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.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
 Z is 
 
       
         
           
           
               
               
           
         
         W 1  is S, O, or N—R; 
         V 1  is Nor C; 
         W 2  is N or C; 
         V 2  is S, O, or N—R; 
         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, or 3; 
         X═Y is C═N, N═C, or C═C; 
         R is H or C 1 -C 6  alkyl; 
         R 1  and R 5  are independently selected from:
 1) H, 
 2) (C═O) a O b C 1 -C 10  alkyl, 
 3) (C═O) a O b aryl, 
 4) (C═O) a O b C 2 -C 10  alkenyl, 
 5) (C═O) a O b C 2 -C 10  alkynyl, 
 6) CO 2 H, 
 7) halo, 
 8) OH, 
 9) O b C 1 -C 6  perfluoroalkyl, 
 10) (C═O) a NR 7 R 8 , 
 11) CN, 
 12) (C═O) a O b C 3 -C 8  cycloalkyl, and 
 13) (C═O) a O b heterocyclyl, 
 
       
       said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ;
 R 2  and R 3  are independently selected from:
 1) H, 
 2) (C═O)O a C 1 -C 6  alkyl, 
 3) (C═O)O a aryl, 
 4) C 1 -C 6  alkyl, 
 5) SO 2 R a , and 
 6) aryl; 
 
 R 4  is selected from:
 1) (C═O) a O b C 1 -C 10  alkyl, 
 2) (C═O) a O b aryl, 
 3) (C═O) a O b C 2 -C 10  alkenyl, 
 4) (C═O) a O b C 2 -C 10  alkynyl, 
 5) CO 2 H, 
 6) halo, 
 7) OH, 
 8) O b C 1 -C 6  perfluoroalkyl, 
 9) (C═O) a NR 7 R 8 , 
 10) CN, 
 11) (C═O) a O b C 3 -C 8  cycloalkyl, and 
 12) (C═O) a O b heterocyclyl, 
 
 
       said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ;
 R 6  is:
 1) (C═O) a O b C 1 -C 10  alkyl, 
 2) (C═O) a O b aryl, 
 3) C 2 -C 10  alkenyl, 
 4) C 2 -C 10  alkynyl, 
 5) (C═O) a O b  heterocyclyl, 
 6) CO 2 H, 
 7) halo, 
 8) CN, 
 9) OH, 
 10) O b C 1 -C 6  perfluoroalkyl, or 
 11) O a (C═O) b NR 7 R 8 , 
 12) oxo, 
 13) CHO, 
 14) (N═O)R 7 R 8 , and 
 15) (C═O) a O b C 3 -C 8  cycloalkyl, 
 
 
       said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R 6a ;
 R 6a  is selected from:
 1) (C═O) r O s (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1, 
 2) O r (C 1 -C 3 )perfluoroalkyl, wherein r is 0 or 1, 
 3) (C 0 -C 6 )alkylene-S(O) m R a , wherein m is 0, 1, or 2, 
 4) oxo, 
 5) OH, 
 6) halo, 
 7) CN, 
 8) (C 2 -C 10 )alkenyl, 
 9) (C 2 -C 10 )alkynyl, 
 10) (C 3 -C 6 )cycloalkyl, 
 11) (C 0 -C 6 )alkylene-aryl, 
 12) (C 0 -C 6 )alkylene-heterocyclyl, 
 13) (C 0 -C 6 )alkylene-N(R b ) 2 , 
 14) C(O)R a , 
 15) (C 0 -C 6 )alkylene-CO 2 R a , 
 16) C(O)H, and 
 17) (C 0 -C 6 )alkylene-CO 2 H, 
 
