyl)-phenyl]-atnine 322 N-(2-dimethylamino-ethyl)-3-[7~ 41,4 (2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]tiiazin-3-ylamino] -benzenesulfonamide N-(2-dimethylamino-ethyl)-4-[7- 14.6 (2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-benzenesulfonamide 2-[7-(2,6-draiethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-ylamino]-thia2ole-4-carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide 14,6 [7-(2,6-dichloro-phenyl)-5-methyl-benzo[ 1,2,4]triazia-3-yl]-[6-(2-pyrrolidin-l-yl-ethoxy)-pyridin-3-yl]-amine 15.3 5-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-ylamino]-2-(2-pyrrolidin-1 -yl-ethoxy)-benzonitrile 25.2 3-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-ylamino] -N-pyrrolidin-3 -yl-benzamide 18.3 rf^V^ o n [7-(2,6-dimethyl-phenyl)~5- 111 \\ £« Yy"VN"N f^lf8^^ methyl-benzo[l,2,4]triazin-3-J'N N -^ x yl]-[4-(4-methyl-piperazine-l-sulfonyl)-phenyl]-amine 137 3-[7-(2,6-dimethyl-phenyl)-5- O- ^_.N.M ,#\ /-,w^ methyl-benzo[l52,4]triazin-3- TlTi ill H I i VvNANA^\'N---'^'-N--' ylamino]-N-[3-(4-methyI- piperazin- 1 -yl)-propyl]-benzamide 27.4 fr^V^ N-(3-dimethylamino-propyl)-3-TirYN*i f^l a i [7-(256-dimethyl-Phenyl)-5- V^N^N-^^V ^'X-" x 1 H ii methyl-benzo[l,2,4]triazdn-3-yl aminoj-benzamide 13.1 ^Y" owp 3-[7~(2,6-dimethyl-phenyl)-5-jyV^J f^Y8"^^1^} methyl-benzo[lA4]triazin-3- "S^^^^ ki *^'J^1 »i •^^^^x'**'^ "" j H y]amino]-N-(3-pyrrolidin-l-y]-propyl)-benzenesulfonamide 29.2 5-[7-(2,r6-dimethyl-phenyl)-5-f^^f^ ^ ^ 'Ukx^xM*M *-/"' ^"O methyl-benzo[l,2,4]triazin-3- T^ It ^i \y ^—-/ \^-N^N-^/ ylamino]-furan-2-carboxylic H acid (3-pyrrolidin- 1 -yl-propyl)-amide 18.3 ^i 2-[7-(2,6-dimethyl-phenyl)-5- N f^^f^ Q / methyl-benzo[l,2,4]triazin-3- II ) *^fNf^YN~N s-~/ "NH ylamino]-thiazole-5-carboxylic ^r^N^N^S,^ acid (2-pyrrolidin-l-yl-ethyl)- H amide 286 4-{3-[7-(2,6-dimethyI-phenyl)- >10000 5-methyl-benzo[l ,2,4]triazin-3-ylamino]-benzenesulfonyl.} -piperazine-1-carboxylic acid tert-butyl ester [7-(2,6-dimethyl-phenyl)-5~ methyl-benzof 1,2,4]triaziii-3-yl]-[3-(piperazine-l-sulfonyl)-phenyl]-amine 48.2 (2,6-dimethyl-phenyl)-5-methyl- 25.5 benzo[l ,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-l -yl- ethyl)-benzenesulfonamide ____. (4-(5-methyl-7-(2,6- dimethylphenyl)benzo[e][ 1,2,4]t riazin-3- yl amino)phenyl)(piperazin-1 - yl)methanone. 4-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3-ylamino]-N-(2~piperazin-l-yl-ethyl)-benzenesulfonami de 28.8 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[ 1,2,4]triazin-3 -yl]-[4-(piperazine-1 -sulfonyl)-phenyl]-amine 128 {3-[7~(2,6-dimethyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-phenyl}-(4-methyI-piperazin- 1 -yl)-methanone 88.6 [7-(2,6-dimethyl-phenyl)-6-methyl-benzo[l,2,4]triazin-3-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-amine 12.3 4-[7-(2,6-dimethyl-phenyl)-6- 10.5 ylamino]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide [7-(2,6-dichloro~phenyl)-5- methyl-benzo[l,2,4]triazin-3- yl]-[2-(2-pyirolidin-l-yl- ethoxy)-pyridin-4~yl]-anjine hydrochloride 4-(6-methyl-7-o-tolyl-benzo[l,2,4]tria2dn-3-ylamino> N-(2-pyrrolidin-l-yl-ethy!)-benzenesulfonamide 12.2 10.2 4-(6-methyl-7-phenyl-benzo[l,2,4]triazin.-3-ylamiho)-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide 315 [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[l ,2,4]triazin-3-yl]«[3-(3-pyrrolidin-l-yl-propane-1 -sulfonyl}-phenyl]-amine 34.8 7~(2,6-dimethyl-phenyl)-5~nitro- 32 3-[4-(2-pyrrolidin-1 -yl-ethoxy)-phenylamino]-benzo[l,2,4]triazin-l -ol 7-(2,6-dimethyl-phenyl)-N3-[4-(2-pyrroIidin-l -yl-ethoxy)-phenyl]-benzo[l,2,4]triazine-3,5-diamine 9.7 N~ {7-(2,6-dimethyl-phenyl)-3- [4-(2-pyrrolidin-1 -yl-ethoxy)- phenylamino]- benzof 1,2,4]triazin-v5 -yl} - acetamide 6.8 N-(2-{6-methylT3-[4-(2-pyrrolidin-1 -yl-ethylsulfamoyl)-phenylamino]- benzo[l,2,4]triazin-7-yl} -phenyl)-acetamide 