Compounds useful as protein kinase inhibitors

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

1 - 44 . (canceled) 
     
     
         45 . A method of inhibiting protein kinase activity in a patient or a biological sample, comprising administering to the patient a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is 
 
       
       
         
           
           
               
               
           
         
         
           R 6  is C 1-4  aliphatic or C 3-6  cycloaliphatic, and is optionally substituted with 1 or 2 halogen atoms; 
           X is O and R 2  is —CH 3 ; or X is NR 5  and, R 2  and R 5 , together with the atoms to which they are attached, form a 1,2,4-triazole; 
           each of R 3  and R 4  is independently H, methyl, or ethyl; or R 3  and R 4 , together with the atoms to which they are attached, form a cyclopropyl ring; and 
           n is 0 or 1. 
         
       
     
     
         46 . The method of  claim 45 , wherein X is O and R 2  is —CH 3 . 
     
     
         47 . The method of  claim 45 , wherein X is NR 5  and, R 2  and R 5 , together with the atoms to which they are attached, form a 1,2,4-triazole. 
     
     
         48 . The method of  claim 45 , wherein R 6  is C 1-4  aliphatic or C 3-6  cycloaliphatic, and is optionally substituted with 1 or 2 halogen atoms. 
     
     
         49 . The method of  claim 45 , wherein R 3  and R 4  are each methyl. 
     
     
         50 . The method of  claim 45 , wherein R 3  is H and R 4  is ethyl. 
     
     
         51 . The method of  claim 45 , wherein R 3  and R 4 , together with the atoms to which they are attached, form a cyclopropyl ring. 
     
     
         52 . The method of  claim 45 , wherein R 6  is cyclopropyl optionally substituted with 1 or 2 halogen atoms. 
     
     
         53 . The method of  claim 45 , wherein R 6  is cyclopentyl optionally substituted with 1 or 2 halogen atoms. 
     
     
         54 . The method of  claim 45 , wherein R 6  is cyclohexyl optionally substituted with 1 or 2 halogen atoms. 
     
     
         55 . The method of  claim 45 , wherein R 6  is C 1-4  aliphatic optionally substituted with 1 or 2 halogen atoms. 
     
     
         56 . The method of  claim 45 , wherein the compound is
 N-cyclopropyl-4-(9-(3,3-difluorocyclopentyl)-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;   4-(9-(3,3-difluorocyclopentyl)-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-fluorocyclopentyl)-3-methoxybenzamide;   N-(3,3-difluorocyclopentyl)-4-(9-(3,3-difluorocyclopentyl)-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;   N-cyclopropyl-4-(9′-(3,3-difluorocyclopentyl)-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzamide;   N-(3,3-difluorocyclopentyl)-4-(9′-(3,3-difluorocyclopentyl)-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzamide;   4-((R)-5-((R)-3,3-difluorocyclopentyl)-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-ylamino)-N-ethyl-3-methoxybenzamide;   N-cyclopropyl-4-((R)-5-((R)-3,3-difluorocyclopentyl)-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-ylamino)-3-methoxybenzamide;   4-((R)-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-N-ethyl-3-methoxybenzamide; or   N-cyclopropyl-4-((R)-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxybenzamide.   
     
     
         57 . The method of  claim 45 , wherein the protein kinase is a PLK. 
     
     
         58 . The method of  claim 57 , wherein the protein kinase is PLK1. 
     
     
         59 . A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient in need thereof, comprising the step of administering to the patient a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is 
 
       
       
         
           
           
               
               
           
         
         
           R 6  is C 1-4  aliphatic or C 3-6  cycloaliphatic, and is optionally substituted with 1 or 2 halogen atoms; 
           X is O and R 2  is —CH 3 ; or X is NR 5  and, R 2  and R 5 , together with the atoms to which they are attached, form a 1,2,4-triazole; 
           each of R 3  and R 4  is independently H, methyl, or ethyl; or R 3  and R 4 , together with the atoms to which they are attached, form a cyclopropyl ring; and 
           n is 0 or 1. 
         
       
     
     
         60 . The method according to  claim 59 , further comprising administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein the additional therapeutic agent is appropriate for the disease being treated and is administered together with the compound of formula I as a single dosage form or separately from the compound as part of a multiple dosage form. 
     
     
         61 . A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof, comprising administering to the patient a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is 
 
       
       
         
           
           
               
               
           
         
         
           R 6  is C 1-4  aliphatic or C 3-6  cycloaliphatic, and is optionally substituted with 1 or 2 halogen atoms; 
           X is O and R 2  is —CH 3 ; or X is NR 5  and, R 2  and R 5 , together with the atoms to which they are attached, form a 1,2,4-triazole; 
           each of R 3  and R 4  is independently H, methyl, or ethyl; or R 3  and R 4 , together with the atoms to which they are attached, form a cyclopropyl ring; and 
           n is 0 or 1.