 
       said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6  alkyl, oxo, and N(R b ) 2 ;
 R 7  and R 8  are independently selected from:
 1) H, 
 2) (C═O)O b C 1 -C 10  alkyl, 
 3) (C═O)O b C 3 -C 8  cycloalkyl, 
 4) (C═O)O b aryl, 
 5) (C═O)O b heterocyclyl, 
 6) C 1 -C 10  alkyl, 
 7) aryl, 
 8) C 2 -C 10  alkenyl, 
 9) C 2 -C 10  alkynyl, 
 10) heterocyclyl, 
 11) C 3 -C 8  cycloalkyl, 
 12) SO 2 R a , 
 13) (C═O)NRb2, 
 
 said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 6a , or 
 R 7  and R 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 6a ; 
 R a  is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl; and 
 R b  is H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6  alkyl, (C═O)C 1 -C 6  alkyl or S(O) 2 R a . 
 
     
     
         2 . The compound of  claim 1 , wherein
 Z is   
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein
 s is 1;   t is 1 or 2;   R 1  and R 5  are independently selected from:
 1) H, 
 2) (C═O) a O b C 1 -C 6  alkyl, 
 3) (C═O) a O b aryl, 
 4) (C═O) a O b C 2 -C 6  alkenyl, 
 5) (C═O) a O b C 2 -C 6  alkynyl, 
 6) CO 2 H, 
 7) halo, 
 8) OH, 
 9) O b C 1 -C 3  perfluoroalkyl, 
 10) (C═O) a NR 7 R 8 , 
 11) CN, 
 12) (C═O) a O b C 3 -C 6  cycloalkyl, and 
 13) (C═O) a O b heterocyclyl, 
   
       said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ;
 R 4  is selected from:
 1) (C═O) a O b C 1 -C 6  alkyl, 
 2) (C═O) a O b aryl, 
 3) (C═O) a O b C 2 -C 6  alkenyl, 
 4) (C═O) a O b C 2 -C 6  alkynyl, 
 5) CO 2 H, 
 6) halo, 
 7) OH, 
 8) O b C 1 -C 3  perfluoroalkyl, 
 9) (C═O) a NR 7 R 8 , 
 10) CN, 
 11) (C═O) a O b C 3 -C 6  cycloalkyl, and 
 12) (C═O) a O b heterocyclyl, 
 
 
       said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ;
 R 6  is:
 1) (C═O) a O b C 1 -C 6  alkyl, 
 2) (C═O) a O b aryl, 
 3) C 2 -C 6  alkenyl, 
 4) C 2 -C 6  alkynyl, 
 5) (C═O) a O b  heterocyclyl, 
 6) CO 2 H, 
 7) halo, 
 8) CN, 
 9) OH, 
 10) O b C 1 -C 3  perfluoroalkyl, or 
 11) O a (C═O) b NR 7 R 8 , 
 12) oxo, 
 13) CHO, 
 14) (N═O)R 7 R 8 , and 
 15) (C═O) a O b C 3 -C 6  cycloalkyl, 
 
 
       said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents selected from R 6a ;
 R 6a  is selected from:
 1) (C═O) r O s (C 1 -C 6 )alkyl, wherein r and s are independently 0 or 1, 
 2) O r (C 1 -C 3 )perfluoroalkyl, wherein r is 0 or 1, 
 3) (C 0 -C 6 )alkylene-S(O) m R a , wherein m is 0, 1, or 2, 
 4) oxo, 
 5) OH, 
 6) halo, 
 7) CN, 
 8) (C 2 -C 6 )alkenyl, 
 9) (C 2 -C 6 )alkynyl, 
 10) (C 3 -C 6 )cycloalkyl, 
 11) (C 0 -C 6 )alkylene-aryl, 
 12) (C 0 -C 6 )alkylene-heterocyclyl, 
 13) (C 0 -C 6 )alkylene-N(R b ) 2 , 
 14) C(O)R a , 
 15) (C 0 -C 6 )alkylene-CO 2 R a , 
 16) C(O)H, and 
 17) (C 0 -C 6 )alkylene-CO 2 H, 
 