10000 {4-[7-(2-chloro-5-methoxy~ phenyl)-6-methyl- benzo[l ,2,4]triazin-3~ylammo]- pbenyl} -(4-methyl-piperazin-1 - yl)-methanone 560 N- {7~(2,6-dimethyI-phenyl)-3- [4-(2-pyrrolidin-l -yl-ethoxy)- phenylamino]- benzo[l ,2,4]triazin-5-yl} - methanesulfonamide 20.4 (4-(7-(4-chloropyridin-3-yl)-6-methylbenzo[e][l ,2,4]triazin-3-ylamino) phenyl)(4-methylpiperazin-1 -yl)methanone 10000 (4-(6-methyl-7-(4-methylpyridin-3-yl)benzo[e][l,2,4]triazin-3-ylamino)phenyl)(4-methylpiperazin-1 -yl)methanone 47.2 N-(4-(2-(pyrrolidin-l -yl)ethoxy)phenyl)-6-methyi-7-(4-methylpyridin-3-yl)benzo[e][l ,2,4]triazin-3-amine 44.3 {4-[7-(5-chloro-2-methyl- phenyl)-6-methyl~ benzo[ 1,2,4]triazin-3-yIamino]- phenyl} -(4-methyI-piperazin-1 - yl)-methanone 7,9 4-[7-(2-Methanesulfonylamino- phenyl)-6-methyl- benzo[ 1,2,4]triazin-3 -ylamino]- N-(2-pyrrolidin-l -yl-ethyl)- benzenesulfonamide 4-[7-(2-amino-phenyl)-6-methy]-benzo[] ,2,4]triazin~3~ ylamino]-N-(2~pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 5000 91.8 N-(4-(2-(pyrrolidin-l- yl)ethoxy)phenyl)~6-methyl-7-(3 -methylthiophen-2-yl) benzo[e] [ 1,2,4]tri azin-3 -amine 60.7 4-[6-methyl-7-(2-trifluoromethyl-phenyl)-benzo[l ,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 66.5 3.4 {4-[7-(2-chloro-5-hydroxy- phenyl)-6-methyl- benzo[ 1,2,4]triazin-3-ylamino]- phenyl} ~(4-methyl-piperazin-1 - yl)-methanone [7-(2-chloro-5-hydroxy-phenyl)- 1.6 5-methyi-benzo[l ,2,4]triazin-3-yl]-[4-(2-pyrrolidine-l-yl-ethoxy)-phenyl]-amine 4-[7-(2-methoxy-phenyl)-6-methyl-benzo[l,254]triazin-3-ylamino]-N-(2-pyrrolidin-l-yl-ethy])-benzenesulfonamide 272 4~[7-(2-Hydroxyrnethyl-phenyl)- 72.2 6-methyl-benzo[l ,2,4']triazin-3-ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)~benzenesulfonami de [7-(5-fluoro-2-methyl-phenyl)-6- 6.6 yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-amine 5-(5-methyl-7-(2,6- 76 dimethylphenyl)benzo[e] [ 1,2,4]t riazin-3-ylamino)-1 -(3-(pyrrolidin-1 -yl)propyl)pyridin-2(lH)-one 4-[7-(lH-indol-4-yl)-5-methyl-benzo[l,2,4]triazin-3-ylanfflio]-N-(2 -pyrrolidin-1 -yl-ethyl)-benzenesul fonamide 339 (5-methyl-7-piperidin-l-yl~ benzo[l,2,4]triazin-3-yl)- pyridin-3-yl-amine > 10000 4-[7-(2,3-dichloro~phenyl)-6-methyl-benzo[l ,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 142 3- {6~methyl-3-[4-(2-pyrrolidin-1 -yl-ethoxy)-phenylamino]~ benzo[l ,2,4]triazin-7-yl} -phenol 17.7 4-[7-(3-hydroxymethyl-phenyl)- 439 6-methyl-benzo[ 1,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 4-chloro-3-[5-methyl-3-(pyridin- 6.5 3-ylamino)-benzo[l ,2,4]triazin-7-yl]-phenol 4-[7-(4-fluoro-2-methyl-phenyl)- 20.4 6-methyl-benzo[ 1,2,4]triazin-3-ylamino]-N-(2-pyrrolidm-l -yl-ethyl)-benzenesulfonamide N- {7-(2,6-dimethyl-phenyl)-3-[4-(2-pyrroIidin-l-yl-ethylsulfamoyl)-phenylainino]~ benzo[ 1,2,4]tri azin-5-yl} -acetamide 29.9 N-[3- {4-[acetyl-(2-pyrrolidin-1 yl-ethyl)-sulfamoyl]-phenylamino} -7-(2,6-dimethyl-phenyl)-benzo[l ,2,4]triazin-5-yl]~acetamide 34.2 4-[7-(2-chloro-5-hydroxy- phenyl)-5-methyl- benzofl ,2,4]triazin-3-ylamino]- N-(2-pyrrolidm-1 -yl-ethyl)- benzenesulfonamide; N- {3-[4-(2-pyrrolidin-l -yl-ethy]sulfamoyl)-phenylamino]-7-o-tolyl-benzo[l ,2,4]triazin-6-yl}-acetamide 11] 4-[7-(5-chloro-thiophen-2-yl)-6- 880 methyl-benzo[l ,2,4]triazin-3-ylamino]-N-(2-pyrroIidin-1 -yl-ethyl)-benzenesulfonamide 4-chloro-3-[5-methyl-3-(2-pyrrolidin-1-yl-ethylamino)-benzo[ 1,2,4]triazin-7-yl]-phenol 4510 5-[7-(2-chloro-5-hydroxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-furan-2-carboxylic acid (2-pyrrolidin-1 -yl-ethyl)-amide 12.2 o 4-[7-(2-chloro-5-hydroxy- phenyl)-5-methyl- benzo[ 1,2,4]triazin-3-ylamino] - benzenesulfonamide 70.3 4-[6-(3-tert-butyl-ureido)-7-o-tolyl-benzo[l ,2,4]triazin-3-ylamino3-N-(2-pyrrolidm-l -yl-ethyl)-benzenesulfonamide 8000 4-(6-methoxy-7-o-tolyl-benzo[l ,2,4]triazin-3-ylamino)-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 10 3-[7-(2-chloro-5-hydroxy- phenyl)-5-methyl- benzofl 32,4]triazin-3-ylamino]- N-(2-dimethylamino-ethyl)- benzamide 4~[7-(5-hydroxymethyl-thiophen~2-yl)-6-methyl-benzofi ,2,4]triazin-3-ylainino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 4.8 1730 4-(6-hydroxy-7-o-tolyl-benzo[ 1,2,4]tri azin-3-ylamino)-N-(2-pyrrolidin-l -yl-ethyl)-benzenesulfonamide 117 2-(7-(2-chloro-5~ hydroxyphenyl)~5-methylbenzo[e][ 1,2,4]triazin-3-ylamino)-N-(2-(pyrrolidin-1 -yl)ethyl)thiazole-4-carboxamide 5.7 5-[5-acetylamino~7-(2,6- dimethyl-phenyl)- benzo[l ,2,4]triazin-3-ylamino]- furan-2-carboxylic acid (2- pyrrol idin-1 -yl-ethyl)-amide 137 4-chloro-3-[3-(6-fluoro-pyridin- >10000 3-ylamino)-5-methyl- benzofl ,2,4]triazin-7~yl]-phenol 5-[7-(4-fluoro-2-methyl-phenyl)- 120 6-methyl-benzo[ 1,2,4]triazin-3-ylamino]-furan-2-carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide 4-fluoro-3-[6-methyl-3-(pyridin- 26.8 3-ylamino)-benzo [ 1,2,4]triazin-7-yl] -phenol 4-chloro-3-[3-(3-dimethylamino- 21.6 phenylamino)-5-methyl-benzo[l ,2,4]triazin-7-yl]-phenol N- {5-[7-(2-chloro-5-hydroxy- phenyl)-5-methyl- benzo[ 1,2,4]triazin-3-ylamino]- pyridin-2 -yl} -acetamide 118.4 [7-Bromo-6-methyl~ benzo[l ,2,4]triazin-3-ylamino]-N-(2-pyrrolidin~l -yl-ethyl)-benzene-4-sulfonamide. Triflate >10000 4-chloro-3-[3 -{6-methoxy-pyridin-3 -ylamino)-5-methyl-benzofl ,2,4]triazin-7-yl]-phenol 11.2 4-chloro-3- {5-methyl-3-[3- (piperazine-1 -sulfonyl)- phenylamino]- benzo[ 1,2,4]triazin-7-yl} -pheno 52.8 3-(3-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)-6-methylbenzo[e][l ,2,4]triazin-7-yl)-4-fluorophenol 13.7 4-[7-(2-fluoro-5-hydroxy- phenyl)-6-methyI- benzo[ 1,2,4]tri azin-3-ylamino]- N-(2-pyrrolidin-l -yl-ethyl)- benzenesul fonamide 8.5 I/^Y-^ o o r-A 4-(6-ethoxy-7-o-tolyl-^YVN"N f^Y^tC^' benzo[l,2,4]triazin-3-ylamino> x^^oAjA^jjAsx N-(2-pyrrolidin-l-yl-ethyl> H ' benzenesulfonamide 27.2 F-YX5V/ [7-(4-fluoro-2-methyl-phenyl)-6-\^\r/"5:V' N-v N ^'Y"0^^"" N "X methyl-benzo[l ,2,4]triazin-3- xk^N^N-^x) -^ yl]-[4-(2-pyrrolidin-l-yl-H ethoxy)-phenyl]-amine 26.1 4-[7-(5-Cyano-2-methyl-N^jCC^N^ ^X/^NO phenyD-6-methyl-^A^^ ^M'-^S/ H benzo[l,2]4]triazin-3-ylamino]-H ' N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide 12.3 H.N-TI Q /0 fA 4-[6-methyl-7-(lH-pyrazol~4-^if^T^ r^YS^N^^N^ yl)-benzo[l,2,4]triaziii-3-^^'H' *$^ ylamino]-N-(2-pyrrolidin-l-y}- H ethyl)-benzenesulfonamide 8000 OH 4-[7-(3-hydroxy-phenyl)-6-([' j O^s ,Q 1 \ methoxy-benzo[l,2,4]triazin-3- X^k x^.-N^.j x#\^S-M-^-s^N-^/ 1 1 ? I T H ylamino]-N-(2-pyrrolidin-]-yl- X, x^N^?^. M^^ M '^^^ 0 H ethyl)-benzenesulfonamide 37.6 X=YCI 4-chloro-3-[5-methyl-3-(4-HO-xV^\^-'^.'- ,-N __, pyrrolidin-1-yl-butylamino)-\J^N H 1450 {4-[7-(2-cbloro-5-hydroxy- phenyl)-5-methyl- benzo[ 1,2,4]triazin-3-ylamino]- phenyl} -piperazin-1 -yl- methanone 4-[7-(2-chloro-5-hydroxy- phenyl)-6-methyl- benzo[l ,2,4]triazin-3-ylamino]~ N-(2-pyrrolidin-l-yl-ethyl)- benzenesulfonamide 4-chloro-3-[3 -(pyridin-3-ylamino)-5-(2-pyrrolidin-1-yl-ethoxy)-benzo[ 1,2,4]triazin-?-yl]-phenol 3.6 1.6 46.5 4-[6-(2-hydroxy-ethoxy)-7-o-tolyl -benzo[ 1,2,4]triazin~3-ylamino]-N-(2 -pyrrolidin-1 -yl-ethyl)-benzenesulfonamide >10000 6.8 4-chloro-3-[5-methyl-3-(6-morpholin-4-yl-pyridin-3-ylamino)-benzo[l,2,4]triazin-7-yl]-phenol 4-chloro-3~{5-methyl-3-[3-(2- pyrrolidin-1 -yl-ethoxy)- phenylamino]- benzo[l ,2,4]triazin~7-yl} -phenol 4-(7-{[2-(2-hydroxy-ethoxy)- r~" — \ X\^,N N ""V'0 N-^X e&yl]-isoProPyl-amin°}-6- J J-L^Jx ^ J^JJ H methyl-benzo[l,2,4]triazin-3-OH H ylamino)-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide 10000 [7-(2'hydroxyethyl- X-X" .