Protein kinase inhibitors

Abstract

A compound of the general formula: or pharmaceutically acceptable salts, hydrates, solvates, crystal forms of diastereomers thereof is described. Method of inhibiting a protein kinase using compounds of Formula I are also described.

1 . A method of inhibiting a protein kinase, comprising administering to a subject a therapeutically effective amount of a compound of the general formula  
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:  
         R 1  is H or C 1-4  alkyl;  
         Q is a bond or 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 , CN, aryl, hetaryl, OCF 3 , OC 1-4  alkyl, OC 2-5  alkylNR 4 R 5 , O-aryl, O-heteroaryl, CO 2 R 4 , CONR 4 R 5 , nitro, NR 4 R 5 , C 1-4  alkylNR 4 R 5 , NR 6 C 1-4  alkylNR 4 R 5 , NR 4 COR 5 , NR 6 CONR 4 R 5 , or NR 4 SO 2 R 5 ;  
         R 4  and R 5  are each independently H, C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  alkyl cyclohetalkyl, aryl, hetaryl, C 1-4  alkyl aryl, C 1-4  alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR 7 ;  
         R 6  is H or C 1-4  alkyl;  
         R 7  is H, C 1-4  alkyl, aryl, hetaryl, C 1-4  alkyl aryl, or C 1-4  alkyl hetaryl;  
         R 2  is 0-2 substituents independently selected from halogen, C 1-4  alkyl, OH, OC 1-4  alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CN, C 1-4  alkylNR 8 R 9 , OC 1-4  alkylNR 8 R 9 , CO 2 R 8 , CONR 8 R 9 , NR 8 R 9 , NR 8 COR 9 ,NR 10 CONR 8 R 9 , and NR 8 SO 2 R 9 ;  
         R 8  and R 9  are each independently H, C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  alkyl cyclohetalkyl, aryl, hetaryl, C 1-4  alkyl aryl, C 1-4  alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR 11 ;  
         R 10  is H, C 1-4  alkyl, aryl or hetaryl;  
         R 11  is H, C 1-4  alkyl, aryl, hetaryl, C 1-4  alkyl aryl, or C 1-4  alkyl hetaryl;  
         Y is halogen, OH, NR 12 R 13 , NR 12 COR 13 , NR 12 CONR 13 , NR 12 SO 2 R 13  or NHSO 2 (phenyl);  
         R 12  and R 13  are each independently H, CH 2 F, CHF 2 , CF 3 , CN, C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S, and NR 14  and R 14  is H or C 1-4  alkyl;  
         n=0-4;  
         W is H, C 1-4  alkyl or 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, or NR 15 R 16 ;  
         R 15  and R 16  are each independently H, C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR 17  and R 17  is H or C 1-4  alkyl;  
         when Y is OH or NHCOCH 3  then R2 is 1-2 substituents; and  
         when Y is NH 2  and R 2  is absent then Y is in the para position.  
       
     
     
         2 . The method of  claim 1 , wherein the protein kinase involves a receptor tyrosine kinase selected from the group consisting of EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR-α, PDGFR-β, 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 of  claim 1 , wherein the protein kinase 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 of  claim 1  wherein the protein kinase involves a tyrosine kinase selected from the group consisting of JAK1, JAK2, JAK3 and TYK2.  
     
     
         5 . The method of  claim 1 , wherein the protein kinase 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 of  claim 1 , wherein the protein kinase is associated with a disease state 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 of  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 Epstein Barr virus (EBV), hepatitis B, hepatitis C, human immunodeficiency virus (HIV), human T-cell leukemia/lymphoma (HTLV 1), Varicella-Zoster Virus (VZV), or human papilloma virus (HPV); and the cancer is leukemia, lymphoma or prostate cancer.  
     
     
         8 . The method of  claim 1 , wherein the protein kinase is associated with a disease state selected from the group consisting of one or more of sarcomas, carcinomas and leukemias.  
     
     
         9 . The method of  claim 8 , wherein the protein kinase is associated with a disease state selected from the group consisting of one or more of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.  
     
     
         10 . The method of  claim 1 , wherein the protein kinase is associated with carcinoma formed from the tissue of the breast, prostate, kidney, bladder or colon.  
     
