Inhibitors of c-jun n-terminal kinases for the treatment of neurodegenerative disorders relating to apoptosis and/or inflammation

Abstract

The present invention provides novel compounds of formula I and their use in the inhibition of c-Jun N-terminal kinases. The present invention further provides the use of these compounds in medicine, in particular in the prevention and/or treatment of neurodegenerative disorders related to apoptosis and/or inflammation.

1 . A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein X is O, S, C(R 4 ) 2 , SO, SO 2  or NR 3 , NR 3 —C(O)— or NR 3 —C(O)—O—;
 R 1  is hydrogen, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-10  aryl, C 3-10  cycloalkyl, C 3-10  cycloalkenyl or C 3-10  heterocyclyl; 
 said R 1  group being optionally substituted with one or more of C 1-6  alkyl, C 1-10  alkoxy, C 3-10  cycloalkyl, halo, hydroxy, oxo, CO 2 R 5 , C 3-10 aryl, C 3-10 heterocyclyl, C 1-6 alkylC 3-10  aryl, NR 6   2  and wherein the C 3-10  heterocyclyl group can be further optionally substituted with C 1-6  alkyl; 
 and R 2  is a thiazole; 
 said R 2  group being optionally substituted with one or more of C 1-6  alkyl, CO 2 H, C 3-10 heterocyclyl, CONR 7 R 7 , CO—C 3-10 heterocyclyl, C 1-6 alkylC 3-10 heterocyclyl and wherein the heterocyclyl group can be further optionally substituted with a C 1-6  alkyl group; 
 wherein
 R 3  is hydrogen or C 1-6  alkyl; 
 R 4  is hydrogen or C 1-6  alkyl; 
 R 5  is hydrogen or C 1-6  alkyl; and 
 R 6  is hydrogen or C 1-6  alkyl; 
 each R 7  is C 1-6  alkyl. 
 
 
   
   
       2 . A compound as claimed in  claim 1  wherein R 1  is an unbranched alkyl group having 2, 3, 4, 5 or 6 carbon atoms. 
   
   
       3 . A compound as claimed in  claim 1  wherein R 1  is an unbranched alkenyl or alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. 
   
   
       4 . A compound as claimed in  claim 1  wherein R 1  is a C 5  or C 6  cycloalkyl or aryl group optionally substituted with one or more of C 1-4  alkyl or a halogen. 
   
   
       5 . A compound as claimed in  claim 4  wherein the aryl group is substituted at the ortho or para position. 
   
   
       6 . A compound as claimed in  claim 4  wherein R 1  is phenyl. 
   
   
       7 . A compound as claimed in  claim 1  wherein R 2  is substituted with CONR 7 R 7 , wherein each R 7  is independently C 1-6  alkyl. 
   
   
       8 . A compound as claimed in  claim 7  wherein each R 7  is independently methyl or ethyl. 
   
   
       9 . A compound as claimed in  claim 7  wherein R 2  is substituted with C 1-6  alkyl. 
   
   
       10 . A compound as claimed in  claim 1  wherein R 2  is optionally substituted with an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. 
   
   
       11 . A compound as claimed in  claim 10  wherein said optional substitution occurs at 2-thiazole position. 
   
   
       12 . A compound as claimed in  claim 1  wherein R 2  is substituted with one or more of C 3-10 heterocyclyl, CO—C 3-10 heterocyclyl C 1-6 alkyl-C 3-10 heterocyclyl and wherein the C 3-10 heterocyclyl group can be further optionally substituted with a C 1-6 alkyl group in which the C 3-10 heterocyclyl is 
     
       
         
         
             
             
         
       
     
     wherein R 7  is a C 4  or C 5 -alkyl or alkenyl group, which, with the nitrogen atom, forms a five or six-membered ring, said alkyl or alkenyl group being optionally interrupted with one or more of O, S or NR 10  wherein R 10  is hydrogen or a C 1-6  alkyl, and optionally substituted with C 1-6  alkyl. 
   
   
       13 . A compound of formula II 
     
       
         
         
             
             
         
       
       wherein R 1  is C 3-8  aryl or C 1-10  alkyl optionally substituted with one or more of halo or CO 2 R 4 ; 
       wherein R 4  is hydrogen or C 1-6  alkyl, 
       R 3  is hydrogen or C 1-6  alkyl, 
       and R 2  is thiazole optionally substituted with one or more of C 1-6  alkyl, CO 2 H, C 3-10 heterocyclyl, CONR 7 R 7 , CO—C 3-10 heterocyclyl, C 1-6 alkylC 3-10 heterocyclyl and wherein the heterocyclyl group can be further optionally substituted with a C 1-6  alkyl group and wherein each R 7  is independently C 1-6  alkyl. 
     
   
   
       14 . A compound as claimed in  claim 13  wherein R 1  is a branched alkyl having 3, 4, 5 or 6 carbon atoms. 
   
   
       15 . A compound selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       16 . (canceled) 
   
   
       17 . A composition comprising a compound as defined in  claim 1  in combination with a pharmaceutically acceptable carrier, diluent or excipient. 
   
   
       18 - 26 . (canceled) 
   
   
       27 . A composition comprising a compound as defined in  claim 15  in combination with a pharmaceutically acceptable carrier, diluent or excipient.