0001 This application claims priority from copending provisional application Serial No. 60/428,862 filed on Nov. 25, 2002 the entire disclosure of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION 0002 This invention relates to compounds that inhibit the activity of protein kinases. Protein kinases are enzymes that catalyze the transfer of a phosphate group from ATP to an amino acid residue, such as tyrosine, serine, threonine, or histidine on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. Specific protein kinases have been implicated in diverse conditions including cancer Blume-Jensen, P., Nature, 411, 355 (2001)) Traxler, P. M., Exp. Opin. Ther. Patents, 8,1599 (1998); Bridges, A. J., Emerging Drugs, 3, 279 (1998); restenosis Mattsson, E., Trends Cardiovascular Medicine 5, 200 (1995); atherosclerosis Raines, E. W., Bioessays, 18, 271 (1996); angiogenesis Shawver, L. K., Drug Discovery Today, 2, 50 (1997); Folkman, J., Nature Medicine, 1, 27 (1995) stroke Paul, R., Nature Medicine 7, 222 (2001); and osteoporosis Boyce, J. Clin. Invest., 90, 1622 (1992). 0003 Tyrosine kinases (TK) are a class of protein kinases. The major family of cytoplasmic protein TKs is the Src family which consists of at least eight members (Src, Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk) that participate in a variety of signaling pathways Schwartzberg, P. L., Oncogene, 17, 1463 (1998). The prototypical member of this tyrosine kinase family is Src, which is involved in proliferation and migration responses in many cell types Sawyer, T., Expert Opin. Investig. Drugs, 10, 1327 (2001). Src activity has been shown to be elevated in breast, colon (90%), pancreatic (>90%) and liver (>90%) tumors. Greatly increased Src activity is also associated with metastasis (>90%) and poor prognosis. Antisense Src message impedes growth of colon tumor cells in nude mice Staley, C. A., Cell Growth Differentiation, 8, 269 (1997), suggesting that Src inhibitors could slow tumor growth. In addition to its role in cell proliferation, Src also acts in stress response pathways, including the hypoxia response. Nude mice studies with colon tumor cells expressing antisense Src message have reduced vascularization Ellis, L. M., J. Biol. Chem., 273, 1052 (1998), which suggests that Src inhibitors could be anti-angiogenic as well as anti-proliferative. 0004 Src disrupts E-cadherin associated cell-cell interactions E. Avezienyte, Nature Cell Bio., 4, 632 (2002). A low molecular weight Src inhibitor prevents this disruption thereby reducing cancer cell metastasis Nam, J. S., Clinical Cancer Res., 8, 2340 (2002). 0005 Src inhibitors may prevent the secondary injury that results from a VEGF-mediated increase in vascular permeability such as that seen following stroke Eliceiri, B. P., Mol. Cell., 4, 915 (1999); Paul, R., Nat. Med. 7, 222 (2001). 0006 Src also plays a role in osteoporosis. Mice genetically engineered to be deficient in Src production were found to exhibit osteopetrosis, the failure to resorb bone Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J. Clin., Invest., 90, 1622 (1992). This defect was characterized by a lack of osteoclast activity. Since osteoclasts normally express high levels of Src, inhibition of Src kinase activity may be useful in the treatment of osteoporosis Missbach, M., Bone, 24, 437 (1999). 0007 Inhibitors of the NMDA (N-methyl-D-asparte) receptor could provide treatment of chronic neuropathic pain Urban, L. Drug Dev. Res., 54, 159 (2002). The activity of NMDA receptors is regulated by Src family kinases (SFKs) (Yu, X. M., Proc. Nat. Acad. Sci., U.S.A., 96, 7697 (1999) and a low molecular weight SFK inhibitor, PP2, decreases phosphorylation of the NMDA receptor NR2 subunit Guo, W. J. Neuro., 22(14), 6208 (2002). SFK inhibitors therefore have potential in the treatment of neuropathic pain. 0008 Tyrosine kinases (TKs) are divided into two classes: the non-transmembrane TKs and transmembrane growth factor receptor TKs (RTKs) Blume-Jensen, P., Nature, 411, 355 (2001). Growth factors, such as epidermal growth factor (EGF), bind to the extracellular domain of their partner RTK on the cell surface which activates the RTK, initiating a signal transduction cascade that controls a wide variety of cellular responses including proliferation and migration. The overexpression of EGF and also of members of the epidermal growth factor receptor (EGFr) family, which includes EGF-r, erbB-2, erbB-3 and erbB-4, is implicated in the development and progression of cancer Rusch, V., Cytokine Growth Factor Rev., 7, 133 (1996), Davies, D. E., Biochem. Pharmacol., 51, 1101 (1996) and Modjtahedi, E., Int. J. Oncol., 4, 277 (1994). Specifically, over expression of the receptor kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers Slamon, D. J., Science, 244, 707 (1989) and Slamon, D. J., Science, 235, 177 (1987). Upregulation of EGFr kinase activity has been associated with epidermoid tumors Reiss, M., Cancer Res., 51, 6254 (1991); breast tumors Macias, A., Anticancer Res., 7, 459 (1987); and tumors involving other major organs Gullick, W. J., Brit. Med. Bull., 47, 87 (1991). 0009 It is also known that deregulation of EGF receptors is a factor in the growth of epithelial cysts in the disease described as polycystic kidney disease Du, J., Amer. J. Physiol., 269 (2 Pt 1), 487 (1995); Nauta, J., Pediatric Res., 37(6), 755 (1995); Gattone, V. H., Developmental Biology, 169(2), 504 (1995); Wilson, P. D., Eur. J. Cell Biol., 61(1), 131, (1993). The compounds of this invention, which inhibit the catalytic function of the EGF receptors, are consequently useful for the treatment of this disease. 0010 In addition to EGFr, there are several other RTKs including FGFr, the receptor for fibroblast growth factor (FGF); flk-1, also known as KDR, and fit-1, the receptors for vascular endothelial growth factor (VEGF); and PDGFr, the receptor for platelet derived growth factor (PDGF). The formation of new blood vessels, a process known as angiogenesis, is essential for tumor growth. Two natural angiogenesis inhibitors, angiostatin and endostatin, dramatically inhibited the growth of a variety of solid tumors. O'Reilly, M. S., Cell, 79, 315 (1994); O'Reilly, M. S., Nature Medicine, 2, 689 (1996); O'Reilly, M. S., Cell, 88, 277 (1997). Since FGF and VEGF are known to stimulate angiogenesis, inhibition of the kinase activity of their receptors should block the angiogenic effects of these growth factors. In addition, the receptor tyrosine kinases tie-1 and tie-2 also play a key role in angiogenesis Sato, T. N., Nature, 376, 70 (1995). Compounds of the invention that inhibit the kinase activity of FGFr, flk-1, fit-1, tie-1 or tie-2 may inhibit tumor growth by their effect on angiogenesis. 0011 PDGF is a potent growth factor and chemoattractant for smooth muscle cells (SMCs). The renarrowing of coronary arteries following angioplasty is due in part to the enhanced proliferation of SMCs in response to increased levels of PDGF. Therefore, compounds that inhibit the kinase activity of PDGFr may be useful in the treatment of restenosis. In addition, since PDGF and PDGFr are overexpressed in several types of human gliomas, small molecules capable of suppressing PDGFr activity, have potential utility as anticancer therapeutics Nister, M., J. Biol. Chem. 266,16755 (1991); Strawn, L. M., J. Biol. Chem. 269, 21215 (1994). 0012 Other RTKs that could potentially be inhibited by compounds of this invention include colony stimulating factor receptor, the nerve growth factor receptors (trkA, trkB and trkC), the insulin receptor, the insulin-like growth factor receptor, the hepatocyte growth factor receptor and the erythropoietin-producing hepatic cell receptor (EPH). 0013 In addition to the RTKs there is another family of TKs termed the cytoplasmic protein or non-receptor TKs. The cytoplasmic protein TKs have intrinsic kinase activity, are present in the cytoplasm and nucleus, and participate in diverse signaling pathways. There are a large number of non-receptor TKs including Abl, Jak, Fak, Syk, Zap-70 and Csk. Inhibitors of Abl kinase are useful for the treatment of chronic myeloid leukemia as evidenced by STI-571, marketed as Gleevec Kantarjian, H., N. Engl. J. Med., 346 (9), 645 (2110). 0014 Two members of the cytoplasmic protein TKs, Ick and ZAP-70 are predominately expressed on T-cells and natural killer (NK) cells. Inhibitors of these kinases can suppress the immune system and therefore have possible therapeutic potential to treat autoimmune diseases such as rheumatoid arthritis, sepsis, and transplant rejection Kamens, J. S., Current Opin. Investig. Drugs, 2, 1213 (2001); Myers, M., Current Pharm. Design, 3, 473 (1997). A low molecular weight Lck inhibitor is effective in preventing allograft rejection Waegell, W. Transplant. Proceed. 34.1411 (2002). 0015 Besides TKs, there are additional kinases including those that phosphorylate serine and/or threonine residues on proteins. A major pathway in the cellular signal transduction cascade is the mitogen-activated protein kinase (MAPK) pathway which consists of the MAP kinase kinases (MAPKK), including mek, and their substrates, the MAP kinases (MAPK), including erk Seger, R., FASEB, 9, 726 (1995). When activated by phosphorylation on two serine residues by upstream kinases, such as members of the raf family, mek catalyzes the phosphorylation of threonine and tyrosine residues on erk. The activated erk then phosphorylates and activates both transcription factors in the nucleus and other cellular targets. Over-expression and/or over-activation of mek or erk is associated with various human cancers Sivaraman, V. S., J. Clin. Invest., 99,1478 (1997). 0016 As mentioned above, members of the raf family of kinases phosphorylate serine residues on mek. There are three serine/threonine kinase members of the raf family known as a-raf, b-raf and c-raf. While mutations in the raf genes are rare in human cancers, c-raf is activated by the ras oncogene which is mutated in a wide number of human tumors. Therefore inhibition of the kinase activity of c-raf may provide a way to prevent ras mediated tumor growth Campbell, S. L., Oncogene, 17, 1395 (1998). 0017 The cyclin-dependent kinases (cdks), including cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E and cdk4/cyclin D, and others, are serine/threonine kinases that regulate mammalian cell division. Increased activity or activation of these kinases is associated with the development of human tumors Garrett, M. D., Current Opin. Genetics Devel., 9, 104 (1999); Webster, K. R., Exp. Opin. Invest. Drugs, 7, 865 (1998). Additional serine/threonine kinases include PDK1, SGK and the protein kinases A, B, and C, known as PKA or cyclic AMP-dependent protein kinase, PKB (Akt), and PKC, of which all three play key roles in signal transduction pathways responsible for oncogenesis Glazer, R. I., Current Pharm. Design, 4(3), 277 (1998). Compounds capable of inhibiting the kinase activity of mek, erk, raf, cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E, cdk4/cyclin D, PDK1, SGK, PKA, PKB (Akt) or PKC may be useful in the treatment of diseases characterized by abnormal cellular proliferation, such as cancer. 0018 The serine/threonine kinase UL97 is a virion-associated protein kinase which is required for the replication of human cytomegalovirus Wolf, D. G., Arch. Virology 143(6), 1223 (1998) and He, Z., J. Virology, 71, 405(1997). Compounds capable of inhibiting the kinase activity of UL97 may be useful antiviral therapeutics. Since certain bacteria require the action of a histidine kinase for proliferation Loomis, W. F., J. Cell Sci., 110, 1141 (1997), compounds capable of inhibiting such histidine kinase activity may be useful antibacterial agents. 0019 Thieno3,2-bpyridines, thieno2,3-bpyridines and certain pyridine and pyrimidine derivatives have been noted as kinase inhibitors. These compounds differ both in nature and placement of substituents at various positions when compared to the compounds of this invention.

SUMMARY OF THE INVENTION 0020 This invention relates to thieno3,2-bpyridine-6-carbonitrile and thieno2,3-bpyridine-5-carbonitrile compounds as well as their pharmaceutically acceptable salts of Formula Ia and Ib: 2

0021 wherein: 0022 X is NH, NR4, O, S(O)m, NHCH2; 0023 m is an integer of 0-2; 0024 n is an integer of 2-5; 0025 q is an integer of 0-5; 0026 R1 is a phenyl ring optionally substituted with one to four substituents selected from the group consisting of -J, NO2, CN, N3, CHO, CF3, OCF3, R4, OR4, S(O)mR4, N4R4, NR4S(O)mR4, OR6OR4, OR6NR4R4, N(R4)R6OR4, N(R4)R6NR4, R4, NR4C(O)R4, C(O)R4, C(O)OR4, C(O)NR4R4, OC(O)R4, OC(O)OR4, OC(O)NR4R4, NR4C(O)R4, NR4C(O)OR4, NR4C(O)NR4R4, R5OR4, R5NR4R4, R5S(O)mR4, R5C(O)R4, R5C(O)OR4, R5C(O)NR4R4, R5OC(O)R4, R5OC(O)OR4, R5OC(O)NR4R4, R5NR4C(O)R4, R5NR4C(O)OR4, R5NR4C(O)NR4R4, or YR7; 0027 R2 is H, R3, -J, C(O)XR3, CHO, wherein the R3 group may be substituted by one or more groups selected from C(O)XR8, CHO, C(O)Q, 1,3-dioxolane, R8, (C(R9)2)qXR8, (C(R9)2)qQ, X(C(R9)2)nXR8, X(C(R9)2)nQ, or X(C(R9)2)q R8; 0028 R3 is alkyl of 1 to 6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, trans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl; 0029 R4 is H, alkyl of 1-6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, a trans-alkenyl of 2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms; 0030 R5 is a divalent group comprising alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms; 0031 R6 is a divalent alkyl group of 2-6 carbon atoms; 0032 R7 is a cycloalkyl ring of 3-7 carbons, an aryl or heteroaryl ring, a aryl or heteroaryl fused to one to three aryl or heteroaryl rings, wherein any of the aryl, cycloalkyl, or heteroaryl rings may be optionally substituted with one to four substituents selected from the group consisting of H, -aryl, CH2-aryl, NH-aryl, O-aryl, S(O)m-aryl, -J, NO2, CN, N3, CHO, CF3, OCF3, R4, OR4, S(O)mR4, NR4R4, NR4S(O)mR4, OR6OR4, OR6NR4R4, N(R4)R6OR4, N(R4)R6NR4R4, NR4C(O)R4, C(O)R4, C(O)OR4, C(O)NR4R4, OC(O)R4, OC(O)OR4, OC(O)NR4R4, NR4C(O)R4, NR4C(O)OR4, NR4C(O)NR4R4, R5OR4, R5NR4R4, R5S(O)mR4, R5C(O)R4, R5C(O)OR4, R5C(O)NR4R4, R5C(O)R4, R5C(O)OR4, R5C(O)NR4R4, R5OC(O)R4, R5OC(O)OR4, R5OC(O)NR4R4, R5NR4C(O)R4, R5NR4C(O)OR4, or R5NR4C(O)NR4R4; 0033 R8 is H, alkyl of 1 to 6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, trans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl; 0034 R9 is R4 or F; 0035 Y is C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHSO2, SO2NH, C(OH)H, X(C(R9)2)q, (C(R9)2)q, (C(R9)2)qX, CC, cis- and trans- -CHCH and cycloalkyl of 3-10 carbon atoms; 0036 Q is NZZ wherein Z and Z may be the same or different and may be H, alkyl of 1 to 6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or heteroaryl, and 0037 Z and Z taken together with the nitrogen to which they are attached may form a heterocyclic ring which may have an additional heteroatom selected from nitrogen, oxygen, and sulfur, and may comprise morpholine, piperazine, piperidine, optionally substituted with R4 on a carbon or a nitrogen, or on nitrogen by a group (C(R9)2)nXR3, C(R9)2)nNZZ, or on carbon by a group (C(R9)2)qXR3, (C(R9)2)qNZZ, 0038 Z and Z taken together with the nitrogen to which they are attached may form a heterocyclic ring which may contain an additional heteroatom selected from nitrogen, oxygen and sulfur; 0039 Z and Z may be H, alkyl of 1 to 6 carbon atoms alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or heteroaryl; and 0040 J is fluoro, chloro, bromo, and iodo. 0041 This invention also relates to compounds of Formulas Ic, Id, I, and If: 3

0042 wherein: 0043 X is NH, NR4, O, S(O)m, NHCH2; 0044 m is an integer of 0-2; 0045 n is an integer of 2-5; 0046 q is an integer of 0-5; 0047 R1 is a phenyl ring optionally substituted with one to four substituents selected from the group consisting of -J, NO2, CN, N3, CHO, CF3, OCF3, R4, OR4, S(O)mR4, NR4R4, NR4S(O)mR4, OR6OR4, OR6NR4R4, N(R4)R6OR4, N(R4)R6NR4R4, NR4C(O)R4, C(O)R4, C(O)R4, C(O)NR4R4, OC(O)R4, OC(O)OR4, OC(O)NR4R4, NR4C(O)R4, NR4C(O)OR4, NR4C(O)NR4R4, R5OR4, R5NR4R4, R5S(O)mR4, R5O(O)R4, R5C(O)OR4, R5C(O)NR4R4, R5CC(O)R4, R5OC(N)OR4, R5OC(O)NR4R4, R5NR4C(O)R4, R5NR4C(O)OR4, R5NR4C(O)NR4R4, or YR7; 0048 R2 is H, R3, -J, C(O)XR3, CHO, wherein the R3 group may be substituted by one or more groups selected from C(N)XR8, CHO, C(O)Q, 1N, 3-dioxolane, R8, (C(R9)2)qXR8, X(C(R9)2)nQ, X(C(R9)2)NXR8, X(C(R9)2)HQ, or X(C(R9)2)q R8; 0049 R3 is alkyl of 1 to 6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, trans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl; 0050 R4 is H, alkyl of 1-6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, a trans-alkenyl of 2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms; 0051 R5 is a divalent group comprising alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms; 0052 R6 is a divalent alkyl group of 2-6 carbon atoms; 0053 R7 is a cycloalkyl ring of 3-7 carbons, an aryl or heteroaryl ring, a aryl or heteroaryl fused to one to three aryl or heteroaryl rings, wherein any of the aryl, cycloalkyl, or heteroaryl rings may be optionally substituted with one to four substituents selected from the group consisting of H, -aryl, CH2-aryl, NH-aryl, O-aryl, S(O)m-aryl, -J, NO2, CN, N3, CHO, CF3, OCF3, R4, OR4, S(O)mR4, NR4R4, NR4S(O)mR4, OR6OR4, OR6NR4R4, N(R4)R6OR4, N(R4)R6NR4R4, NR4C(O)R4, C(O)R4, C(O)OR4, C(O)NR4R4, OC(O)R4, OC(O)OR4, OC(O)NR4R4, NR4C(O)R4, NR4C(O)OR4, NR4C(O)NR4R4, R5OR4, R5NR4R4, R5S(O)mR4, R5C(O)R4, R5C(O)OR4, R5C(O)NR4R4, R5C(O)R4, R5C(O)OR4, R5C(O)NR4R4, R5OC(O)R4, R5OC(O)OR4, R5OC(O)NR4R4, R5NR4C(O)R4, R5NR4C(O)OR4, or R5NR4C(O)NR4R4; R8 is H, alkyl of 1 to 6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, trans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl; 0054 R9 is R4 or F; 0055 Y is C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHSO2, SO2NH, C(OH)H, X(C(R9)2)q, (C(R9)2)q, (C(R9)2)qX, CC, cis- and trans- -CHCH and cycloalkyl of 3-10 carbon atoms; 0056 Q is NZZ wherein Z and Z may be the same or different and may be H, alkyl of 1 to 6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or heteroaryl, and 0057 Z and Z taken together with the nitrogen to which they are attached may form a heterocyclic ring which may have an additional heteroatom selected from nitrogen, oxygen, and sulfur, and may comprise morpholine, piperazine, piperidine, optionally substituted with R4 on a carbon or a nitrogen, or on nitrogen by a group (C(R9)2)nXR3, C(R9)2)nNZZ, or on carbon by a group (C(R9)2)qXR3, (C(R9)2)qNZZ, 0058 Z and Z taken together with the nitrogen to which they are attached may form a heterocyclic ring which may contain an additional heteroatom selected from nitrogen, oxygen and sulfur; Z and Z may be H, alkyl of 1 to 6 carbon atoms alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or heteroaryl; and 0059 R may be for example a phenyl ring optionally substituted with one to four substituents selected from the group consisting of -J, CF3, OCF3, R4, OR4, and YR7; and R7 is an aryl or heteraryl ring, optionally substituted with one to four substituents selected from the group consisting of H, -J, CF3, OCF3, R4 and OR4. 0060 In particular R1 may be a phenyl ring optionally substituted with one to four substituents selected from the group consisting of Cl, R4 and OR4. 0061 An example of X is NH. 0062 R4 may be for example alkyl of 1-6 carbon atoms. 0063 An example of R2 is R3 where R3 is substituted aryl or heteroaryl, wherein the substituent on R3 may be one or more groups selected from (CR9)2)qQ; e.g., wherein q is 1 to 3 and/or wherein R9 is H. Q may be for example NZZ wherein Z and Z may be the same or different and may be H, alkyl of 1 to 6 carbon atoms; or Z and Z taken together with the nitrogen to which they are attached may for a heterocyclic ring which may have an additional heteroatom selected from nitrogen and oxygen, said ring may be substituted on nitrogen or carbon by R4 or on carbon by (CH2)2OH. 0064 In some embodiments an example of R2 is R3 where R3 is alkynyl of 2-6 carbon atoms, aryl or heteroaryl; which groups may be substituted by one or more groups selected from 0065 R8, (CH2)qOR8, (CH2)qNHR8, (CH2)qNR4R8, (CH2)qQ, 0066 O(CH2)nOR8, NH(CH2)nOR8, NR4(CH2)nOR8, 0067 O(CH2)nNHR8, NH(CH2)nNHR8, NR4(CH2)nNHR8 0068 O(CH2)nNR4R8, NH(CH2)nCR8, NR4(CH2)nNR4R8, 0069 O(CH2)nQ, NH(CH2)nQ, NR4(CH2)nQ, 0070 O(CH2)qR8, NH(CH2)qR8, or NR4(CH2)qR8; 0071 R4 is H, alkyl of 1-6 carbon atoms; 0072 R8 is H, alkyl of 1-6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, trans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl; 0073 Y is C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHSO2, S, O, NR4; 0074 Q is NZZ wherein Z and Z may be the same or different and are selected from H, alkyl of 1 to 6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or heteroaryl, and 0075 Z and Z taken together with the nitrogen to which they are attached may form a heterocyclic ring which may have an additional heteroatom selected from nitrogen, oxygen, and sulfur, and may comprise morpholine, piperazine, piperidine, optionally substituted with R4 on a carbon or a nitrogen, or on nitrogen by a group (CH2)nOR3, (CH2)nNHR3, (CH2)nNR4R3, (CH2)nNZZ, or on carbon by a group (CH2)qOR3, (CH2)qNHR3, (CH2)qNR4R3, (CH2)qNZZ; 0076 Z and Z may be the same or different and are selected from H, alkyl of 1 to 6 carbon atoms; 0077 Z and Z taken together with the nitrogen to which they are attached may form a heterocyclic ring which may contain an additional heteroatom selected from nitrogen, oxygen and sulfur; and 0078 J is fluoro, chloro, bromo, and iodo. 0079 Preferred compounds of the invention or a pharmaceutically acceptable salt thereof include: 0080 7-(2,4-Dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0081 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-phenylthieno3,2-bpyridine-6-carbonitrile; 0082 2-Bromo-7-(2,4-dichloro-5-methoxyphenyl)amino-thieno3,2-bpyridine-6-carbonitrile; 0083 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile; 0084 4-(2,4-Dichloro-5-methoxyphenyl)aminothieno2,3-bpyridine-5-carbonitrile; 0085 4-(3-Chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)thieno2,3-bpyridine-5-carbonitrile; 0086 4-(2,4-Dichloro-5-methoxyphenyl)amino-2-iodothieno2,3-bpyridine-5-carbonitrile; 0087 4-(2,4-Dichloro-5-methoxyphenyl)amino-2-methylthieno2,3-bpyridine-5-carbonitrile; 0088 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-methylthieno3,2-bpyridine-6-carbonitrile; 0089 7-(2,4-Dichlorophenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0090 7-(2,4-Dichlorophenoxy)thieno3,2-bpyridine-6-carbonitrile; 0091 7-(2,4-Dichlorophenyl)thiothieno3,2-bpyridine-6-carbonitrile; 0092 7-(2,4-Dichlorobenzyl) aminothieno3,2-bpyridine-6-carbonitrile; 0093 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0094 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-morpholinylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0095 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-methylpiperazin-1-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0096 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(4-4-(2-hydroxyethyl)Piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0097 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(piperidin-1-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0098 4-6-Cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2-ylbenzoic acid; 0099 4-6-Cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2-ylbenzamide; 0100 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(4-methoxyphenyl)ethynylthieno3,2-bpyridine-6-carbonitrile; 0101 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(pyridin-2-ylethynyl)thieno3,2-bpyridine-6-carbonitrile; 0102 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-3-(dimethylamino)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile; 0103 2-(1-Benzofuran-2-yl)-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0104 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(3-formylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0105 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-3-(morpholin-4-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0106 4-(2,4-Dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno2,3-bpyridine-5-carbonitrile; 0107 4-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(morpholin-4-ylmethyl)phenylthieno2,3-bpyridine-5-carbonitrile; 0108 4-5-Cyano-4-(3,4,5-trimethoxy-phenylamino)-thieno2,3-bpyridin-2-yl-butyric acid methyl ester; 0109 2-(4-Hydroxybutyl)-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile; 0110 2-4-(4-Morpholinyl)butyl-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile; 0111 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(trimethylsilyl)ethynylthieno3,2-bpyridine-6-carbonitrile; 0112 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-ethynylthieno3,2-bpyridine-6-carbonitrile; 0113 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(pyridin-4-ylethynyl)thieno3,2-bpyridine-6-carbonitrile; 0114 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(pyridin-3-ylethynyl)thieno3,2-bpyridine-6-carbonitrile; 0115 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-5-(1,3-dioxolan-2-yl)thien-3-ylthieno3,2-bpyridine-6-carbonitrile; 0116 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(5-formylthien-3-yl)thieno3,2-bpyridine-6-carbonitrile; 0117 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methylthien-3-ylthieno3,2-bpyridine-6-carbonitrile; 0118 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-5-(morpholin-4-ylmethyl)thien-3-ylthieno3,2-bpyridine-6-carbonitrile; 0119 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-hydroxypiperidin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0120 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(hydroxymethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0121 2-Iodo-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0122 2-(4-Formylphenyl)-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0123 2-4-(4-Methylpiperazin-1-ylmethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0124 2-4-(Morpholin-4-ylmethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0125 2-4-(Hydroxymethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0126 2-Iodo-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0127 2-Bromo-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0128 7-(4-Phenoxyphenyl)amino-2-(E)-2-pyridin-4-ylethenylthieno3,2-bpyridine-6-carbonitrile; 0129 tert-Butyl (2E)-3-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridin-2-ylprop-2-enoate; 0130 4-(2,4-Dichloro-5-methoxyphenyl)amino-2-3-(4-methylpiperazin-1-yl)prop-1-ynylthieno2,3-bpyridine-5-carbonitrile; 0131 4-(2,4-Dichloro-5-methoxyphenyl)amino-2-(pyridin-3-ylethynyl)thieno2,3-bpyridine-5-carbonitrile; 0132 (2E)-3-(6-Cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridin-2-yl)prop-2-enoate; 0133 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(2-formyl-1-methyl-1H-imidazol-5-yl)thieno3,2-bpyridine-6-carbonitrile; 0134 2-(4-Formylphenyl)-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0135 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(1E)-3-(4-methylpiperazin-1-yl)-3-oxoprop-1-enylthieno3,2-bpyridine-6-carbonitrile; 0136 2-3-(4-Methylpiperazin-1-yl)prop-1-ynyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0137 2-4-(4-Methylpiperazin-1-yl)methylphenyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0138 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-1-methyl-2-(4-methylpiperazin-1-yl)methyl-1H-imidazol-5-yl thieno3,2-bpyridine-6-carbonitrile; 0139 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-3-(4-methylpiperazin-1-yl)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile; 0140 2-4-(Dimethylamino)methylphenyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0141 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(dimethylamino)phenylthieno3,2-bpyridine-6-carbonitrile; 0142 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(diethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0143 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-ethylpiperazin-1-ylmethyl)phenylthieno 3,2-bpyridine-6-carbonitrile; 0144 7-(2-Chloro-5-methoxyphenyl)amino-2-4-(dimethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0145 7-(2-Chloro-5-methoxyphenyl)amino-2-4-(4-methylpiperazin-1-ylmethyl)phenylthieno 3,2-bpyridine-6-carbonitrile; 0146 2-4-(Dimethylamino)methylphenyl7-(5-methoxy-2-methylphenyl)amino-thieno3,2-bpyridine-6-carbonitrile; 0147 7-(5-Methoxy-2-methylphenyl)amino-2-4-(4-methylpiperazin-1-ylmethyl) phenylthieno 3,2-bpyridine-6-carbonitrile; 0148 7-(2,4-Dichlorophenyl)amino-2-4(dimethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0149 7-(2,4-Dichlorophenyl)amino-2-4-(4-methylpiperazin-1-ylmethyl) phenyl thieno 3,2-bpyridine-6-carbonitrile; 0150 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-6-(4-methylpiperazin-1-ylmethyl)pyridin-3-yl thieno 3,2-bpyridine-6-carbonitrile; 0151 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-6-(dimethylamino)methylpyridin-3-ylthieno3,2-bpyridine-6-carbonitrile; 0152 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-ylmethyl)furan-3-yl thieno 3,2-bpyridine-6-carbonitrile; 0153 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-5-(dimethylamino)methylfuran-3-ylthieno3,2-bpyridine-6-carbonitrile; 0154 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-methylpiperazin-1-ylmethyl)phenyl-1-oxo-1H-thieno 3,2-bpyridine-6-carbonitrile; 0155 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-methylpiperazin-1-ylmethyl)phenyl-1,1-dioxo-1H-thieno 3,2-bpyridine-6-carbonitrile; 0156 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(dimethylamino)methylphenyl-1-oxo-1H-thieno3,2-bpyridine-6-carbonitrile; 0157 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(dimethylamino)methylphenyl-1-dioxo-1H-thieno3,2-bpyridine-6-carbonitrile; 0158 2-4-(Dimethylamino)methylphenyl-1-oxo-7-(3,4,5-trimethoxyphenyl)amino-1H-thieno3,2-bpyridine-6-carbonitrile 0159 2-4-(Dimethylamino)methylphenyl-1,1-dioxo-7-(3,4,5-trimethoxyphenyl)amino-1H-thieno3,2-bpyridine-6-carbonitrile; 0160 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-iodothieno3,2-bpyridine-6-carbonitrile; 0161 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-4-(morpholin-4-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0162 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-4-(morpholin-4-ylbut-1-ynyl)thieno3,2-bpyridine-6-carbonitrile; 0163 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-3-(dimethylamino)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile; 0164 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0165 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-4-(4-methylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0166 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-3-(diethylamino)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile; 0167 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formyl-2-furyl)thieno3,2-bpyridine-6-carbonitrile; 0168 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(1,3-dioxolan-2-yl)-2-furylthieno3,2-bpyridine-6-carbonitrile; 0169 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methyl-2-furylthieno 3,2-bpyridine-6-carbonitrile; 0170 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-ethylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0171 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-pyrrolidin-1-ylpiperidin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0172 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-2-(dimethylamino)ethyl(methyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0173 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(dimethylamino)phenylthieno3,2-bpyridine-6-carbonitrile; 0174 7-(2,4-dichloro-5-methoxyphenyl)amino-2-3-(4-methylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0175 7-(2,4-dichloro-5-methoxyphenyl)amino-2-3-(dimethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0176 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-(dimethylamino)methyl-2-furylthieno3,2-bpyridine-6-carbonitrile; 0177 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(1,3-dioxolan-2-yl)thien-2-ylthieno3,2-bpyridine-6-carbonitrile; 0178 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(2-formylthien-3-yl)thieno3,2-bpyridine-6-carbonitrile; 0179 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formylthien-2-yl)thieno3,2-bpyridine-6-carbonitrile; 0180 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-(dimethylamino)methylthien-3-ylthieno3,2-bpyridine-6-carbonitrile; 0181 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methylthien-2-ylthieno3,2-bpyridine-6-carbonitrile; 0182 7-(2,4-dichloro-5-methoxyphenyl)amino-2-2-(4-methylpiperazin-1-yl)methylthien-3-ylthieno3,2-bpyridine-6-carbonitrile; 0183 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-3-(dimethylamino)propyl(methyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0184 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(6-(dimethylamino) methylpyridin-2-ylethynyl)thieno3,2-bpyridine-6-carbonitrile; 0185 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(dimethylamino) methylthien-2-ylthieno3,2-bpyridine-6-carbonitrile; 0186 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-(pyridin-4-ylmethyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0187 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1H-pyrrol-3-yl)thieno3,2-bpyridine-6-carbonitrile; 0188 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-(2-methoxyethyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0189 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(2-(methylthio)ethylaminomethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0190 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(thiomorpholin-4-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0191 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(piperazin-1-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile; 0192 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-morpholin-4-ylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0193 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0194 7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-4-(diethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0195 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-(dimethylamino)methylpyridin-2-ylethynyl)thieno3,2-bpyridine-6-carbonitrile; 0196 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1H-pyrazol-4-ylethynyl)thieno3,2-bpyridine-6-carbonitrile; 0197 7-(2,4-dichlorophenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile; 0198 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methylpyridin-2-ylthieno3,2-bpyridine-6-carbonitrile; 0199 2-4-(butylamino)methylphenyl-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile; 0200 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(1-oxidothiomorpholin-4-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0201 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(diethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0202 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-(3-hydroxypropyl)aminomethylphenylthieno3,2-bpyridine-6-carbonitrile; 0203 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(morpholin-4-ylmethyl)pyridin-2-Ithieno3,2-bpyridine-6-carbonitrile; 0204 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(6-morpholin-4-ylpyridin-3-yl)thieno3,2-bpyridine-6-carbonitrile; 0205 7-(2,4-dichloro-5-ethoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile; 0206 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(1-dioxidothiomorpholin-4-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0207 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-pyridin-2-ylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0208 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-phenylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0209 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4(2R,5S)-2,5-dimethylpiperazin-1-Imethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0210 7-(2,4-dichlorphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0211 7-(2,4-dichloro-5-ethoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0212 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-methylpiperazin-1-yl)carbonylphenylthieno3,2-bpyridine-6-carbonitrile; 0213 7-(2,4-dichlorophenyl)amino-2-4-(4-methylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0214 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-4-(2-methoxyphenyl)Piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0215 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-(3-methyl butyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0216 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-4-(methylsulfonyl)Piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0217 7-(2,4-dichloro-5-ethoxyphenyl)amino-2-4-(4-methylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile; 0218 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-4-(pyridin-2-ylmethyl)Piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile; 0219 7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-2-(dimethylamino)ethyl-1H-pyrrol-3-ylthieno3,2-bpyridine-6-carbonitrile; 0220 7-(2,4-dichlorophenyl)amino-2-4-(dimethylamino)phenylthieno3,2-bpyridine-6-carbonitrile; 0221 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1-methyl-1H-imidazol-5-yl)ethynylthieno3,2-bpyridine-6-carbonitrile; 0222 7-(2,4-dichloro-5-methoxyphenyl)amino-2-6-(dimethylamino)methylpyridin-2-ylthieno3,2-bpyridine-6-carbonitrile; 0223 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1H-pyrazol-4-yl)thieno3,2-bpyridine-6-carbonitrile; 0224 7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-(2-hydroxyethyl)-1H-pyrazol-4-ylethynylthieno3,2-bpyridine-6-carbonitrile; 0225 7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-ylthieno3,2-bpyridine-6-carbonitrile; 0226 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(dimethylamino)methylpyridin-2-ylthieno3,2-bpyridine-6-carbonitrile; 0227 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(diethylamino)methylpyridin-2-ylthieno3,2-bpyridine-6-carbonitrile; 0228 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-2-(dimethylamino)ethylphenylthieno3,2-bpyridine-6-carbonitrile; 0229 7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-(2-hydroxyethyl)-1H-pyrazol-4-ylthieno3,2-bpyridine-6-carbonitrile; 0230 4-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridin-2-yl-N,N-dimethylbenzamide; 0231 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methyl-3-furylthieno3,2-bpyridine-6-carbonitrile; and 0232 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formyl-3-furyl)thieno3,2-bpyridine-6-carbonitrile. 0233 For purposes of this invention a heteroaryl is an aromatic heterocyclic ring system of one to three fused rings. The heteroaryl moieties are five or six membered rings containing 1 to 4 heteroatoms selected from the group consisting of S, N, and O; e.g. heteroaryl may have 5 to 14 ring members. One ring of the ring system may be fully unsaturated, partially saturated, or fully saturated. The heteroaryl moieties include, but are not limited to, thiophene, furan, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiazole, oxazole, isothiazole, isoxazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,3,5-triazine, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperidine, piperazine, pyrrolidine, aziridine, oxirane, tetrahydrothiophene, tetrahydrofuran, 1,2-pyran, 1,4-pyran, dioxane, 1,3-dioxolane, tetrahydropyran, naphthalene, 1,2,3,4-tetrahydronaphthalene, indan, indene, isoindene, indole, 2,3-dihydroindole, 2-indazole, isoindazole, quinoline, isoquinoline, tetrahydroquinoline, benzofuran, benzothiophene, benzimidazole, benzotriazole, benzothiazole, benzoxazole, benzisoxazole, 1,2-benzopyran, cinnoline, phthalazine, quinazoline, 1,8-naphthyridine, pyrido3,2-bpyridine, pyrido3,4-bpyridine, pyrido4,3-bpyridine, pyrido2,3-dpyrimidine, purine, and pteridine. The heteroaryl may be oxidized on a nitrogen atom to provide the corresponding N-oxide, such as pyridine-N-oxide or quinoline N-oxide. The heteroaryl may also be oxidized on a tri-substitued nitrogen atom to provide the corresponding N-oxide, such as N-ethylpiperazine-N-oxide. In another embodiment the heteroaryl may contain a carbonyl group on one of the carbon atoms, such as pyrrolidinone, 1,3,4-oxadiazol-2-one, or 2-indanone. 0234 For purposes of this invention alkyl includes both straight and branched alkyl moieties, preferably of of 1-6 carbon atoms and includes iso-propyl, n-butyl and the like. 0235 For purposes of this invention the term cycloalkyl refers to alicyclic hydrocarbon groups of 3-7 carbon atoms and includes a simple carbocycle as well as a carbocycle containing an alkyl substituent, for example, cyclopropyl, cyclohexyl, adamantyl and the like. 0236 For purposes of this invention the term aryl is defined as an aromatic hydrocarbon moiety and may be substituted or unsubstituted and may contain for example 6-14 carbon atoms and have one to three rings. An aryl may be selected from but not limited to, the group: phenyl or biphenyl and may be optionally mono-, di-, tri- or tetra-substituted with substituents selected from, but not limited to, the group consisting of alkyl, acyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, cyano, halogen, hydroxy, or nitro. 0237 For purposes of this invention alkenyl is defined as a radical aliphatic hydrocarbon that contains at least one carbon-carbon double bond and includes both straight and branched carbon chains of 2-6 carbon atoms in all possible configurational isomers, for example cis and trans, and includes ethenyl, 3-hexen-1-yl and the like. 0238 For purposes of this invention alkynyl includes both straight or branched carbon chain of 2-6 carbon atoms that contains at least one carbon-carbon triple bond and includes propenyl and the like. 0239 In one embodiment of this invention the alkyl, alkenyl and alkynyl groups can be substituted with such substituents as phenyl, substituted phenyl, hydroxy, halogen, alkoxy, thioalkyl, carboxy, alkoxycarbonyl and acyl. 0240 For purposes of this invention alkoxy comprises a group of 1-6 carbon atoms having an alkyl group attached to an oxygen atom and includes methoxy, t-butoxy and also includes polyethers such as O(CH2)2OCH3. A thioalkyl group of 1-6 carbon atoms is defined as an alkyl group attached to a sulfur atom and includes methylthio and the like. A carboxy group is defined as C(O)OH, and an alkoxycarbonyl group is defined as C(O)OR where R is a group of 1-6 carbon atoms and includes methoxycarbonyl, allyloxycarbonyl and the like. An acyl group is defined as a group C(O)R where R is an aliphatic (e.g., alkyl) or aryl radical and includes acetyl, trifluoroacetyl, benzoyl and the like. 0241 The compounds of this invention may include a divalent group defined herein as a linking group, for example, CH2CH2. 0242 The compounds of this invention may contain one or more asymmetric carbon atoms and may thus give rise to stereoisomers, such as enantiomers and diastereomers. While shown without respect to stereochemistry in Formulas (Ia)-(If), the present invention includes all the individual possible stereoisomers; as well as the racemic mixtures and other mixtures of R and S stereoisomers (scalemic mixtures which are mixtures of unequal amounts of enantiomers) and pharmaceutically acceptable salts thereof. It should be noted that stereoisomers of the invention having the same relative configuration at a chiral center may nevertheless have different R and 5 designations depending on the substitution at the indicated chiral center. Some of the compounds of this invention may contain one or more double bonds; in such cases, the compounds of this invention include each of the possible configurational isomers as well as mixtures of these isomers. 0243 Pharmaceutically acceptable salts of the compounds of Formulas (Ia)-(If) with an acidic moiety can be formed from organic and inorganic bases. For example alkali metal salts: sodium, lithium, or potassium and N-tetraalkylammonium salts such as N-tetrabutylammonium salts. Similarly, when a compound of this invention contains a basic moiety, salts can be formed from organic and inorganic acids. For example salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. 0244 This invention provides a process of producing a compound of Formula (Ia) and Formula (Ib) as defined herein or a pharmaceutically acceptable salt thereof, which comprises one of the following 0245 a) reacting a compound of formula: 4

