Claims for Patent: 6,479,512

Summary for Patent: 6,479,512

Title:	Tyrosine kinase inhibitors
Abstract:	The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.
Inventor(s):	Fraley; Mark E. (North Wales, PA), Hambaugh; Scott R. (Norristown, PA), Hungate; Randall W. (Lansdale, PA)
Assignee:	Merck & Co., Inc. (Rahway, NJ)
Application Number:	09/690,602
Patent Claims:	1. A compound of Formula I ##STR56## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ##STR57## W.sup.1 is S, O, or N--R; V.sup.1 is N or C; W.sup.2 is N or C; V.sup.2 is S, O, or N--R; a is 0 or 1; b is 0 or 1; s is 1 or 2; t is 1, 2, or 3; X.dbd.Y is C.dbd.N, N.dbd.C, or C.dbd.C; R is H or C.sub.1 -C.sub.6 alkyl; R.sup.1 is selected from: 1) H, 2) (C.dbd.O).sub.a O.sub.b C.sub.1 -C.sub.10 alkyl, 3) (C.dbd.O).sub.a O.sub.b aryl, 4) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.10 alkenyl, 5) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.10 alkynyl, 6) CO.sub.2 H, 7) halo, 8) OH, 9) O.sub.b C.sub.1 -C.sub.6 perfluoroalkyl, 10) (C.dbd.O).sub.a NR.sup.7 R.sup.8, 11) CN, 12) (C.dbd.O).sub.a O.sub.b C.sub.3 -C.sub.8 cycloalkyl, and 13) (C.dbd.O).sub.a O.sub.b heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R.sup.6 ; R.sup.2 and R.sup.3 are independently selected from: 1) H, 2) (C.dbd.O)O.sub.a C.sub.1 -C.sub.6 alkyl, 3) (C.dbd.O)O.sub.a aryl, 4) C.sub.1 -C.sub.6 alkyl, 5) SO.sub.2 R.sup.a, and 6) aryl; R.sup.4 is selected from: 1) H, provided that Z is not IIA when X.dbd.Y is C.dbd.C, 2) (C.dbd.O).sub.a O.sub.b C.sub.1 -C.sub.10 alkyl, 3) (C.dbd.O).sub.a O.sub.b aryl, 4) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.10 alkenyl, 5) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.10 alkynyl, 6) CO.sub.2 H, 7) halo, 8) OH, 9) O.sub.b C.sub.1 -C.sub.6 perfluoroalkyl, 10) (C.dbd.O).sub.a NR.sup.7 R.sup.8, 11) CN, 12) (C.dbd.O).sub.a O.sub.b C.sub.3 -C.sub.8 cycloalkyl, and 13) (C.dbd.O).sub.a O.sub.b heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R.sup.6 ; R.sup.6 is: 1) (C.dbd.O).sub.a O.sub.b C.sub.1 -C.sub.10 alkyl, 2) (C.dbd.O).sub.a O.sub.b aryl, 3) C.sub.2 -C.sub.10 alkenyl, 4) C.sub.2 -C.sub.10 alkynyl, 5) (C.dbd.O).sub.a O.sub.b heterocyclyl, 6) CO.sub.2 H, 7) halo, 8) CN, 9) OH, 10) O.sub.b C.sub.1 -C.sub.6 perfluoroalkyl, 11) O.sub.a (C.dbd.O).sub.b NR.sup.7 R.sup.8, 12) oxo, 13) CHO, 14) (N.dbd.O)R.sup.7 R.sup.8, and 15) (C.dbd.O).sub.a O.sub.b C.sub.3 -C.sub.8 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R.sup.6a ; R.sup.6a is selected from: 1) (C.dbd.O).sub.r O.sub.s (C.sub.1 -C.sub.10)alkyl, wherein r and s are independently 0 or 1, 2) O.sub.r (C.sub.1 -C.sub.3)perfluoroalkyl, wherein r is 0 or 1, 3) (CO.sub.0 -C.sub.6)alkylene-S(O).sub.m R.sup.a, wherein m is 0, 1, or 2, 4) oxo, 5) OH, 6) halo, 7) CN, 8) (C.sub.2 -C.sub.10)alkenyl, 9) (C.sub.2 -C.sub.10)alkynyl, 10) (C.sub.3 -C.sub.6)cycloalkyl, 11) (C.sub.0 -C.sub.6)alkylene-aryl, 12) (C.sub.0 -C.sub.6)alkylene-heterocyclyl, 13) (C.sub.0 -C.sub.6)alkylene-N(R.sup.b).sub.2, 14) C(O)R.sup.a, 15) (C.sub.0 -C.sub.6)alkylene-CO.sub.2 R.sup.a, 16) C(O)H, and 17) (C.sub.0 -C.sub.6)alkylene-CO.sub.2 H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R.sup.b, OH, (C.sub.1 -C.sub.6)alkoxy, halogen, CO.sub.2 H, CN, O(C.dbd.O)C.sub.1 -C.sub.6 alkyl, oxo, and N(R.sup.b).sub.2 ; R.sup.7 and R.sup.8 are independently selected from: 1) H, 2) (C.dbd.O)O.sub.b C.sub.1 -C.sub.10 alkyl, 3) (C.dbd.O)O.sub.b C.sub.3 -C.sub.8 cycloalkyl, 4) (C.dbd.O)O.sub.b aryl, 