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 N or 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 selcted 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 selcted 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 R6 a , 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(H)-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 MMP 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.