Claims for Patent: 6,306,874

Summary for Patent: 6,306,874

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), Arrington; Kenneth L. (Elkins Park, PA), Bilodeau; Mark T. (Lansdale, PA), Hartman; George D. (Lansdale, PA), Hoffman; William F. (Lansdale, PA), Kim; Yuntae (Harleysville, PA), Hungate; Randall W. (Newbury Park, CA)
Assignee:	Merck & Co., Inc. (Rahway, NJ)
Application Number:	09/690,598
Patent Claims:	1. A compound of Formula I ##STR190## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein a is 0 or 1; b is 0 or 1; m is 0, 1, or 2; s is 1 or 2; t is 1, 2, or3; 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 and R.sup.5 are independently 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 H-Cl.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) (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.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)NR.sup.7 R.sup.8, 12) oxo, 13) CHO, 14) NR.sup.7 R.sup.8 or the N-oxide, or 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) (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.1 -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)NR.sup.b.sub.2, said alkyl, cycloalkyl, aryl, heterocyclyl, 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 monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R.sup.6a ; R.sup.a is: (1) (C.sub.1 -C.sub.6)alkyl, (2) (C.sub.3 -C.sub.6)cycloalkyl, (3) aryl, or (4) heterocyclyl; and (5) R.sup.b is: (1) H, (2) (C.sub.1 -C.sub.6)alkyl, (3) aryl, (4) heterocyclyl, (5) (C.sub.3 -C.sub.6)cycloalkyl, (6) (C.dbd.O)OC.sub.1 -C.sub.6 alkyl, (7) (C.dbd.O)C.sub.1 -C.sub.6 alkyl, or (8) S(O).sub.2 R.sup.a. 2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein s is 1; t is 1 or 2; X.dbd.Y is C.dbd.C; R.sup.1 and R.sup.5 are independently 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 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.4 is selected from: 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.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) (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.6 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.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, or 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 is 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.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.6)alkenyl, 9) (C.sub.2 -C.sub.6)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 ; and 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, heterocyclyl, 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 monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R.sup.6a. 3. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.2, R.sup.3, and R.sup.5 are H. 4. The compound of claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein t is 1, s is 1, and R.sup.1 is H. 5. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier. 6. A method of treating 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. 7. A method of treating cancer in accordance with claim 6 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. 8. A method of treating cancer in accordance with claim 6 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma. 9. A method of treating 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. 10. A method in accordance with claim 9 wherein the disease is an ocular disease. 11. A method of treating retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1. 12. A method of treating diabetic retinopathy which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1. 13. A method of treating 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. 14. A method of treating inflammatory diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 15. A method according to claim 14 wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions. 16. A method of treating a tyrosine kinase-dependent disease or condition which comprises administering a therapeutically effective amount of a compound of claim 1. 17. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier. 18. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier. 19. A method of treating bone associated pathologies selected from osteosarcoma, osteoarhritis, and rickets which comprises administering a therapeutically effective amount of a compound of claim 1. 20. The composition of claim 5 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. 21. The composition of claim 20, 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. 22. The composition of claim 20, wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene. 23. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy. 24. A method of treating 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. 25. 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 prnyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) another angiogensesis inhibitor. 26. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 and paclitaxel or trastuzumab. 27. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 and a GPIIb/IIIa antagonist. 28. The method of claim 27 wherein the GPIIb/IIIa antagonist is tirofiban. 29. A method of reducing tissue damage following a cerebral ischemic event which comprises administering a therapeutically effective amount of a compound of claim 1. 30. A compound selected from: 3-{5-[3-(4-methyl-piperazin-1-yl)-propoxy]-1H-indol-2-yl }-1H-quinolin-2-one; 3-(5-{2-[(2-methoxyethyl)amino]ethoxy}-1H-indol-2-yl)-2(1H)-quinolinone; 3-[5-(2-{(2-methoxyethyl)[(2-methoxy-5-pyrimidinyl)methyl]amino }ethoxy)-1H-indol-2-yl]-2(1H)-quinolinone; 3-(5-{[(2S,4R)-4-methoxypyrrolidinyl]methoxy}-1H-indol-2-yl)-2(1H)-quinolin one; 3-[5-({(2S,4R)-4-methoxy-1-[(2-methyl-5-pyrimidinyl)methyl]pyrrolidinyl}met hoxy)-1H-indol-2-yl]-2(1H)-quinolinone; 1-(2-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}ethyl)-4-piperi dinecarboxylic acid ethyl ester; 1-(2-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}ethyl)-4-piperi dinecarboxylic acid; 3-[(2S,4R)-4-methoxy-2-({[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl] oxy}methyl)pyrrolidinyl]propanoic acid; 3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2- one; 3-[5-(4-methanesulfonyl-1-oxy-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quino lin-2-one; 3-[5-(4-acetyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one; N-Cyclopropyl-N-[2-(2-oxo-1,2-dihydro-quinolin-3-yl)-1H-indol-5-ylmethyl]-m ethanesulfonamide; 3-[5-(1-piperazinylcarbonyl)-1H-indol-2-yl]-2(1H)-quinolinone; 3-{5-[(4-methyl-1-piperazinyl)carbonyl]-1H-indol-2-yl }-2(1H)-quinolinone; 1-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]carbonyl}-4-piperidina minium trifluoroacetate; 1-({[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}acetyl)piperazin- 4-ium trifluoroacetate; 3-{5-[2-(1,1-dioxido-4-thiomorpholinyl)-2-oxoethoxy]-1H-indol-2-yl }-2(1H)-quinolinone; N-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]methyl }-4-piperidine carboxamide; 3-{5-[1-(4-morpholinyl)ethyl]-1H-indol-2-yl}-2(1H)-quinolinone; 3-{5-[1-(1-pyrrolidinyl)ethyl]-1H-indol-2-yl }-2(1H)quinolinone; 3-{5-[1-(4-acetyl-1-piperazinyl)ethyl]-1H-indol-2-yl }-2(1H)-quinolinone; 3-(5-{1-[4-(methylsulfonyl)-1-piperazinyl]ethyl}-1H-indol-2-yl)-2(1H)-quino linone; 4-amino-N-[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]-1-piperidineca rboxamide; and 4-amino-N-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]methyl}-1-pipe ridinecarboxamide, or a pharmaceutically acceptable salt or stereoisomer thereof. 31. A compound which is 3-{5-[3-(4-methyl-piperazin-1-yl)-propoxy]-1H-indol-2-yl }-1H-quinolin-2-one ##STR191## or a pharmaceutically acceptable salt thereof. 32. A compound which is 3-[5-(1-piperazinylcarbonyl)-1H-indol-2-yl]-2(1H)-quinolinone ##STR192## or a pharmaceutically acceptable salt thereof. 33. A compound which is 4-amino-N-[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]-1-piperidinec arboxamide ##STR193## or a pharmaceutically acceptable salt thereof. 34. A compound which is N-[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl)methyl}-4-piperidine carboxamide ##STR194## or a pharmaceutically acceptable salt thereof. 35. A compound which is 3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2 -one ##STR195## or a pharmaceutically acceptable salt thereof. 36. A compound which is 3-[5-({(2S,4R)4-methoxy-1-[(2-methyl-5-pyrimidinyl)methyl]pyrrolidin}metho xy)-1H-indol-2-yl]-2(1H)-quinolinone ##STR196## or a pharmaceutically acceptable salt or stereoisomer thereof.

Details for Patent 6,306,874

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2019-10-19
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2019-10-19
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2019-10-19