5) (C.dbd.O)O.sub.b heterocyclyl, 6) C.sub.1 -C.sub.10 alkyl, 7) aryl, 8) C.sub.2 -C.sub.10 alkenyl, 9) C.sub.2 -C.sub.10 alkynyl, 10) heterocyclyl, 11) C.sub.3 -C.sub.8 cycloalkyl, 12) SO.sub.2 R.sup.a, and 13) (C.dbd.O)NRb2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R.sup.6a, or R.sup.7 and R.sup.8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R.sup.6a ; R.sup.a is (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, aryl, or heterocyclyl; and R.sup.b is H, (C.sub.1 -C.sub.6)alkyl, aryl, heterocyclyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.dbd.O)OC.sub.1 -C.sub.6 alkyl, (C.dbd.O)C.sub.1 -C.sub.6 alkyl or S(O).sub.2 R.sup.a. 2. The compound of claim 1, wherein W.sup.1 is S or N--R and V.sup.2 is S or N--R. 3. The compound of claim 2, wherein R.sup.1 is selected from: 1) H, 2) (C.dbd.O).sub.a O.sub.b C.sub.1 -C.sub.6 alkyl, 3) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.6 alkenyl, 4) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.6 alkynyl, 5) CO.sub.2 H, 6) halo, 7) OH, 8) O.sub.b C.sub.1 -C.sub.3 perfluoroalkyl, 9) CN, and 10) (C.dbd.O).sub.a O.sub.b C.sub.3 -C.sub.6 cycloalkyl; R.sup.2 and R.sup.3 are independently selected from: 1) H, 2) (C.dbd.O)O.sub.a C.sub.1 -C.sub.6 alkyl, 3) C.sub.1 -C.sub.6 alkyl, and 4) SO.sub.2 R.sup.a ; R.sup.4 is selected from: 1) H, provided that Z is not IIA when X.dbd.Y is C.dbd.C, 2) (C.dbd.O).sub.a O.sub.b C.sub.1 -C.sub.6 alkyl, 3) (C.dbd.O).sub.a O.sub.b aryl, 4) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.6 alkenyl, 5) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.6 alkynyl, 6) CO.sub.2 H, 7) halo, 8) OH, 9) O.sub.b C.sub.1 -C.sub.3 perfluoroalkyl, 10) (C.dbd.O).sub.a NR.sup.7 R.sup.8, 11) CN, 12) (C.dbd.O).sub.a O.sub.b C.sub.3 -C.sub.6 cycloalkyl, and 13) (C.dbd.O).sub.a O.sub.b heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R.sup.6 ; R.sup.6 is: 1) (C.dbd.O).sub.a O.sub.b C.sub.1 -C.sub.6 alkyl, 2) (C.dbd.O).sub.a O.sub.b aryl, 3) C.sub.2 -C.sub.6 alkenyl, 4) C.sub.2 -C.sub.6 alkynyl, 5) (C.dbd.O).sub.a O.sub.b heterocyclyl, 6) CO.sub.2 H, 7) halo, 8) CN, 9) OH, 10) O.sub.b C.sub.1 -C.sub.3 perfluoroalkyl, 11) O.sub.a (C.dbd.O).sub.b NR.sup.7 R.sup.8, 12) oxo, 13) CHO, 14) (N.dbd.O)R.sup.7 R.sup.8, and 15) (C.dbd.O).sub.a O.sub.b C.sub.3 -C.sub.6 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents seicted from R.sup.6a ; R.sup.6a is selected from: 1) (C.dbd.O).sub.r O.sub.s (C.sub.1 -C.sub.6)alkyl, wherein r and s are independently 0 or 1, 2) O.sub.r (C.sub.1 -C.sub.3)perfluoroalkyl, wherein r is 0 or 1, 3) (C.sub.0 -C.sub.6)alkylene-S(O).sub.m R.sup.a, wherein m is 0, 1, or 2, 4) oxo, 5) OH, 6) halo, 7) CN, 8) (C.sub.2 -C.sub.10)alkenyl, 9) (C.sub.2 -C.sub.10)alkynyl, 10) (C.sub.3 -C.sub.6)cycloalkyl, 11) (C.sub.0 -C.sub.6)alkylene-aryl, 12) (C.sub.0 -C.sub.6)alkylene-heterocyclyl, 13) (C.sub.0 -C.sub.6)alkylene-N(R.sup.b).sub.2, 14) C(O)R.sup.a, 15) (C.sub.0 -C.sub.6)alkylene-CO.sub.2 R.sup.a, 16) C(O)H, and 17) (C.sub.0 -C.sub.6)alkylene-CO.sub.2 H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R.sup.b, OH, (C.sub.1 -C.sub.6)alkoxy, halogen, CO.sub.2 H, CN, O(C.dbd.O)C.sub.1 -C.sub.6 alkyl, oxo, and N(R.sup.b).sub.2 ; R.sup.7 and R.sup.8 are independently selected from: 1) H, 2) (C.dbd.O)O.sub.b C.sub.1 -C.sub.6 alkyl, 3) (C.dbd.O)O.sub.b C.sub.3 -C.sub.6 cycloalkyl, 4) (C.dbd.O)O.sub.b aryl, 5) (C.dbd.O)O.sub.b heterocyclyl, 6) C.sub.1 -C.sub.6 alkyl, 7) aryl, 8) C.sub.2 -C.sub.6 alkenyl, 9) C.sub.2 -C.sub.6 alkynyl, 10) heterocyclyl, 11) C.sub.3 -C.sub.6 cycloalkyl, 12) SO.sub.2 R.sup.a, and 13) (C.dbd.O)NR.sup.b.sub.2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R.sup.6a, or R.sup.7 and R.sup.8 can be taken together with the nitrogen to which they are attached to form a monocyclic, 5-7 membered heterocycle and optionally containing, in addition to the nitrogen, one additional heteroatom selected from N, O and S, said heterocycle optionally substituted with one or more substituents selected from R.sup.6a. 4. The compound of claim 1, wherein ##STR58## X.dbd.Y is C.dbd.C; R is H or C.sub.1 -C.sub.6 alkyl; R.sup.1 is selected from: 1) H, 2) (C.dbd.O).sub.a O.sub.b C.sub.1 -C.sub.6 alkyl, 3) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.6 alkenyl, 4) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.6 alkynyl, 5) CO.sub.2 H, 6) halo, 7) OH, 8) O.sub.b C.sub.1 -C.sub.3 perfluoroalkyl, 9) CN, and 10) (C.dbd.O).sub.a O.sub.b C.sub.3 -C.sub.8 cycloalkyl; R.sup.2 and R.sup.3 are independently selected from: 1) H, 2) (C.dbd.O)O.sub.a C.sub.1 -C.sub.6 alkyl, 3) C.sub.1 -C.sub.6 alkyl, and 4) SO.sub.2 R.sup.a ; R.sup.4 is selected from: 1) (C.dbd.O).sub.a O.sub.b C.sub.1 -C.sub.10 alkyl, 2) (C.dbd.O).sub.a O.sub.b aryl, 3) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.10 alkenyl, 4) (C.dbd.O).sub.a O.sub.b C.sub.2 -C.sub.10 alkynyl, 5) CO.sub.2 H, 6) halo, 7) OH, 8) O.sub.b C.sub.1 -C.sub.6 perfluoroalkyl, 9) (C.dbd.O).sub.a NR.sup.7 R.sup.8, 10) CN, 11) (C.dbd.O).sub.a O.sub.b C.sub.3 -C.sub.8 cycloalkyl, and 12) (C.dbd.O).sub.a O.sub.b heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R.sup.6 ; R.sup.7 and R.sup.8 are independently selected from: 1) H, 2) (C.dbd.O)O.sub.b C.sub.1 -C.sub.10 alkyl, 3) (C.dbd.O)O.sub.b C.sub.3 -C.sub.8 cycloalkyl, 4) (C.dbd.O)O.sub.b aryl, 5) (C.dbd.O)O.sub.b heterocyclyl, 6) C.sub.1 -C.sub.10 alkyl, 7) aryl, 8) C.sub.2 -C.sub.10 alkenyl, 9) C.sub.2 -C.sub.10 alkynyl, 10) heterocyclyl, 11) C.sub.3 -C.sub.8 cycloalkyl, 12) SO.sub.2 R.sup.a, and 13) (C.dbd.O)NR.sup.b.sub.2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R.sup.6a, or R.sup.7 and R.sup.8 can be taken together with the nitrogen to which they are attached to form a monocyclic 5-7 memebered heterocycle and optionally containing, in addition to the nitrogen, one additional heteroatom selected from N, O and S, said heterocycle optionally substituted with one or more substituents selected from R.sup.6a. 5. The compound of claim 4, wherein s is 1; t is 1 or 2; R is H or C.sub.1 -C.sub.6 alkyl; R.sup.1 is selected from: 1) H, 2) OC.sub.1 -C.sub.6 alkyl, 3) C.sub.1 -C.sub.6 alkyl, 4) halo, 5) OH, 6) OC.sub.1 -C.sub.3 perfluoroalkyl, 7) OC.sub.1 -C.sub.3 perfluoroalkyl, 8) OC.sub.3 -C.sub.6 cycloalkyl, and 9) C.sub.3 -C.sub.6 cycloalkyl; R.sup.2 and R.sup.3 are H; R.sup.4 is selected from: 1) OC.sub.1 -C.sub.6 alkyleneNR.sup.7 R.sup.8, 2) (C.dbd.O).sub.a C.sub.0 -C.sub.6 alkyl, said alkyl optionally substituted with OH, CO.sub.2 H, or OC.sub.1 -C.sub.6 alkyl, 3) OC.sub.0 -C.sub.6 alkylene-heterocyclyl, optionally substituted with one to three substituents selected from R.sup.6a, 4) C.sub.0 -C.sub.6 alkyleneNR.sup.7 R.sup.8, 5) (C.dbd.O)NR.sup.7 R.sup.8, and 6) OC.sub.1 -C.sub.3 alkylene-(C.dbd.O)NR.sup.7 R.sup.8. 6. A compound selected from: 3-[5-(2-piperidin-1-yl-ethoxy)-benzimidazol-2-yl]-quinolin-2-one; 3-[5-(2-piperidin-1-yl-propoxy)-benzimidazol-2-yl]-quinolin-2-one; 2-(2-oxo-1,2-dihydro-quinolin-3-yl)-benzoimidazole-5-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide; 3-[5-(1-piperazinylcarbonyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinone; and 3-{5-[(4-amino-1-piperidinyl)carbonyl]-1H-benzimidazol-2-yl}-2(1H)-quinolin one, or a pharmaceutically acceptable salt or stereoisomer thereof. 7. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier. 8. A method of treating or preventing cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1. 9. A method of treating cancer or preventing cancer in accordance with claim 8 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. 10. A method of treating or preventing cancer in accordance with claim 8 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma. 11. A method of treating or preventing a disease in which angiogenesis is implicated, which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 12. A method in accordance with claim 11 wherein the disease is an ocular disease. 13. A method of treating or preventing retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1. 14. A method of treating or preventing diabetic retinopathy which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1. 15. A method of treating or preventing age-related macular degeneration which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 16. A method of treating or preventing inflammatory diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 17. A method according to claim 16 wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions. 18. A method of treating or preventing a tyrosine kinase-dependent disease or condition which comprises administering a therapeutically effective amount of a compound of claim 1. 19. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier. 20. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier. 21. A method of treating or preventing bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets which comprises administering a therapeutically effective amount of a compound of claim 1. 22. The composition of claim 7 further comprising a second compound selected from: 1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) another angiogenesis inhibitor. 23. The composition of claim 22, wherein the second compound is another angiogenesis inhibitor selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon-.alpha., interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF. 24. The composition of claim 22, wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene. 25. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy. 26. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a compound selected from: 1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) another angiogenesis inhibitor. 27. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy and a compound selected from: 1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) another angiogenesis inhibitor. 28. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 and paclitaxel or trastuzumab. 29. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 and a GPIIb/IIIa antagonist. 30. The method of claim 29 wherein the GPIIb/IIIa antagonist is tirofiban. 31. A method of reducing or preventing tissue damage following a cerebral ischemic event which comprises administering a therapeutically effective amount of a compound of claim 1.

Details for Patent 6,479,512

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2039-02-26
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2039-02-26