0246 or an S-oxide or S-dioxide thereof; wherein R2 is as defined herein with a compound of formula R1XH where R1 and X are as defined herein to give a compound of formula I(a) or (Ib); or 0247 b) reacting a compound of formula 1a or 1b or an S-oxide or S-dioxide thereof in which R2 is a reactive substituent group to give a compound of formula Ia or Ib in which R2 is a different substituent group as defined herein; or 0248 c) converting a compound of formula (Ia) or (Ib) to a pharmaceutically acceptable salt thereof. 0249 This invention also provides a process of producing a compound of Formula (Ia) and Formula (Ib), 5

0250 wherein R2 is iodine, comprising: 0251 a. treating with a base, in an inert solvent at reduced temperature a compound of Formula (a) or (a); 6

0252 b. adding iodine to the compound in step (a) to form a compound of Formula (b) or (b); and 7

0253 c. adding a compound of formula R1XH to the compound in step (b) to form a compound of Formula (Ia) or (lb), wherein R2 is iodine. 0254 This invention includes a compound of Formula (b) or (b) 8

0255 This invention also provides a process of producing a compound of Formula (Ia) or (lb) 9

0256 wherein R2 is bromine, comprising: 0257 a. treating with a base, in an inert solvent at reduced temperature a compound of Formula (a) or (a); 10

0258 b. adding bromine or 1,1-dibromo-1,1,2,2-tetrafluoroethane to the compound in step (a) to form a compound of Formula (z) or (z); and 11

0259 c. adding a compound of formula R1XH to the compound in step (b) to form a compound of Formula (Ia) or (Ib), wherein R2 is bromine. 0260 This invention includes a compound of Formula (z) or (z) 12

0261 The above-identified processes are explained in greater detail under the Detailed Description of the Invention. 0262 In a preferred embodiment of this invention an inert solvent is a compound that does not react chemically with the compounds of this invention. A preferred inert solvent includes for example tetrahydrofuran (THF). 0263 For purposes of this invention a reduced temperature is a temperature 0 C. In a preferred embodiment this temperature is 78 to 0 C. 0264 For purposes of this invention an elevated temperature is a temperature of about 50 C. to about 150 C. 0265 In another embodiment, the present invention provides a method for the treatment or inhibition of a pathological condition or disorder in a mammal. The present invention accordingly provides to a mammal, a pharmaceutical composition that comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. The compound of this invention may be provided alone or in combination with other therapeutically effective compounds or therapies for the treatment or prevention of a pathological condition or disorder in a mammal. 0266 The compounds are preferably provided orally or subcutaneously. The compounds may be provided by intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; liposome-mediated delivery; topical; nasal; anal; vaginal; sublingual; uretheral; transdermal; intrathecal; ocular; or otic delivery. In order to obtain consistency in providing the compound of this invention it is preferred that a compound of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 5 g/kg or preferably at a dose range of 0.1 to 1 g/kg. Such compounds may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day. The effective amount will be known to one of skill in the art; it will also be dependent upon the form of the compound. One of skill in the art could routinely perform empirical activity tests to determine the bioactivity of the compound in bioassays and thus determine what dosage is the effective amount to administer. 0267 The compounds of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent, a color additive, or a carrier. The carrier may be for example a diluent, an aerosol, a topical carrier, an aqueous solution, a nonaqueous solution or a solid carrier. The carrier may be a polymer or a toothpaste. A carrier in this invention encompasses any of the standard pharmaceutically accepted carriers, such as phosphate buffered saline solution, acetate buffered saline solution, water, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules. 0268 When provided orally or topically, such compounds would be provided to a subject by delivery in different pharmaceutical carriers. Typically, such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, or glycols. The specific carrier would need to be selected based upon the desired method of delivery, for example, phosphate buffered saline (PBS) could be used for intravenous or systemic delivery and vegetable fats, creams, salves, ointments or gels may be used for topical delivery. 0269 The compounds of the present invention may be delivered together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions are liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (for example, Tris-HCl, acetate, phosphate), pH and ionic strength, additives such as albumins or gelatin to prevent absorption to surfaces, detergents (for example, TWEEN 20, TWEEN 80, PLURONIC F68, bile acid salts), solubilizing agents (for example, glycerol, polyethylene glycerol), anti-oxidants (for example ascorbic acid, sodium metabisulfate), preservatives (for example, thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (for example, lactose, mannitol), covalent attachment of polymers such as polyethylene glycol, complexation with metal ions, or incorporation of the compound into or onto particulate preparations of hydrogels or liposomes, micro-emulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance of the compound or composition. The choice of compositions will depend on the physical and chemical properties of the compound capable of treating or inhibiting a pathological condition or disorder. 0270 The compound of the present invention may be delivered locally via a capsule that allows a sustained release of the compound over a period of time. Controlled or sustained release compositions include formulation in lipophilic depots (for example, fatty acids, waxes, oils). 0271 For purposes of this invention a pathological condition or disorder is linked to kinase molecules and inhibition of the signals generated by these molecules. Generated signals regulate a number of cellular functions such as cell growth, differentiation and cell death. The signals generated by these molecules have been implicated in initiation of tissue level responses, discussed in detail in the Background of the Invention. The tissue level response triggers cellular damage or deregulated cellular growth. Deregulated cell growth occurs as a result of perturbed signals that moderate or alter cellular behaviour or function. One method of treating a pathological condition or disorder would be to intercept the generated signal before it reachs the tissue. As described in detail previously specific kinases are associated with cellular events that have been implicated in pathological conditions or disorders including, but not limited to, cancer, stroke, osteoporosis, polycystic kidney disease, autoimmune disease, rheumatoid arthritis, neuropathic pain, and transplant rejection. 0272 A pathological condition or disorder is mediated in a mammal when it is linked to kinase molecules as described above. For purpose of this invention a condition or disorder mediated in a mammal is one that effects or acts to alter the mammal's normal state. 0273 For purposes of this invention cancer is a cellular tumor. The natural course of the cancer is fatal. Metastasis develops as a result of adhesion of tumor cells to the vascular endothelium. As the tumor grows, cells are shed in the circulation and spawn an independent tumor nodule known as a metastasis. 0274 The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter.

DETAILED DESCRIPTION OF THE INVENTION 0275 The compounds of this invention were prepared according to the following schemes: (1) from commercially available starting materials or: (2) from known starting materials which can be prepared as described in literature procedures or: (3) from new intermediates described in the schemes and experimental procedures. Optically active isomers may be prepared, for example, by resolving racemic derivatives or by asymmetric synthesis. The resolution can be carried out by methods known to those skilled in the art such as in the presence of a resolving agent, by chromatography, or combinations thereof. 0276 Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps, protecting groups, if required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the art. Reactions are run under inert atmospheres where appropriate. 0277 The preparation of the compounds and intermediates of this invention encompassed by formulas Ia and Ib is described as follows. 0278 As shown in Scheme 1, decarboxylation of a 3-amino-2-thiophenecarboxylate of formula 1 with N-methylpiperazine in N-methylpyrrolidinone provides 3-aminothiophenes of formula 2. This decarboxylation can also be performed in a base such as aqueous sodium hydroxide at elevated temperatures. Addition of ethyl (ethoxymethylene) cyanoacetate to compounds of formula 2, in a solvent such as toluene, provides the intermediate propenoate. Thermal cyclization of these intermediate propionates in a solvent system such as biphenyl and diphenyl ether results in 7-oxo-4,7-dihydrothieno3,2-bpyridine-6-carbonitriles of formula 3. Compounds of formula 3 can also be prepared by the alternate route depicted in Scheme 1. Treatment of 3-amino-2-thiophenecarboxylates of formula 1 with the dimethylacetal of dimethylformamide provides amidines of formula 4. Addition of these amidines to the anion of acetonitrile, generated at low temperature, preferably 78 C. by the action of n-butyl lithium on acetonitrile, in a solvent such as tetrahydrofuran, provides 7-oxo-4,7-dihydrothieno3,2-bpyridine-6-carbonitriles of formula 3. 0279 Treatment of compounds of formula 3 with a chlorinating agent, preferably phosphorous oxychloride, provides compounds of formula 5. Addition of a compound of formula R1XH, where X is NH or NR4, to compounds of formula 5, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ia of the invention where X is NH or NR4. Alternatively addition of a compound of formula R1XH, where X is NH or NR4, to a compound of formula 5 in the presence of a palladium catalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, and potassium phosphate in a solvent such as ethylene glycol dimethyl ether at elevated temperatures of preferentially 90 C. provides compounds of formula Ia of the invention where X is NH or NR4. Addition of a compound of formula R1XH, where X is O, to compounds of formula 5, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ia of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 5, in a solvent such as dimethylformamide, provides compounds of formula Ia of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 5, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ia of the invention where X is NHCH2. Alternatively the ethyl ester group of 6, ethyl 7-chlorothieno3,2-bpyridine-6-carboxylate Thompson, M.; Forbes, I. F. EP 126970 is hydrolyzed to the corresponding 6-carboxylic acid 7 with aqueous sodium hydroxide in a cosolvent such as ethanol at elevated temperature. The corresponding 6-carboxamide analog 8 is prepared by treatment of 7 with a reagent such as thionyl chloride or alternatively N,N-carbonyldiimidazole and the like, followed by the addition of aqueous ammonium hydroxide or alternatively ammonia gas. Dehydration of 8 with a reagent such as cyanuric chloride provides the key intermediate 7-chlorothieno3,2-bpyridine-6-carbonitrile 5, where R2 is H. 13

0280 Compounds of formula Ia of the invention can also be prepared according to the routes depicted in Scheme 2. Ethyl 2-bromo-7-chlorothieno3,2-bpyridine-6-carboxylate, 9, Elliott, R.; O'Hanlon, P. J.; Rodgers, N. B. Tetrahedron, 43(14), 3295 (1987) is converted to the corresponding acid 10 by treatment with aqueous sodium hydroxide in a cosolvent such as ethanol at elevated temperatures of 60-70 C. The corresponding 6-carboxamide analog 11 is prepared by treatment of 10 with a reagent such as thionyl chloride or alternatively N,N-carbonyldiimidazole and the like, followed by the addition of aqueous ammonium hydroxide or alternatively ammonia gas. Treatment of 11 with a reagent such as phosphorous oxychloride provides the key intermediate 2-bromo-7-chlorothieno3,2-bpyridine-6-carbonitrile 12. Addition of a compound of formula R1XH, where X is NH or NR4, to compounds of formula 12, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ia of the invention where X is NH or NR4. Addition of a compound of formula R1XH, where X is 0, to compounds of formula 5, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ia of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 5, in a solvent such as dimethylformamide, provides compounds of formula Ia of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 5, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ia of the invention where X is NHCH2. 0281 Scheme 2 also depicts an alternate route for the preparation of the key intermediate 12. 0282 Treatment of thiophene 5 with a base, preferentially lithium diisopropylamine (LDA) but also including n-butyl lithium, t-butyl lithium or sodium hydride in an inert solvent, preferably tetrahydrofuran, but also including diethyl ether, in the optional presence of TMEDA (N,N, N,N-tetramethylethylenediamine), at reduced temperature, preferably at about 78 C., followed by the addition of 1,2-dibromo-1,1,2,2,-tetrafluoroethane or bromine, followed by warming to room temperature provides 12. 0283 Treatment of thiophene 5 with a base, preferentially lithium diisopropylamine (LDA) but also including n-butyl lithium, t-butyl lithium or sodium hydride in an inert solvent, preferably tetrahydrofuran, but also including diethyl ether, in the optional presence of TMEDA (N,N, N,N-tetramethylethylenediamine), at reduced temperature, preferably at about 78 C., followed by the addition of iodine, followed by warming to room temperature provides 13. 0284 Addition of a compound of formula R1XH where X is NH or NR4 to compound 13, optionally in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ia of the invention where R2 is 1. Addition of a compound of formula R1XH, where X is O, to compounds of formula 13, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ia of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 13, in a solvent such as dimethylformamide, provides compounds of formula Ia of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 13, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ia of the invention where X is NHCH2. 15

0285 Scheme 3 depicts the preparation of compounds of formula Ia of the invention with additional R2 groups. Treatment of thiophene 5 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of a compound of formula R2LG, where LG is a leaving group, preferably iodo, and R2 is preferably an alkyl group, provides compounds of formula 5, where R2 is alkyl. Addition of a compound of formula R1XH, where X is NH or NR4, to compounds of formula 5, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ia of the invention where X is NH or NR4. Alternatively addition of a compound of formula R1XH, where X is NH or NR4, to a compound of formula 5 in the presence of a palladium catalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, and potassium phosphate in a solvent such as ethylene glycol dimethyl ether at elevated temperatures of preferentially 90 C. provides compounds of formula Ia of the invention where X is NH or NR4. Addition of a compound of formula R1XH, where X is O, to compounds of formula 5, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ia of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 5, in a solvent such as dimethylformamide, provides compounds of formula Ia of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 5, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ia of the invention where X is NHCH2. Alternatively, treatment of thiophene 5 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of a formylating agent, preferably N,N-dimethylformamide (DMF) provides compounds of formula 5, where R2 is formyl. Reaction of the formyl group of 5 with a Wittig reagent, such as (tert-butoxycarbonylmethylene)-triphenylphosphorane in an inert solvent, preferably dichloromethane, provides ,-unsaturated esters of formula 14. Addition of a compound of formula R1XH where X is NH or NR4, to compounds of formula 14, preferentially under palladium catalyzed coupling conditions, including the use of tris(dibenzylideneacetone)-dipalladium(0) and (2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, in a solvent such as ethylene glycol dimethyl ether at elevated temperatures such as 90 C., provides compounds of formula Ia of the invention where R2 is an unsaturated ester. Compounds of formula Ia of the where R2 is an unsaturated ester can be converted into compounds of formula Ia of the invention where R2 is an unsaturated acid, by treatment with aqueous base in the presence of an optional cosolvent such as ethanol or methanol. Compounds of formula Ia of the invention where R2 is an ,-unsaturated amide can be obtained by treatment of compounds of formula Ia of the invention where R2 is an ,-unsaturated acid with an agent such as N,N-carbonyldiimidazole followed by the addition of an amine of formula QH. 17

0286 Additional compounds of the invention of formula Ia where R2 is an alkenyl, alkynyl, heteroaryl or aryl group can be prepared as depicted in Scheme 4 from compounds of formula Ia where R2 is either I or Br. Treatment of compounds of formula Ia where R2 is either I or Br with an alkenyl or alkynyl of formula R3H in the presence of a palladium catalyst provides compounds of formula Ia where R2 is either an alkenyl or alkynyl group. This alkenyl or alkynyl group can be substituted by groups including aryl and heteroaryl and also alkyl and alkylamino among others. 0287 For the addition of alkenyls of formula R3H the preferred palladium catalyst is palladium acetate in the presence of a ligand, preferably tri-o-tolylphosphine, in a solvent system that includes triethylamine or preferably a mixture of triethylamine and N,N-dimethylformamide. For the addition of alkynyls of formula R3H the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) along with a catalytic amount of copper(I)iodide in a solvent mixture that includes triethylamine and benzene. 0288 Treatment of compounds of formula Ia where R2 is either I or Br with an aryl or heteroaryl organoboron compound of formula R3BL1L2 in the presence of a palladium catalyst provides compounds of formula Ia where R2 is either an aryl or heteroaryl group. In compounds of formula R3BL1L2, the L1L2 groups represent ligands and include such groups as lower alkoxy or preferably hydroxy. The aryl or heteroaryl group of compound R3BL1L2 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3BL1L2 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3BL1L2 the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) in a solvent mixture that includes saturated aqueous sodium bicarbonate and ethylene glycol dimethyl ether. 0289 Compounds of formula Ia where R2 is either aryl or heteroaryl can also be prepared by reaction of a compound of formula Ia where R2 is either I or Br with an aryl or heteroaryl stannane compound of formula R3SnR3 in the presence of a palladium catalyst. In compounds of formula R3SnR3 the R group is a lower alkyl group such as butyl or methyl. The aryl or heteroaryl group of compound R3SnR3 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, acetal, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3SnR3 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3SnR3 the preferred palladium catalyst is bis(triphenylphosphine)Palladium (II) chloride in a solvent such as dioxane. 0290 Compounds of formula Ia where R2 is an alkynyl group can be prepared by the alternative route shown in Scheme 4. Treatment of a compound of formula Ia, where R2 is either Br or I with (trimethylsilyl)acetylene in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)Palladium(0), with a catalytic amount of copper(I) iodine in a solvent system such as triethylamine and benzene, provides compounds of formula Ia where R2 is a 2-(trimethylsilyl)ethynyl group. Reaction of compounds of formula Ia where R2 is a 2-(trimethylsilyl)ethynyl group with aryliodines or heteroaryliodines in the presence of a palladium catalyst, preferably bis(triphenylphosphine)Palladium(II)chloride, in the presence of triphenylphosphine, potassium carbonate and copper(I) iodide, in a solvent mixture of tetrahydrofuran and methanol, provides compounds of formula Ia where R2 is a 2-(aryl)ethynyl or a 2-(heteroaryl)ethynyl group. In addition the 2-(trimethylsilyl)ethynyl group can be cleaved by treatment with potassium carbonate in methanol to provide compounds of formula Ia where R2 is an ethynyl group. 18