     
         11 . The method of  claim 1 , wherein the protein kinase is associated with a hyperplastic or neoplastic disorder arising in adipose tissue.  
     
     
         12 . The method of  claim 11 , wherein the hyperplastic or neoplastic disorder is an adipose cell tumor.  
     
     
         13 . The method of  claim 12 , wherein the adipose cell tumor is one or more of lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibemomas, hemangioma and liposarcoma.  
     
     
         14 . The method of  claim 1 , comprising administering a compound of the general formula II:  
       
         
           
           
               
               
           
         
         wherein A, W, R 1 , R 2 , n and Y are as defined in  claim 1 .  
       
     
     
         15 . A solvate or crystal form of a compound of the general formula I  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is H or C 1-4 alkyl;  
         Q is a bond or 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 , CN, aryl, hetaryl, OCF 3 , OC 1-4  alkyl, OC 2-5  alkylNR 4 R 5 , O-aryl, O-heteroaryl, CO 2 R 4 , CONR 4 R 5 , nitro, NR 4 R 5 , C 1-4  alkylNR 4 R 5 , NR 6 C 1-4  alkylNR 4 R 5 , NR 4  COR 5 , NR 6 CONR 4 R 5 , or NR 4 SO 2 R 5 ;  
         R 4  and R 5  are each independently H, C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  alkyl cyclohetalkyl, aryl, hetaryl, C 1-4  alkyl aryl, C 1-4  alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR 7 ;  
         R 6  is H or C 1-4 alkyl;  
         R 7  is H, C 1-4  alkyl, aryl, hetaryl, C 1-4  alkyl aryl, or C 1-4  alkyl hetaryl;  
         R 2  is 0-2 substituents independently selected from halogen, C 1-4  alkyl, OH, OC 1-4  alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CN, C 1-4  alkylNR 8 R 9 , OC 1-4  alkylNR 8 R 9 , CO 2 R 8 , CONR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , NR 10 CONR 8 R 9 , and NR 8 SO 2 R 9 ;  
         R 8  and R 9  are each independently H, C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  alkyl cyclohetalkyl, aryl, hetaryl, C 1-4  alkyl aryl, C 1-4  alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR 11 ;  
         R 10  is H, C 1-4  alkyl, aryl or hetaryl;  
         R 11  is H, C 1-4  alkyl, aryl, hetaryl, C 1-4  alkyl aryl, or C 1-4  alkyl hetaryl;  
         Y is halogen, OH, NR 12 R 13 , NR 12 COR 13 , NR 12 CONR 13 , NR 12 SO 2 R 13  or NHSO 2 (phenyl);  
         R 12  and R 13  are each independently H, CH 2 F, CHF 2 , CF 3 , CN, C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S, and NR 14  and R 14  is H or C 1-4  alkyl;  
         n=0-4;  
         W is H, C 1-4  alkyl or 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, or NR 15 R 16 ;  
         R 15  and R 16  are each independently H, C 1-4  alkyl, C 1-4  alkyl cycloalkyl, C 1-4  alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR 17  and R 17  is H or C 1-4  alkyl;  
         when Y is OH or NHCOCH 3  then R 2  is 1-2 substituents; and  
         when Y is NH 2  and R 2  is absent then Y is in the para position.  
       
     
     
         16 . The compound of  claim 15 , having the general formula II:  
       
         
           
           
               
               
           
         
         wherein A, W, R 1 , R 2 , n and Y are as defined in  claim 15 .  
       
     
     
         17 . The compound of  claim 15 , where W is C 1-4  alkyl wherein the compound possesses S chirality at the chiral carbon bearing W.  
     
     
         18 . The compound of  claim 15 , wherein the compound is a mixture of R and S isomers and the mixture comprises at least 70% of the S isomer.  
     
     
         19 . The compound of  claim 18 , wherein the compound comprises at least 80% of the S isomer.  
     
     
         20 . The compound of  claim 19 , wherein the compound comprises at least 90% of the S isomer.  
     
     
         21 . The compound of  claim 20 , wherein the compound comprises at least 95%.of the S isomer.  
     
     
         22 . The compound of  claim 21  wherein the compound comprises at least 99% of the S isomer.  
     
     
         23 . The compound of  claim 15 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . A method having the formula  
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof.