Azaindoles useful as inhibitors of janus kinases

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. 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 treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplantation, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to said patient a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 3  is H, Cl or F; 
 X 1  is N or CR 4 ; 
 R 2  is H, F, R′, OH, OR′, COR′, COOH, COOR′, CONH 2 , CONHR′, CON(R′) 2 , or CN; 
 R 4  is H, F, R′, OH, OR′, COR′, COOH, COOR′, CONH 2 , CONHR′, CON(R′) 2 , or CN; 
 or R 2  and R 4 , taken together, form a 5-7 membered aryl or heteroaryl ring optionally substituted with 1-4 occurrences of R 10 ; 
 R′ is a C 1-3  aliphatic optionally substituted with 1-4 occurrences of R 5 ; 
 each R 5  is independently selected from halogen, CF 3 , OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN or unsubstituted C 1-2  aliphatic, or two R 5  groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O; 
 each R 10  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SH, SCH 3 , NCH 3 , CN or unsubstituted C 1-2 aliphatic; 
 R 1  is 
 
       
       
         
           
           
               
               
           
         
         
           R″ is H or is a —C 1-2  aliphatic optionally substituted with 1-3 occurrences of R 11 ; 
           each R 11  is independently selected from halogen, OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, CON(R 15 ) 2  or unsubstituted C 1-2  aliphatic, or two R 11  groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O; 
           R 6  is a C 1-4  aliphatic optionally substituted with 1-5 occurrences of R 12 ; 
           each R 12  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SH, SCH 3 , NCH 3 , CN or unsubstituted C 1-2 aliphatic, or two R 12  groups, together with the carbon to which they are attached, form a cyclopropyl ring; 
           Ring A is a 4-8 membered saturated nitrogen-containing ring comprising up to two additional heteroatoms selected from N, O or S and optionally substituted with 1-4 occurrences of R 13 ; 
           each R 13  is independently selected from halogen, R′, NH 2 , NHR′, N(R′) 2 , SH, SR′, OH, OR′, NO 2 , CN, CF 3 , COOR′, COOH, COR′, OC(O)R′ or NHC(O)R′; or any two R 13  groups, on the same substituent or different substituents, together with the atom(s) to which each R 13  group is bound, form a 3-7 membered saturated, unsaturated, or partially saturated carbocyclic or heterocyclic ring optionally substituted with 1-3 occurrences of R 5 ; 
           R 8  is C 1-4  aliphatic substituted with 1-5 occurrences of R 12 ; 
           R 9  is C 1-2  alkyl; or 
           R 8  and R 9  are taken together to form a 3-7 membered carbocyclic or heterocyclic saturated ring optionally substituted with 1-5 occurrences of R 12 ; 
           R 14  is H or unsubstituted C 1-2  alkyl; 
           R 15  is H or unsubstituted C 1-2  alkyl; and 
           R 7  is a C 2-3  aliphatic or cycloaliphatic optionally substituted with up to 6 occurrences of F. 
         
       
     
     
         46 . The method of  claim 45 , comprising the additional step of 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 diabetes, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disease being treated. 
     
     
         47 . The method according to  claim 45 , wherein the disease or disorder is allergic or type I hypersensitivity reactions, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, a solid malignancy, a hematologic malignancy, a leukemia, a lymphoma and a myeloproliferative disorder. 
     
     
         48 . The method according to  claim 47 , wherein said disease or disorder is asthma. 
     
     
         49 . The method according  claim 47 , wherein said disease or disorder is transplant rejection. 
     
     
         50 . The method according  claim 47 , wherein said disease or disorder is rheumatoid arthritis. 
     
     
         51 . The method according to  claim 47 , wherein said disease is a myeloproliferative disorder selected from polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome or systematic mast cell disease. 
     
     
         52 . The method according to  claim 45 , wherein the compound of Formula (I) has formula I-A: 
       
         
           
           
               
               
           
         
       
     
     
         53 . The method according to  claim 52 , wherein R 3  is H or Cl. 
     
     
         54 . The method according to  claim 52 , wherein R 2  is H, F, R′, OH or OR′. 
     
     
         55 . The method according to  claim 52 , wherein the compound is of formula I-A and R 4  is H, F, R′, OH or OR′, or R 2  and R 4  are taken together to form a 6-membered aryl ring. 
     
     
         56 . The method according to  claim 52 , wherein R 7  is CH 2 CH 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 F or CH 2 CH 2 CHF 2 . 
     
     
         57 . The method according to  claim 52 , wherein R″ is H or CH 3 . 
     
     
         58 . The method according to  claim 52 , wherein R 8 , R 9  and the carbon atom to which they are attached form 
       
         
           
           
               
               
           
         
       
     
     
         59 . The method according to  claim 52 , wherein R 8  and R 9  are taken together to form a ring selected from 
       
         
           
           
               
               
           
         
       
       wherein one or more carbon atoms in of said ring are optionally and independently replaced by N, O or S. 
     
     
         60 . The method according to  claim 52 , wherein Ring A is 
       
         
           
           
               
               
           
         
       
       and R 13,  is H or R 13 .