--A ^ • M . M - "V „ M / isopropylamino)-6-methyl- HO/^N yVN'N f^Y K /\^N^NX^5/ benzo[l32,4]triazin-3-ylami"no]-H N-(2-pyrrolidin-l-yl-ethyl)-benzene-4-sulfonamide 10000 c, 3-[7-(2-chloro-5-hydroxy-HoXXV.N^ ^ phenyD-5-methyl-^-^-M^M^^X^c-N-xx^-M-^ benzo[l,2,4]triazin-3-ylamino]- 1 /S^* x- 1 H ° ' N-(2-dimethylamino-ethyl)-benzenesulfonamide 4.2 f^ o o | — \ 4-[7-(3-hydroxy-piperidin-l-yl)-HO-^NY^Y^N j ^^^^M^^N^^^ H ylamino]-N-(2-pyrrolidin-l-yl-ethyl)-benzenesul fonamide 1772 x^V'01 ^NH 4-chloro-3-[5-methyI-3-(6- 1 1 I . HO-x^#;4\x^Y'N^N f^^ piperazin-l-yI-pyridin-3- y ^j^ .xj^ ^i-v^ N r^ N N ^-^ ylamino)-benzo[l!2,4]triazin-7- ! ** yl]-phenol 3.3 rpY" 7-(2,6-dimethyl-phenyl)~N5-jyV^N . f*Y°^^tl'^) methyl-N3-[4.(2-pyirolidin-l-yl- s. >^i^\ "^^-. /^s, .x1^ ~~-— ' ] N !1 ethoxy)-phenyl]-^tw benzo[l,2,4]triazine-3,5-diamine 10.6 c| {4-[7-(2-chloro-5~hydroxy- 1 \ N . Jl ~ phenyl)~5 -methyl -HO"'^^NVX ^I" N r^ix N ] 1 Jl J JL JJ IN benzo[l,2,4]triazin-3-ylamino]-N=^N N-^^ ^-" ^ H phenyl}-(4-methyl-piperazin-l- yl)-methanone 2.9 4-[7-(2-chloro-5-hydroxy- 1 Jl w ^ V' -. N x phenyl)-5-methyl-HO^^S^Y N ,^YS-N-^-N^ H /; / •L^- A- As J ' benzo[l,2,4]triazin-3-ylamino]- 1^ N N M N-methyl-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfon amide 3 _, 4-[7-(2-chloro-5-hydroxy- ?' H Q.,,0 rr^vr-N\/^rr'N,-N X^Y'S^N"^X^' phenylamino)-6-methyl- \f#^ /x\^^N^-N'^x' benzo[l,2,4]triazin-3-ylarnino]-1 H OH . N-(2-pynolidin-l-yl-ethyl)- benzenesulfonamide 10000 f^YCl 4-chloro-3-{6-methyl-3-[4-(2-HO'^^^rf^V'^N r*#r^]r"°"v-/*v"N"^\ pyrrolidin-1-yl-ethoxy)- -^^^•H N'^^ phenylamino]-H benzo[ 1 32,4]triazin-7-yl } -phenol 4.2 C| 5-[7-(2-chloro-5-hydroxy- HO-^^V^V^N ft^Y^N-^'"^ Pheny1)-5'meth>rl- ^.^A, -A AX.XN H benzofl,2,4]triazin-3-ylamino]- j^ N N LJ pyridine-2-carbox'ylic acid (2-pyrrolidin-1 -yl-ethyl)-amide 2.6 {5-[7-(2~chloro-5-hydroxy- phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-pyndin-2-yl} ~[4-(2-hydroxy-ethyl)-piperazin-1 -yl]-rnethanone 10.3 -OH 4-chloro-3-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-pyridin-3-ylamino} ~5-methyl-benzof 1,2,4]tri azin-7-yl)-phenol 4-'chloro-3- {5-methyl-3-[4-(3-pyrrolidin-1 -yl-propane-1 -sulfonyl)-phenylamino]-benzof 1,2)4]triazin-7-yl} -phenol 4-chloro-3-{5-methyl-3-[4-(piperazine-1 -sulfonyl)-NH phenylaminoj- benzo[l,2,4]triazin-7-yl}-phenol 6.6 4-chloro-3-{5-methyl-3-[3-(4- methyl-piperazine-1 -sulfonyl)- phenylamino]- benzo[ 1,2,4]triazin-7-yl} -phenol 433 4-chloro-3-{6-chloro-3-[4-(2- pyrrolidin-1 -yl-ethoxy)- phenylamino]- benzo[ 1,2,4]triazin-7~yl} -phenol 1.2 4-[7-(5-cyano-2-methyl-phenyl)- 25.2 5-methyl-benzo[ 1,2,4]triazin-3 -ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonarnide o,,p 4-[7-(3 -methanesulfonyl amino-pheayI)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-l -yl-ethyl)-benzenesulfonamide 2900 N / ^ N-(3-{5-methyl-3-[4-(2- 3977 phenylamino]- benzo[l,2,4]triazin-7-yl}- phenyl)-acetamide 4-[5-methyl-7-(3-methylammo- 631 phenyl)-benzo[l,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 4-[7-(3-amino-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-l -yl-ethyl)-benzenegulfonaniide 282 •\ 4-[7-(5-amino-2-chloro-phenyl)- 51 ylamino]-N-(2-pyrrolidin- 1 -yl-ethyl)-benzenesu]fonamide [7-(2,6-dichloro-phenyl)-5- methyl-benzof 1,2,4]triazin-3-yl]-[4-(piperazine-1 -sulfonyl)-phenyl]-amine 60.5 [7-(2,6-dichloro-phenyl)-5- methyl-benzo[l ,2,4]triazin-3-yl]-[4-(piperazine-1 -sulfonyl)-phenyl]-amine 22.7 [7-(2-chloro-phenyl)-5-methyl-benzo[ 1 J2,4]triazin~3-yl]-[4-(2~ pyrrolidin-1 -yl-ethoxy)-pbenyl]- 34.8 amine (5-methyl-7-phenyl- benzofl ,2,4]triazin-3-yl)-[4-(2- pyrrolidin-1 -yl-ethoxy)-phenyl] - amme 341 {4-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[l ,2,4]triazin~3-ylaminoj-phenyl} -piperazin-1-yl-methanone 10.2 Cl 4-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[l ,2,4]triazin-3- ylamino] -N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 14 3-{6-methyl-3-[4-(2-pyrrolidin- 1 -yl-ethylsulfamoyl)- phenylamino]- benzo[l ,2,4]triazin-7-yl} - benzamide 4-[7-(2,6-dichloro-phenyl)-5-methyl-benzof 1,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 2216 44.2 4-[7-(2,6-dichloro~phenyl)-5-methyl-benzo[l ,2,4]triazin-3-ylaminoj-phenol 281 383 2-(4-{6-[7-(2;6-dichloro- phenyl)-5-methyl- benzofl ,2,4]triazin-3-ylamino]- 2-methyl-pyrimidin-4-yl}- piperazin-1 -yl)-ethanol 4-chloro-3-(3-{6-[4-(2-hydroxy- 68.8 ethyl)-piperazin-1 -yl]-2-methyl-pyrimidin-4-ylamino} -5-methyl-benzofl ,2,4]triazin-7-yl)-phenol [7-(2,6-dichloro-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-[2-methyl-6-(2-pyrrolidin-l -yl-ethoxy)-pyrimidin-4-yl]- 365 amine 4-chloro-3-{5-methyl-3-[4-(4- methyl-piperazine-1 -sulfonyl)- phenylamino]- benzofl ,2,4]tri azin-7-yl} -phenol 63.4 Cl 4-[7-(2-chloro-5-hydroxy- phenyl)-5-methyl- benzo[ 1,2,4]triazin-3 -ylamino]- N-isopropyl-N-(2-pyrrolidin-1 - yl-ethyl)-benzenesulfonamide [7-(2,6-dichloro-phenyl)-5-methyl-benzo[l ,2,4]triazin-3~ yl]-[4-(3-pyrrolidin-l -yl-propane-l-sulfonyl)-phenyl]-amine 4.8 21.6 4-chloro-3-{5-methyl-3-[4- (piperidine-4-sulfonyl)- phenylamino]- benzo[ 1,2,4]tri azin-7-yl} -phenol 5.2 4-chloro-3-{5-methyl-3-[2- 77.7 methyl-6-(2-pyrrolidin-1 -yl-ethoxy)-pyrimidin-4-ylamino]-benzo[l ,2,4]tri azin-7-yl} -phenol 4-[7-(2-chloro~5-hydroxy- phenyl)-5-methyl- benzo[ 1,2,4]triazin-3-ylamino]- N-ethyl-N-(2-pyrrolidin-l -yl- ethyl)-benzenesulfonamide 3.2 4-[7-(2-chloro-S-hydroxy-phenyl)-5-methyl- ' ' benzo[ 1 ,2,4]triazin-3-ylamino]~ N-methyl-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide 6.6 4-[7-(2-bromo-5-hydroxy- phenyl)-5-methyl- benzo[ 1 ,2,4]triazin-3-ylamino]-' N-(2-pyrroIidin- 1 -yl-ethyl)- benzenesulfonamide 4-[7-(2,6-dichloro-3-hydroxy-phenyl)~5-methyl- benzo[l,2,4]triazin-3-ylamino]-N-(2-pyrrolidin- 1 -yl-ethyl)-benzenesulfonamide 4.1 1.5 4-chloro-3-{5-methyl-3-[3-(2- pyrrolidin-1-yl-ethylsulfanyl)- phenylamino]- benzo[l ,2,4]triazin-7-yl} -phenol 3.4 4-chloro-3-[3-(4-{[(2- 4.3 diethylamino-ethyl)-methyl-amino]-methyl} -phenylamino)-5-methyl-benzo[l ,2,4]triazin-7-yl]-phenol 'Tchloro-3-{5-in^iyl3|4 (4-[7-(2-chloro~5 -hydroxy- phenyl)-5~methyl- benzo[l ,2,4]triazin-3-ylamino]- phenyl}-(l,l-dioxo~116- thiomorpholin-4-yl)-methanone 3.0 4-chloro-3-[3-(4- {[(2-hydroxy-ethyl)-isopropyl-aminoj-methyl} -phenylamino)-5-methyl-benzof 1,2,4]triazin-7~ yl]-phenol 1.5 4-[7-(6-chloro-2-fluoro-3 -hydroxy-phenyl)-5-methyI-benzo[l ,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 0.700 4-[7-(2-fluoro-3 -hydroxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylainino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 5.2 4-(7-(2-chloro-6-hydroxyphenyl)-5-methylbenzo[e][l ,2,4]triazin-3-ylamino)-N-(2-(pyrrolidm-1 -yl)ethyl)benzensulfonamide 12.6 4-[7-(3-fluoro-4-hydroxy-phenyl)-5-methyl» benzo[l,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-l -yl-ethyl)-benzenesulfonamide 156 4-[7-(2-fluoro-6-hydroxy- phenyl)-5-methyl- benzo[l ,2,4]triazin-3-ylamino]- N-(2-pyrrolidin-l -yl-ethyl)- benzenesulfonamide 4-[7-(2-chloro-5~hydroxy-phenyl)-6-methyl-benzo[l,2,4]inazm-3>-y[airano]-N -methyl-N-(2-pyrrolidin-1 -yl -ethyl)-benzenesulfonamide 123 3.7 4-[7-(2-chloro-5-hydroxy- phenyl)-5-methyl- benzo [ 1,2,4]tri azin-3 -yl amino]- N-methyl-N-(2-pyrrolidin-1 -yl- ethyl)-benzamide 2,4-dichloro-3-{5-methyl-3-[4- (2-pyrrolidin-1 -yl-ethoxy)- phenylamino]- benzo[ 1,2,4]triazin-7-yl} -phenol 1.6 1.1 4-chloro-2-fluoro-3-{5-methyl- 1.0 3-[4-(3-pyrrolidin-l -yl-propane-1 -sulfonyl)-phenylamino]-benzo[l ,2,4]triazin-7~yl} -phenol 4-[7-(2,6-difluoro-3-hydroxy- phenyl)-5-methyl- benzo[l ,2,4]triazin-3-ylamino]- N-(2-pyrrolidin-1 -yl -ethyl)- benzenesulfonamide 3.1 2,4-dichloro-3-{5~methyl-3-[4- (piperidine-4-sulfonyl)- phenylamino]- benzo[l ,2,4]triazin-7-yl}-phenol 2.4 i Acetic acid 4-chloro-3-{5- methyl-3-[4-(2-pyrrolidin-l~yl- ethoxy)-phenylamino]- benzo[ 1,2,4]triazin-7-yl} -phenyl ester 4-[7-(5-hydroxy-2-methyl-phenyl)-5-methyl-benzo[l,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonamide 53.2 0.955 Benzoic acid 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-l -yl-ethylsulfamoyl)-phenylamino]-benzof 1,2,4]triazin-7~yl} -phenyl ester 79.2 Benzoic acid 4-chloro-3-{5-methyl-3'[4-(2-pyiTolidin-l-yl-ethoxy)-phenylamino]-benzo[l ,2,4]triazin-7-yl} -phenyl ester >10000 2,4-dichloro-3-{5-methyI-3-[4- 2.1 ~~y (3-pyrrolidin-l-yl-propane-l-sulfonyl)-phenyl amino]-benzo[l ,2,4]triazin-7-yl}-phen,ol 2,4-difluoro-3- (5-methyl-3-[4-(3-pyrrolidin- 1 -yl -propane- 1 -sulfonyl)-phenylamino]-benzo[l,2,4]triazin-7-yl} -phenol 3.8 4-[7-(6-chloro-2-fluoro-3-hydroxy-phenyl)-5 -methyl-benzo[l ,2,4]triazin-3-ylammo]-N-methyl-N-(2-pyrrolidin- 1 -yl-ethyl)-benzenesulfonamide 1.2 4-[7-(6-chloro-2 -fluoro-3 -hydroxy-phenyl)-5-methyl-benzofl ,2,4]triazrn-3-ylamino]-N-methyl-N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide 0.542 [7-(2,6-dichloro-phenyl)-5-methyl-1-oxy- benzo[l,2,4]triaziii-3-yl]-[4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl]-amine 90.3 Acetic acid 4-chloro-3-{5-methyl-3-[3-(2-pyrrolidin-l-yl-ethoxy)-phenylamino]-benzofl ,2,4}triazin-7-yl} -phenyl ester 133 4-methyl-benzoic acid 4-chloro- 267 3- {5-methyl-3-[4-(2-pyrrolidin-1 -yl-ethoxy)-phenylamino]-benzofl ,2,4]triazin-7-yl} -phenyl ester 2,2-dimethyl-propionic acid 4- > 10000 chloro-3- {5-methyI-3-[4-(2- pyrrolidin-1 -yl-ethoxy)- phenylamino]- ben/of 1,2,4]triazin-7~yl} -phenyl ester Isobutyric acid 4-chloro-3- {5- 10000 methyl-3-[4-(2-pyrrolidin-l -yl-ethoxy)~phenylamino]-benzo[l,2,4]triazin-7-yl} -phenyl ester 4-[7-(2,6-dichloro-3-hydroxy- phenylV5-meth!"- benzo[l,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin- 1 -yl~ ethyl)-benzenesulfonamide 3.6 Table 2. Tests Results of Inhibition of Selected Kinases by Some Compounds of the Invention « All data represent ICso in nM. 4-(6-methyl-7-o-tolyl-benzo[l,2,4]triazin-3-ylamino)-N-(2-pyrrolidin-1 -yl-ethyl)-benzenesulfonami de 24.3 NH N-{7-(2,6~dimethyl-phenyl)-3-[4-(2-pyrrolidin- 3 -yl-ethoxy)-phenylamino]-benzofl ,2,4]triazin~5-yl}-acetamide {4-[7-(2-chloro-5- methoxy-phenyl)-6- methyl- benzof 1,2,4]triazin-3- ylaminoj-phenyl} -(4- methyl-piperazin-1 ~yl)- methanorie 11.5 3.5 N-{7-(2,6-dimethyl-phenyl)-3-[4-(2-pyrrolidin-1 -yl-ethoxy)-phenylamino]-benzo[ 1,2,4]triazm~5-yl) -methanesulfonamide 15.7 3-{6-methyl-3-[4-(2- pyrrolidin-1 -yl-ethoxy)-phenylamino]-benzo[ 1s2,4]triazin-7-yl} -phenol 7.4 4-chloro-3-[5-methyl-3-(pyri din-3 -ylamino)-benzof 1,2,4]triazin-7-yl]-phenol 23.5 r— ^ ' ' 4-[7-(4-fluoro-2-methyl-phenyl)-6-methyl-benzo[l ,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1 -yl-ethyl)-benzeriesulfonamide 73.7 N-{7-(2,6-dimethyl- phenyl)-3-[4-(2- pyrrolidin-1-yl- ethylsulfamoyl)- phenylamino]- benzof 1,2,4]triazin-5- yl}-acetamide 1850 0479] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims. We claim: 1. A compound of structure (I) for treatment of disorders related with compromised vasculostatis or vascular permeability leakage: (Figure Remove) wherein each of A is independently selected from a group consisting of (CH)o-t, N, NH, O, S, and a part of a ring fusion to form a second ring, where the second ring is an aromatic, a heteroaromatic, a bicyclic aromatic, a bicyclic aromatic heterocyclic ring, or a bicyclic with only the first ring being aromatic or heteroaromatic; each of B is independently selected from a group consisting of (CH)o-i, N, NH, O, S, and a part of a ring fusion to form a second ring, where the second ring is an aromatic, a heteroaromatic, a bicyclic aromatic, a bicyclic aromatic heterocyclic ring, or a bicyclic with only the first ring being aromatic or heteroaromatic; Ro is selected from a group consisting of H and lower alkyl; L is selected from a group consisting of a bond, and a substituted or unsubstituted alkyl, alkenyl, or alkynyl linking moiety; R! is selected from a group consisting of C(R')3, OR1, N(R')2, NR'C(O)R', NR'C(O)O(R'), NR'C(O)N(R')2, SR', C(O)(O)R', C(O), C(O)N(R')2, SO3R', OSO2R', SO2R', SOR, S(O)N(R')2, OS(O)(O)N(R')2, S(O)(O)N(R')2, S(O)N(R')2, PO4R', OPO2R', PO3R', PO2R', and a 3-6 membered heterocycle with one or more heterocyclic atoms with each heteroatom independently being capable of carrying any R' group on it, wherein R is selected from a group consisting of hydrogen, lower alkyl, alkyl-hydroxyl, thiol-alkyl, alkyl-thiol, aminoalkyl, alkylamino, branched alkyl, branched alkyl hydroxyl, branched thio-alkyl, branched alkyl-thiol, branched aminoalkyl, brnached alkylamino, and a closed 3-6 membered (Figure Remove) carbocycle or heterocycle, with each heteroatom in the 3-6 membered heterocycle being capable of carrying any R' group on it, and wherein each R' is independent in case there is more than one R'; R2 is a substitutent situated at position 5,6 or 8 of the ring, wherein R2is selected from a group consisting of methyl, ethyl, «-propyl, wo-propyl, n-buty\, iso-butyl, tert-butyl, wo-pentyl, phenyl, substituted phenyl, halogen, branched or unbranched alkylamino, branched or unbranched aminoalkyl, branched or unbranched alkyloxo, branched or unbranched oxyalkyl, branched or unbranched thioalkyl, branched or unbranched alkylthiol, CF3, sulfonamido, substituted sulfonamido, sulfonate, sulfonate ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carboxo, amido, ureido, substituted carboxo, substituted amido, substituted ureido, or a 3-6 membered carbocycle or heterocycle attached to positions 5, 6 or 8 directly or through group L, each heteroatom independently being capable of carrying any group R2, with the further proviso that either one, two or three substituents R2 are present in the ring, each of the substituents R2 being the same or different; R3 selected from a group consisting of hydrogen, alkyl, alkoxy, halogen, CF3, cyano, substituted alkyl, or hydroxyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, C(R")3, OR", N(R")2, NR"C(O)R", NR"C(O)NR", R", C (0)(0)R", OC(0)R", C(0)N(R")2, C(O), OC(O)N(R")2, SO3R", OSO2R", S02R", SOR", PO4R", OPO2R", PO3R", PO2R", wherein R" is hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, lower alkyl, branched lower alkyl, alkyl-hydroxyl, branched alkyl-hydroxyl, amino-alkyl, branched amino-alkyl, alkylamino, branched alkyl-amino, thiol-alkyl, branched thiol-alkyl, alkyl-thiol, branched thiol-alkyl, or may form a closed 3-6 membered heterocycle with one or more heterocyclic atoms, branched alkyl, branched alkyl hydroxyl, where each R" is independent in case there is more than one R"; n is an integer having the value between 1 and 5, with the further proviso that if n > 2, then each group R3 is independent of the other groups R3, with the further proviso that if each A is (CH)o, L is a bond, with the further proviso that if each B is (CH)o, Rs is any substitutent described above other than hydrogen and is bonded directly to the position 7 of the adjacent ring; and pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individuals diastereoners thereof. 