Inhibitors of protein kinases

Abstract

Compounds of general Formula (I): wherein R 1 , R 2 , R 3 , R a , A, B and x are as defined herein are inhibitors of protein kinases in particular members of the cyclin-dependent kinase family and/or the glycogen synthase kinase 3 family and are useful in preventing and/or treating any type of pain, inflammatory disorders, cancer, immunological diseases, proliferative diseases, infectious diseases, cardiovascular diseases, metabolic disorders, renal diseases, neurologic and neuropsychiatric diseases and neurodegenerative diseases.

1 . A method for the treatment of a proliferative disease, the method comprising administering to a subject in need of such treatment an effective amount of a compound of general Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, polymorph, tautomer and stereoisomer thereof wherein: 
         R a  is H or methyl; 
         R 1  is selected from the group consisting of: 
         carbocyclic or —C 1-6  alkyl-carbocyclic, wherein the carbocyclic group is cyclohexyl or cyclopentyl; 
         heterocyclic or —C 1-6  alkyl-heterocyclic group, wherein the heterocyclic group is piperidine, piperazine, morpholine or pyrrolidine; 
         aryl or —C 1-6  alkyl-aryl; 
         heteroaryl or —C 1-6  alkyl-heteroaryl, wherein the heteroaryl group is pyridine, thiazole or thiophene;
 wherein any of the aforesaid carbocyclic, heterocyclic, aryl or heteroaryl groups may optionally be substituted by one or more groups independently selected from: 
 halo, OH, NH 2  and, for carbocyclic and heterocyclic groups, ═O; or 
 C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —NHC(O)(C 1-4  alkyl), —S(C 1-4  alkyl), —SO(C 1-4  alkyl), —SO 2 (C 1-4  alkyl) or —SO 2 NH(C 1-4  alkyl) any of which may be further substituted with halo or OH; or 
 R 3 , —C 1-4  alkyl-R 3 , OR 3 , NHR 3 , —NHC 1-4  alkyl-R 3 , —OC 1-4  alkyl-R 3 , SR 3 , SOR 3  or SO 2 R 3 ;
 wherein R 3  is an aryl, heteroaryl, carbocyclic or heterocyclic group any of which may be substituted with one or more halo, C 1-4  alkyl, —O(C 1-4  alkyl), NH 2 , —NH(C 1-4  alkyl), —C(O)(C 1-4  alkyl), —NHC(O)(C 1-4  alkyl) groups, any of which alkyl groups may be substituted with halo or OH; 
 
 
         each R 2  is independently halo, OH, NH 2 ; or 
         C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —C(O)(C 1-4  alkyl), any of which may be further substituted with halo or OH; or 
         R 4 , —C 1-4  alkyl-R 4 , OR 4 , NHR 4 , —NHC 1-4  alkyl-R 4 , —OC 1-4  alkyl-R 4 , SR 4 , SOR 4  or SO 2 R 4 ;
 wherein R 4  is an aryl, heteroaryl, carbocyclic or heterocyclic group any of which may be further substituted with one or more halo, OH, C 1-4  alkyl, —O(C 1-4  alkyl), NH 2 , —NH(C 1-4  alkyl), —C(O)(C 1-4  alkyl), —NHC(O)(C 1-4  alkyl) groups, any of which alkyl groups may be substituted with halo or OH; and 
 
         x is 0-4. 
       
     
     
         2 . The method of  claim 1 , wherein said proliferative disease is a member of the group consisting of benign neoplasms, dysplasias, hyperplasias showing metastatic growth, neoplasms showing metastatic growth, benign neoplasia-like carcinoma, malignant neoplasia-like carcinoma, sarcoma, carcinosarcoma, cancer of blood-forming tissues, tumors of nerve tissues, and cancer of skin cells. 
     
     
         3 . The method of  claim 1 , wherein said proliferative disease is cancer. 
     
     
         4 . The method of  claim 3 , wherein said cancer is a member of the group consisting of a carcinoma of the bladder, breast, colon, kidney, epidermal, liver, lung, oesophagus, gall, bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, or skin, a hematopoietic tumor of lymphoid lineage, a hematopoietic tumor of myeloid lineage, thyroid follicular cancer, a tumor of mesenchymal origin, a tumor of the central or peripheral nervous system, melanoma, semmoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentoum, keratoctanthoma, thyroid follicular cancer, Kaposi's sarcoma, basal cell carcinoma, small intestine cancer, small intestinal tumor, gastrointestinal tumor, glioblastoma, liposarcoma, germ cell tumor, head and neck tumor, cancer of the mouth, throat, larynx and esophagus, cancer of bone and its supportive and connective tissues, benign osteoma, cartilage tumor, osteosarcoma, tumor of the urinary bladder and the internal and external organs and structures of the urogenital system, soft tissue tumor, soft tissue sarcoma, Wilm's tumor, and cancer of the endocrine and exocrine glands. 
     
     
         5 . The method of  claim 3 , wherein said cancer is a member of the group consisting of adenocarcinoma, colon adenoma, small cell lung cancer, non-small cell lung carcinoma, exocrine pancreatic carcinoma, squamous cell carcinoma, leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute leukemia, chronicmyelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia, fibrosarcoma, habdomyosarcoma, astrocytoma, neuroblastoma, glioma, schwannoma, tumor of the ear, nose and throat area, malignant bone tumor, benign bone tumor, malignant osteogenic sarcoma, malignant chondrosarcoma, and benign chondroma. 
     
     
         6 . The method of  claim 1  wherein the compound is cis-3-acetamido-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclo-hexanecarboxamide. 
     
     
         7 . A method for inhibiting cyclin-dependent protein kinase activity in a subject which comprises administering to the subject in need of such treatment an effective amount of a compound of general formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, polymorph, tautomer and stereoisomer thereof wherein: 
         R a  is H or methyl; 
         R 1  is selected from the group consisting of: 
         carbocyclic or —C 1-6  alkyl-carbocyclic, wherein the carbocyclic group is cyclohexyl or cyclopentyl; 
         heterocyclic or —C 1-6  alkyl-heterocyclic group, wherein the heterocyclic group is piperidine, piperazine, morpholine or pyrrolidine; 
         aryl or —C 1-6  alkyl-aryl; 
         heteroaryl or —C 1-6  alkyl-heteroaryl, wherein the heteroaryl group is pyridine, thiazole or thiophene;
 wherein any of the aforesaid carbocyclic, heterocyclic, aryl or heteroaryl groups may optionally be substituted by one or more groups independently selected from: 
 halo, OH, NH 2  and, for carbocyclic and heterocyclic groups, ═O; or 
 C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —NHC(O)(C 1-4  alkyl), —S(C 1-4  alkyl), —SO(C 1-4  alkyl), —SO 2 (C 1-4  alkyl) or —SO 2 NH(C 1-4  alkyl) any of which may be further substituted with halo or OH; or 
 R 3 , —C 1-4  alkyl-R 3 , OR 3 , NHR 3 , —NHC 1-4  alkyl-R 3 , —OC 1-4  alkyl-R 3 , SR 3 , SOR 3  or SO 2 R 3 ;
 wherein R 3  is an aryl, heteroaryl, carbocyclic or heterocyclic group any of which may be substituted with one or more halo, C 1-4  alkyl, —O(C 1-4  alkyl), NH 2 , —NH(C 1-4  alkyl), —C(O)(C 1-4  alkyl), —NHC(O)(C 1-4  alkyl) groups, any of which alkyl groups may be substituted with halo or OH; 
 
 
         each R 2  is independently halo, OH, NH 2 ; or 
         C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —C(O)(C 1-4  alkyl), any of which may be further substituted with halo or OH; or 
         R 4 , —C 1-4  alkyl-R 4 , OR 4 , NHR 4 , —NHC 1-4  alkyl-R 4 , —OC 1-4  alkyl-R 4 , SR 4 , SOR 4  or SO 2 R 4 ;
 wherein R 4  is an aryl, heteroaryl, carbocyclic or heterocyclic group any of which may be further substituted with one or more halo, OH, C 1-4  alkyl, —O(C 1-4  alkyl), NH 2 , —NH(C 1-4  alkyl), —C(O)(C 1-4  alkyl), —NHC(O)(C 1-4  alkyl) groups, any of which alkyl groups may be substituted with halo or OH; and 
 
         x is 0-4. 
       
     
     
         8 . The method of  claim 7  wherein the protein kinase is CDK2/CycA. 
     
     
         9 . The method of  claim 7  wherein the protein kinase is CDK4/CycD1. 
     
     
         10 . The method of  claim 7  wherein the protein kinase is CDK5/p35NCK. 
     
     
         11 . The method of  claim 7  wherein the protein kinase is CDK6/CycD1. 
     
     
         12 . The method of  claim 7  wherein the protein kinase is CDK9/CycT.