0291 Some additional routes to the compounds of the invention of formula Ia are shown in Scheme 5. Compounds of formula Ia where the group R2 is R3CHO can be converted to compounds of formula Ia where the group R2 is R3CH2Q via reductive amination. Treatment of compounds of formula Ia where the group R2 is R3CHO with an amine of formula QH in the presence of a reducing agent, preferably sodium triacetoxyborohydride, in a solvent system that includes dichloromethane and N,N-dimethylformamide or NMP optionally in the presence of acetic acid, provides compounds of formula Ia where the group R2 is R3CH2Q. Compounds of formula Ia where the group R2 is R3CH2OH may be obtained as a by-product of this reaction, via reduction of the formyl group of compounds of formula Ia where the group R2 is R3CHO. 0292 Compounds of formula Ia where the group R2 is R3CHO can be prepared by hydrolysis of the acetal group of compounds of formula Ia where the group R2 is R3-acetal, preferably with aqueous hydrochloric acid in the presence of a cosolvent such as tetrahydrofuran. 0293 Scheme 5 also depicts the preparation of compounds of formula Ia where the group R2 is R3(C(R8)2)qCO2H, and R3(C(R8)2)qCOQ from compounds of formula Ia where the group R2 is R3(C(R8)2)qCO2R4. Compounds of formula Ia where the group R2 is R3(C(R8)2)qCO2R4 are converted to the corresponding acids of formula Ia where the group R2 is R3(C(R8)2)qCO2H by treatment with aqueous sodium hydroxide in a cosolvent such as ethanol at elevated temperatures. The corresponding amides of formula Ia where the group R2 is R3(C(R8)2)q-Q are prepared by treatment of the acid with N,N-carbonyldiimidazole or alternatively thionyl chloride or the like, followed by the addition of an amine of formula QH. 20

0294 Scheme 6 depicts preparation of compounds of the invention of formula Ib. Addition of a compound of formula R1XH, where X is NH or NR4, to compounds of formula 15, Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977) in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ib of the invention where X is NH or NR4. Alternatively addition of a compound of formula R1XH, where X is NH or NR4, to a compound of formula 15 in the presence of a palladium catalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, and potassium phosphate in a solvent such as ethylene glycol dimethyl ether at elevated temperatures of preferentially 90 C. provides compounds of formula Ib of the invention where X is NH or NR4. Addition of a compound of formula R1XH, where X is 0, to compounds of formula 15, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ib of the invention where X is 0. Addition of a compound of formula R1XH, where X is S, to compounds of formula 15, in a solvent such as dimethylformamide, provides compounds of formula Ib of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 15, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ib of the invention where X is NHCH2. 0295 Scheme 6 also depicts a route for the preparation of key intermediates of formula 16. Treatment of thiophene 15 with a base, preferentially lithium diisopropylamine (LDA) but also including n-butyl lithium, t-butyl lithium or sodium hydride in an inert solvent, preferably tetrahydrofuran, but also including diethyl ether, in the optional presence of TMEDA (N,N, N,N-tetramethylethylenediamine), at reduced temperature, preferably at about 78 C., followed by the addition of 1,2-dibromo-1,1,2,2,-tetrafluoroethane or bromine, followed by warming to room temperature provides 16. 0296 Treatment of thiophene 15 with a base, preferentially lithium diisopropylamine (LDA) but also including n-butyl lithium, t-butyl lithium or sodium hydride in an inert solvent, preferably tetrahydrofuran, but also including diethyl ether, in the optional presence of TMEDA (N,N, N,N-tetramethylethylenediamine), at reduced temperature, preferably at about 78 C., followed by the addition of iodine, followed by warming to room temperature provides 16. 0297 Addition of a compound of formula R1XH where X is NH or NR4, to compounds of formula 16, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ib of the invention where where X is NH or NR4. Addition of a compound of formula R1XH, where X is 0, to compounds of formula 16, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ib of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 16, in a solvent such as dimethylformamide, provides compounds of formula Ib of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 16, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ib of the invention where X is NHCH2. 0298 Scheme 6 also depicts an alternate route for the preparation of key intermediate 15, starting from compound 17 Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977). The ethyl ester group of ethyl 4-chlorothieno2,3-bpyridine-5-carboxylate, 17, is hydrolyzed to the corresponding 5-carboxylic acid 18 with aqueous sodium hydroxide in a cosolvent such as ethanol at elevated temperature. The corresponding 5-carboxamide analog 19 is prepared by treatment of 18 with a reagent such as thionyl chloride or alternatively N,N-carbonyldiimidazole and the like, followed by the addition of aqueous ammonium hydroxide or alternatively ammonia gas. Dehydration of 19 with a reagent such as cyanuric chloride provides the key intermediate 4-chlorothieno3,2-bpyridine-5-carbonitrile 15. 0299 Scheme 6 also depicts the preparation of compounds of the invention of formula Ib where R2 is alkyl. Treatment of 15 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of a R2LG, where LG is a leaving group, preferably iodo, provides the key intermediate 20 where R2 is alkyl. Addition of a compound of formula R1XH where X is NH or NR4 to compounds of formula 20, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ib of the invention where X is NH or NR4. Alternatively addition of a compound of formula R1XH where X is NH or NR4 to a compound of formula 20 in the presence of a palladium catalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, and potassium phosphate in a solvent such as ethylene glycol dimethyl ether at elevated temperatures of preferentially 90 C. provides compounds of formula Ib of the invention where X is NH or NR4. Addition of a compound of formula R1XH, where X is O, to compounds of formula 20, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ib of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 20, in a solvent such as dimethylformamide, provides compounds of formula Ib of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 20, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ib of the invention where X is NHCH2. 22

0300 Scheme 7 depicts an alternate route for the preparation of compounds of the invention of formula Ib. A suitably substituted thiophene of formula 21 is nitrated, preferably with nitric acid in acetic anhydride at reduced temperature to provide 2-nitrothiophenes of formula 22. Reduction of the nitro group of compounds of formula 22 with a reducing agent, preferably hydrogen gas in the presence of a catalyst, preferably palladium hydroxide in a solvent, which includes methanol, provides compounds of formula 23. Addition of ethyl (ethoxymethylene)cyanoacetate in a solvent such as toluene followed by cyclization at high temperatures, preferably in a solvent system of biphenyl and diphenyl ether at reflux, and subsequent chlorination with phosphorous oxychloride, preferably with a catalytic amount of N,N-dimethylformamide, results in compounds of formula 24. Addition of a compound of formula R1XH where X is NH or NR4 to compounds of formula 24, optionally in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ib of the invention where X is NH or NR4. Alternatively addition of a compound of formula R1XH where X is NH or NR4 to a compound of formula 24 in the presence of a palladium catalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, and potassium phosphate in a solvent such as ethylene glycol dimethyl ether at elevated temperatures of preferentially 90 C. provides compounds of formula Ib of the invention where X is NH or NR4. Addition of a compound of formula R1XH where X is NH or NR4, where X is O, to compounds of formula 24, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ib of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 24, in a solvent such as dimethylformamide, provides compounds of formula Ib of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 24, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ib of the invention where X is NHCH2. 23

0301 Additional compounds of the invention of formula Ib where R2 is an alkenyl, alkynyl, heteroaryl or aryl group from compounds of formula Ib where R2 is either I or Br can be prepared as depicted in Scheme 8. Treatment of compounds of formula 1b where R2 is either I or Br with an alkenyl or alkynyl of formula R3H in the presence of a palladium catalyst provides compounds of formula Ib where R2 is either an alkenyl or alkynyl group. This alkenyl or alkynyl group can be substituted by groups including aryl and heteroaryl and also alkyl and alkyl amino among others. This aryl or heteroaryl group can also be substituted by groups such as alkoxy, alkylamino and others. For the addition of alkenyls of formula R3H the preferred palladium catalyst is palladium acetate in the presence of a ligand, preferably tri-o-tolylphosphine, in a solvent system that includes triethylamine or preferably a mixture of triethylamine and N,N-dimethylformamide. For the addition of alkynyls of formula R3H the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) along with a catalytic amount of copper(I)iodide in a solvent mixture that includes triethylamine and benzene. 0302 Treatment of compounds of formula Ib where R2 is either I or Br with an aryl or heteroaryl organoboron compound of formula R3BL1L2 in the presence of a palladium catalyst provides compounds of formula Ib where R2 is either an aryl or heteroaryl group. In compounds of formula R3BL1L2, the L1L2 groups represent ligands and include such groups as lower alkoxy or preferably hydroxy. The aryl or heteroaryl group of compound R3BL1L2 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3BL1L2 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3BL1L2 the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) in a solvent mixture that includes saturated aqueous sodium bicarbonate and ethylene glycol dimethyl ether. 0303 Compounds of formula Ib where R2 is either aryl or heteroaryl can also be prepared by reaction of a compound of formula Ib where R2 is either I or Br with an aryl or heteroaryl stannane compound of formula R3SnR3 in the presence of a palladium catalyst. In compounds of formula R3SnR3 the R group is a lower alkyl group such as butyl or methyl. The aryl or heteroaryl group of compound R3SnR3 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, acetal, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3SnR3 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3SnR3 the preferred palladium catalyst is bis(triphenylphosphine)Palladium (i) chloride in a solvent such as dioxane. 0304 Compounds of formula Ib where R2 is an alkynyl group can be prepared by the alternative route shown in Scheme 8. Treatment of a compound of formula 11b, where R2 is either Br or I with (trimethylsilyl)acetylene in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)Palladium(0), with a catalytic amount of copper(I) iodine in a solvent system such as triethylamine and benzene, provides compounds of formula Ib where R2 is a 2-(trimethylsilyl)ethynyl group. Reaction of compounds of formula Ib where R2 is a 2-(trimethylsilyl)ethynyl group with aryliodines or heteroaryliodines in the presence of a palladium catalyst, preferably bis(triphenylphosphine)Palladium(II)chloride, in the presence of triphenylphosphine, potassium carbonate and copper(I) iodide, in a solvent mixture of tetrahydrofuran and methanol, provides compounds of formula Ib where R2 is a 2-(aryl)ethynyl or a 2-(heteroaryl)ethynyl group. In addition the 2-(trimethylsilyl)ethynyl group can be cleaved by treatment with potassium carbonate in methanol to provide compounds of formula Ib where R2 is an ethynyl group. 24

0305 Some additional routes to the compounds of the invention of formula Ib are shown in Scheme 9. Compounds of formula Ib where the group R2 is R3CHO can be converted to compounds of formula Ib where the group R2 is R3CH2Q via reductive amination. Treatment of compounds of formula Ib where the group R2 is R3CHO with an amine of formula QH in the presence of a reducing agent, preferably sodium triacetoxyborohydride, in a solvent system that includes dichloromethane and N,N-dimethylformamide or NMP, provides compounds of formula Ib where the group R2 is R3CH2Q. Compounds of formula Ib where the group R2 is R3CH2OH may be obtained as a by-product of this reaction, via reduction of the formyl group of compounds of formula Ib where the group R2 is R3-CHO. 0306 Compounds of formula Ib where the group R2 is R3CHO can be prepared by hydrolysis of the acetal group of compounds of formula Ib where the group R2 is R3-acetal, preferably with aqueous hydrochloric acid in the presence of a cosolvent such as tetrahydrofuran. 0307 Scheme 9 also depicts the preparation of compounds of formula Ib where the group R2 is R3 substituted with (C(R8)2)qCO2H, and (C(R8)2)qCOQ from compounds of formula Ib where the group R2 is R3 substituted by (C(R8)2)qCO2R4. Compounds of formula Ib where the group R2 is R3 substituted with (C(R8)2)qCO2R4 are converted to the corresponding acids of formula Ib where the group R2 is R3 substituted by (C(R8)2)qCO2H by treatment with aqueous sodium hydroxide in a cosolvent such as ethanol at elevated temperatures. The corresponding amides of formula Ib where the group R2 is R3 substituted with (C(R8)2)qCOQ are prepared by treatment of the acids with N,N-carbonyldiimidazole or alternatively thionyl chloride or the like, followed by the addition of an amine of formula QH. 26

0308 Scheme 10 depicts the preparation of key sulfoxide intermediate 25. Oxidation of 12 or 13 with an oxidizing agent such as m-chloroperbenzoic acid, peracetic acid or an oxaziridine provides the sulfoxide derivative 25. The reaction conditions must be controlled to prevent overoxidation to the sulfone. If both the sulfoxide and sulfone are obtained in the reaction, they can be separated by standard laboratory techniques. Addition of a compound of formula R1XH where X is NH or NR4 to compounds of formula 25, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ic of the invention where X is NH or NR4. Addition of a compound of formula R1XH, where X is O, to compounds of formula 25, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Ic of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 25, in a solvent such as dimethylformamide, provides compounds of formula Ic of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 25, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ic of the invention where X is NHCH2. 0309 Compounds of the invention of formula Ic where R2 is an alkene, alkyne, heteroaryl or aryl group can be prepared as depicted in Scheme 10 from compounds of formula Ic where R2 is either I or Br. Treatment of compounds of formula Ic where R2 is either I or Br with an alkene or alkyne of formula R3H in the presence of a palladium catalyst provides compounds of formula Ic where R2 is either an alkene or alkyne group. This alkene or alkyne group can be substituted by groups including aryl and heteroaryl and also alkyl and alkylamino among others. 0310 For the addition of alkenes of formula R3H the preferred palladium catalyst is palladium acetate in the presence of a ligand, preferably tri-o-tolylphosphine, in a solvent system that includes triethylamine or preferably a mixture of triethylamine and N,N-dimethylformamide. For the addition of alkynes of formula R3H the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) along with a catalytic amount of copper(I)iodide in a solvent mixture that includes triethylamine and benzene. 0311 Treatment of compounds of formula Ic where R2 is either I or Br with an aryl or heteroaryl organoboron compound of formula R3BL1L2 in the presence of a palladium catalyst provides compounds of formula Ic where R2 is either an aryl or heteroaryl group. In compounds of formula R3BL1L2, the L1L2 groups represent ligands and include such groups as lower alkoxy or preferably hydroxy. The aryl or heteroaryl group of compound R3BL1L2 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3BL1L2 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3BL1L2 the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) in a solvent mixture that includes saturated aqueous sodium bicarbonate and ethylene glycol dimethyl ether. 0312 Compounds of formula Ic where R2 is either aryl or heteroaryl can also be prepared by reaction of a compound of formula Ic where R2 is either I or Br with an aryl or heteroaryl stannane compound of formula R3SnR3 in the presence of a palladium catalyst. In compounds of formula R3SnR3 the R group is a lower alkyl group such as butyl or methyl. The aryl or heteroaryl group of compound R3SnR3 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, acetal, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3SnR3 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3SnR3 the preferred palladium catalyst is bis(triphenylphosphine)Palladium (II) chloride in a solvent such as dioxane. 0313 Compounds of formula Ic where R2 is an alkyne group can also be prepared by the route shown in Scheme 10. Treatment of a compound of formula Ic, where R2 is either Br or I with (trimethylsilyl)acetylene in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)Palladium(0), with a catalytic amount of copper(I) iodine in a solvent system such as triethylamine and benzene, provides compounds of formula Ic where R2 is a 2-(trimethylsilyl)ethynyl group. Reaction of compounds of formula Ic where R2 is a 2-(trimethylsilyl)ethynyl group with aryliodines or heteroaryliodines in the presence of a palladium catalyst, preferably bis(triphenylphosphine)Palladium(II)chloride, in the presence of triphenylphosphine, potassium carbonate and copper(I) iodide, in a solvent mixture of tetrahydrofuran and methanol, provides compounds of formula Ic where R2 is a 2-(aryl)ethynyl or a 2-(heteroaryl)ethynyl group. In addition the 2-(trimethylsilyl)ethynyl group can be cleaved by treatment with potassium carbonate in methanol to provide compounds of formula Ic where R2 is an ethynyl group. 28

0314 Scheme 11 depicts the preparation of key sulfone intermediate 26. Oxidation of 12 or 13 with an excess of an oxidizing agent such as m-chloroperbenzoic acid, peracetic acid or an oxiziridine provides the sulfone derivative 26. If both the sulfoxide and sulfone are obtained in the reaction, they can be separated by standard laboratory techniques. Addition of a compound of formula R1XH where X is NH or NR4, to compound 26, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Id of the invention where X is NH or NR4. Addition of a compound of formula R1XH, where X is O, to compounds of formula 26, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula Id of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 26, in a solvent such as dimethylformamide, provides compounds of formula Id of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 26, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Id of the invention where X is NHCH2. 0315 Compounds of the invention of formula Id where R2 is an alkene, alkyne, heteroaryl or aryl group can be prepared as depicted in Scheme 11 from compounds of formula Id where R2 is either I or Br. Treatment of compounds of formula Id where R2 is either I or Br with an alkene or alkyne of formula R3H in the presence of a palladium catalyst provides compounds of formula Id where R2 is either an alkene or alkyne group. This alkene or alkyne group can be substituted by groups including aryl and heteroaryl and also alkyl and alkylamino among others. 0316 For the addition of alkenes of formula R3H the preferred palladium catalyst is palladium acetate in the presence of a ligand, preferably tri-o-tolylphosphine, in a solvent system that includes triethylamine or preferably a mixture of triethylamine and N,N-dimethylformamide. For the addition of alkynes of formula R3H the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) along with a catalytic amount of copper(I)iodide in a solvent mixture that includes triethylamine and benzene. 0317 Treatment of compounds of formula Id where R2 is either I or Br with an aryl or heteroaryl organoboron compound of formula R3BL1L2 in the presence of a palladium catalyst provides compounds of formula Id where R2 is either an aryl or heteroaryl group. In compounds of formula R3BL1L2, the L1L2 groups represent ligands and include such groups as lower alkoxy or preferably hydroxy. The aryl or heteroaryl group of compound R3BL1L2 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3BL1L2 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3BL1L2 the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) in a solvent mixture that includes saturated aqueous sodium bicarbonate and ethylene glycol dimethyl ether. 0318 Compounds of formula Id where R2 is either aryl or heteroaryl can also be prepared by reaction of a compound of formula Id where R2 is either I or Br with an aryl or heteroaryl stannane compound of formula R3SnR3 in the presence of a palladium catalyst. In compounds of formula R3SnR3 the R group is a lower alkyl group such as butyl or methyl. The aryl or heteroaryl group of compound R3SnR3 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, acetal, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3SnR3 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3SnR3 the preferred palladium catalyst is bis(triphenylphosphine)Palladium (II) chloride in a solvent such as dioxane. 0319 Compounds of formula Id where R2 is an alkyne group can also be prepared by the route shown in Scheme 11. Treatment of a compound of formula Id, where R2 is either Br or I with (trimethylsilyl)acetylene in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)Palladium(0), with a catalytic amount of copper(I) iodine in a solvent system such as triethylamine and benzene, provides compounds of formula Id where R2 is a 2-(trimethylsilyl)ethynyl group. Reaction of compounds of formula Id where R2 is a 2-(trimethylsilyl)ethynyl group with aryliodines or heteroaryliodines in the presence of a palladium catalyst, preferably bis(triphenylphosphine)Palladium(II)chloride, in the presence of triphenylphosphine, potassium carbonate and copper(I) iodide, in a solvent mixture of tetrahydrofuran and methanol, provides compounds of formula Id where R2 is a 2-(aryl)ethynyl or a 2-(heteroaryl)ethynyl group. In addition the 2-(trimethylsilyl)ethynyl group can be cleaved by treatment with potassium carbonate in methanol to provide compounds of formula Id where R2 is an ethynyl group. 30

0320 Alternate routes for the preparation of the key intermediate 25 and 26 are shown in Scheme 12. Oxidation of 5 with an oxidizing agent provides the sulfoxide 27 or the sulfone 28. Excess amounts of oxidizing agent would be expected to provide the sulfone via an intermediate sulfoxide. Treatment of sulfoxide 27 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of 1,2-dibromo-1,1,2,2,-tetrafluoroethane or bromine provides 25 where LGBr. Analogously, treatment of 27 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of iodine provides 25 where LGI. In a similar fashion, treatment of sulfone 28 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of 1,2-dibromo-1,1,2,2,-tetrafluoroethane or bromine provides 26 where LGBr. Analogously, treatment of 28 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of iodine provides 26 where LGI. 32

0321 Scheme 13 depicts the preparation of key sulfoxide intermediate 29. Oxidation of 16 with an oxidizing agent such as m-chloroperbenzoic acid, peracetic acid or an oxiziridine provides the sulfoxide derivative 29. The reaction conditions are controlled to prevent over oxidation to the sulfone. If both the sulfoxide and sulfone are obtained in the reaction, they can be separated by standard laboratory techniques. Addition of a compound of formula R1XH where X is NH or NR4, to compound 29, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula Ie of the invention where X is NH or NR4. Addition of a compound of formula R1XH, where X is O, to compounds of formula 29, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula 1e of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 29, in a solvent such as dimethylformamide, provides compounds of formula Ie of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 29, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula Ie of the invention where X is NHCH2. 0322 Compounds of the invention of formula Ie where R2 is an alkene, alkyne, heteroaryl or aryl group can be prepared as depicted in Scheme 13 from compounds of formula Ie where R2 is either I or Br. Treatment of compounds of formula Ie where R2 is either I or Br with an alkene or alkyne of formula R3H in the presence of a palladium catalyst provides compounds of formula Ie where R2 is either an alkene or alkyne group. This alkene or alkyne group can be substituted by groups including aryl and heteroaryl and also alkyl and alkylamino among others. 0323 For the addition of alkenes of formula R3H the preferred palladium catalyst is palladium acetate in the presence of a ligand, preferably tri-o-tolylphosphine, in a solvent system that includes triethylamine or preferably a mixture of triethylamine and N,N-dimethylformamide. For the addition of alkynes of formula R3H the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) along with a catalytic amount of copper(I)iodide in a solvent mixture that includes triethylamine and benzene. 0324 Treatment of compounds of formula Ie where R2 is either I or Br with an aryl or heteroaryl organoboron compound of formula R3BL1L2 in the presence of a palladium catalyst provides compounds of formula Ie where R2 is either an aryl or heteroaryl group. In compounds of formula R3BL1L2, the L1L2 groups represent ligands and include such groups as lower alkoxy or preferably hydroxy. The aryl or heteroaryl group of compound R3BL1L2 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3BL1L2 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3BL1L2 the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) in a solvent mixture that includes saturated aqueous sodium bicarbonate and ethylene glycol dimethyl ether. 0325 Compounds of formula Ie where R2 is either aryl or heteroaryl can also be prepared by reaction of a compound of formula Ie where R2 is either I or Br with an aryl or heteroaryl stannane compound of formula R3SnR3 in the presence of a palladium catalyst. In compounds of formula R3SnR3 the R group is a lower alkyl group such as butyl or methyl. The aryl or heteroaryl group of compound R3SnR3 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, acetal, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3SnR3 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3SnR3 the preferred palladium catalyst is bis(triphenylphosphine)Palladium (II) chloride in a solvent such as dioxane. 0326 Compounds of formula Ie where R2 is an alkyne group can also be prepared by the route shown in Scheme 13. Treatment of a compound of formula Ie, where R2 is either Br or I with (trimethylsilyl)acetylene in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)Palladium(0), with a catalytic amount of copper(I) iodine in a solvent system such as triethylamine and benzene, provides compounds of formula Ie where R2 is a 2-(trimethylsilyl)ethynyl group. Reaction of compounds of formula Ie where R2 is a 2-(trimethylsilyl)ethynyl group with aryliodines or heteroaryliodines in the presence of a palladium catalyst, preferably bis(triphenylphosphine)Palladium(II)chloride, in the presence of triphenylphosphine, potassium carbonate and copper(I) iodide, in a solvent mixture of tetrahydrofuran and methanol, provides compounds of formula Ie where R2 is a 2-(aryl)ethynyl or a 2-(heteroaryl)ethynyl group. In addition the 2-(trimethylsilyl)ethynyl group can be cleaved by treatment with potassium carbonate in methanol to provide compounds of formula Ie where R2 is an ethynyl group. 33

0327 Scheme 14 depicts the preparation of key sulfone intermediate 30. Oxidation of 16 with an excess of an oxidizing agent such as m-chloroperbenzoic acid, peracetic acid or an oxaziridine provides the sulfone derivative 30. If both the sulfoxide and sulfone are obtained in the reaction, they can be separated by standard laboratory techniques. Addition of a compound of formula R1XH where X is NH or NR4 to compound 30, in the presence of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., provides compounds of formula If of the invention where where X is NH or NR4. Addition of a compound of formula R1XH, where X is O, to compounds of formula 30, optionally with the addition of a base such as potassium carbonate in a solvent such as dimethylformamide at elevated temperature, provides compounds of formula If of the invention where X is O. Addition of a compound of formula R1XH, where X is S, to compounds of formula 30, in a solvent such as dimethylformamide, provides compounds of formula If of the invention where X is S. Addition of a compound of formula R1XH, where X is NHCH2, to compounds of formula 30, optionally with the addition of a base such as N,N-diisopropylamine in a solvent such as 2-ethoxyethanol at elevated temperature, provides compounds of formula If of the invention where X is NHCH2. 0328 Compounds of the invention of formula If where R2 is an alkene, alkyne, heteroaryl or aryl group can be prepared as depicted in Scheme 14 from compounds of formula If where R2 is either I or Br. Treatment of compounds of formula If where R2 is either I or Br with an alkene or alkyne of formula R3H in the presence of a palladium catalyst provides compounds of formula If where R2 is either an alkene or alkyne group. This alkene or alkyne group can be substituted by groups including aryl and heteroaryl and also alkyl and alkylamino among others. 0329 For the addition of alkenes of formula R3H the preferred palladium catalyst is palladium acetate in the presence of a ligand, preferably tri-o-tolylphosphine, in a solvent system that includes triethylamine or preferably a mixture of triethylamine and N,N-dimethylformamide. For the addition of alkynes of formula R3H the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) along with a catalytic amount of copper(I)iodide in a solvent mixture that includes triethylamine and benzene. 0330 Treatment of compounds of formula If where R2 is either I or Br with an aryl or heteroaryl organoboron compound of formula R3BL1L2 in the presence of a palladium catalyst provides compounds of formula If where R2 is either an aryl or heteroaryl group. In compounds of formula R3BL1L2, the L1L2 groups represent ligands and include such groups as lower alkoxy or preferably hydroxy. The aryl or heteroaryl group of compound R3BL1L2 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3BL1L2 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3BL1L2 the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) in a solvent mixture that includes saturated aqueous sodium bicarbonate and ethylene glycol dimethyl ether. 0331 Compounds of formula If where R2 is either aryl or heteroaryl can also be prepared by reaction of a compound of formula If where R2 is either I or Br with an aryl or heteroaryl stannane compound of formula R3SnR3 in the presence of a palladium catalyst. In compounds of formula R3SnR3 the R group is a lower alkyl group such as butyl or methyl. The aryl or heteroaryl group of compound R3SnR3 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, acetal, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3SnR3 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3SnR3 the preferred palladium catalyst is bis(triphenylphosphine)Palladium (II) chloride in a solvent such as dioxane. 0332 Compounds of formula If where R2 is an alkyne group can also be prepared by the route shown in Scheme 14. Treatment of a compound of formula If, where R2 is either Br or I with (trimethylsilyl)acetylene in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)Palladium(0), with a catalytic amount of copper(I) iodine in a solvent system such as triethylamine and benzene, provides compounds of formula If where R2 is a 2-(trimethylsilyl)ethynyl group. Reaction of compounds of formula If where R2 is a 2-(trimethylsilyl)ethynyl group with aryliodines or heteroaryliodines in the presence of a palladium catalyst, preferably bis(triphenylphosphine)Palladium(II)chloride, in the presence of triphenylphosphine, potassium carbonate and copper(I) iodide, in a solvent mixture of tetrahydrofuran and methanol, provides compounds of formula If where R2 is a 2-(aryl)ethynyl or a 2-(heteroaryl)ethynyl group. In addition the 2-(trimethylsilyl)ethynyl group can be cleaved by treatment with potassium carbonate in methanol to provide compounds of formula If where R2 is an ethynyl group. 35

0333 Alternate routes for the preparation of the key intermediate 29 and 30 are shown in Scheme 15. Oxidation of 15 with an oxidizing agent provides the sulfoxide 31 or the sulfone 32. Excess amounts of oxidizing agent would be expected to provide the sulfone via an intermediate sulfoxide. Treatment of sulfoxide 31 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of 1,2-dibromo-1,1,2,2,-tetrafluoroethane provides 29 where LGBr. Analogously, treatment of 31 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of iodine provides 29 where LGI. In a similar fashion, treatment of sulfone 32 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of 1,2-dibromo-1,1,2,2,-tetrafluoroethane provides 30 where LGBr. Analogously, treatment of 32 with a base, preferentially lithium diisopropylamine (LDA), in an inert solvent such as tetrahydrofuran at reduced temperature, preferably 78 C., followed by the addition of iodine provides 30 where LGI. 37