2. The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) . The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) and The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) 8. The compound as claimed in claim 1 selected from the group consisting of: (Lxxxviii) (Figure Remove) 9. The compound as claimed in claim 1 having the formula: The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) 11. The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) 12. The compound as claimed in claim 1 having the formula: 13. The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) 14. The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) and 15. The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) 16. The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) 17. The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) 18. The compound as claimed in claim 1 selected from the group consisting of: and 19. (CXCH) The compound as claimed in claim 1 selected from the group consisting of: (Figure Remove) The compound as claimed in claim 1 selected from the group consisting of: 21. (Figure Remove) 22. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier therefore. 23. An article of manufacture comprising packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material comprises a label which indicates that the pharmaceutical composition can be used for treatment of disorders associated with compromised vasculostasis, and wherein the pharmaceutical composition comprises at least one compound of claim 1. 24. An article of manufacture comprising packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material comprises a label which indicates that the pharmaceutical composition can be used for treatment of disorders associated with vascular permeability leakage or compromised vasculostasis selected from myocardial infarction, stroke, congestive heart failure, an ischemia or reperfusion injury, cancer, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, autoimmune disease, vascular leakage syndrome, inflammatory disease, edema, transplant rejection, burn, or acute or adult respiratory distress syndrome (ARDS), and wherein the pharmaceutical composition comprises at least one compound of claim 1. 25. The article of manufacture of claim 23, wherein the disorder is cancer. 26. A process for making a pharmaceutical composition comprising combining a combination of at least one compound of claim 1 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, and a pharmaceutically acceptable carrier. 26. A compound of structure (I), substantially as hereinbefore described with reference to the foregoing examples. 27. A pharmaceutical composition, substantially as hereinbefore described with reference to the foregoing examples. 28. An article of manufacture comprising packaging material and a pharmaceutical composition, substantially as hereinbefore described with reference to the foregoing examples. 29. A process for making a pharmaceutical composition, substantially as hereinbefore described with reference to the foregoing examples. |
|---|
| Patent Number | 270674 | |||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Indian Patent Application Number | 6617/DELNP/2006 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| PG Journal Number | 02/2016 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Publication Date | 08-Jan-2016 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Grant Date | 08-Jan-2016 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Date of Filing | 08-Nov-2006 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Name of Patentee | TARGEGEN, INC | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Applicant Address | 55 CORPORATE DRIVE, BRIDGEWATER, NEW JERSEY 08807, UNITED STATES OF AMERICA | |||||||||||||||||||||||||||||||||||||||||||||||||||
Inventors:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
| PCT International Classification Number | C07D253/00; C07D253/00 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| PCT International Application Number | PCT/US2005/012057 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| PCT International Filing date | 2005-04-07 | |||||||||||||||||||||||||||||||||||||||||||||||||||
PCT Conventions:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||