Kinase inhibitors

Abstract

Methods using compounds of the general formula: or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof to treat protein kinase-associated disease states is described.

1 . A method of treating a protein kinase-associated disease state, the method comprising administering a therapeutically effective amount to a subject in need thereof of at least one compound according to the general formula:  
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:  
       D is:  
       
         
           
           
               
               
           
         
       
       where X 1 , X 2 , X 3 , X 4  are optionally substituted carbon, or one of X 1 , X 2 , X 3 , X 4  is N; R2 is 0-4 substituents independently chosen from H, halogen, C 1-4  alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , aryl, hetaryl, C 1-4 alkylOC 1-4  alkyl, C 1-4 alkylOaryl, C 1-4 alkylNR3R4, CO 2 R3, CONR3R4, CONR3SO 2 R4, NR3R4, C 1-4  alkylNR3R4, nitro, NR3COR4, NR5CONR3R4, NR3SO 2 R4, C 1-4 alkylNR3COR4, C 1-4 alkylNR5CONR3R4, C 1-4 alkylNR3SO2R4; and R3, R 4 are each independently H, halogen, CH 2 F, CHF 2 , CF 3 , C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  cyclohetalkyl, aryl, C 1-4  alkyl aryl, hetaryl, C 1-4  alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from O, S, NR6; and R5 is selected from H, C 1-4  alkyl, halogen, CH 2 F, CHF 2 , CF 3 , aryl or hetaryl; and R6 is selected from H, C 1-4  alkyl, aryl, hetaryl, C 1-4  alkyl aryl, C 1-4  alkyl hetaryl;  
       R1 is H, C 1-4  alkyl, C 1-6  cycloalkyl;  
       Q is a bond, CH 2 , C 1-4  alkyl;  
       A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C 1-4  alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CN, NR8R9, aryl, hetaryl, C 1-4 aryl, C 1-4 hetaryl, C 1-4  alkylNR8R9, OC 1-4  alkylNR8R9, nitro, NR10C 1-4 NR8R9, NR8COR9, NR10CONR8R9, NR8SO 2 R9, CONR8R9, CO 2 R8 where R8 and R9 are each independently H, C 1-4  alkyl, aryl or which together form an optionally substituted 4-8 membered ring which may contain a heteroatom selected from O, S, NR11, where R11 is C 1-4  alkyl, and R10 is selected from H, C 1-4  alkyl; and  
       W is selected from H, C 1-4 alkyl, C 2-6 alkenyl; where C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl, NR12R13; and R12, and R13 are each independently H, C 1-4 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14 and R14 is selected from H, C 1-4  alkyl.  
     
   
   
       2 . The method according to  claim 1  wherein the disease state involves a receptor tyrosine kinase selected from the group consisting of EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR.alpha., PDGFR.beta., CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R.  
   
   
       3 . The method according to  claim 1  wherein the disease state involves a cellular tyrosine kinase selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.  
   
   
       4 . The method according to  claim 1  wherein the disease state involves a tyrosine kinase selected from the group consisting of JAK1, JAK2, JAK3 and TYK2.  
   
   
       5 . The method according to  claim 1  wherein the disease state involves a serine/threonine kinase selected from the group consisting of ERK2, c-Jun, p38 MAPK, PKA, PKB, PKC, a cyclin-dependent kinase, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, and CDK11.  
   
   
       6 . The method according to  claim 1  wherein the disease state is selected from the group consisting of atopy, a cell mediated hypersensitivity, a rheumatic disease, an autoimmune disease, a viral disease and a cancer.  
   
   
       7 . The method according to  claim 6 , wherein the atopy is allergic asthma, atopic dermatitis (eczema), or allergic rhinitis; the cell mediated hypersensitivity is allergic contact dermatitis or hypersensitivity pneumonitis; the rheumatic disease is systemic Lupus erythematosus (SLE), rheumatoid arthritis, juvenile arthritis, Sjögren's syndrome, scleroderma, polymyositis, ankylosing spondylitis or psoriatic arthritis; the autoimmune disease is type I diabetes, an autoimmune thyroid disorder or Alzheimer's disease; the viral disease is caused by Epstein Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV), human papilloma virus (HPV); the cancer is leukemia, lymphoma and prostate cancer.  
   