0334 Additional compounds of the invention of formula Ia where R2 is an alkenyl or alkynyl group can be prepared as depicted in Scheme 16. Treatment of intermediates 12 or 13 with an alkenyl or alkynyl reagent of formula R3H in the presence of a palladium catalyst provides intermediates of 33 where R3 is either an alkenyl or alkynyl group. This alkenyl or alkynyl group can be substituted by groups including aryl and heteroaryl and also alkyl and alkyl amino among others. This aryl or heteroaryl group can also be substituted by groups such as alkoxy, alkylamino and others. For the addition of alkenyls of formula R3H the preferred palladium catalyst is palladium acetate in the presence of a ligand, preferably tri-o-tolylphosphine, in a solvent system that includes triethylamine or preferably a mixture of triethylamine and N,N-dimethylformamide. For the addition of alkynyls of formula R3H the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) along with a catalytic amount of copper(I)iodide in a solvent mixture that includes triethylamine and benzene. Addition of a compound of formula R1NH2 to compounds of formula 33, optionally with the addition of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., or under palladium catalyzed coupling conditions, including the use of tris(dibenzylideneacetone)-dipalladium(0) and (2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, in a solvent such as ethylene glycol dimethyl ether at elevated temperatures such as 90 C. provides compounds of formula Ia. 0335 Treatment of intermediates of formula 12 or 13 with an aryl or heteroaryl organoboron compound of formula R3BL1L2 in the presence of a palladium catalyst provides intermediates of formula 33 where R3 is either an aryl or heteroaryl group. In compounds of formula R3BL1L2, the L1L2 groups represent ligands and include such groups as lower alkoxy or preferably hydroxy. The aryl or heteroaryl group of compound R3BL1L2 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3BL1L2 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3BL1L2 the preferred palladium catalyst is tetrakis(triphenylphosphine)Palladium (0) in a solvent mixture that includes saturated aqueous sodium bicarbonate and ethylene glycol dimethyl ether. Addition of a compound of formula R1NH2 to compounds of formula 33, optionally with the addition of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., or under palladium catalyzed coupling conditions, including the use of tris(dibenzylideneacetone)-dipalladium(0) and (2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, in a solvent such as ethylene glycol dimethyl ether at elevated temperatures such as 90 C. provides compounds of formula Ia. 0336 Compounds of formula Ia where R2 is either aryl or heteroaryl can also be prepared by reaction of intermediates of formula 12 or 13 with an aryl or heteroaryl stannane compound of formula R3SnR3 in the presence of a palladium catalyst. In compounds of formula R3SnR3 the R group is a lower alkyl group such as butyl or methyl. The aryl or heteroaryl group of compound R3SnR3 can be substituted by groups including aryl and heteroaryl and also formyl, carboxylate, acetal, alkyl and alkylamino among others. The aryl or heteroaryl group of compound R3SnR3 can also be fused to a second aryl or heteroaryl group. For the addition of compounds of formula R3SnR3 the preferred palladium catalyst is bis(triphenylphosphine)Palladium (II) chloride in a solvent such as dioxane. Addition of a compound of formula R1NH2 to compounds of formula 33, optionally with the addition of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., or under palladium catalyzed coupling conditions, including the use of tris(dibenzylideneacetone)-dipalladium(0) and (2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, in a solvent such as ethylene glycol dimethyl ether at elevated temperatures such as 90 C. provides compounds of formula Ia. 38

0337 Some additional routes to the compounds of the invention of formula Ia are shown in Scheme 17. Intermediates of formula 34 can be converted to intermediates of formula 35 via reductive amination with an amine of formula QH and a reducing agent, preferably sodium triacetoxyborohydride, in a solvent system that includes dichloromethane and N,N-dimethylformamide or 1-methyl-2-pyrrolidinone, optionally in the presence of acetic acid. Addition of a compound of formula R1NH2 to compounds of formula 35, optionally with the addition of pyridine hydrochloride in a solvent such as 2-ethoxyethanol at elevated temperatures of 110-130 C., or in the presence of sodium hydride in a solvent such as tetrahydrofuran at elevated temperatures of 60-70 C., or under palladium catalyzed coupling conditions, including the use of tris(dibenzylideneacetone)-dipalladium(0) and (2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl, in a solvent such as ethylene glycol dimethyl ether at elevated temperatures such as 90 C. provides compounds of formula Ia. 40

0338 Additional compounds of the invention of formula Ia where R2 is an alkenyl group can be prepared as depicted in Scheme 18 from reaction of compounds of formula Ia where R2 is an alkynyl group with a heteroaryl compound containing an NH group in the ring. Such heteroaryl compounds include 1,2,3-triazole, imidazole, pyrrole and the like. The reaction is carried out in the presence of cesium hydroxide in a solvent such as 1-methyl-2-pyrrolidinone. 41

0339 Additional compounds of the invention of formula Ia where R2 is a substituted heteroaryl group can be prepared as depicted in Scheme 19 from reaction of compounds of formula Ia where R3 is heteroaryl group containing an NH group with a reagent of formula LG-(C(R9)2)qXR8 or LG-(C(R9)2)q-Q, wherein LG is a leaving group such as Cl, Br, I, mesylate or tosylate. Such reagents include 4-(2-chloroethyl)morpholine, 2-chloroethanol, 2-(dimethylamino)ethyl chloride and the like. The heteroaryl group containing an NH group includes pyrazole, pyrrole and the like. The reaction is carried out in the presence of a base such as cesium carbonate in a solvent such as dimethylformamide at a slightly elevated temperature such as 50 C. 42

REFERENCE EXAMPLE 1

7-Oxo-4,7-dihydrothieno3,2-bpyridine-6-carbonitrile 0340 A mixture of methyl 3-amino-2-thiophenecarboxylate (18.3 g, 116.5 mmol) and 80 mL of N,N-dimethylformamide dimethyl acetal is heated at reflux for 90 minutes. The reaction mixture is concentrated in vacuo resulting in a dark brown oil. This material is stirred with diethyl ether. Addition of hexane results in the formation of a small amount of brown solid, which is removed by filtration. Concentration of the filtrate provides 10.65 g of the intermediate amidine as a bright yellow oil. 0341 To a solution of 40 mL of 2.5 M n-butyl lithium in tetrahydrofuran at 78 C. is added acetonitrile (6.3 mL). After stirring for 10 min, a solution of the amidine in 100 mL of tetrahydrofuran is added dropwise over 40 minutes. The reaction mixture is stirred at 78 C. for 2 hours, then 6.3 mL of acetic acid is added. The mixture is allowed to come to room temperature and stirring is continued overnight. The reaction mixture is concentrated in vacuo and the residue is partitioned between water and ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is heated at reflux in 60 mL of acetic acid for 3 hours then stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and the crude product is purified by flash column chromatography eluting with a gradient of ethyl acetate to 10% methanol in ethyl acetate. A portion of the product is stirred with methanol and filtered to provide 7-oxo-4,7-dihydrothieno3,2-bpyridine-6-carbonitrile as an orange solid, mp 265-275 C. (dec.); 1H NMR (DMSO-d6) 7.32 (d, J6 Hz, 1H), 8.16 (d, J6 Hz,1H), 8.67 (s, 1H); MS 177.0 (MH). 0342 Analysis for C8H4N2OS-0.10H2O: 0343 Calcd: C, 53.98; H, 2.38; N, 15.74. 0344 Found: C, 54.04; H, 2.38; N, 15.85.

REFERENCE EXAMPLE 2

7-Chlorothieno3,2-bpyridine-6-carbonitrile 0345 A mixture of 7-oxo-4,7-dihydrothieno3,2-bpyridine-6-carbonitrile (3.00 g, 17.0 mmol) and 25 mL of phosphorous oxychloride is heated at reflux for 10 minutes. The reaction mixture is cooled to room temperature and the dark solids are removed by filtration. The filtrate is poured into hexane and allowed to stand at room temperature. The solvent is decanted off and the residual oil is dissolved in ethyl acetate and the solution is washed with water. The organic layer is dried over magnesium sulfate, filtered and passed through silica gel. The filtrate is concentrated in vacuo to give 770 mg of the desired product as a dark orange solid. A portion of this material is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 7-chlorothieno3,2-bpyridine-6-carbonitrile as tan crystals, mp 110-111 C.; 1H NMR (DMSO-d6) 7.81 (d, J5 Hz, 1H), 8.59 (d, J5 Hz, 1H), 9.12 (s, 1H); MS 194.9 (MH). 0346 Analysis for C8H3ClN2S: 0347 Calcd: C, 49.37; H, 1.55; N, 14.39 0348 Found: C, 49.57; H, 1.44; N, 14.48.

Alternate Preparation of Reference Example 2

7-Chlorothieno3,2-bpyridine-6-carbonitrile 0349 To a solution of 7-chlorothieno3,2-bpyridine-6-carboxamide (10.8 g, 51 mmol) in 80.0 mL of N,N-dimethylformamide is added cyanuric chloride (5.72 g, 31 mmol). After 30 minutes the suspension is poured into ice water. The solid is filtered, washed with ice water and dried in vacuo to give 9.0 g of 7-chlorothieno3,2-bpyridine-6-carbonitrile as an off white solid, mp 105-107 C.; 1H NMR (DMSO-d6) 7.83 (s, 1H), 8.61 (s, 1H), 9.12 (s, 1H); MS 195.0,197.0 (MH). 0350 Analysis for C8H3ClN2S: 0351 Calcd: C, 49.37; H, 1.55; N, 14.39.

REFERENCE EXAMPLE 3

5-Phenyl-3-thienylamine 0352 A mixture of methyl 3-amino-5-phenylthiophene-2-carboxylate (2.50 g, 10.7 mmol), 3.5 mL of N-methylpiperazine and 12 mL of N-methylpyrrolidinone is heated at 160 C. for 4 hours. The reaction mixture is cooled to room temperature and poured into 100 mL of water. The solids are collected by filtration washing with 50 mL of water. Ethyl acetate and hexane are added and the filtrate is decanted off from the gummy black residue. The filtrate is concentrated to provide 850 mg of 5-phenyl-3-thienylamine as a yellow solid, mp 76-78 C.; 1H NMR (DMSO-d6) 4.87 (s, 2H), 5.98(d, J1.5 Hz, 1H), 6.95(d, J1.5 Hz, 1H), 7.28 (m, 1H), 7.37(t, J7 Hz, 2H), 7.53 (d, J7 Hz, 2H); MS 176.2 (MH). 0353 Analysis for C8H3ClN2S: 0354 Calcd: C, 68.53; H, 5.18; N, 7.99 0355 Found: C, 68.73; H, 4.79; N, 7.86.

REFERENCE EXAMPLE 4

Ethyl-2-cyano-3-(5-phenyl-3-thienyl)amino-2-propenoate 0356 A mixture of 5-phenyl-3-thienylamine (1.00 g, 5.7 mmol) and ethyl (ethoxymethylene)cyanoacetate (950 mg, 5.7 mmol) in 20 mL of toluene is heated at reflux for 45 minutes. The reaction mixture is filtered while warm and the collected solid is washed with diethyl ether to provide 198 mg of ethyl 2-cyano-3-(5-phenyl-3-thienyl)amino-2-propenoate as white crystals, mp 190-193 C.; MS 296.9 (MH). 0357 Analysis for C16H14N2O2S: 0358 Calcd: C, 64.41; H, 4.73; N, 9.39 0359 Found: C, 64.32; H, 4.67; N, 9.21. 0360 Upon cooling an additional 705 mg of ethyl 2-cyano-3-(5-phenyl-3-thienyl)amino-2-propenoate is collected from the filtrate.

REFERENCE EXAMPLE 5

7-Oxo-2-phenyl-4,7-dihydrothieno3,2-bpyridine-6-carbonitrile 0361 A mixture of ethyl 2-cyano-3-(5-phenyl-3-thienyl)amino-2-propenoate (696 mg, 2.33 mmol) in 15 mL of Dowtherm-A is heated at reflux for 3 hours. The reaction mixture is cooled to room temperature and the solids are collected by filtration washing with hexane to give 170 mg of a light brown solid. The solid is suspended in hot methanol and ethyl acetate and the mixture is filtered while warm to give 7-oxo-2-phenyl-4,7-dihydrothieno3,2-bpyridine-6-carbonitrile as a brown solid, mp>300 C.; 0362 1H NMR (DMSO-d6) 7.43-7.55 (m, 3H), 7.63 (s, 1H), 7.83 (d, J7 Hz, 2H), 8.67 (s, 1H), 13.3 (s, 1H); MS 253.1 (MH). 0363 Analysis for C14H8N2OS-0.1H2O: 0364 Calcd: C, 66.17; H, 3.23; N, 11.02 0365 Found: C, 66.14; H, 3.42; N, 11.00.

REFERENCE EXAMPLE 6

2-Bromo-7-chlorothieno3,2-bpyridine-6-carbonitrile 0366 A mixture of ethyl 2-bromo-7-hydroxythieno3,2-bpyridine-6-carboxylate (1.3 g, 4.3 mmol) Elliott, R.; O'Hanlon, P. J.; Rodgers, N. B. Tetrahedron, 43(14), 3295 (1987) in 20 mL of ethanol and 6 mL of 2.5 N sodium hydroxide is heated at reflux for 4 hours. The mixture is poured into ice water and the pH is adjusted to 5-6 by the addition of acetic acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration washing with water to provide 840 mg of 2-bromo-7-hydroxythieno3,2-bpyridine-6-carboxylic acid. A mixture of 2-bromo-7-hydroxythieno2,3-bpyridine-6-carboxylic acid (810 mg, 2.95 mmol) and N,N-carbonyldiimidazole (1.0 g, 6.17 mmol) in 15 mL of N,Ndimethylformamide is heated at 65 C. for 2 hours. The mixture is poured into 50 mL of ice cold aqueous ammonium hydroxide and stirred for 14 hours. The resultant solids are collected by filtration washing with water to provide 800 mg of 2-bromo-7-hydroxythieno3,2-bpyridine-6-carboxamide. A mixture of 2-bromo-7-hydroxythieno3,2-bpyridine-6-carboxamide (273 mg, 1.0 mmol) and 3 mL of phosphorous oxychloride is heated at reflux for 1 hour. The solvent is removed in vacuo and the residue is poured into ice water and treated with sodium bicarbonate. The resultant solids are collected by filtration washing with water. The solids are purified by flash column chromatography eluting with chloroform to provide 240 mg of 2-bromo-7-chlorothieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 198-199 C.; 1H NMR (DMSO-d6) 8.12 (s, 1H), 9.11 (s, 1H); MS 273.1, 275.1, 277.1 (MH)0367 Analysis for C8H2BrClN2S: 0368 Calcd: C, 35.13; H, 0.74; N, 10.24 0369 Found: C, 34.98; H, 0.80; N, 10.24.

Alternate Preparation of Reference Example 6

2-Bromo-7-chlorothieno3,2-bpyridine-6-carbonitrile 0370 To a solution of 7-chlorothieno3,2-bpyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (5.0 mL) is slowly added lithium diisopropylamine (0.7 mL, 1.40 mmol, 2M in tetrahydrofuran) at 78 C. over 5 minutes. After 30 minutes, 1,2-dibromo-1,1,2,2,-tetrafluoroethane (0.16 mL, 1.3 mmol) is added slowly to the solution of the anion. The temperature is maintained at 78 C. for 4 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo to afford a dark solid residue. The residue is purified by flash column chromatography eluting with a gradient of 2% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 103 mg of 2-bromo-7-chlorothieno3,2-bpyridine-6-carbonitrile as an off white solid, mp 190-191 C.; 1H NMR (DMSO-d6) 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8,274.8, 276.9 (MH). 0371 Analysis for C8H2BrClN2S-0.3H2O: 0372 Calcd: C, 34.45; H, 0.94; N, 10.04 0373 Found: C, 34.51; H, 1.01; N, 10.04.

Second Alternate Preparation of Reference Example 6

2-Bromo-7-chlorothieno3,2-bpyridine-6-carbonitrile 0374 To a solution of 7-chlorothieno3,2-bpyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (9.0 mL) at 78 C. is slowly added lithium diisopropylamine (0.62 mL, 1.24 mmol, 2M in tetrahydrofuran) over 10 minutes. After 40 minutes, a solution of bromine (198 mg, 1.24 mmol) in 1.5 mL of tetrahydrofuran is added slowly to the solution of the anion. The temperature is maintained at 78 C. for 5 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 90% dichloromethane in hexane to provide 48 mg of 2-bromo-7-chlorothieno3,2-bpyridine-6-carbonitrile as a pink solid, 1H NMR (DMSO-d6) 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8,274.8, 276.8 (MH).

REFERENCE EXAMPLE 7

7-Chlorothieno3,2-bpyridine-6-carboxylic Acid 0375 A mixture of ethyl 7-chlorothieno3,2-bpyridine-6-carboxylate (2.98 g, 12.3 mmol) Thompson, M.; Forbes, I. F. EP 126970 in 40 mL of ethanol and 15 mL of 2.5 N sodium hydroxide is heated at reflux for 1 hour. The mixture is cooled to 0 C. and the pH is adjusted to 4 by the addition of 4 N hydrochloric acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration washing with water to provide 2.47 g of 7-chlorothieno3,2-bpyridine-6-carboxylic acid as a white solid, 1H NMR (DMSO-d6) 7.73 (d, J6 Hz, 1H), 8.44 (d, J6 Hz, 1H), 9.07 (s, 1H).

REFERENCE EXAMPLE 8

7-Chlorothieno3,2-bpyridine-6-carboxamide 0376 A mixture of 7-chlorothieno3,2-bpyridine-6-carboxylic acid (13.8 g, 65 mmol) and thionyl chloride (234 mL) is heated at reflux for 2 hours. After cooling the excess thionyl chloride is removed by rotary evaporation. The residue is suspended in acetone (350 mL) and the resulting suspension cooled in an ice-bath. Aqueous ammonia (S.G. 0.880, 62 mL) is added gradually, keeping the temperature below 10 C. After concentration of the mixture, the resulting suspension is filtered off, washed with water and air-dried to give 10.9 g of 7-chlorothieno3,2-bpyridine-6-carboxamide as a beige solid, mp 180-182 C.; 1H NMR (DMSO-d6) 7.71 (s, 1H), 7.89 (s, 1H), 8.14 (s, 1H), 8.35 (s, 1H), 8.73 (s, 1H); MS 213.0,215.0 (MH). 0377 Analysis for C8H5ClN2OS: 0378 Calcd: C, 45.18; H, 2.37; N, 13.17. 0379 Found: C, 45.38; H, 2.26; N, 13.11. 0380 Found: C, 49.32; H, 1.50; N, 14.41.

REFERENCE EXAMPLE 9

7-Chloro-2-iodothieno3,2-bpyridine-6-carbonitrile 0381 To a solution of 7-chlorothieno3,2-bpyridine-6-carbonitrile (735 mg, 3.78 mmol) in 20 mL of tetrahydrofuran at 78 C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (2.2 mL, 4.40 mmol). After stirring for 20 minutes, a solution of iodine (1.15 g, 4.53 mmol) in 4 mL of tetrahydrofuran is added dropwise over 20 minutes. The reaction mixture is stirred at 78 C. for 5 hours, then 20 mL of chloroform and 10 mL of water are added. The mixture is stirred at room temperature overnight, then partitioned between water and chloroform. The organic layer is washed with a solution of sodium thiosulfate, followed by water, then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 750 mg of 6-chloro-2-iodothieno3,2-bpyridine-7-carbonitrile as yellow crystals, mp 209-211 C.; 1H NMR (DMSO-d6) 8.17 (s, 1H), 9.05 (s, 1H). 0382 Analysis for C8H2ClIN2S: 0383 Calcd: C, 29.98; H, 0.63; N, 8.74 0384 Found: C, 29.61; H, 0.87; N, 8.68.

REFERENCE EXAMPLE 10

4-Chloro-2-iodothieno2,3-bpyridine-5-carbonitrile 0385 To a solution of 4-chlorothieno2,3-bpyridine-5-carbonitrile (1.2 g, 6.16 mmol) Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977) in 72 mL of tetrahydrofuran at 78 C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (3.7 mL, 7.40 mmol). After stirring for 35 minutes, a solution of iodine (1.9 g, 7.40 mmol) in 8 mL of tetrahydrofuran is added dropwise over 20 minutes. The reaction mixture is stirred at 78 C. for 4 hours, then 85 mL of dichloromethane and 20 mL of water are added. The mixture is allowed to warm to room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic layer is washed with a solution of sodium thiosulfate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with dichloromethane to provide 1.0 g of 4-chloro-2-iodothieno2,3-bpyridine-5-carbonitrile as colorless crystals, mp 181-182 C.; 1H NMR (DMSO-d6) 8.00 (s, 1H), 8.88 (s, 1H); MS 320.8 (MH). 0386 Analysis for C8H2ClIN2S: 0387 Calcd: C, 29.98; H, 0.63; N, 8.74 0388 Found: C, 30.12; H, 0.83; N, 8.35.

REFERENCE EXAMPLE 11

4-Chlorothieno2,3-bpyridine-5-carboxylic Acid 0389 A mixture of ethyl 4-chlorothieno2,3-bpyridine-5-carboxylate (800 mg, 3.31 mmol) Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977) in 15 mL of ethanol and 5 mL of 2.5 N sodium hydroxide is heated at reflux for 90 minutes. The mixture is cooled to 0 C. and the pH is adjusted to 4 by the addition of 2 N hydrochloric acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration and washed with water to provide 250 mg of 4-chlorothieno2,3-bpyridine-5-carboxylic acid as a white solid, mp 172-174 C.; 1H NMR (DMSO-d6) 7.62 (d, J6 Hz, 1H), 8.14 (d, J6 Hz, 1H), 8.94 (s, 1H); MS 212.0 (MH). 0390 Analysis for C8H4ClNO2S: 0391 Calcd: C, 44.98; H, 1.89; N, 6.56 0392 Found: C, 44.99; H, 2.14; N, 6.43. 0393 An additional 230 mg of 4-chlorothieno2,3-bpyridine-5-carboxylic acid is obtained from the filtrate.

REFERENCE EXAMPLE 12

4-Chlorothieno2,3-bpyridine-5-carboxamide 0394 A mixture of 4-chlorothieno2,3-bpyridine-5-carboxylic acid (250 mg, 1.16 mmol) and 5 mL of thionyl chloride is heated at reflux for 2 hours. The mixture is concentrated in vacuo and dried. Acetone is added to the residue and the solution is cooled to 0 C. Aqueous ammonium hydroxide (15 mL) is slowly added and the reaction mixture is stirred at 0 C. for 2 hours. The reaction mixture is concentrated in vacuo and water is added to the residue. The resultant solids are collected by filtration washing with water to provide 175 mg of 4-chlorothieno2,3-bpyridine-5-carboxamide as a white solid, mp 159-160 C.; 1H NMR (DMSO-d6) 7.57 (d, J6 Hz, 1H), 7.84 (s, 1H), 8.11 (s, 1H), 8.12 (d, J6 Hz, 1H), 8.61 (s, 1H); 0395 MS 213.0, 214.9 (MH). 0396 Analysis for C8H5ClN2OS: 0397 Calcd: C, 45.18; H, 2,37; N, 13.17 0398 Found: C, 44.88; H, 2.35; N, 12.77.

REFERENCE EXAMPLE 13

4-Chlorothieno2,3-bpyridine-5-carbonitrile 0399 A mixture of 4-chlorothieno2,3-bpyridine-5-carboxamide (145 mg, 0.68 mmol) and cyanuric chloride (200 mg, 1.08 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 30 minutes. Ice is added to the reaction mixture and the resultant solids are collected by filtration washing with water to provide 84 mg of 4-chlorothieno2,3-bpyridine-5-carbonitrile as a white solid, mp 100-103 C.; 1H NMR (DMSO-d6) 7.66 (d, J6 Hz, 1H), 8.26 (d, J6 Hz, 1H), 9.03 (s, 1H); MS 195.0 (MH). 0400 Analysis for C8H3ClN2S0.4H2O: 0401 Calcd: C, 47.60; H, 1.90; N, 13.88 0402 Found: C, 47.65; H, 1.55; N, 13.90.

REFERENCE EXAMPLE 14

4-Chloro-2-methylthieno2,3-bpyridine-5-carbonitrile 0403 To a solution of 4-chlorothieno2,3-bpyridine-5-carbonitrile (0.3 g, 1.54 mmol) in 15 mL of tetrahydrofuran at 78 C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (0.93 mL, 1.85 mmol). After stirring for 45 min, a solution of iodomethane (0.115 mL, 1.85 mmol) in 1 mL of tetrahydrofuran is added dropwise. The reaction mixture is stirred at 78 C. for 4 hours, then dichloromethane and water are added. The mixture is allowed to warm to room temperature, then partitioned between water and dichloromethane. The organic layer is washed with a solution of sodium thiosulfate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:9 ethyl acetate:hexane to provide 0.1 g of 4-chloro-2-methylthieno2,3-bpyridine-5-carbonitrile as colorless crystals, mp 101-102 C.; 1H NMR (DMSO-d6) 2.68 (s, 3H), 7.39 (s, 1H), 8.92 (s, 1H); MS 209.0 (MH). 0404 Analysis for C9H5ClN2S: 0405 Calcd: C, 51.80; H, 2.42; N, 13.42 0406 Found: C, 52.11; H, 2.14; N, 13.08.

REFERENCE EXAMPLE 15

7-Chloro-2-methylthieno3,2-bpyridine-6-carbonitrile 0407 To a solution of 7-chlorothieno3,2-bpyridine-6-carbonitrile (500 mg, 2.57 mmol) in 15 mL of tetrahydrofuran at 78 C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (1.6 mL, 3.21 mmol). After stirring for 40 minutes, iodomethane (616 mg, 0.27 mL, 4.34 mmol) is added dropwise over 7 minutes. The reaction mixture is stirred at 78 C. for 5 hours, then the mixture is partitioned between 20 mL of dichloromethane and 10 mL of water. The organic layer is washed with a saturated aqueous ammonium chloride solution, followed by saturated aqueous sodium chloride, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 274 mg of 7-chloro-2-methylthieno3,2-bpyridine-6-carbonitrile as a white solid, mp 163-164 C.; 1H NMR (DMSO-d6) 82.73 (s, 3H), 7.55 (s, 1H), 9.03 (s, 1H); MS 209.0, 211.1 (MH). 0408 Analysis for C9H5ClN2S: 0409 Calcd: C, 51.80; H, 2.42; N, 13.42 0410 Found: C, 51.56; H, 2.25; N, 13.43.

REFERENCE EXAMPLE 16

4-Thiophen-2-yl-butyric Acid Methyl Ester 0411 A mixture of 4-(2-thienyl)butyric acid (4.25 g, 25.0 mmol) and 3 mL of concentrated sulfuric acid in 25 mL of methanol is heated at reflux for 2 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer is separated and passed through a short pad of silica gel. The filtrate is concentrated and purified by flash column chromatography eluting with 1:5 ethyl acetate:hexane to provide 4.02 g of 4-thiophen-2-yl-butyric acid methyl ester as a yellow oil, 1H NMR (DMSO-d6) 1.85 (quintet, J7 Hz, 2H), 2.35 (t, J7 Hz, 2H), 2.81 (t, J7 Hz, 2H), 3.59 (s, 3H), 6.84 (m, 1H), 6.95 (m, 1H), 7.32 (dd, J5, 1 Hz, 1H); MS 185.0 (MH)0412 Analysis for C9H12O2S: 0413 Calcd: C, 58.67; H, 6.56; N, 0.00 0414 Found: C, 58.87; H, 6.57; N, 0.02.

REFERENCE EXAMPLE 17

4-(5-Nitro-thiophen-2-yl)-butyric Acid Methyl Ester 0415 To 8 mL of acetic anhydride at 20 C. is added 1.2 mL of nitric acid (d1.5). The mixture is kept at 20 C., and a solution of 4-thiophen-2-yl-butyric acid methyl ester (1.84 g, 10.0 mmol) in 12 mL of acetic anhydride is added dropwise. The reaction mixture is stirred for 10 minutes after completion of addition, and poured into an ice-water mixture. The product is extracted with ethyl acetate and the organic layer is washed with 10 N aqueous sodium hydroxide solution, dried and concentrated. The residue is purified by flash column chromatography eluting with 1:4 ethyl acetate:hexane to provide 1.32 g of 4-(5-nitro-thiophen-2-yl)-butyric acid methyl ester as a yellow oil; 1H NMR (DMSO-d6) 1.93 (quintet, J7 Hz, 2H), 2.41 (t, J7 Hz, 2H), 2.88 (t, J7 Hz, 2H), 3.59 (s, 3H), 7.04 (d, J5 Hz, 1H), 8.01 (d, J5 Hz, 1H); MS 229.0 (M)0416 Analysis for C9H11NO4S: 0417 Calcd: C, 47.15; H, 4.84; N, 6.11 0418 Found: C, 47.17; H, 4.91; N, 6.36.

REFERENCE EXAMPLE 18

4-(5-Amino-thiophen-2-yl)-butyric Acid Methyl Ester 0419 A mixture of 4-(5-nitro-thiophen-2-yl)-butyric acid methyl ester (2.29 g, 10.0 mmol) and palladium hydroxide (500 mg, 20% on carbon) in 30 mL of ethyl acetate and 30 mL of methanol is hydrogenated at 50 psi for 48 hours. The reaction mixture is filtered and concentrated. The residue is purified by flash column chromatography eluting with 1:3 ethyl acetate:hexane to provide 1.32 g of 4-(5-amino-thiophen-2-yl)-butyric acid methyl ester as a dark oil; 1H NMR (DMSO-d6) 1.74 (m, 2H), 2.38 (m, 2H), 2.54 (m, 2H), 3.59 (s, 3H), 5.66 (d, J3 Hz, 1H), 6.24 (d, J3 Hz, 1H); MS 200.2 (MH).

REFERENCE EXAMPLE 19

4-(4-Chloro-5-cyano-thieno2,3-bpyridin-2-yl)-butyric Acid Methyl Ester 0420 A mixture of 4-(5-amino-thiophen-2-yl)-butyric acid methyl ester (1.00 g, 5.0 mmol) and ethyl (ethoxymethylene)cyanoacetate (930 mg, 5.5 mmol) in 50 mL of toluene is heated at reflux for 1 hour. The reaction mixture is concentrated and 50 mL of Dowtherm-A is added. The mixture is heated at reflux for 3 hours and cooled to room temperature. The crude reaction mixture is passed through a short pad of silica gel, eluting with dichloromethane followed by 10% methanol in dichloromethane. The crude product is further purified by flash column chromatography eluting with 10% methanol in dichloromethane followed by another flash column chromatography eluting with 10% methanol in ethyl acetate to provide 136 mg of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno2,3-bpyridin-2-yl)butanoate as a tan solid. 0421 A mixture of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno2,3-bpyridin-2-yl)butanoate (136 mg) and 2 drops of N,N-dimethylformamide in 5 mL of phosphorous oxychloride is heated at reflux for 10 minutes and concentrated. To the residue is added dichloromethane and the solution is washed with 1% aqueous sodium bicarbonate solution. The organic layer is dried and concentrated. The residue is purified by flash column chromatography eluting with dichloromethane to provide 126 mg of 4-(4-chloro-5-cyano-thieno2,3-bpyridin-2-yl)-butyric acid methyl ester as a tan solid, mp 55-57 C.; 1H NMR (DMSO-d6) 1.98 (quintet, J7 Hz, 2H), 2.42 (t, J7 Hz, 2H), 3.04 (t, J7 Hz, 2H), 3.59 (s, 3H), 7.42 (s, 1H), 8.94 (s, 1H); MS 295.1 (MH)0422 Analysis for C13H11ClN2O2S: 0423 Calcd: C, 52.97; H, 3.76; N, 9.50 0424 Found: C, 52.80; H, 3.90; N, 9.25.

REFERENCE EXAMPLE 20

7-Chloro-2-formylthieno3,2-bpyridine-6-carbonitrile 0425 To a solution of 7-chlorothieno3,2-bpyridine-6-carbonitrile (200 mg, 1.03 mmol) in 6 mL of tetrahydrofuran at 78 C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (0.645 mL, 1.29 mmol). After stirring for 40 minutes, N,N-dimethylformamide (99 mg, 1.35 mmol) is added dropwise over 5 minutes. The reaction mixture is stirred at 78 C. for 4 hours, then dichloromethane is added and the reaction mixture is allowed to warm to room temperature. Water is added and the organic phase is separated and the aqueous phase is extracted with dichloromethane. The organic phases are combined and washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 30% ethyl acetate in hexane to provide 62 mg of 7-chloro-2-formylthieno3,2-bpyridine-6-carbonitrile as a white solid, mp 188-189 C.; 1H NMR (DMSO-d6) 8.72 (s, 1H), 9.26 (s, 1H), 10.28 (s, 1H); MS 221.9, 223.9 (MH)0426 Analysis for C9H3ClN2OS: 0427 Calcd: C, 48.55; H, 1.36; N, 12.58 0428 Found: C, 48.69; H, 1.48; N, 12.30.

REFERENCE EXAMPLE 21

tert-Butyl (2E)-3-(7-chloro-6-cyanothieno3,2-bpyridin-2-yl)prop-2-enoate 0429 To a solution of 7-chlorothieno3,2-bpyridine-6-carbonitrile (100 mg, 0.45 mmol) in 5 mL of dichloromethane is added, in portions, (tert-butoxycarbonylmethylene)triphenylphosphorane (0.645 mL, 1.29 mmol). After stirring for 2.5 hours, the reaction mixture is allowed to stand at room temperature overnight. The mixture is concentrated to its volume and is purified by flash column chromatography eluting with dichloromethane to provide 126 mg of tert-butyl (2E)-3-(7-chloro-6-cyanothieno3,2-bpyridin-2-yl)prop-2-enoate as a white solid, mp 193-194 C.; 1H NMR (CDCl3) 1.55 (s, 9H), 6.46 (d, J16 Hz,1H), 7.26 (s, 1H), 7.70 (s, 1H), 7.77 (d, J16 Hz, 1H), 8.84 (s, 1H); MS 321.1, 323.2 (MH)0430 Analysis for C15H13ClN2O2S: 0431 Calcd: C, 56.16; H, 4.08; N, 8.73 0432 Found: C, 55.76; H, 3.76; N, 8.50.

REFERENCE EXAMPLE 22

7-Chloro-2-4-(dimethylamino)phenylthieno3,2-bpyridine-6-carbonitrile 0433 A mixture of 7-chloro-2-iodothieno3,2-bpyridine-6-carbonitrile (321 mg, 1.0 mmol), 4-(dimethylamino)phenylboronic acid (248 mg, 1.5 mmol) and 58 mgs of tetrakis(triphenylphosphine)Palladium (0) in 13 mL of ethylene glycol dimethyl ether and 11 mL of aqueous saturated sodium bicarbonate is heated at reflux for 6 hours. 4-(dimethylamino)phenylboronic acid (105 mg) and tetrakis(triphenylphosphine)Palladium (0) (29 mg) are added and the reaction mixture is heated at reflux for 6 hours. The mixture is treated with water and extracted into dichloromethane and the organic phase is washed with brine and dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in dichloromethane to provide 187 mg (60%) of 7-chloro-2-4-(dimethylamino)phenylthieno3,2-bpyridine-6-carbonitrile as an orange solid, mp 270-272 C.; 1H NMR (CDCl3) 3.07 (s, 6H), 6.73 (d, J5 Hz, 2H), 7.58 (s, 1H), 7.63 (d, J5 Hz, 2H), 8.74 (s, 1H); HRMS found: 314.05127.

REFERENCE EXAMPLE 23

7-Chloro-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile 0434 A mixture of 7-chloro-2-iodo-thieno3,2-bpyridine-6-carbonitrile (1.00 g, 3.12 mmol), 4-formylphenylboronic acid (936 mg, 6.24 mmol) and 108 mgs of tetrakis(triphenylphosphine)Palladium (0) in 30 mL of ethylene glycol dimethyl ether and 25 mL of aqueous saturated sodium bicarbonate is heated at reflux for 4 hours. The mixture is cooled and the precipitate is collected by filtration washing with ethyl acetate and diethyl ether to provide 818 mg of 7-chloro-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp 300-305 C.; 1H NMR (CDCl3) 7.93 (d, J8 Hz, 2H), 7.96 (s, 1H), 8.03 (d, J8 Hz, 2H), 8.87 (s, 1H), 10.1 (s, 1H), MS 298.0, 300.0 (MH)H.

REFERENCE EXAMPLE 24

7-Chloro-2-4-(dimethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile 0435 A mixture of 7-chloro-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile (700 mg, 2.34 mmol) and 6.0 mL of 2.0 M dimethylamine in tetrahydrofuran in 30 mL of dichloromethane and 5 mL of dimethylformamide is cooled to 0-5 C. Sodium triacetoxyborohydride (2.5 g, 11.7 mmol) is added in portions and after 5 minutes 0.10 mL of acetic acid is added. The mixture is stirred at room temperature for 2 hours then quenched by the addition of ice water and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of dichloromethane to 10% methanol in dichloromethane to provide 496 mg (65%) of 7-chloro-2-4-(dimethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp 166-168 C.; 1H NMR (DMSO-d6) 2.21 (s, 6H), 3.52 (s, 2H), 7.48 (d, J8 Hz, 2H), 7.95 (d, J8 Hz, 2H), 8.28 (s, 1H), 9.11 (s, 1H); MS 328.1, 330.1(MH); 0436 HRMS found: 328.06622 0437 Analysis for C17H14ClN3S0.3H2O: 0438 Calcd: C, 61.27; H, 4.42; N, 12.61 0439 Found: C, 61.22; H, 4.13; N, 12.50.

EXAMPLE 1

7-(2,4-Dichloro-5-methoxyanilino)aminothieno3,2-bpyridine-6-carbonitrile 0440 A mixture of 2,4-dichloro-5-methoxyaniline (336 mg, 1.75 mmol) and 60% sodium hydride (70 mg, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 30 minutes. The solution is cooled and 7-chlorothieno3,2-bpyridine-6-carbonitrile (200 mg, 1.02 mmol) is added. The reaction mixture is heated at reflux for 3.5 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 131 mg of 7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as a tan solid, mp 216-220 C.; 1H NMR (DMSO-d6) 3.85 (s, 3H), 7.40 (3, 1H), 7.46 (d, J5 Hz, 1H), 7.76 (s, 1H), 8.11 (d, J5 Hz, 1H), 8.61 (s, 1H), 9.71 (s, 1H); MS 350.2 (MH). 0441 Analysis for C15H9Cl2N3OS0.25H2O: 0442 Calcd: C, 50.79; H, 2.70; N, 11.85. 0443 Found: C, 50.79; H, 2.48; N, 11.56.

EXAMPLE 2

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-phenylthieno3,2-bpyridine-6-carbonitrile 0444 A mixture of 7-oxo-2-phenyl-4,7-dihydrothieno3,2-bpyridine-6-carbonitrile (878 mg, 3.48 mmol) and 10 mL of phosphorous oxychloride is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and hexane is added. The solids are collected by filtration and stirred with saturated aqueous sodium bicarbonate. The solids are collected by filtration washing with water, ethyl acetate and methanol to provide 751 mg of 7-chloro-2-phenylthieno3,2-bpyridine-6-carbonitrile that is not purified. 0445 A mixture of 2,4-dichloro-5-methoxyaniline (336 mg, 1.75 mmol) and 60% sodium hydride (69 mg, 1.73 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 40 minutes. The solution is cooled and 7-chloro-2-phenylthieno3,2-bpyridine-6-carbonitrile (270 mg, 1.0 mmol) is added. The reaction mixture is heated at reflux for 5.5 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The aqueous layer is acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is treated with ethyl acetate and hexane and the insoluble material is collected by filtration. The solid is suspended in hot methanol and ethyl acetate and the mixture is filtered while warm to provide 50 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-phenylthieno3,2-bpyridine-6-carbonitrile as a light brown solid, mp 274-276 C.; 1H NMR (DMSO-d6) 3.86 (s, 3H), 7.40 (s, 1H), 7.44-7.53 (m, 3H), 7.73 (d, J7 Hz, 2H), 7.78 (s, 1H), 7.94 (s, 1H), 8.63 (s, 1H), 9.78 (s, 1H); MS 426.1 (MH). 0446 Analysis for C21H13Cl2N3OS0.25H2O: 0447 Calcd: C, 58.54; H, 3.16; N, 9.75. 0448 Found: C, 58.50; H, 3.07; N, 9.49.

EXAMPLE 3

2-Bromo-7-(2,4-dichloro-5-methoxyphenyl)amino-thieno3,2-bpyridine-6-carbonitrile 0449 A mixture of 2,4-dichloro-5-methoxyaniline (221.8 mg, 1.16 mmol) and 60% sodium hydride (46.2 mg, 1.16 mmol) in 6 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 2-bromo-7-chlorothieno3,2-bpyridine-6-carbonitrile (150 mg, 0.55 mmol) is added. The resulting reaction mixture is heated at reflux for 5 hours, cooled to room temperature, and then partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 40% ethyl acetate in hexane to provide 114.6 mg of 2-bromo-7-(2,4-dichloro-5-methoxyphenyl)amino-thieno3,2-bpyridine-6-carbonitrile as a white solid, mp 228-229 C.; 1H NMR (DMSO-d6) 3.86 (s, 3H), 7.40 (s, 1H), 7.71 (s, 1H), 7.80 (s, 1H), 8.61 (s, 1H), 9.80 (s, 1H); MS 426.0, 428.0 (MH). 0450 Analysis for C15H8BrCl2N3OS: 0451 Calcd: C, 41.98; H, 1.88; N, 9.79. 0452 Found: C, 42.08; H, 2.09; N, 9.62.

EXAMPLE 4

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile 0453 A mixture of 2,4-dichloro-5-methoxyaniline (380 mg, 2.0 mmol) and 60% sodium hydride (80 mg, 2.0 mmol) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-iodothieno3,2-bpyridine-6-carbonitrile (320 mg, 1.0 mmol) is added and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2% methanol in chloroform to provide 240 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 233-234 C.; 1H NMR (DMSO-d6) 63.85 (s, 3H), 7.38 (s, 1H), 7.77 (s, 1H), 7.79 (s, 1H), 8.56 (s, 1H), 9.74 (s, 1H); MS 475.9 (MH). 0454 Analysis for C15H8Cl2N3OS: 0455 Calcd: C, 37.84; H, 1.69; N, 8.83. 0456 Found: C, 37.44; H, 1.75; N, 8.80.

EXAMPLE 5

4-(2,4-Dichloro-5-methoxyphenyl)aminothieno2,3-bpyridine-5-carbonitrile 0457 A mixture of 2,4-dichloro-5-methoxyaniline (300 mg, 1.57 mmol) and 60% sodium hydride (70 mg, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 30 minutes The solution is cooled and 4-chlorothieno2,3-bpyridine-5-carbonitrile (150 mg, 0.8 mmol) Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977) is added. The reaction mixture is heated at reflux for 3.5 hours. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:3 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material is collected by filtration to provide 60 mg of 4-(2,4-dichloro-5-methoxyphenyl)aminothieno2,3-bpyridine-5-carbonitrile as a tan solid, mp 197-199 C.; 1H NMR (DMSO-d6) 3.85 (s, 3H), 7.38 (s, 1H), 7.68 (d, J5.7 Hz, 1H), 7.76 (s, 1H), 7.81 (d, J5.7 Hz, 1H), 8.43 (s, 1H), 9.80 (s, 1H); MS 348.2 (MH). 0458 Analysis for C15H9Cl21N3OS: 0459 Calcd: C, 51.44; H, 2.59; N, 12.00. 0460 Found: C, 51.57; H, 2.99; N, 11.60.

EXAMPLE 6

4-(3-Chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenyl)aminothieno2,3-bpyridine-5-carbonitrile 0461 A mixture of (3-chloro-4-(1-methyl-1H-imidazol-2-yl)sulfanylaniline (135 mg, 0.57 mmol), pyridine hydrochloride (66 mg, 0.57 mmol) and 4-chlorothieno2,3-bpyridine-5-carbonitrile (0.1 g, 0.52 mmol) in 4 mL of 2-ethoxyethanol is heated at reflux for 24 hours. The solution is cooled and the solvent is evaporated. The resultant residue is treated with a minimum amount of methanol and the product is purified by flash column chromatography eluting with 3% methanol in dichloromethane. The fractions containing product are combined and concentrated. Ethyl acetate is added and the insoluble material collected by filtration to provide 55 mg of 4-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenyl)aminothieno2,3-bpyridine-5-carbonitrile as a tan solid, mp>240 C.; 1H NMR (DMSO-d6) 3.61 (s, 3H), 6.53 (d, J9 Hz, 1H), 7.15 (m, 1H), 7.17 (s, 1H), 7.44 (m, 1H), 7.52 (s, 1H), 7.54 (s, 1H), 7.81 (d, J6 Hz, 1H), 8.53 (s, 1H), 9.76 (s, 1H); MS 396.2 (MH). 0462 Analysis for C18H12ClN5S2.0.05H2O: 0463 Calcd: C, 54.33; H, 3.04; N, 17.60. 0464 Found: C, 54.21; H, 3.06; N, 17.56.

EXAMPLE 7

4-(2,4-Dichloro-5-methoxyphenyl)amino-2-iodothieno2,3-bpyridine-5-carbonitrile 0465 A mixture of 2,4-dichloro-5-methoxyaniline (1.1 g, 5.7 mmol) and 60% sodium hydride (285 mg, 9.9 mmol) in 30 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-chloro-2-iodothieno2,3-bpyridine-5-carbonitrile (1.0 g, 3.12 mmol) is added. The reaction mixture is heated at reflux for 5 hours then allowed to stir at room temperature overnight. The resultant dark solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 0.5:9.5 methanol dichloromethane to provide 0.28 g of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno2,3-bpyridine-5-carbonitrile as an off white solid, mp 231-233 C. An additional 0.09 g is obtained by chromatography of a mixture of unreacted starting material and product using a gradient of 9:1 to 1:1 hexane:ethyl acetate. 1H NMR (DMSO-d6) 3.87 (s, 3H), 7.36 (s, 1H), 7.76 (s, 1H), 8.11 (s, 1H), 8.39 (s, 1H), 9.76 (s, 1H); MS 473.8 (MH). 0466 Analysis for C15H8Cl21N3OS0.05H2O: 0467 Calcd: C, 37.84; H, 1.69; N, 8.83. 0468 Found: C, 37.77; H, 1.71; N, 8.81.

EXAMPLE 8

4-(2,4-Dichloro-5-methoxyphenyl)amino-2-methylthieno2,3-bpyridine-5-carbonitrile 0469 A mixture of 2,4-dichloro-5-methoxyaniline (0.15 g, 0.73 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-chloro-2-methylthieno2,3-bpyridine-5-carbonitrile (0.06 g, 0.29 mmol) is added. The reaction mixture is heated at reflux for 3 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 3:7 ethyl acetate:hexane The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 79 mg of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-methylthieno2,3-bpyridine-5-carbonitrile as a tan solid, mp 179-181 C.; 1H NMR (DMSO-d6) 2.57 (s, 3H), 3.85 (s, 3H), 7.32 (s, 1H), 7.39 (s, 1H), 7.74 (s, 1H), 8.35 (s, 1H), 9.61 (s, 1H); MS 362.1 (MH)0470 Analysis for C16H11Cl2N3OS 0471 Calcd: C, 52.76; H, 3.04; N, 11.54. 0472 Found: C, 52.46; H, 3.22; N, 11.14.

EXAMPLE 9

7-(2,4-Dichloro-5-methoxyphenyl) amino-2-methylthieno3,2-bpyridine-6-carbonitrile 0473 A mixture of 2,4-dichloro-5-methoxyaniline (507 mg, 2.64 mmol) and 60% sodium hydride (105.6 mg, 2.64 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-methylthieno3,2-bpyridine-6-carbonitrile (275.3 mg, 1.32 mmol) is added. The reaction mixture is heated at reflux for 6 hours, cooled to room temperature and partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane followed by preparative thin layer chromatography developing with 20% ethyl acetate in dichloromethane, to provide 108 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-methylthieno3,2-bpyridine-6-carbonitrile as an off white solid, mp 213-214 C.; 1H NMR (DMSO-d6) 2.51 (s, 3H), 3.85 (s, 3H), 7.20 (s, 1H), 7.35 (s, 1H), 7.75 (s, 1H), 8.55 (s, 1H), 9.56 (s, 1H); MS 362.1, 364.3 (MH). 0474 Analysis for C16H11Cl2N3OS: 0475 Calcd: C, 52.76; H, 3.04; N, 11.54. 0476 Found: C, 52.86; H, 2.95; N, 11.56.

EXAMPLE 10

7-(2,4-Dichlorophenyl)aminothieno3,2-bpyridine-6-carbonitrile 0477 A mixture of 2,4-dichloroaniline (333.8 mg, 2.06 mmol) and 60% sodium hydride (82.4 mg, 2.06 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chlorothieno3,2-bpyridine-6-carbonitrile (200 mg, 1.03 mmol) is added. The resulting reaction mixture is heated at reflux for 7 hours, cooled to room temperature, and concentrated in vacuo. The residue is treated with water for 1 hour. The precipitate is filtered, washed with water, and air dried. The resultant solid is purified by flash column chromatography eluting with a gradient of 1% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 173.1 mg of 7-(2,4-dichlorophenyl)aminothieno3,2-bpyridine-6-carbonitrile as a white solid, mp 198-200 C.; 1H NMR (DMSO-d6) 7.47 (d, J4 Hz, 1H), 7.54 (dd, J6, 2 Hz, 1H), 7.59 (d, J6 Hz, 1H), 7.81 (d, J2 Hz, 1H), 8.12 (d, J4 Hz, 1H), 8.61 (s, 1H), 9.67 (s, 1H); MS 318.1, 320.2 (MH). 0478 Analysis for C14H7Cl2N3S-0.3H2O: 0479 Calcd: C, 51.64; H, 2.35; N, 12.91. 0480 Found: C, 51.64; H, 2.08; N, 12.86.

EXAMPLE 11

7-(2,4-Dichlorophenoxy)thieno3,2-bpyridine-6-carbonitrile 0481 A mixture of 7-chlorothieno3,2-bpyridine-6-carbonitrile (200 mg, 1.03 mmol), potassium carbonate (194.9 mg, 1.41 mmol) and 2,4-dichlorophenol (218.3 mg, 1.34 mmol) in 3 mL of N,N-dimethylformamide is stirred at 110 C. for 4 hours and allowed to cool to ambient temperature. The reaction mixture is treated with water and stirred at ambient temperature for 10 minutes. The crude solid is collected by filtration washing with water, dried in vacuo, then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 244 mg of 7-(2,4-dichlorophenoxy)thieno3,2-bpyridine-6-carbonitrile as a white solid, mp 158-160 C.; 1H NMR (DMSO-d6) 7.63 (dd, J6, 2 Hz, 1H), 7.68 (d, J4 Hz, 1H), 7.74 (d, J6 Hz, 1H), 7.80 (d, J2 Hz, 1H), 8.33 (d, J4 Hz, 1H), 9.03 (s, 1H); MS 320.9, 322.9 (MH). 0482 Analysis for C14H6Cl2N2OS: 0483 Calcd: C, 52.35; H, 1.88; N, 8.72. 0484 Found: C, 52.28; H, 1.69; N, 8.49.

EXAMPLE 12 0485 7-(2,4-Dichlorophenyl)thiothieno3,2-bpyridine-6-carbonitrile 0486 A mixture of 7-chlorothieno3,2-bpyridine-6-carbonitrile (200 mg, 1.03 mmol) and 2,4-dichlorothiophenol (202.9 mg, 1.13 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 1 hour, and then concentrated in vacuo. The resulting residue is treated with water and stirred for 1 hour. The precipitate is filtered, washed with water, air dried, and then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 249.0 mg of 7-(2,4-dichlorophenyl)thiothieno3,2-bpyridine-6-carbonitrile as a white solid, mp 126-128 C.; 1H NMR (DMSO-d6) 7.47 (dd, J6, 2 Hz, 1H), 7.54 (d, J6 Hz, 1H), 7.73 (d, J4 Hz, 1H), 7.88 (d, J2 Hz, 1H), 8.43 (d, J4 Hz, 1H), 9.09 (s, 1H); MS 336.9, 339.0 (MH). 0487 Analysis for C14H6Cl2N2S2: 0488 Calcd: C, 49.86; H, 1.79; N, 8.31. 0489 Found: C, 49.87; H, 1.67; N, 8.18.

EXAMPLE 13

7-(2,4-Dichlorobenzyl) aminothieno3,2-bpyridine-6-carbonitrile 0490 A mixture of 7-chlorothieno3,2-bpyridine-6-carbonitrile (200 mg, 1.03 mmol), 2,4-dichlorobenzylamine (217.6 mg, 0.17 mL, 1.24 mmol), N,N-diisopropylethylamine in 5 mL of 2-ethoxyethanol is heated at reflux for 4 hours. After cooling the mixture is concentrated in vacuo and the residue is treated with a saturated aqueous sodium bicarbonate solution for 1 hour. The precipitate is collected by filtration, washed with water, dried in vacuo, and then purified by flash column chromatography eluting with a gradient of 2% methanol in dichloromethane to 4% methanol in dichloromethane to provide 261.2 mg of 7-(2,4-dichlorobenzyl)aminothieno3,2-bpyridine-6-carbonitrile as a white solid, mp 215-216 C.; 1H NMR (DMSO-d6) 4.95 (d, J5 Hz, 2H), 7.28 (d, J6 Hz, 1H), 7.40 (dd, J6, 2 Hz, 1H), 7.46 (dd, J4, 2 Hz, 1H), 7.69 (d, J2 Hz, 1H), 8.12 (d, J5 Hz, 1H), 8.16 (m, 1H) 8.47 (d, J6 Hz, 1H); MS 334.0, 335.8 (MH). 0491 Analysis for C15H9Cl2N3S: 0492 Calcd: C, 53.90; H, 2.71; N, 12.57. 0493 Found: C, 53.58; H, 2.43; N, 12.49.

EXAMPLE 14

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile 0494 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (240 mg, 0.50 mmol), 4-formylphenylboronic acid (150 mg, 1.0 mmol) and 4 mg of tetrakis(triphenylphosphine)Palladium(0) in 20 mL of ethylene glycol dimethyl ether and 16 mL of saturated aqueous sodium bicarbonate is heated at reflux for 2 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with chloroform to provide 160 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 261-262 C.; 1H NMR (DMSO-d6) 3.87 (s, 3H), 7.41 (s, 1H), 7.63 (s, 1H), 7.90-8.03 (m, 4H), 8.15 (s, 1H), 8.65 (s, 1H), 9.83 (s, 1H), 10.05 (s, 1H); 0495 MS 454.0 (MH). 0496 Analysis for C22H13Cl2N3O2S1.0H2O: 0497 Calcd: C, 55.94; H, 3.20; N, 8.90. 0498 Found: C, 56.24; H, 2.87; N, 9.02.

EXAMPLE 15 0499 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-morpholinylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile 0500 Morpholine (16 mg, 0.18 mmol) is added to a suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile (66 mg, 0.15 mmol) in 5 mL of dichloromethane and 0.5 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (85 mg, 0.40 mmol) is added. After stirring at 0 C. for 1.5 hours, acetic acid (0.02 mL) is added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between water and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography to provide 48 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-morpholinylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 244-245 C.; 1H NMR (DMSO-d6) 2.36 (m, 4H), 3.50 (s, 2H), 3.57 (m, 4H), 3.85 (s, 3H), 7.31 (s, 1H), 7.42 (d, J8 Hz, 2H), 7.68 (d, J8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 525.2 (MH).

EXAMPLE 16

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-methylpiperazin-1-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile 0501 N-methylpiperazine (177 L, 1.6 mmol) is added to a suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile (560 mg, 1.23 mmol) in 12 mL of dichloromethane and 3 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (1.3 g, 6.13 mmol) is added. After stirring at 0 C. for 10 minutes, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 5.5 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 215 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-methylpiperazin-1-ylmethyl) phenylthieno3,2-bpyridine-6-carbonitrile as white crystals, mp 226-228 C.; 1H NMR (DMSO-d6) 2.17 (s, 3H), 2.37 (br s, 8H), 3.49 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.40 (d, J8 Hz, 2H), 7.67(d, J8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 538.2 (MH). 0502 Analysis for C27H25Cl2N5OS-0.25H2O: 0503 Calcd: C, 59.72; H, 4.73; N, 12.90. 0504 Found: C, 59.60; H, 4.51; N, 12.88.

EXAMPLE 17

7-(2-4-Dichloro-5-methoxyphenyl)amino-2-(4-4-(2-hydroxyethyl)piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0505 4-(2-Hydroxyethyl)Piperazine (104 mg, 0.80 mmol) is added to a suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile (227 mg, 0.50 mmol) in 15 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (800 mg, 3.8 mmol) is added. After stirring at 0 C. for 1.5 hours, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 10% methanol in dichloromethane to provide 100 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-4-(2-hydroxyethyl)Piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile as white crystals, mp 189-190 C.; 1H NMR (DMSO-d6) 2.27-2.44 (m, 10H), 3.41-3.50 (m, 4H), 3.85 (s, 3H), 4.36 (s, 1H), 7.37 (s, 1H), 7.40 (d, J8 Hz, 2H), 7.67 (d, J8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.74 (s, 1H); MS 566.3 (MH).

EXAMPLE 18

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(Piperidin-1-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile 0506 Piperidine (50 mg, 0.59 mmol) is added to a suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile (200 mg, 0.44 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (500 mg, 2.4 mmol) is added. After stirring at 0 C. for 1.5 hours, a few drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to 5% methanol in ethyl acetate to provide 41 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(piperidin-1-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 218-220 C.; 1H NMR (DMSO-d6) 1.38 (m, 2H), 1.50 (m, 4H), 2.33 (m, 4H), 3.46 (m, 2H), 3.85 (s, 3H), 7.38 (s, 1H), 7.40 (d, J8 Hz, 2H), 7.67 (d, J8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.72 (s, 1H); MS 521.3 (MH).

EXAMPLE 19

4-6-Cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2-ylbenzoic acid 0507 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (500 mg, 1.05 mmol), 4-carboxylphenylboronic acid (350 mg, 2.12 mmol) and 100 mg of tetrakis(triphenylphosphine)Palladium(0) in 50 mL of ethylene glycol dimethyl ether and 35 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of chloroform to 10% methanol in chloroform to provide 4-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2-ylbenzoic acid as yellow crystals, mp>300 C.; 1H NMR (DMSO-d6) 3.86 (s, 3H), 7.40 (s, 1H), 7.78 (s, 1H), 7.86 (d, J8 Hz, 2H), 8.03 (d, J8 Hz, 2H), 8.03 (s, 1H), 8.08 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 13.14 (s, 1H); MS 470.2 (MH).

EXAMPLE 20

4-6-Cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2-ylbenzamide 0508 1,1-Carbonyldiimidazole (100 mg, 0.61 mmol) is added to a suspension of 4-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2-ylbenzoic acid (130 mg, 0.28 mmol) in 10 mL of N,N-dimethylformamide. After stirring at 60 C. for 2 hours the reaction mixture is allowed to cool to room temperature and ammonia gas is bubbled through the mixture for 15 minutes. The mixture is stirred at room temperature for an additional 60 minutes and poured into 50 g of ice and stirred for 30 minutes. The mixture is adjusted to pH 4 with concentrated hydrochloric acid and stirred for 60 minutes. The resulting precipitate is collected by filtration washing with water and dried under reduced pressure. The resulting solid is purified by flash column chromatography eluting with a gradient of ethyl acetate to 20% methanol in ethyl acetate to provide 12.3 mg of 4-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2-ylbenzamide as a gray solid, mp>300 C.; 1H NMR (DMSO-d6) 3.86 (s, 3H), 7.40 (s, 1H), 7.48 (s, 1H), 7.78 (s, 1H), 7.82 (d, J8 Hz, 2H), 7.97 (d, J8 Hz, 2H), 8.06 (s, 2H), 8.08 (s, 1H), 8.63 (s, 1H), 9.78 (s, 1H); MS 468.9, 471.1 (MH).

EXAMPLE 21

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(4-methoxyphenyl)ethynylthieno3,2-bpyridine-6-carbonitrile 0509 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (134 mg, 0.28 mmol), 1-ethynyl-4-methoxybenzene (50 L, 0.39 mmol), 3 mg of tetrakis(triphenylphosphine)Palladium(0) and 5 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 24 hours. An additional 1 mL of triethylamine and 4 mL of benzene are added and the reaction is heated at reflux for 6 hours. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of ethyl acetate. The insoluble material is removed by filtration, washing with ethyl acetate. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 4:1 hexane:ethyl acetate to provide 92 mg of 7-(2,4-dichloro-5-carbonitrile as yellow crystals, mp 249-250 C.; 1H NMR (DMSO-d6) 3.81 (s, 3H), 3.86 (s, 3H), 7.01 (d, J7 Hz, 2H), 7.40 (s, 1H), 7.55 (d, J7 Hz, 2H), 7.70 (s, 1H), 7.79 (s, 1H), 8.65 (s, 1H), 9.81 (s, 1H); MS 477.9, 479.9 (MH). 0510 Analysis for C24H15Cl2N3O2S-1 (C2H4)2O-0.2 C6H14: 0511 Calcd: C, 60.71; H, 3.70; N, 8.30. 0512 Found: C, 60.60; H, 3.45; N, 8.08.

EXAMPLE 22

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(pyridin-2-ylethynyl)thieno3,2-bpyridine-6-carbonitrile 0513 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (300 mg, 0.63 mmol), 2-ethynylpyridine (90 L, 0.82 mmol), 7.3 mg of tetrakis(triphenylphosphine)Palladium(0) and 3 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 5 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of ethyl acetate. The insoluble material is removed by filtration, washing with ethyl acetate. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride. The combined aqueous layers are extracted with dichloromethane. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The aqueous layer is adjusted to pH 6 and extracted with chloroform. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residues are combined and purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated. The resultant solid is recrystallized from ethyl acetate and hexane to provide 92 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(pyridin-2-ylethynyl)thieno3,2-bpyridine-6-carbonitrile as light brown crystals, mp 237-239 C.; 0514 1H NMR (DMSO-d6) 3.86 (s, 3H), 7.35-7.52 (m, 2H), 7.73 (d, J8 Hz, 1H), 7.80 (s, 1H), 7.83-7.92 (m, 2H), 8.60-8.72 (m, 2H), 9.89 (s, 1H); MS 449.1, 450.9 (MH).

EXAMPLE 23

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-3-(dimethylamino)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile 0515 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (300 mg, 0.63 mmol), 1-dimethylamino-2-propyne (90 L, 0.84 mmol), 7.5 mg of tetrakis(triphenylphosphine)Palladium(0) and 3 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of chloroform. The insoluble material is removed by filtration, washing with chloroform. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride. The combined aqueous layers are brought to pH 8 by adding 2 N sodium hydroxide. The aqueous layer is extracted with chloroform, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 225 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-3-(dimethylamino)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile as red crystals, mp 164-166 C.; 1H NMR (DMSO-d6) 2.21 (s, 6H), 3.53 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.62 (s, 1H), 9.77 (s, 1H); MS 429.3, 431.2 (MH).

EXAMPLE 24

2-(1-Benzofuran-2-yl)-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0516 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (500 mg, 1.05 mmol), 2-benzofuranboronic acid (340 mg, 2.10 mmol) and 65 mg of tetrakis(triphenylphosphine)Palladium(0) in 70 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 2.5 hours. An additional 50 mg of tetrakis(triphenylphosphine)Palladium(0) is added and the reaction is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 160 mg of 2-(1-benzofuran-2-yl)-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 281-282 C.; 1H NMR (DMSO-d6) 3.87 (s, 3H), 7.29-7.45 (m, 3H), 7.61 (s, 1H), 7.69-7.73 (m, 2H), 7.81 (s, 1H), 8.02 (s, 1H), 8.65 (s, 1H), 9.82 (s, 1H); MS 464.2, 465.9 (MH). 0517 Analysis for C23H13Cl2N3O2S-0.25H2O: 0518 Calcd: C, 58.67; H, 2.89; N, 8.92. 0519 Found: C, 58.56; H, 2.82; N, 8.69.

EXAMPLE 25

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(3-formylphenyl)thieno3,2-bpyridine-6 carbonitrile 0520 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (500 mg, 1.05 mmol), 3-formylphenylboronic acid (330 mg, 2.2 mmol) and 65 mg of tetrakis(triphenylphosphine)Palladium(0) in 70 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1.5 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo. The residue is recrystallized from ethyl acetate to provide 62 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(3-formylphenyl)thieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 262-263 C.; 1H NMR (DMSO-d6) 3.86 (s, 3H), 7.39 (s, 1H), 7.69-7.82 (m, 2H), 7.98 (s, 1H), 8.03-8.14 (m, 2H), 8.23 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 10.08 (s, 1H); MS 452.0,453.9 (MH). 0521 Analysis for C22H13Cl2N3O2S: 0522 Calcd: C, 58.16; H, 2.88; N, 9.25. 0523 Found: C, 57.80; H, 2.85; N, 9.16.

EXAMPLE 26

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-3-(morpholin-4-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile 0524 Morpholine (100 L, 1.15 mmol) is added to a suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(3-formylphenyl)thieno3,2-bpyridine-6-carbonitrile (400 mg, 0.88 mmol) in 8 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (1.0 g, 4.73 mmol) is added. After stirring at 0 C. for 1 hour, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to 5% methanol in ethyl acetate to provide 154 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-3-(morpholin-4-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 205-207 C.; 1H NMR (DMSO-d6) 2.38 (m, 4H), 3.51 (s, 2H), 3.59 (m, 4H), 3.86 (s, 3H), 7.32-7.48 (m, 3H), 7.64-7.70 (m, 2H), 7.77 (s, 1H), 7.91 (s, 1H), 8.61 (s, 1H), 9.74 (s, 1H); MS 523.1, 525.0 (MH). 0525 Analysis for C26H22Cl2N4O2S-0.50H2O: 0526 Calcd: C, 58.43; H, 4.34; N, 10.48. 0527 Found: C, 58.49; H, 4.10; N, 10.39.

EXAMPLE 27

4-(2,4-Dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno2,3-bpyridine-5-carbonitrile 0528 A mixture of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno2,3-bpyridine-5-carbonitrile (0.25 g, 0.52 mmol), 4-formylphenylboronic acid (0.16 mg, 1.05 mmol), and 30 mg of tetrakis(triphenylphosphine)Palladium(0) in 45 mL of ethylene glycol dimethyl ether is prepared. To the mixture is added 20 mL of a saturated sodium carbonate solution and the reaction mixture is heated at reflux for 1 hour. The mixture is allowed to warm to room temperature and partitioned between water and dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is triturated with ethyl acetate and the resulting solid is filtered and washed with diethyl ether to provide 0.16 g of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno2,3-bpyridine-5-carbonitrile as an off white solid, mp>240 C.; 1H NMR (DMSO-d6) 3.87 (s, 3H), 7.42 (s, 1H), 7.79 (s, 1H), 7.94 (d, J8.3 Hz, 2H), 8.07 (d, J8.3 Hz, 2H), 8.46 (s, 1H), 8.47 (s, 1H), 9.92 (s, 1H), 10.06 (s, 1H); MS 452.0 (MH). 0529 Analysis for C22H13Cl2N3O2S: 0530 Calcd: C, 58.16; H, 2.88; N, 9.25. 0531 Found: C, 58.09; H, 2.53; N, 9.00.

EXAMPLE 28

4-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(morpholin-4-ylmethyl)phenylthieno2,3-bpyridine-5-carbonitrile 0532 A suspension of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno2,3-bpyridine-5-carbonitrile (0.1 g, 0.24 mmol) in 1 mL of N,N-dimethylformamide and 4 mL of dichloromethane is prepared. To the mixture is added morpholine (0.03 mL, 0.32 mmol). The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (0.26 g, 1.2 mmol) is added. After stirring at 0 C. for 30 minutes a drop of acetic acid is added and the mixture is stirred at 0 C. for an additional 4 hours. Additional morpholine (0.01 mL, 0.1 mmol) and sodium triacetoxyborohydride are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The resultant light brown solution is partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride and water, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is triturated with acetone and water to provide 86 mg of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(morpholin-4-ylmethyl)phenylthieno2,3-bpyridine-5-carbonitrile as a white solid, mp 106-108 C.; 1H NMR (DMSO-d6) 2.38 (br s, 4H), 3.51 (br s, 2H), 3.59 (br s, 4H), 3.86 (s, 3H), 7.40 (s, 1H), 7.46 (d, J8.0 Hz, 2H), 7.67 (d, J8.0 Hz, 2H), 7.77 (s, 1H), 8.19 (s, 1H), 8.42 (s, 1H), 9.80 (s, 1H); MS 525.0 (MH). 0533 Analysis for C26H22Cl2N4O2S 0534 Calcd: C, 59.43; H, 4.22; N, 10.66. 0535 Found: C, 59.34; H, 4.02; N, 10.26.

EXAMPLE 29

4-5-Cyano-4-(3,4,5-trimethoxyphenylamino)-thieno2,3-bpyridin-2-yl-butyric Acid Methyl Ester 0536 A mixture of 4-(4-chloro-5-cyano-thieno2,3-bpyridin-2-yl)-butyric acid methyl ester (60 mg, 0.20 mmol), 3,4,5-trimethoxyaniline (92 mg, 0.50 mmol), and pyridine hydrochloride (10 mg, 0.09 mmol) in 10 mL of 2-ethoxyethanol is heated at reflux for 24 hours. The solution is cooled and the solvent is evaporated. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 62 mg of 4-5-cyano-4-(3,4,5-trimethoxy-phenylamino)-thieno2,3-bpyridin-2-yl-butyric acid methyl ester as a tan solid, mp 101-103 C.; 1H NMR (DMSO-d6) 1.94 (quintet, J7 Hz, 2H), 2.41 (t, J7 Hz, 2H), 2.88 (t, J7 Hz, 2H), 3.60 (s, 3H), 3.67 (s, 3H), 3.75 (s, 6H), 6.60 (s, 2H), 7.28 (s, 1H), 8.40 (s, 1H), 9.62 (s, 1H); MS 442.1 (MH). 0537 Analysis for C22H23N3O5S: 0538 Calcd: C, 59.85; H, 5.25; N, 9.52. 0539 Found: C, 59.72; H, 5.41; N, 9.40.

EXAMPLE 30

2-(4-Hydroxybutyl)-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile 0540 To a solution of 4-5-cyano-4-(3,4,5-trimethoxyphenylamino)-thieno2,3-bpyridin-2-yl-butyric acid methyl ester (1.10 g, 2.5 mmol) in 15 mL of tetrahydrofuran at room temperature is added dropwise lithium borohydride in tetrahydrofuran (10 mL, 2.0 M, 20 mmol). The mixture is heated at reflux for 1 hour, and cooled to room temperature. Methanol (20 mL) is added, and stirring is continued at room temperature overnight. The reaction mixture is partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic layer is dried, and concentrated. The residue is purified by flash column chromatography eluting with with 2:1 ethyl acetate:hexane to provide 563 mg of 2-(4-hydroxybutyl)-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile as a white solid, mp 125-127 C.; 1H NMR (DMSO-d6) 1.50 (m, 2H), 1.72 (m, 2H), 2.91 (t, J7 Hz, 2H), 3.42 (m, 2H), 3.68 (s, 3H), 3.76 (s, 6H), 4.42 (t, J5 Hz, 1H), 6.75 (s, 2H), 7.44 (s, 1H), 8.45 (s, 1H), 10.23 (s, 1H); MS 414.4 (MH).

EXAMPLE 31

2-4-(4-Morpholinyl)butyl-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile 0541 To a solution of 2-(4-hydroxybutyl)-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile (413 mg, 1.0 mmol) and carbon tetrabromide (464 mg, 1.4 mmol) in 10 mL of dichloromethane is added a solution of triphenylphosphine (314 mg, 1.2 mmol) in 5 mL of dichloromethane with stirring. The mixture is stirred at room temperature for 2 hours and concentrated. The residue is purified by flash column chromatography eluting with a gradient of 9:1 hexane:ethyl acetate to 1:2 hexane:ethyl acetate to provide crude 2-(4-bromobutyl)-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile. The crude 2-(4-bromobutyl)-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile is heated 70 C. in 2 mL of morpholine in the presence of sodium iodide (100 mg, 0.67 mmol) for 1 hour. The mixture is concentrated, and the residue is purified by flash column chromatography eluting with a gradient of ethyl acetate to 10% methanol in ethyl acetate to provide 2-4-(4-morpholinyl)butyl-4-(3,4,5-trimethoxyphenyl)amino-thieno2,3-bpyridine-5-carbonitrile as a yellow oil; 1H NMR (DMSO-d6) 1.49 (quintet, J7 Hz, 2H), 1.68 (quintet, J7 Hz, 2H), 2.31 (m, 6H), 2.87 (t, J7 Hz, 2H), 3.55 (m, 4H), 3.67 (s, 3H), 3.74 (s, 6H), 6.59 (s, 2H), 7.23 (s, 1H), 8.37 (s, 1H), 9.46 (s, 1H); MS 483.5 (MH).

EXAMPLE 32

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(trimethylsilyl)ethynylthieno3,2-bpyridine-6-carbonitrile 0542 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (500 mg, 1.05 mmol), (trimethylsilyl)acetylene (237 L, 1.67 mmol), 12.5 mg of tetrakis(triphenylphosphine)Palladium(0) and 5 mg of copper(I) iodide in 3.5 mL of triethylamine and 12 mL of benzene is heated at reflux for 20 hours. The mixture is cooled to room temperature and 50 mL of chloroform are added. The mixture is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered through a celite pad and concentrated in vacuo. The resulting brown solid is suspended in diethyl ether. The solids are collected by filtration and washed with diethyl ether to yield 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(trimethylsilyl)ethynylthieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 169-171 C.; 1H NMR (CDCl3) 0.26 (s, 9H), 3.88 (s, 3H), 6.79 (s, 1H), 6.89 (s, 1H), 7.51 (s, 1H), 7.56 (s, 1H), 8.65 (s, 1H); MS 444.1, 446.1 (MH). 0543 Analysis for C20H17Cl2N3OSSi0.15 CHCl3: 0544 Calcd: C, 52.12; H, 3.72; N, 9.05. 0545 Found: C, 52.23; H, 3.41; N, 9.12.

EXAMPLE 33 0546 7-(2,4-Dichloro-5-methoxyphenyl)amino-2-ethynylthieno3,2-bpyridine-6-carbonitrile 0547 To the suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(trimethylsilyl)ethynyl thieno3,2-bpyridine-6-carbonitrile (97 mg, 0.22 mmol) in 10 mL of methanol is added potassium carbonate (46 mg, 0.33 mmol) The mixture is stirred at room temperature for 30 minutes, concentrated in vacuo and then partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 38 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-ethynylthieno3,2-bpyridine-6-carbonitrile as white crystals, mp 198-200 C.; 1H NMR (DMSO-d6) 3.85 (s, 3H), 5.01 (s, 1H), 7.38 (s, 1H), 7.72 (s, 1H), 7.79 (s, 1H), 8.63 (s, 1H), 9.85 (s, 1H); MS 372.0 (MH). 0548 Analysis for C17H9Cl2N3OS-0.60 C4H10O: 0549 Calcd: C, 55.64; H, 3.61; N, 10.03. 0550 Found: C, 55.34; H, 3.45; N, 9.64.

EXAMPLE 34

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(pyridin-4-ylethynyl)thieno3,2-bpyridine 6-carbonitrile 0551 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(trimethylsilyl)ethynyl thieno3,2-bpyridine-6-carbonitrile (365 mg, 0.82 mmol), 4-iodopyridine (252 mg, 1.23 mmol), potassium carbonate (565 mg, 4.09 mmol), 30 mg of bis(triphenylphosphine)Palladium(II) chloride, 43 mg of triphenylphosphine and 8 mg of copper(I) iodide in 10 mL of tetrahydrofuran and 2 mL of methanol is heated at reflux overnight. The mixture is cooled to room temperature and 50 mL of chloroform are added. The mixture is washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by two flash column chromatographies, first eluting with 5% methanol in dichloromethane and then eluting with 1:1 ethyl acetate:hexane to provide 174 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(pyridin-4-ylethynyl)thieno3,2-bpyridine-6-carbonitrile as orange crystals, mp 221-223 C.; 1H NMR (CDCl3) 3.86 (s, 3H), 7.43 (s, 1H), 7.59 (d, J5 Hz, 2H), 7.81 (s, 1H), 7.89 (s, 1H), 8.61-8.71 (m, 3H), 9.89 (s, 1H); MS 451.2 (MH). 0552 Analysis for C22H12Cl2N4OS-0.11 CHCl3: 0553 Calcd: C, 57.17; H, 2.62; N, 12.06. 0554 Found: C, 57.42; H, 2.65; N, 11.68.

EXAMPLE 35

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(pyridin-3-ylethynyl)thieno3,2-bpyridine-6-carbonitrile 0555 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (160 mg, 0.33 mmol), 3-ethynylpyridine (45 mg, 0.43 mmol), 5 mg of tetrakis(triphenylphosphine)Palladium(0) and 20 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 5 mL of methanol is added. The solvents are removed in vacuo and the residue is treated with 50 mL of chloroform. The insoluble material is removed by filtration, washing with chloroform. The filtrate is washed with water. The residue is suspended in acetone, combined with the chloroform phase and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% methanol in dichloromethane to 10% methanol and 1% ammonium hydroxide in dichloromethane. The fractions containing product are combined and concentrated to provide 99 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(pyridin-3-ylethynyl)thieno3,2-bpyridine-6-carbonitrile as light brown crystals, mp 249-250 C.; MS 451.0(MH). 0556 Analysis for C22H12Cl2N4OS: 0557 Calcd: C, 58.55; H, 2.68; N, 12.41. 0558 Found: C, 58.49; H, 2.65; N, 12.11.

EXAMPLE 36

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-5-(1.3-dioxolan-2-yl)thien-3-ylthieno3,2-bpyridine-6-carbonitrile 0559 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (564 mg, 1.18 mmol), tributyl-(5-1,3dioxolan-2-yl-thiophen-3-yl)-stannane (680 mg, 1.52 mmol) and a pinch of bis(triphenylphosphine)Palladium(II) chloride in 15 mL of dioxane is heated at reflux for 5 hours. Additional bis(triphenylphosphine)Palladium(li) chloride is added and the reaction is heated at reflux overnight. Additional bis(triphenylphosphine)Palladium(II) chloride and 10 mL of dioxane are added and the reaction is heated at reflux for 5 hours. The reaction mixture is concentrated in vacuo and partitioned between water and chloroform. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo to provide 447 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(1,3-dioxolan-2-yl)thien-3-ylthieno3,2-bpyridine-6-carbonitrile as white crystals, mp 219-221 C.; 1H NMR (DMSO-d6) 3.85 (s, 3H), 3.92-4.10 (m, 4H), 6.08 (s, 1H), 7.36 (s, 1H), 7.63 (s, 1H), 7.75 (s, 1H), 7.80 (s, 1H), 7.97 (s, 1H), 8.60 (s, 1H), 9.69 (s, 1H); MS 502.1 (MH). 0560 Analysis for C22H15Cl2N3O3S2: 0561 Calcd: C, 52.39; H, 3.00; N, 8.33. 0562 Found: C, 52.58; H, 3.21; N, 7.93.

EXAMPLE 37

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(5-formylthien-3-yl)thieno3,2-bpyridine-6-carbonitrile 0563 To the suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(1,3-dioxolan-2-yl)thien-3-ylthieno3,2-bpyridine-6-carbonitrile (337 mg, 0.67 mmol) in 10 mL of tetrahydrofuran is added 5 mL of 2N hydrochloric acid. The mixture is stirred at room temperature, overnight. The mixture is slowly poured into 30 mL of saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 271 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formylthien-3-yl)thieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 259-261 C.; 1H NMR (DMSO-d6) 3.85 (s, 3H), 7.38 (s, 1H), 7.76 (s, 1H), 7.93 (s, 1H), 8.42 (s, 1H), 8.50 (s, 1H), 8.63 (s, 1H), 9.76 (s, 1H), 9.98 (s, 1H); MS 458.1 (MH). 0564 Analysis for C20H11Cl2N3O2S20.05 CH2Cl20.10 CHCl3: 0565 Calcd: C, 50.78; H, 2.37; N, 8.82. 0566 Found: C, 50.59; H, 2.21; N, 8.74.

EXAMPLE 38

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methylthien-3-ylthieno3,2-bpyridine-6-carbonitrile 0567 1-Methylpiperazine (70 L, 0.63 mmol) is added to a suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formylthien-3-yl)thieno3,2-bpyridine-6-carbonitrile (225 mg, 0.49 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (520 mg, 2.45 mmol) is added. After stirring at 0 C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 133 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-25-(4-methylpiperazin-1-yl)methylthien-3-ythieno3,2-bpyridine-6-carbonitrile as white crystals, mp 224-226 C.; 1H NMR (DMSO-d6) 2.18 (s, 3H), 2.25-2.55 (m, 8H), 3.68 (s, 2H), 3.85 (s, 3H), 7.35 (s, 1H), 7.37 (s, 1H), 7.74 (s, 1H), 7.75 (s, 1H), 7.82 (s, 1H), 8.58 (s, 1H), 9.68 (s, 1H); MS 523.1, 544.2 (MH). 0568 Analysis for C25H23Cl2N5OS2-0.50H2O: 0569 Calcd: C, 54.24; H, 4.37; N, 12.65. 0570 Found: C, 54.57; H, 4.34; N, 12.30.

EXAMPLE 39

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-5-(morpholin-4-ylmethyl)thien-3-ylthieno3,2-bpyridine-6-carbonitrile 0571 Morpholine (50 L, 0.57 mmol) is added to a suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formylthien-3-yl)thieno3,2-bpyridine-6-carbonitrile (200 mg, 0.43 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (460 mg, 2.17 mmol) is added. After stirring at 0 C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 169 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(morpholin-4-ylmethyl)thien-3-ylthieno3,2-bpyridine-6-carbonitrile as a white solid, mp 209-212 C.; MS 531.0(MH). 0572 Analysis for C24H20Cl2N4O2S2: 0573 Calcd: C, 54.24; H, 3.79; N, 10.54. 0574 Found: C, 54.16; H, 3.43; N, 10.40.

Examples 40 & 41

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(4-hydroxypiperidin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile and

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(hydroxymethyl)phenylthieno3,2 bpyridine-6-carbonitrile 0575 4-Hydroxypiperidine (100 mg, 0.99 mmol) is added to a suspension of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile (165 mg, 0.36 mmol) in 5 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (0.55 g, 2.60 mmol) is added. After stirring at 0 C. for 4 hours, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 1.5 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of ethyl acetate to 5% methanol in ethyl acetate to provide 98 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-hydroxypiperidin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 149-150 C.; 1H NMR (DMSO-d6) 1.35-1.45 (m, 2H), 1.65-1.75 (m, 2H), 2.00-2.10 (m, 2H), 2.62-2.70 (m, 2H), 3.47 (s, 3H), 3.85 (s, 3H), 4.54 (d, J4 Hz, 1H), 7.37 (s, 1H), 7.40 (d, J8 Hz, 2H), 7.67 (d, J8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.59 (s, 1H), 9.72 (s, 1H); MS 536.9 (MH). 0576 Analysis for C27H24Cl2N4O2S-2.00H2O0.1 C4H8O20.15 C6H14: 0577 Calcd: C, 56.90; H, 5.21; N, 9.38. 0578 Found: C, 56.61; H, 4.85; N, 8.99. 0579 From the above flash column chromatography is also isolated 61 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(hydroxymethyl)phenylthieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 239-240 C.; 1H NMR (DMSO-d6) 3.86 (s, 3H), 4.54 (d, J6 Hz, 2H), 5.29 (t, J6 Hz, 1H), 7.38 (s, 1H), 7.43 (d, J8 Hz, 2H), 7.69(d, J8 Hz, 2H), 7.77 (s, 1H), 7.90 (s, 1H), 8.61 (s, 1H), 9.72 (s, 1H); MS 456.1 (MH). 0580 Analysis for C22H15Cl2N3O2S-0.70H2O: 0581 Calcd: C, 56.34; H, 3.52; N, 8.96. 0582 Found: C, 56.73; H, 3.65; N, 8.55.

EXAMPLE 42

2-Iodo-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0583 A mixture of 4-phenoxyaniline (1.05 g, 5.67 mmol), pyridine hydrochloride (100 mg, 0.76 mmol) and 4-chloro-2-iodothieno3,2-bpyridine-6-carbonitrile (1 g, 3.12 mmol) in 50 mL of 2-ethoxyethanol is heated at reflux for 1.5 hours. The solution is poured into saturated aqueous sodium bicarbonate and the resulting solid is collected by filtration, washed with water and dried under reduced pressure. The solid is purified by flash column chromatography eluting with chloroform. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 1.38 g of 2-iodo-7-(4-phenoxyphenyl)aminothieno2,3-bpyridine-6-carbonitrile as white crystals, mp 260-262 C.; 1H NMR (DMSO-d6) 7.09 (t, J8 Hz, 4H), 7.17 (t, J8 Hz, 1H), 7.36 (d, J8 Hz, 2H), 7.43 (t, J8 Hz, 2H), 7.73 (s, 1H), 8.53 (s, 1H), 9.56 (s, 1H); MS 468.0 (MH). 0584 Analysis for C20H12IN3OS-0.10 CHCl3: 0585 Calcd: C, 50.16; H, 2.54; N, 8.73. 0586 Found: C, 50.15; H, 2.31; N. 8.55.

EXAMPLE 43

2-(4-Formylphenyl)-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0587 A mixture of 2-iodo-7-(4-phenoxyphenyl)aminothieno2,3-bpyridine-5-carbonitrile (600 mg, 1.28 mmol), 4-formylphenylboronic acid (380 mg, 2.53 mmol) and 75 mg of tetrakis(triphenylphosphine)Palladium(0) in 53 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:1 hexane:ethyl acetate to provide 2-(4-formylphenyl)-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 230-232 C.; 1H NMR (DMSO-d6) 7.06-7.20 (m, 5H), 7.36-7.45 (m, 4H), 7.92-8.05 (m, 4H), 8.11 (s, 1H), 8.63 (s, 1H), 9.67 (s, 1H), 10.05 (s, 1H); MS 446.2 (MH). 0588 Analysis for C27H17N3O2S-0.40H2O: 0589 Calcd: C, 71.31; H, 3.95; N, 9.24. 0590 Found: C, 70.97; H, 3.48; N, 9.16.

EXAMPLE 44

2-4-(4-Methylpiperazin-1-ylmethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0591 1-Methylpiperazine (65 L, 0.59 mmol) is added to a suspension of 2-(4-formylphenyl)-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile (200 mg, 0.45 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (474 mg, 2.24 mmol) is added. After stirring at 0 C. for 10 minutes, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 138 mg of 2-4-(4-methylpiperazin-1-ylmethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as white crystals, mp 199-201 C.; 1H NMR (DMSO-d6) 2.17 (s, 3H), 2.37 (br s, 8H), 3.50 (s, 2H), 7.05-7.18 (m, 5H), 7.35-7.44 (m, 6H), 7.66 (d, J8 Hz, 2H), 7.86 (s, 1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 532.3 (MH). 0592 Analysis for C32H29N5OS: 0593 Calcd: C, 72.29; H, 5.50; N, 13.17 0594 Found: C, 72.14; H, 5.61; N, 13.11.

EXAMPLES 45 & 46

2-4-(Morpholin-4-ylmethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine 6-carbonitrile

2-4-(Hydroxymethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0595 Morpholine (51 L, 0.58 mmol) is added to a suspension of 2-(4-formylphenyl)-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile (200 mg, 0.45 mmol) in 8 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (474 mg, 2.24 mmol) is added. After stirring at 0 C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with ethyl acetate to provide 79 mg of 2-4-(morpholin-4-ylmethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as white crystals, mp 254-256 C.; 1H NMR (DMSO-d6) 2.36 (s, 4H), 3.51 (s, 2H), 3.58 (s, 4H), 7.04-7.18 (m, 5H), 7.34-7.45 (m, 6H), 7.67 (d, J8 Hz, 2H), 7.86 (s, 1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 519.2 (MH). 0596 Analysis for C31H26N4O2S: 0597 Calcd: C, 71.79; H, 5.05; N, 10.80. 0598 Found: C, 71.96; H, 4.97; N, 10.60. 0599 From the above flash column chromatography, is also isolated 37 mg of 2-4-(hydroxymethyl)phenyl-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as yellow crystals, mp 225-228 C.; 1H NMR (DMSO-d6) 4.54 (d, J6 Hz, 2H), 5.31 (t, J6 Hz, 1H), 7.06-7.19 (m, 5H), 7.35-7.43 (m, 6H), 7.67 (d, J8 Hz, 2H), 7.86 (s, 1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 450.3 (MH). 0600 Analysis for C27H19N3O2S-0.50H2O: 0601 Calcd: C, 70.71; H, 4.39; N, 9.16 0602 Found: C, 70.53; H, 4.02; N, 9.03.

EXAMPLE 47

2-Iodo-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0603 A mixture of 3,4,5-trimethoxyaniline (964 mg, 5.26 mmol), pyridine hydrochloride (100 mg, 0.76 mmol) and 4-chloro-2-iodothieno3,2-bpyridine-6-carbonitrile (937 mg, 2.92 mmol) in 50 mL of 2-ethoxyethanol is heated at reflux overnight. The solution is poured into saturated aqueous sodium bicarbonate and the resulting solid is collected by filtration, washed with water and dried under reduced pressure. The resultant solid is purified by flash column chromatography eluting with 2% methanol in dichloromethane. The fractions containing product are combined and concentrated to provide 1.17 g of 2-iodo-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as white crystals, mp 254-256 C.; 1H NMR (DMSO-d6) 3.70-3.78 (m, 9H), 6.66 (s, 2H), 7.72 (s, 1H), 8.53 (s, 1H), 9.56 (s, 1H); MS 468.1 (MH). 0604 Analysis for C17H141N3O3S: 0605 Calcd: C, 43.70; H, 3.02; N, 8.99. 0606 Found: C, 43.96; H, 2.91; N, 8.98.

EXAMPLE 48

2-Bromo-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0607 A mixture of 4-phenoxyaniline (430 mg, 2.32 mmol), pyridine hydrochloride (244 mg, 2.11 mmol) and 2-bromo-4-chlorothieno3,2-bpyridine-6-carbonitrile (578 mg, 2.11 mmol) in 10 mL of 2-ethoxyethanol is heated at 125 C. for 4 hours. The mixture is poured into diethyl ether and the solids are collected by filtration. The solids are stirred with saturated aqueous sodium bicarbonate for 1 hour. The solids are collected by filtration, washed with water and diethyl ether to give 717 mg of 2-bromo-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as a tan solid, mp 248-250 C.; 1H NMR (DMSO-d6) 7.01-7.19 (m, 5H), 7.23-7.47 (m, 4H), 7.66 (s, 1H), 8.57 (s, 1H), 9.62 (s, 1H); MS 422.1, 424.1 (MH). 0608 Analysis for C20H12BrN3OS-0.2H2O: 0609 Calcd: C, 56.40; H, 2.93; N, 9.87. 0610 Found: C, 56.34; H, 2.66; N, 9.91.

EXAMPLE 49

7-(4-Phenoxyphenyl)amino-2-(E)-2-pyridin-4-ylethenylthieno3,2-bpyridine-6-carbonitrile 0611 A mixture of 2-bromo-7-(4-phenoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile (200 mg, 0.47 mmol), 4-vinylpyridine (79.7 mg, 0.75 mmol), palladium acetate (21.1 mg, 0.094 mmol) and tri-o-tolylphosphine (7.2 mg, 0.024 mmol) in 4 mL of N,N-dimethylformamide and 2.3 mL of triethylamine is heated at 125 C. for 4 hours. After cooling to room temperature the reaction mixture is concentrated in vacuo and the residue is diluted with dichloromethane. The organic phase is washed with water and saturated aqueous sodium chloride, then dried over sodium sulfate, filtered and concentrated in vacuo. 0612 The reaction is repeated a second time with the modification that the reaction mixture is now heated at 1250 C. for only 60 minutes. The crude products are combined and purified by thin layer preparative chromatography developing with 7% methanol in dichloromethane. A second thin layer preparative chromatography developing with 5% methanol in dichloromethane gives 16 mg of 7-(4-phenoxyphenyl)amino-2-(E)-2-pyridin-4-ylethenylthieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp 240-241 C.; 1H NMR (DMSO-d6) 7.02-7.21 (m, 6H), 7.32-7.47 (m, 4H), 7.57-7.62 (m, 2H), 7.67 (s, 1H), 7.83 (d, J16 Hz, 1H), 8.56-8.62 (m, 3H), 9.60 (s, 1H); MS 446.9 (MH). 0613 Analysis for C27H18N4OS-0.5H2O: 0614 Calcd: C, 71.19; H, 4.20; N, 12.30. 0615 Found: C, 71.06; H, 3.85; N, 12.09.

EXAMPLE 50

tert-Butyl (2E)-3-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridin-2-ylprop-2-enoate 0616 A mixture of tert-butyl (2E)-3-(7-chloro-6-cyanothieno3,2-bpyridin-2-yl)prop-2-enoate (1.29 g, 3.74 mmol), 2,4-dichloro-5-methoxyaniline (862 mg, 4.49 mmol), Tris(dibenzylideneacetone)-dipalladium(0) (343 mg, 0.37 mmol), potassium phosphate (1.29 g, 5.61 mmol) and 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl (456 mg, 1.16 mmol) in 36 mL of ethylene glycol dimethyl ether is heated at 90 C. for 3 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer is extracted with additional ethyl acetate and the organic layers are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of hexane to 40% ethyl acetate in hexane to provide 974 mg of tert-butyl (2E)-3-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridin-2-ylprop-2-enoate as a light tan solid, mp 224 C. dec; 1H NMR (DMSO-d6) 1.48 (s, 9H), 3.85 (s, 3H), 6.26 (d, J16 Hz, 1H), 7.37 (s, 1H), 7.75 (d, J16 Hz, 1H), 7.78 (s, 1H), 7.91 (s, 1H), 8.62 (s, 1H), 9.80 (s, 1H); MS 476.0, 478.0 (MH). 0617 Analysis for C22H19Cl2N3O3S-0.4H2O: 0618 Calcd: C, 54.64; H, 4.13; N, 8.69. 0619 Found: C, 54.51; H, 3.96; N, 8.50.

EXAMPLE 51

4-(2,4-Dichloro-5-methoxyphenyl)amino-2-3-(4-methylpiperazin-1-yl)prop-1-ynylthieno2,3-bpyridine-5-carbonitrile 0620 A mixture of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno2,3-bpyridine-5-carbonitrile (160 mg, 0.34 mmol), 1-methyl-4-prop-2-ynyl-piperazine (70 mg, 0.5 mmol), 15 mg of tetrakis(triphenylphosphine)Palladium(0) and copper iodide (8 mg, 0.016 mmol) in 7 mL of benzene and 2 mL of triethylamine is heated at reflux for 7 hours. The reaction mixture is cooled to room temperature and partitioned between water and dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is triturated with ether and hexanes to provide 110 mg of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-3-(4-methylpiperazin-1-yl)prop-1-ynylthieno2,3-bpyridine-5-carbonitrile as an off white solid, mp 175 C. (decomposition); 1H NMR (DMSO-d6) 2.17 (s, 3H), 2.37 (bs, 4H), 2.54 (bs, 4H), 3.62 (s, 2H), 3.85 (s, 3H), 7.38 (s, 1H), 7.76 (s, 1H), 7.91 (s, 1H), 8.47 (bs, 1H), 9.83 (bs, 1H); MS 486.2 (MH). 0621 Analysis for C23H21Cl2N5OS: 0622 Calcd: C, 56.79; H, 4.35; N, 14.40 0623 Found: C, 56.39; H, 4.33; N, 14.06.

EXAMPLE 52

4-(2,4-Dichloro-5-methoxyphenyl)amino-2-(pyridin-3-ylethynyl)thieno2.3-bpyridine-5-carbonitrile 0624 A mixture of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno2,3-bpyridine-5-carbonitrile (220 mg, 0.50 mmol), 3-ethynylpyridine (72 mg, 0.7 mmol), 20 mg of tetrakis(triphenylphosphine)Palladium(0) and copper iodide (6 mg, 0.22 mmol) in 7 mL of benzene and 2 mL of triethylamine is heated at reflux for 5 hours. The reaction mixture is cooled to room temperature and a solid appears. The solid is triturated with hot ethyl acetate, filtered, washed with hexanes and dried under vacuum to provide 100 mg of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-(pyridin-3-ylethynyl)thieno2,3-bpyridine-5-carbonitrile as a tan solid, mp 191 C. (decomposition); 1H NMR (DMSO-d6TFA) 3.88 (s, 3H), 7.37 (s, 1H), 7.43 (s, 1H), 7.78 (s, 1H), 7.85 (bs, 1H), 8.16 (s, 1H), 8.39 (bs, 1H), 8.54 (s, 1H), 10.02 (bs, 1H); MS 451.0 (MH). 0625 Analysis for C22H12Cl2N4OS0.1H2O: 0626 Calcd: C, 58.55; H, 2.68; N, 12.41. 0627 Found: C, 58.31; H, 2.71; N, 12.36.

EXAMPLE 53

(2E)-3-(6-Cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridin-2-yl)prop-2-enoate 0628 A solution of tert-butyl (2E)-3-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2yl)prop-2-enoate (910.8 mg, 1.91 mmol), trifluoroacetic acid (2.18 g, 19.1 mmol) in 27 mL of dichloromethane is stirred at room temparature for 3 days, then concentrated in vacuo. The residue is triturated with ether to provide 741 mg of (2E)-3-(6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridin-2-yl)prop-2-enoic acid as a beige solid, mp>250 C.; 1H NMR (DMSO-d6) 3.84 (s, 3H), 6.28 (d, J16 Hz, 1H), 7.38 (s, 1H), 7.70-7.88 (m, 2H), 7.90 (s, 1H), 8.62 (s, 1H), 9.81 (s, 1H), 12.50 (s, 1H); MS 420.1, 422.0 (MH). 0629 Analysis for C18H11Cl2N3O3S: 0630 Calcd: C, 51.44; H, 2.64; N, 10.00 0631 Found: C, 51.52; H, 2.81; N, 9,68.

EXAMPLE 54

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(2-formyl-1-methyl-1H-imidazol-5-yl)thieno3,2-bpyridine-6-carbonitrile 0632 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (443.2 mg, 0.93 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole-2-carbaldehyde (743.1 mg, 1.86 mmol), dichlorobis(triphenylphosphine)Palladium(II) (33.0 mg, 0.047 mmol) and triethylamine (103.2 mg, 1.02 mmol) in 8.0 mL of 1,4-dioxane is heated at 110 C. for 3 hours. After cooling, the mixture is treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in dichloromethane to 50% ethyl acetate in dichloromethane to provide 222.7 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(2-formyl-1-methyl-1H-imidazol-5-yl)thieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp 225-227 C.; 1H NMR (DMSO-d6) 3.86 (s, 3H), 4.08 (d, 3H), 7.41 (s, 1H), 7.63 (s, 1H), 7.77 (s, 1H), 7.90 (s, 1H), 8.67 (s, 1H), 9.77 (s, 1H), 9.87 (s, 1H); MS 458.1, 460.1 (MH). 0633 Analysis for C20H13Cl2N5O2S0.5H2O: 0634 Calcd: C, 51.40; H, 3.02; N, 14.98 0635 Found: C, 51.43; H, 2.88; N, 14.60.

EXAMPLE 55

2-(4-Formylphenyl)-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0636 A mixture of 2-iodo-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile (500 mg, 1.07 mmol), 4-formylphenylboronic acid (240.7 mg, 1.61 mmol), tetrakis(triphenylphosphine)Palladium(0) (61.8 mg, 0.054 mmol) in 16 mL of saturated aqueous sodium bicarbonate and 20 mL of ethylene glycol dimethyl ether is heated at reflux for 3 h. After cooling, the mixture is treated with water. The precipitate is filtered, washed with water, ethyl acetate, and ether, then dried in vacuo to provide 447.2 mg of 2-(4-formylphenyl)-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp 268-270 C.; 1H NMR (DMSO-d6) 3.73 (s, 3H), 3.75 (s, 6H), 6.69 (s, 2H), 7.94 (d, J8 Hz, 2H), 8.00 (d, J8 Hz, 2H), 8.10 (s, 1H), 8.64 (s, 1H), 9.64 (s, 1H), 10.00 (s, 1H); HRMS 446.11691 (MH).

EXAMPLE 56

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(1E)-3-(4-methylpiperazin-1-yl)-3-oxoprop-1-enylthieno3,2-bpyridine-6-carbonitrile 0637 A mixture of (2E)-3-6-cyano-7-2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-2-ylprop-2-enoic acid (68.8 mg, 0.16 mmol), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (109.3 mg, 0.21 mmol), diisopropylethylamine (103.4 mg, 0.80 mmol), 1-methylpiperazine (16 mg, 0.1 mmol) in 2.5 mL of dichloromethane is stirred at room temperature under nitrogen for 18 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The organic phases are combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 7% methanol in dichloromethane to provide 43.8 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1E)-3-(4-methylpiperazin-1-yl)-3-oxoprop-1-enylthieno3,2-bpyridine-6-carbonitrile as an off white solid, mp 218-220 C.; 1H NMR (DMSO-d6) 2.19 s, 3H), 2.31 (s, 4H), 3.55 (s, 2H), 3.62 (s, 2H), 3.84 (s, 3H), 7.16 (d, J15 Hz, 1H), 7.31 (s, 1H),7.62 (d, J15 Hz, 1H), 7.73 (s, 1H), 7.92 (s, 1H), 8.58 (s, 1H), 9.77 (s, 1H); MS 502.2, 504.2 (MH). 0638 Analysis for C23H21Cl2N5O2S: 0639 Calcd: C, 54.98; H, 4.21; N, 13.94. 0640 Found: C, 54.67; H, 4.28; N, 13.55.

EXAMPLE 57

2-3-(4-Methylpiperazin-1-yl)prop-1-ynyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0641 A mixture of 2-iodo-7-(3,4,5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile (200 mg, 0.43 mmol), 1-methyl-4-prop-2-ynyl-piperazine (89.1 mg, 0.65 mmol), 9.9 mg of tetrakis(triphenylphosphine)Palladium(0) and 2.1 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 7 hours. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of chloroform. The insoluble material is removed by filtration, washing with chloroform. The filtrate is concentrated in vacuo and the residue is purified by preparative thin layer chromatography developing with 10% methanol in dichloromethane to provide 112.1 mg of 2-3-(4-methylpiperazin-1-yl)prop-1-ynyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as a beige solid, mp 180-182 C.; 1H NMR (DMSO-d6) 2.35 (s, 3H), 2.50 (s, 2H), 2.56 (s, 6H), 3.62 (s, 2H), 3.71 (s, 3H), 3.74 (s, 6H), 6.68 (s, 2H), 7.59 (s, 1H), 8.61 (s, 1H), 9.62 (s, 1H); MS 478.2, (MH). 0642 Analysis for C25H27N5O3S0.5H2O: 0643 Calcd: C, 61.71; H, 5.80; N, 14.39. 0644 Found: C, 61.84; H, 5.58; N, 14.53.

EXAMPLE 58

2-4-(4-Methylpiperazin-1-yl)methylphenyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0645 1-Methylpiperazine (135.2 mg, 1.35 mmol) is added to a suspension of 2-(4-formylphenyl)-7-3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile (200 mg, 0.45 mmol) in 8 mL of dichloromethane and 1.1 mL of N,N-dimethylformamide The reaction mixture is cooled to 0 C. and sodium triacetoxyborohydride (572.2 mg, 2.70 mmol) is added. After stirring at 0 C. for 10 minutes, 0.13 mL of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 12% methanol in dichloromethane to give a solid which is triturated with ether and ethyl acetate (1:1), to provide 125.2 mg of 2-4-(4-methylpiperazin-1-yl)methylphenyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as a beige solid, mp 189-191 C.; 1H NMR (DMSO-d6) 62.15 (s, 3H), 2.35 (s, 8H), 3.47 (s, 2H), 3.72 (s, 3H), 3.75 (s, 6H), 6.67 (s, 2H), 7.39 (d, J8 Hz, 2H), 7.66 (d, J8 Hz, 2H), 7.86 (s, 1H), 8.60 (s, 1H), 9.55 (s, 1H); MS 530.2 (MH). 0646 Analysis for C29H31N5O3S1.0H2O: 0647 Calcd: C, 63.60; H, 6.07; N, 12.79.

EXAMPLE 59

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-1-methyl-2-(4-methylpiperazin-1-yl)methyl-1H-imidazol-5-ylthieno3,2-bpyridine-6-carbonitrile 0648 To a solution of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(2-formyl-1-methyl-1H-imidazole-5-yl)thieno3,2-bpyridine-6-carbonitrile (200.6 mg, 0.44 mmol) 1-methylpiperazine (132.2 mg, 1.32 mmol) in 4.3 mL of dichloromethane and 1.1 mL of N,N-dimethylformamide is added sodium triacetoxyborohydride (559.5 mg, 2.64 mmol) in portions at 0-5 C. followed by 0.13 mL of acetic acid. The resulting reaction mixture is stirred for 30 minutes, allowed to warm to room temperature and stirred for 5 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% methanol in dichloromethane to 20% methanol in dichloromethane to provide 145.2 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-methyl-2-(4-methylpiperazine-1-yl)methyl-1H-imidazole-5-ylthieno3,2-bpyridine-6-carbonitrile as an off white solid, mp 234-235 C.; 1H NMR (DMSO-d6) 2.18 (s, 3H), 2.41 (s, 8H), 3.59 (s, 2H), 3.77 (s, 3H), 3.85 (s, 3H), 7.14 (s, 1H), 7.37 (s, 1H), 7.63 (s, 1H), 7.75 (s, 1H), 8.60 (s, 1H), 9.74 (s, 1H); MS 542.2, 544.1 (MH). 0649 Analysis for C25H25Cl2N7OS0.9H2O: 0650 Calcd: C, 53.74; H, 4.83; N, 17.55. 0651 Found: C, 53.39; H, 4.61; N, 17.45.

EXAMPLE 60

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-3-(4-methylpiperazin-1-yl)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile 0652 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile (200 mg, 0.42 mmol), 1-methyl-4-prop-2-ynyl-piperazine (87.0 mg, 0.65 mmol), 9.7 mg of tetrakis(triphenylphosphine)Palladium(0) and 2.0 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 5 hours. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is purified by preparative thin layer chromatography developing with 12% methanol in dichloromethane to give a solid which is triturated with ether containing several drops of dichloromethane, to provide 89.6 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-3-(4-methylpiperazin-1-yl)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp 172-173 C.; 0653 1H NMR (DMSO-d6) 2.18 (s, 3H), 2.37 (s, 4H), 2.49 (s, 4H), 3.59 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.62 (s, 1H), 9.82 (s 1H); MS 486.1, 488.1 (MH). 0654 Analysis for C23H2lCl2N5OS: 0655 Calcd: C, 56.79; H, 4.35; N, 14.40. 0656 Found: C, 56.39; H, 4.28; N, 14.19.

EXAMPLE 61

2-4-(Dimethylamino)methylphenyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2 bpyridine-6-carbonitrile 0657 A suspension of 2 M dimethylamine in tetrahydrofuran (1.13 mL, 2.25 mmol) and 2-(4-formylphenyl)-7-3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile (200 mg, 0.45 mmol) in 4.5 mL of dichloromethane and 1.1 mL of N,N-dimethylformamide is cooled to 0 C. and sodium triacetoxyborohydride (572.2 mg, 2.70 mmol) is added. After stirring at 0 C. for 5 minutes, 0.13 mL of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 17 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 1% methanol in dichloromethane to 10% methanol in dichloromethane to provide 147.2 mg 2-4-(dimethylamino)methylphenyl-7-(3,4,5-trimethoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp 199-201 C.; 1H NMR (DMSO-d6) 2.15 (s, 6H), 3.41 (s, 2H), 3.72 (s, 3H), 3.75 (s, 6H), 6.67 (s, 2H), 7.39 (d, J8 Hz, 2H), 7.66 (d, J8 Hz, 2H), 7.87 (s, 1H), 8.60 (s, 1H), 9.54 (s, 1H); MS 475.2 (MH). 0658 Analysis for C26H26N4O3S0.6H2O: 0659 Calcd: C, 64.34; H, 5.65; N, 11.54. 0660 Found: C, 64.19; H, 5.68; N, 11.49.

EXAMPLE 62

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-4-(dimethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile 0661 To a suspension of 2-(4-formylphenyl)-7-2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile (312 mg, 0.69 mmol) and 1.73 mL of 2 M dimethylamine in tetrahydrofuran (3.45 mmol) in 6.9 mL of dichloromethane and 1.7 mL of N,N-dimethylformamide at 0 C. is added sodium triacetoxyborohydride (877 mg, 4.14 mmol). After stirring at 0 C. for 5 minutes, 0.20 mL of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 17 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography developing with a gradient of from 1% to 10% methanol in dichloromethane to give a solid which is washed with hexane to provide 222 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(dimethylamino)methylphenylthieno3,2-bpyridine-6 carbonitrile as a tan solid, mp 224-225 C.; 1H NMR (DMSO-d6) 2.17 (s, 6H), 3.44 (s, 2H), 3.86 (s, 3H), 7.37 (s, 1H), 7.40 (d, J8 Hz, 2H), 7.68 (d, J8 Hz, 2H), 7.76 (s, 1H), 7.90 (s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 483.1, 485.1 (MH). 0662 Analysis for C24H2O2N4OS0.5H2O: 0663 Calcd: C, 58.54; H, 4.30; N, 11.38. 0664 Found: C, 58.45; H, 4.20; N, 11.27.

EXAMPLE 63

N-(6-Cyanothieno3,2-bpyridin-7-yl)-N-(2,4-dichloro-5-methoxyphenyl)acetamide 0665 A mixture of 7-(2,4-dichloro-5-methoxyanilino)aminothieno3,2-bpyridine-6-carbonitrile (332 mg, 0.95 mmol), acetic anhydride (976 mg, 9.5 mmol), and 4-(dimethylamino)pyridine (140 mg, 1.14 mmol) in 3 mL of pyridine are heated at reflux for 2 hours. The mixture is cooled to room temperature and concentrated in vacuo. Dichloromethane and water are added and the organic layer is extracted, dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo and the residue is purified by chromatography eluting with 2% methanol in dichloromethane to provide 280 mg of N-(6-cyanothieno3,2-bpyridin-7-yl)-N-(2,4-dichloro-5-methoxyphenyl)acetamide as a white solid, mp 202-204 C.; 1H NMR (DMSO-d6) 2.23 (s, 3H), 3.95 (s, 3H), 7.69 (d, J6 Hz, 1H), 7.84 (s, 2H), 8.35 (d, J6 Hz, 1H), 9.11 (s, 1H); MS 392.0 (MH). 0666 Analysis for C17H11Cl2N3O2S: 0667 Calcd: C, 52.05; H, 2.83; N, 10.71. 0668 Found: C, 52.44; H, 2.93; N, 10.45.

EXAMPLE 64

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(E)-2-phenylvinylthieno3,2-bpyridine-6-carbonitrile 0669 A mixture of 4-(2,4-dichloro-5-methoxyphenyl)amino-2-iodothieno3,2-bpyridine-5-carbonitrile (250 mg, 0.53 mmol), E-styrylboronic acid (90 mg, 0.60 mmol), 20 mg of tetrakis(triphenylphosphine)Palladium(0), 390 mg of potassium phosphate, and 0.1 mL of water in 3 mL of toluene is heated at 110 C. overnight. The mixture is cooled to room temperature and ethyl acetate and water are added. The solid is collected by filtration, dissolved in a hot mixture of methanol and dichloromethane and passed through celite. The filtrate is concentrated in vacuo and dried to give 48 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(E)-2-phenylvinylthieno3,2-bpyridine-6-carbonitrile as a light yellow solid. The ethyl acetate layer is separated, dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo and the residue is purified by chromatography eluting with a gradient of 0 to 5% methanol in dichloromethane. The fractions are concentrated and the solid is triturated with hot ether, filtered and dried to provide an additional 49 mg of product, mp 236-238 C.; 1H NMR (DMSO-d6) 3.85 (s, 3H), 7.15 (d, J16 Hz, 1H), 7.31-7.42 (m, 4H), 7.54 (d, J16 Hz, 1H), 7.56-7.65 (m, 3H), 7.77 (s, 1H), 8.58 (s, 1H), 9.66 (s, 1H); HRMS 452.0.3872 (MH).

EXAMPLE 65

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-ylethynylthieno3,2-bpyridine-6-carbonitrile 0670 A mixture of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1H-pyrazol-4-ylethynyl)thieno3,2-bpyridine-6-carbonitrile (57 mg, 0.13 mmol), 4-(2-chloroethyl)morpholine hydrochloride (24 mg, 0.13 mmol), and cesium carbonate (42 mg, 0.13 mmol) in 1 mL of dimethylformamide is heated at 50 C. overnight. The mixture is cooled to room temperature and then added to water. The resulting precipitate is collected by filtration. The collected solid is purified by flash column chromatography, eluting with 1:7 methanol:ethyl acetate to provide 50 mg of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-ylethynylthieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp greater than 200 C.; 1H NMR (DMSO-d6) 2.44 (br s, 4H), 2.62 (t, 2H), 3.53 (br s, 4H), 3.81 (s, 3H), 4.23 (br s, 2H), 6.77 (s, 1H), 7.57 (s, 1H), 7.71 (s, 1H), 7.80 (br, 1H), 8.24 (br, 1H), 8.37 (s, 1H), 13.36 (br s, 1H); MS 553.1 (MH).

EXAMPLE 66

7-(2,4-Dichloro-5-methoxyphenyl)amino-2-(E)-2-(2H-1,2,3-triazol-2-yl)vinylthieno3,2-bpyridine-6-carbonitrile 0671 To a mixture of 1,2,3-triazole (50 L, 0.81 mmol) and cesium hydroxide monohydrate (18 mg, 0.11 mmol) in 1-methyl-2-pyrrolidinone (5 mL) is added slowly 7-(2,4-dichloro-5-methoxyphenyl)amino-2-ethynylthieno3,2-bpyridine-6-carbonitrile (200 mg, 0.54 mmol). The mixture is heated to 120 C. for 12 hours, cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of methanol in dichloromethane (0-2%) to provide 90 mg (38%) of 7-(2,4-dichloro-5-methoxyphenyl)amino-2-(E)-2-(2H-1,2,3-triazol-2-yl)vinylthieno3,2-bpyridine-6-carbonitrile as a yellow solid, mp 315-316 C.; 1H NMR (DMSO-d6-TFA) 3.88 (s, 3H), 7.50 (s, 1H), 7.65 (d, J14 Hz, 1H), 7.85 (s, 1H), 7.88 (s, 1H), 8.15 (s, 2H), 8.32 (d, J14 Hz,1H), 9.01 (s, 1H); MS 443.0 (MH). 0672 Analysis for C19H12Cl2N6OS0.1 CH2Cl2: 0673 Calcd: C, 50.77; H, 2.72; N, 18.60 0674 Found: C, 50.54; H, 2.32; N, 18.25.

EXAMPLE 67

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formyl-2-furyl)thieno3,2-bpyridine-6-carbonitrile 0675 Prepared as for example 37, MS 441.1,446.1 (MH), mp>250.

EXAMPLE 68

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(1,3-dioxolan-2-yl)-2-furylthieno3,2-bpyridine-6-carbonitrile 0676 Prepared as for example 36, MS 488.1, 490.1, mp 187-189.

EXAMPLE 69

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methyl-2-furylthieno 3,2-bpyridine-6-carbonitrile 0677 Prepared as for example 15, MS 527.9, 529.9 (MH), mp 215-217.

EXAMPLE 70

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-ethylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0678 Prepared as for example 15, MS 552.0 (MH), mp 198-200.

EXAMPLE 71

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4--(4-pyrrolidin-1-ylpiperidin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0679 Prepared as for example 15, HRMS 452.0387, mp 230 decomposition.

EXAMPLE 72

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-2-(dimethylamino)ethyl(methyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0680 Prepared as for example 15, MS 540 (MH), mp>245.

EXAMPLE 73

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(dimethylamino)phenylthieno3,2-bpyridine-6-carbonitrile 0681 Prepared as for example 14, MS 469.0, 471.1 (MH), mp 255-258.

EXAMPLE 74

7-(2,4-dichloro-5-methoxyphenyl)amino-2-3-(4-methylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0682 Prepared as for example 15, MS 538.0, 540.0 (MH), mp 178-180.

EXAMPLE 75

7-(2,4-dichloro-5-methoxyphenyl)amino-2-3-(dimethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile 0683 Prepared as for example 15, MS 483.0, 485.0 (MH), mp 204-206.

EXAMPLE 76

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(dimethylamino)methyl1-2-furylthieno3,2-bpyridine-6-carbonitrile 0684 Prepared as for example 15, MS 473.0, 475.0 (MH), mp 200-202.

EXAMPLE 77

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(1-3-dioxolan-2-yl)thien-2-ylthieno3,2-bpyridine-6-carbonitrile 0685 Prepared as for example 36, MS 503.8, 505.8 (MH), mp 213-217.

EXAMPLE 78

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(2-formylthien-3-yl)thieno3,2-bpyridine-6-carbonitrile 0686 Prepared as for example 14, MS 459.9 (MH), mp 128-130.

EXAMPLE 79

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formylthien-2-yl)thieno3,2-bpyridine-6-carbonitrile 0687 Prepared as for example 37, MS 459.9, 461.8 (MH), mp>245.

EXAMPLE 80

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(dimethylamino)methylthien-3-ylthieno3,2-bpyridine-6-carbonitrile 0688 Prepared as for example 15, MS 488.9, 490.9 (MH), mp 184-186.

EXAMPLE 81

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methylthien-2-ylthieno3,2-bpyridine-6-carbonitrile 0689 Prepared as for example 15, MS 544.0, 546.0 (MH), softens 182, mp 200-202.

EXAMPLE 82

7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-iodothieno3,2-bpyridine-6-carbonitrile 0690 Prepared as for example 47. MS 523.8(MH), mp 290-291.

EXAMPLE 83

7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-4-(morpholin-4-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile 0691 Prepared as for example 14, MS 573.3(MH), mp 150-152.

EXAMPLE 84

7-(2,4-dichloro-5-methoxyphenyl)amino-2-2-(4-methylpiperazin-1-yl)methylthien-3-ylthieno3,2-bpyridine-6-carbonitrile 0692 Prepared as for example 15, MS 544.2 (MH), mp 218-219.

EXAMPLE 85

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-3-(dimethylamino)propyl(methyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0693 Prepared as for example 15, MS 554.3 (MH), mp 205 decomp.

EXAMPLE 86

7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-4-(morpholin-4-ylbut-1-ynyl)thieno3,2-bpyridine-6-carbonitrile 0694 Prepared as for example 21, MS 535.3, 537.2 (MH), mp 195-200.

EXAMPLE 87

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(6-(dimethylamino)methylpyridin-2-ylethynyl)thieno3,2-bpyridine-6-carbonitrile 0695 Prepared as for example 21, MS 508.2, 510.2 (MH), mp 190-191.

EXAMPLE 88

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(dimethylamino)methylthien-2-ylthieno3,2-bpyridine-6-carbonitrile 0696 Prepared as for example 15, MS 486.8, 488.8 (MH), mp 210-212.

EXAMPLE 89

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-(pyridin-4-ylmethyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0697 Prepared as for example 15, MS 546.1 (MH), mp 128-130.

EXAMPLE 90

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1H-pyrrol-3-yl)thieno3,2-bpyridine-6-carbonitrile 0698 Prepared as for example 14, MS 415.0 (MH), mp>245.

EXAMPLE 91

7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-3-(dimethylamino)Drop-1-ynylthieno3,2-bpyridine-6-carbonitrile 0699 Prepared as for example 21, MS 479.0, 481.1 (MH), mp 204-207.

EXAMPLE 92

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-(2-methoxyethyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0700 Prepared as for example 15, MS 513.0 (MH), mp 162-164.

EXAMPLE 93

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(2-(methylthio)ethylaminomethyl)phenylthieno3,2-bpyridine-6-carbonitrile 0701 Prepared as for example 15, MS 527.0 (MH), mp 154-156.

EXAMPLE 94

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(thiomorpholin-4-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile 0702 Prepared as for example 15, MS 541.0 (MH), mp 198-201.

EXAMPLE 95

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(piperazin-1-ylmethyl)phenylthieno3,2-bpyridine-6-carbonitrile 0703 Prepared as for example 15, MS 524.1 (MH), mp 218-220.

EXAMPLE 96

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-morpholin-4-ylphenyl)thieno3,2-bpyridine-6-carbonitrile 0704 Prepared as for example 36, MS 511.0, 513.0 (MH), mp>250.

EXAMPLE 97

7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile 0705 Prepared as for example 14, MS 502.0 (MH), mp 279-281.

EXAMPLE 98

7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-4-(diethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile 0706 Prepared as for example 15, MS 559.0 (MH), mp 200-203.

EXAMPLE 99

7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-4-(4-methylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0707 Prepared as for example 15, MS 585.0 (MH), mp 221-224.

EXAMPLE 100

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-(dimethylamino)methylpyridin-2-ylethynyl)thieno3,2-bpyridine-6-carbonitrile 0708 Prepared as for example 21, MS 508.0 (MH), mp 215-217.

EXAMPLE 101

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1H-pyrazol-4-ylethynyl)thieno3,2-bpyridine-6-carbonitrile 0709 Prepared as for example 34, MS 440.0 (MH), mp200 decomposition.

EXAMPLE 102

7-(2,4-dichlorophenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile 0710 Prepared as for example 1, MS 445.8, 447.8 (MH), mp 230-233.

EXAMPLE 103

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methylpyridin-2-ylthieno3,2-bpyridine-6-carbonitrile 0711 Prepared as for example 36, MS 539.0 (MH), mp 229-232.

EXAMPLE 104

2-4-(butylamino)methylphenyl-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridine-6-carbonitrile 0712 Prepared as for example 15, MS 511.0 (MH), mp 167-169.

EXAMPLE 105

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(1-oxidothiomorpholin-4-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0713 Prepared as for example 15, MS 557.0 (MH), mp 242-245.

EXAMPLE 106

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(diethylamino)methylphenylthieno3,2-bpyridine-6-carbonitrile 0714 Prepared as for example 15, MS 511.0 (MH), mp 160-162.

EXAMPLE 107

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-(3-hydroxypropyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0715 Prepared as for example 15, MS 513.1 (MH), mp 141-143.

EXAMPLE 108

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(morpholin-4-ylmethyl)pyridin-2-Ithieno3,2-bpyridine-6-carbonitrile 0716 Prepared as for example 36, MS 526.0, 528.0 (MH), mp 227-229.

EXAMPLE 109

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(6-morpholin-4-ylpyridin-3-yl)thieno3,2-bpyridine-6-carbonitrile 0717 Prepared as for example 36, MS 512.1, 514.1 (MH), mp 225-227.

EXAMPLE 110

7-(2,4-dichloro-5-ethoxyphenyl)amino-2-iodothieno3,2-bpyridine-6-carbonitrile 0718 Prepared as for example 1, MS 489.9, 491.9 (MH), mp 232-233.

EXAMPLE 111

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(1,1-dioxidothiomorpholin-4-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0719 Prepared as for example 15, MS 573.1 (MH), mp>245.

EXAMPLE 112

7-(2-4-dichloro-5-methoxyphenyl)amino-2-4-(4-Pyridin-2-ylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0720 Prepared as for example 15, MS 601.2 (MH), mp 245-247.

EXAMPLE 113

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-phenylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0721 Prepared as for example 15, MS 600.2 (MH), mp 238-240.

EXAMPLE 114

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4(2R,5S)-2,5-dimethylpiperazin-1-Imethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0722 Prepared as for example 15, MS 552.2 (MH), mp 165-168.

EXAMPLE 115

7-(2,4-dichlorophenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6-carbonitrile 0723 Prepared as for example 14, MS 424.0, 426.1 (MH), mp 170-171.

EXAMPLE 116

7-(2,4-dichloro-5-ethoxyphenyl)amino-2-(4-formylphenyl)thieno3,2-bpyridine-6 carbonitrile 0724 Prepared as for example 14, MS 468.1, 470.1 (MH), mp>245.

EXAMPLE 117

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-(4-methylpiperazin-1-yl)carbonylphenylthieno3,2-bpyridine-6-carbonitrile 0725 Prepared as for example 20, MS 552.1, 554.1 (MH), mp 240-243 dec.

EXAMPLE 118

7-(3-chloro-4-(1-methyl-1H-imidazol-2-yl)thiophenylamino)-2-3-(diethylamino)prop-1-ynylthieno3,2-bpyridine-6-carbonitrile 0726 Prepared as for example 21, MS 507.1, 509.2(MH), mp 190-194.

EXAMPLE 119

7-(2,4-dichlorophenyl)amino-2-4-(4-methylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0727 Prepared as for example 15, MS 508.1, 510.1 (MH), mp 245-247.

EXAMPLE 120

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-4-(2-methoxyphenyl)Piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0728 Prepared as for example 15, MS 630.1 (MH), mp 176-179.

EXAMPLE 121

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-(3-methylbutyl)aminomethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0729 Prepared as for example 15, MS 525.1 (MH), mp 195-197.

EXAMPLE 122

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-4-(methylsulfonyl)piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0730 Prepared as for example 15, MS 602.1 (MH), mp 211-213.

EXAMPLE 123

7-(2,4-dichloro-5-ethoxyphenyl)amino-2-4-(4-methylpiperazin-1-yl)methylphenylthieno3,2-bpyridine-6-carbonitrile 0731 Prepared as for example 15, MS 552.2, 554.2 (MH), mp 227-229.

EXAMPLE 124

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(4-4-(pyridin-2-ylmethyl)piperazin-1-ylmethylphenyl)thieno3,2-bpyridine-6-carbonitrile 0732 Prepared as for example 15, MS 615.1 (MH), mp 105-107.

EXAMPLE 125

7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-2-(dimethylamino)ethyl-1H-pyrrol-3-ylthieno3,2-bpyridine-6-carbonitrile 0733 Prepared as for example 65, MS 486.2 (MH), mp 230 decomposition.

EXAMPLE 126

7-(2,4-dichlorophenyl)amino-2-4-(dimethylamino)phenylthieno3,2-bpyridine-6-carbonitrile 0734 Prepared as for example 50, MS 439.2, 441.1 (MH), mp 239-241.

EXAMPLE 127

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1-methyl-1H-imidazol-5-yl)ethynylthieno3,2-bpyridine-6-carbonitrile 0735 Prepared as for example 21, MS 454.1 (MH), mp>260.

EXAMPLE 128

7-(2,4-dichloro-5-methoxyphenyl)amino-2-6-(dimethylamino)methylpyridin-2-ylthieno3,2-bpyridine-6-carbonitrile 0736 Prepared as for example 36, MS 484.1, 486.1 (MH), mp 221-223.

EXAMPLE 129

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(1H-pyrazol-4-yl)thieno3,2-bpyridine-6-carbonitrile 0737 Prepared as for example 14, MS 416.0 (MH), mp250 decomposition.

EXAMPLE 130

7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-(2-hydroxyethyl)-1H-pyrazol-4-ylethynylthieno3,2-bpyridine-6-carbonitrile 0738 Prepared as for example 65, MS 484.0 (MH), mp 172.5.

EXAMPLE 131

7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-ylthieno3,2-bpyridine-6-carbonitrile 0739 Prepared as for example 65, MS 529.1 (MH), mp 155.2.

EXAMPLE 132

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(dimethylamino)methylpyridin-2-ylthieno3,2-bpyridine-6-carbonitrile 0740 Prepared as for example 36, MS 484.0, 486.0 (MH), mp 229-231.

EXAMPLE 133

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(diethylamino)methylpyridin-2-ylthieno3,2-bpyridine-6-carbonitrile 0741 Prepared as for example 36, MS 512.0, 514.0 (MH), mp 192-193.

EXAMPLE 134

7-(2,4-dichloro-5-methoxyphenyl)amino-2-4-2-(dimethylamino)ethylphenylthieno3,2-bpyridine-6-carbonitrile 0742 Prepared as for example 14, MS 497.0, 499.0 (MH), mp 196-197.

EXAMPLE 135

7-(2,4-dichloro-5-methoxyphenyl)amino-2-1-(2-hydroxyethyl)-1H-pyrazol-4-ylthieno3,2-bpyridine-6-carbonitrile 0743 Prepared as for example 60, MS 460.0 (MH), mp250 decomposition.

EXAMPLE 136

4-6-cyano-7-(2,4-dichloro-5-methoxyphenyl)aminothieno3,2-bpyridin-2-yl-N,N-dimethylbenzamide 0744 Prepared as for example 14, MS 497.1, 499.0 (MH), mp 246-249.

EXAMPLE 137

7-(2,4-dichloro-5-methoxyphenyl)amino-2-5-(4-methylpiperazin-1-yl)methyl-3-furylthieno3,2-bpyridine-6-carbonitrile 0745 Prepared as for example 15, MS 528.1, 530.1 (MH), mp 189-192.

EXAMPLE 138

7-(2,4-dichloro-5-methoxyphenyl)amino-2-(5-formyl-3-furyl)thieno3,2-bpyridine-6 carbonitrile 0746 Prepared as for example 14, MS 444.0, 446.0 (MH), mp 223-224. 0747 Evaluation of representative compounds of this invention in several standard pharmacological test procedures indicated that the compounds of this invention possess significant antiproliferative activity and are inhibitors of protein tyrosine kinases. Based on the activity shown in the standard pharmacological test procedures, the compounds of this invention are therefore useful as antineoplastic agents. In particular, these compounds are useful in treating, inhibiting the growth of, or eradicating neoplasms such as those of the breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, liver, prostate and skin. 0748 In addition to having antineoplastic properties, the compounds of the present invention are expected to be useful in treating a variety of protein tyrosine kinase associated disorders including, but not limited to, osteoarthritis, restenosis, atherosclerosis, fibroplasia, angiofibromas, hemangiomas, diabetes, acute and chronic nephropathies, Kaposi's sarcoma, atheroma, neovascular glaucoma, neovascularization associated with macular degeneration, rheumatoid arthritis, psoriatic arthritis, transplant rejection, T-cell mediated hypersensitivity diseases, including gluten-sensitive enteropathy (Celiac disease), contact and delayed-type hypersensitivity, psoriasis, contact dermatitis, protection from ischemic or reperfusion injury such as that incurred during organ transplantation, stroke or myocardial infarction, transplantation tolerance induction, lupus, graft versus host disease, glomerulonephritis, serum sickness, respiratory and skin allergies, autoimmune alopecia, pernicious anemia, Hashimoto's thyroiditis, autoimmune hyperthyroidism, Addison's disease, multiple sclerosis, inflammatory bowel disease, acute inflammatory responses (for example acute respiratory distress syndrome), Behcet's disease, atopic dermatitis, systemic sclerosis and eczema. 0749 The test procedures used and results obtained are shown below. 0750 Anchorace Independent Src-transformed Fibroblast Proliferation Assay 0751 Rat2 fibroblasts stably transformed with a plasmid containing a CMV promotor controlled v-Src/Hu c-Src fusion gene in which the catalytic domain of human c-Src was inserted in place of the v-Src catalytic domain in the v-Src gene are used for the measurement of src dependent suspension growth. Ultra-low cluster plates (Costar 3474) are seeded with 10,000 cells per well on Day 1. Compound is added in serial two-fold dilutions from 10 micromolar to 0.009 micromolar on Day 2 and MTS reagent (Promega) is added on Day 5 (100 microliters of MTS/medium mix100 microliters of medium already on the cells and the absorbance is measured at 490 nm. The results are analyzed as follows to yield an IC50 for proliferation (micromolar units) as follows: % inhibition(Abs490 nm sampleblank)/(Abs490 nm no cmpd controlblank)100%. The results obtained for representative compounds of this invention are listed in Table 1. Multiple entries for a given compound indicate that it was tested multiple times. 1TABLE 1SrcSrcSrccellscellscellsExampleIC50 M% inh at 10 M% inh at 100 M1nt2>1033743.155.66373183392010391123, 2312231334140.66150.56, 0.26160.67170.37181.019>10201.02132, 32221.0235.6243.8251.1261.02719, 28285.92917, 503023, 253135, 35321.5330.88348.6350.98361.6371.1380.36, 0.49,0.45390.85400.71, 0.43410.56425434442.44524626477448304914507.4519.952615345541.51, 1.015597563.93, 2.205770580.165, 0.245591.21, 2.296010.1610.217,0.279620.183,0.402

0752 Anchorage Independent Lck-transformed Fibroblast Proliferation Assay 0753 Rat2 fibroblasts stably transformed with a plasmid containing a CMV promotor controlled v-Src/Hu Lck fusion gene in which the catalytic domain of human Lck was inserted in place of the v-Src catalytic domain in the v-Src gene are used for The measurement of src dependent suspension growth. Ultra-low cluster plates (Costar 3474) are seeded with 10,000 cells per well on Day 1. Compound is added in serial two-fold dilutions from 10 micromolar to 0.009 micromolar on Day 2 and MTS reagent (Promega) is added on Day 5 (100 microliters of MTS/medium mix100 microliters of medium already on the cells and the absorbance is measured at 490 nm. The results are analyzed as follows to yield an IC50 for proliferation (micromolar units) as follows: % inhibition(Abs490 nm sampleblank)/(Abs490 nm no cmpd controlblank)100%. The results obtained for representative compounds of this invention are listed in Table 2. Multiple entries for a given compound indicate that it was tested multiple times. 2TABLE 2LckcellsExampleIC50 M332150.35160.22, 0.089, 0.048170.14380.17, 0.18, 0.13390.68580.048590.27, 0.32610.017, 0.015, 0.014620.079

0754 Src Kinase Assay 0755 Recombinant human Src enzyme was obtained from PanVera (P3044). Biotinylated peptide corresponding to residues 6-20 of Cdk1 was used as a substrate (Biotin-KVEKIGEGTYGVVYK-COOH). Homogeneous fluorescence resonance energy transfer kinase assays were performed using the europium/APC detection format (LANCE, Perkin Elmer). Src enzyme (10 ng) was mixed with biotinylated peptide (final concentration 2 M), 50 mM Hepes (pH 7.5), 10 mM MgCl2, 20 ug/ml BSA, 0.001% Brij-35 (Sigma), 100 M ATP, 1% DMSO. The kinase reaction was incubated for 70 min at 37 C. The reaction was stopped with EDTA at a final concentration of 30 mM EDTA/25 mM Hepes (pH 7.5)/10 g/ml BSA. The mixture was combined with Eu-labeled anti-phosphotyrosine antibody PT66 (Perkin Elmer, AD0068) and Streptavidin Surelight-APC (Perkin Elmer, CR130-100) in 50 mM Hepes (pH 7.5)/20 g/ml BSA, and incubated for 30 min according to manufacturer's specifications. Fluorescence intensity at 665 nm was used to monitor the extent of the kinase reaction. Multiple entries for a given compound indicate that it was tested multiple times. The results obtained for representative compounds of this invention are listed in Table 3. 3TABLE 3Src CellsSrcIC50 MLckEnzymeor % inhib atCellsEXIC50 nM10 MIC50 M64not tested6.4, 5.67.4, 7.965not tested0.7>1066not tested26%, 26%>10 (n 2)67not tested3.7, 3.71.5, 1.768not tested6.1, 6.02.8, 3.06954, 502.8, 3.41.9, 2.2707.3, 9.20.68, 0.580.12, 0.1171not tested1.6, 0.900.20, 0.11729.4, 151.3, 0.700.12, 0.07773120, 941.4, 1.11.2, 1.17426, 161.5, 0.980.6, 0.517526.3, 34.71.5, 0.970.32, 0.2776not tested4.9, 2.60.91, 0.9977not tested2.4, 1.51.9, 1.779not tested2.4, 2.81.5, 1.68013, 140.79, 0.580.074, 0.0738123, 262.3, 2.40.18, 0.2284320, 580, 3473.33.485not tested3.3, 3.160.587not tested4.95, 2.351, 1.8588not tested2.4, 2.30.16, 0.2589not tested1.5, 1.211, 1.0, 1.0690not tested2.6, 3.12.7, 2.4928.8, 110.829, 0.4860.145, 0.1039315, 161.22, 0.6380.341, 0.2769458, 465.52, 2.92, 3.170.932, 0.907, 1.17958.4, 8.3, 6.9, 5.30.614, 0.185, 0.2210.193, 0.133, 0.16896not tested>10 (n 2)5.88, 1.80100not tested>10 (n 2)3.34, 1.93101not tested0.804, 0.8100.938, 0.80410311, 9.60.401, 0.4450.058, 0.07110410, 120.837, 0.9390.252, 0.2351058.5, 7.00.473, 0.5500.222, 0.23510610, 6.60.495, 0.561, 0.313,0.103, 0.095, 0.058,0.2100.0711079, 110.531, 0.5430.063, 0.06510813, 120.474, 0.3190.201, 0.240109not tested>104.511116, 160.572, 0.4110.283, 0.428112not tested>10, 5.78>10 (n 2)113not tested62, 18%>10, >10114not tested0.598, 0.2450.156, 0.17411715, 110.388, 0.2740.129, 0.17111951, 483.51, 1.751.22, 1.34120not tested5.6, 2.248.9, >10121not tested1, 2.19, 2.160.525, 0.576, 0.95112218, 230.733, 1.68, 2.010.897, 1.08, 1.56123943, 1020>10 (n 2)3.23, 4.69124not tested0.914, 0.5760.803, 1.88125not tested>10 (n 2)>10, 5.8127not tested0%, 9%>1012866, 692.1, 0.790.539, 0.557129not tested3.23, 2.191.46, 1.40130not tested5.59, 3.203.64, 4.07131not tested16%, 17%>10 (n 2)13211, 150.777, 0.5150.112, 0.096133not tested0.436, 0.2890.082, 0.0971347.6, 100.505, 0.3370.13, 0.17136not tested5.53, 1.51, 1.690.463, .331, 0.341137not tested0.303, 0.2110.067, 0.053

0756 Raf/Mek Kinase Cascade Assay 0757 Raf-1 (c-Raf) is used to phosphorylate and activate inactive GST-MEK1 which then can phosphorylate and activate inactive p42 GST-MAPK, which subsequently is measured for phosphorylation of the TEY sequence (aa's 202-204) by a phospho-specific antibody from Sigma (cat. 77439219041) Reagents: Sf9 insect cell lysate containing full length 6his-tagged recombinant human c-Raf. (Specific Activity: 200U/ml). Human Non-active Mek-1-GST and human GST-MAP kinase (recombinant proteins produced in E. coli). 0758 Stock Solutions Raf/Mek Cascade Assay: 0759 1. Assay Dilution Buffer (ADB): 20 mM MOPS, pH 7.2, 25 mM B-glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM dithiothreitol. 0760 2. Magnesium/ATP Cocktail: 500 M cold ATP and 75 mM magnesium chloride in ADB. 0761 4. Active Kinase: Human Active c-Raf: Use at 0.4U per assay point. 0762 5. Non-active GST-MEK1: Use at 0.1 g per assay point. 0763 6. Non-active GST-p42 MAP Kinase: Use at 1.0 g per assay point. 0764 Stock Solutions ELISA: 0765 1. TBSTTris (50 mM, pH 7.5), NaCl (150 mM), Tween-20 (0.05%) 0766 2. Superblock (Pierce) 0767 3. Anti-GST Ab (Pharmacia) 0768 4. Anti-Phospho MAPK (Sigma) 0769 5. Anti-Mouse Ab/Europium conjugate (Wallac) 0770 Assay Procedure: 0771 First Stage: c-Raf Dependent Activation of GST-MEK and GST-MAPK 0772 1. Add 20 ml of ADB per assay (i.e. per well of a 96 well plate) 0773 2. Add 10 ml of 0.5 mM cold ATP and 75 mM magnesium chloride in ADB. 0774 3. Add 2 ml of c-Raf (0.4 U/assay), in conjunction with 1.6 ml non-active MEK1 (0.4 mg/assay). 0775 4. Add 4 ml of non-active GST-p42 MAP Kinase (1.0 mg/assay). 0776 5. Incubate for 60 minutes at 30 C. in a shaking incubator. 0777 6. Transfer this mixture to an anti-GST Ab coated 96 well plate (Nunc Immunosorb plates coated o/n with a-GST, then blocked with Pierce Superblock). 0778 7. Incubate for 60 minutes at 30 C. in a shaking incubator Wash 3 with TBST, add Anti-Phospho MAPK (Sigma) (1:3000) 0779 6. Incubate for 60 minutes at 30 C. in a shaking incubator 0780 7. Wash 3 with TBST, add Anti-Mouse Ab/Europium conjugate (Wallac) (1:500) 0781 8. Incubate for 60 minutes at 30 C. in a shaking incubator 0782 9. Wash 3 with TBST, Read plates in Wallac Victor model Plate Reader. 0783 10. Collect data analyze in Excel for single point and IC50 determinations. 0784 Single point assay% inhibition at 10 mg/ml (% Inhibition1-cpd.treated sample/untreated control). IC50 determinationsdone on compounds from single point assays with >80% inhibition. Typically, the Raf/Mek assay is run at compound concentrations from 10 M to 1 nM in half log dilutions. (% inhibition is determined for each compound concentration). Multiple entries for a given compound indicate that it was tested multiple times. The results obtained measure Raf and/or Mek kinase inhibition, and for representative compounds of this invention are listed in Table 4. 0785 Cell Based Screen for Inhibitors of Raf and/or Mek Kinase. 0786 Materials 0787 Cell Lines: Human tumor cell lines LoVo which are known to be growth inhibited by low nM concentrations of a reference standard inhibitor of Ras and human adenocarcinoma cell line CaCo-2, which is known to be growth resistant to the same reference compound. 0788 Cell Media: RPMI 1640 with 10% Fetal Bovine Serum supplemented with L-glutamine and Pennicilin/Streptomycin. 0789 Compounds: Supplied usually as a 10 mM stock in 100% DMSO. 0790 Normal Saline: 150 mM NaCl 0791 Trichloroacetic Acid (TCA): 50% (w/v) in water 0792 Sulforhodamine B (SRB): 0.4% (w/v) in 1% Acetic Acid 0793 Tris Base: 10 mM in water 0794 Methods 0795 Cells are plated at 2000 cells per well for cell line LoVo, 1,750 cells for cell line BXPC3, 1,000 cells for cell line WM266-4 and 1500 cells for cell line CaCo-2 in 96 well plates. Cells are plated in media (200 l) and allowed to adhere overnight at 37 C. At 24 hours post plating, compounds are added directly at a volume of 0.5 l. For the qualitative screen (compounds screened at 25 M) compound is added directly to cells. For the quantitative screen, compound is first diluted in DMSO to generate concentrations of compound or reference standard of: 1, 5, 10 and 25 M. It is advisable to make the dilutions in an identical 96 well plate so that compounds can be added using a multichannel micropipettor set at 0.5 l. The cells are then incubated for four days after which the media is removed using a 12 well manifold by first tipping the plate forward at a 45 degree angle and then inserting the manifold in an upright orientation to prevent the tips of the manifold from disturbing cells at the bottom of the plate. 200 l of normal saline is then added to each well using an 8 well multichannel pipettor, followed by the careful addition of 50 l of 50% TCA. The plates are then incubated for 2 hours at 4 C., after which the supernatant is removed using the same technique as above and the plated washed twice with 200 l water. The plates are then air dried and 50 l of SRB stock solution is carefully added so that the entire bottom of each well is covered. This again can be used using an 8 well multichannel pipettor. The SRB is incubated with fixed cells for 15 minutes at room temperature after which the SRB is removed with the manifold as described above and the plates washed twice with 350 l of 1% acetic acid per well each time. The plates are then air dried after which the bound SRB is released from protein by the addition of 200 l of Tris base. Resolubilizing the SRB is aided by placing the plates on a rotator for 15-30 minutes. The absorbance of each well is determined at 550 or 562 nm using a microtiter plate reader. 0796 Each compound or dilution thereof is performed in triplicate. Outliers are identified by visual inspection of the data. Each plate should have a 0 control (vehicle only). 0797 Qualitative screen: To calculate % inhibition of a compound at 25 M, the following formula is used: 1(experimental absorbance 25 M compound/0 control absorbance)100% inhibition at 25 M. Compounds having>50% inhibition at 25 M are placed in the quantitative assay. 0798 Quantitative Assay: A standard curve is constructed by plotting the concentration of compound against the average absorbance calculated at that concentration. A curve is plotted and the concentration at which the curve passes through the 50% the absorbance mark seen in the 0 control well is the IC50 calculated for that compound. Multiple entries for a given compound indicate that it was tested multiple times. The results obtained for representative compounds of this invention are listed in Table 4. 4TABLE 4Raf/MEKLovoBXPC3WM266-4enzymecellscellscellsEXIC50 nMIC50 MIC50 MIC50 M83410.036, 0.038>1>186221, 3320.094, 0.1600.350.35914750.0640.0920.095, 0.085985.60.0330.0380.04994.50.0390.041>1118not tested0.0730.071not tested