 
       said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6  alkyl, oxo, and N(R b ) 2 ; and
 R 7  and R 8  are independently selected from:
 1) H, 
 2) (C═O)O b C 1 -C 6  alkyl, 
 3) (C═O)O b C 3 -C 6  cycloalkyl, 
 4) (C═O)O b aryl, 
 5) (C═O)O b heterocyclyl, 
 6) C 1 -C 6  alkyl, 
 7) aryl, 
 8) C 2 -C 6  alkenyl, 
 9) C 2 -C 6  alkynyl, 
 10) heterocyclyl, 
 11) C 3 -C 6  cycloalkyl, 
 12) SO 2 R a , 
 13) (C═O)NR b   2 , 
 
 
       said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 6a , or
 R 7  and R 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 6a . 
 
     
     
         4 . The compound of  claim 3 , wherein R 2 , R 3 , and R 5  are H. 
     
     
         5 . The compound of  claim 4 , wherein t is 1, s is 1, and R 1  is H. 
     
     
         6 . The compound of  claim 5  wherein R 4  is selected from:
 1) OC 1 -C 6  alkyleneNR 7 R 8 ,   2) (C═O) a C 0 -C 6  alkylene-Q, wherein Q is H, OH, CO 2 H, or OC 1 -C 6  alkyl,   3) OC 0 -C 6  alkylene-heterocyclyl, optionally substituted with one to three substituents selected from R 6a ,   4) C 0 -C 6  alkyleneNR 7 R 8 ,   5) (C═O)NR 7 R 8 , and   6) OC 1 -C 3  alkylene-(C═O)NR 7 R 8 .   
     
     
         7 . A compound according to  claim 1  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)-quinolinone; 
       3-[5-({(2S,4R)-4-methoxy-1-[(2-methyl-5-pyrimidinyl)methyl]pyrrolidinyl}methoxy)-1H-indol-2-yl]-2(1H)-quinolinone; 
       1-(2-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}ethyl)-4-piperidine-carboxylic acid ethyl ester; 
       1-(2-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}ethyl)-4-piperidinecarboxylic 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-quinolin-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]-methanesulfonamide; 
       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-piperidinaminium 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)-quinolinone; 
       4-amino-N-[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]-1-piperidinecarboxamide; and 
       4-amino-N-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]methyl}-1-piperidinecarboxamide, or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         8 . A pharmaceutical composition which is comprised of a compound in accordance with  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         9 . 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 . 
     
     
         10 . A method of treating cancer or preventing cancer in accordance with  claim 9  wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. 
     
     
         11 . A method of treating or preventing cancer in accordance with  claim 9  wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma. 
     
     
         12 . 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 . 
     
     
         13 . A method in accordance with  claim 12  wherein the disease is an ocular disease. 
     
     
         14 . 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 . 
     
     
         15 . 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 . 
     
     
         16 . 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 . 
     
     
         17 . 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 . 
     
     
         18 . A method according to  claim 17  wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions. 
     
     
         19 . 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 . 
     
     
         20 . A pharmaceutical composition made by combining the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         21 . A process for making a pharmaceutical composition which comprises combining a compound of  claim 1  with a pharmaceutically acceptable carrier. 
     
     
         22 . 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 . 
     
     
         23 . The composition of  claim 8  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.   
     
     
         24 . The composition of  claim 23 , 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 NMP inhibitor, an integrin blocker, interferon-α, 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. 
     
     
         25 . The composition of  claim 23 , wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene. 
     
     
         26 . A method of treating cancer which comprises administering a therapeutically effective amount of a compound of  claim 1  in combination with radiation therapy. 
     
     
         27 . 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.   
     
     
         28 . 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.   
     
     
         29 . A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of  claim 1  and paclitaxel or trastuzumab. 
     
     
         30 . 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. 
     
     
         31 . The method of  claim 30  wherein the GPIIb/IIIa antagonist is tirofiban. 
     
     
         32 . 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 .