   
       8 . The method according to  claim 1 , where said compound is of the general formula II  
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:  
       D is:  
       
         
           
           
               
               
           
         
       
       where X 1 , X 2 , X 3 , X 4  are optionally substituted carbon, or one of X 1 , X 2 , X 3 , X 4  is N; R2 is 0-4 substituents independently chosen from H, halogen, C 1-4  alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , aryl, hetaryl, C 1-4 alkylOC 1-4  alkyl, C 1-4 alkylOaryl, C 1-4 alkylNR3R4, CO 2 R3, CONR3R4, CONR3SO 2 R4, nitro, NR3R4, C 1-4  alkylNR3R4, NR3COR4, NR5CONR3R4, NR3SO 2 R4, C 1-4 alkylNR3COR4, C 1-4 alkylNR5CONR3R4, C 1-4 alkylNR3SO 2 R4; and R3, R4 are each independently H, halogen, CH 2 F, CHF 2 , CF 3 , C 1-4  alkyl, C  1-4  alkyl cycloalkyl, C 1-4  cyclohetalkyl, aryl, C 1-4  alkyl aryl, hetaryl, C 1-4  alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from O, S, NR6; and R5 is selected from H, C 1-4  alkyl, halogen, CH 2 F, CHF 2 , CF 3 , aryl or hetaryl; and R6 is selected from H, C 1-4  alkyl, aryl, hetaryl, C 1-4  alkyl aryl, C 1-4  alkyl hetaryl;  
       R1 is H, C 1-4  alkyl, C 1-6  cycloalkyl;  
       W is H, C 1-4  alkyl; and  
       A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C 1-4  alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CN, nitro, NR8R9, aryl, hetaryl, C 1-4 aryl, C 1-4 hetaryl, C 1-4  alkylNR8R9, OC 1-4  alkylNR8R9, NR10C 1-4 NR8R9, NR8COR9, NR10CONR8R9, NR8SO 2 R9, CONR8R9, CO 2 R8 where R8 and R9 are each independently H, C 1-4  alkyl, aryl or which together form an optionally substituted 4-8 membered ring which may contain a heteroatom selected from O, S, NR11, where R11 is C 1-4  alkyl, and R10 is selected from H, C 1-4  alkyl.  
     
   
   
       9 . The method according to  claim 1 , wherein said compound is selected from the group consisting of: 
 6-(1H-benzimidazol-1-yl)-N-[(1R)-1-phenylethyl]pyrazin-2-amine,    6-(1H-benzimidazol-1-yl)-N-[(1S)-1-(4-methoxyphenyl)ethyl]pyrazin-2-amine,    6-(1H-benzimidazol-1-yl)-N-[(1S)-1-(4-bromophenyl)ethyl]pyrazin-2-amine,    1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazole-6-carboxamide,    6-(1H-Benzimidazol-1-yl)-N-benzylpyrazin-2-amine,    1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazole-5-carboxamide,    6-(1H-Benzimidazol-1-yl)-N-(4-fluorobenzyl)pyrazin-2-amine,    6-{5-[(Morpholino-1-yl)carbonyl]-1H-benzimidazol-1-yl}-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    6-(1H-imidazo[4,5-b]pyridin-1-yl)-N-[(1R)-1-phenylethyl]pyrazin-2-amine,    6-{6-[(Morpholino-1-yl)carbonyl]-1H-benzimidazol-1-yl}-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    N-[1-(6-{[(1S)-1-Phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]cyclopropanecarboxamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino }pyrazin-2-yl)-1H-benzimidazol-5-yl]nicotinamide,    N-[1-(6-{[(1S)-1-Phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide,      6 -(1H-Benzimidazol-1-yl)-N-[(1R)-1-phenylethyl]pyrazin-2-amine,    6-[6-(4,5-dihydro-1,3-oxazol-2-yl)-1H-benzimidazol-1-yl]-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    1-[6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl]-N-(2-hydroxyethyl)-1H-benzimidazole-6-carboxamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]methanesulfonamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]methanesulfonamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]isonicotinamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]isonicotinamide,    6-(1H-Benzimidazol-1-yl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    6-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-benzimidazol-1-yl]-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    1-[6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl]-N-(2-hydroxyethyl)-1H-benzimidazole-5-carboxamide,    6-(5-Methyl-1H-benzimidazol-1-yl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]nicotinamide,    N-methyl-1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazole-5-carboxamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]-2,2-dimethylpropanamide,    N-methyl-1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazole-6-carboxamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]-2,2-dimethylpropanamide,    1-(6-{[(1S)-1-Phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine,    2-Methoxy-N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]acetamide,    1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine,    2-Methoxy-N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]acetamide,    N-Benzyl-1-[6-([(1S)-1-phenylethyl]amino)pyrazin-2-yl]-1H-benzimidazole-5-carboxamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]pyrazine-2-carboxamide,    1-(6-{[(1S)-1-Phenylethyl]amino}pyrazin-2-yl)-N-phenyl-1H-benzimidazole-5-carboxamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]pyrazine-2-carboxamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]acetamide,    6-{5-[(4-Methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    N-[1-(6-{[(1S)-1-Phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]acetamide,    [1-(6-{[(1S)-1-Phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]methanol,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]benzamide,    [1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]methanol,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]benzamide,    1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-N-[2-(dimethylamino)ethyl]-1H-benzimidazole-5-carboxamide,    1-[6-{[(1S)-1-Phenylethyl]amino}pyrazin-2-yl]-N-(pyridin-3-ylmethyl)-1H-benzimidazol-5-amine,    tert-butyl (2S)-2-({[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]amino}carbonyl)pyrrolidine-1-carboxylate,    6-(3H-imidazo[4,5-c]pyridin-3-yl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    6-(1H-benzimidazol-1-yl)-N-[1-(4-fluorophenyl)ethyl]pyrazin-2-amine,    6-(1H-imidazo[4,5-c]pyridin-1-yl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    6-(1H-benzimidazol-1-yl)-N-[(1S)-1-(4-pyridin-3-ylphenyl)ethyl]pyrazin-2-amine,    (2S)-N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]pyrrolidine-2-carboxamide,    N-[(1S)-1-phenylethyl]-6-(5-pyridin-4-yl-1H-benzimidazol-1-yl)pyrazin-2-amine,    N-[(1S)-1-phenylethyl]-6-(5-pyridin-3-yl-1H-benzimidazol-1-yl)pyrazin-2-amine,    6-(5-bromo-1H-benzimidazol-1-yl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine,    N-[3-(1H-imidazol-1-yl)propyl]-1-[6-([(1S)-1-phenylethyl]amino)pyrazin-2-yl]-1H-benzimidazole-6-carboxamide,    N-1H-benzimidazole-6-carboxamide,    N-(3-morpholin-4-ylpropyl)-1-[6-([(1S)-1-phenylethyl]amino)pyrazin-2-yl]-1H-benzimidazole-6-carboxamide,    N-(3-morpholin-4-ylpropyl)-1-[6-([(1S)-1-phenylethyl]amino)pyrazin-2-yl]-1H-benzimidazole-5-carboxamide,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]piperidine-3-carboxamide,    6-(1H-benzimidazol-1-yl)-N-[(1S)-1-pyridin-3-ylethyl]pyrazin-2-amine,    6-(1H-benzimidazol-1-yl)-N-[(1S)-1-(1,1′-biphenyl-4-yl)ethyl]pyrazin-2-amine,    N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]benzenesulfonamide, and    6-(1H-benzimidazol-1-yl)-N-[(1S)-1-(1,1′-biphenyl-4-yl)ethyl]pyrazin-2-amine.    
   
   
       10 . The method according to  claim 1 , wherein said compound is selected from the group consisting of: