Mk2 inhibitors

Abstract

The present invention relates to compounds of general Formula I or a pharmaceutically acceptable salt thereof. The compounds can be used in the treatment of immune, autoimmune, inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases or proliferative diseases.

1 . A compound of Formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         A is CH or N; 
         Y is a bond, or —C(O)NH—; 
         X is a bond, —CH 2 —, —CH 2 CH 2 —; 
         V is —CH 2 —, O, C(O), —CHF—, or —CF 2 —, with the proviso that if V is O, X is —CH 2 CH 2 — and that if V is C(O), X is —CH 2 ; 
         W is a bond or —CH 2 —; 
         R1 is hydrogen or F; 
         R2 is a (1-12C)heteroaryl or (6-10C)aryl both optionally substituted with one or more groups independently selected from R4; 
         R3 is a hydrogen; (3-6C)cycloalkyl; (1-6C)alkyl, —(CH 2 ) m OR5; —(CH 2 ) m NR5R6; or —C(O)CH 2 NR5R6; 
         R4 is taken from halogen; OH; SH; nitrile, nitro, NH 2 ; (3-6C)cycloalkyl, (3-6C)cycloalkoxy, (1-6C)alkoxy or (1-6C)alkyl, all optionally substituted with one or more halogen; phenoxy; —O(CH 2 ) m OR5, —O(CH 2 ) m NR7R8, —OC(O)R7 with the proviso that R7 is not hydrogen, —O(1-12C)heteroaryl), —S(1-6C)alkyl); —S(3-6C)cycloalkyl)-; NR7R8; —NR9(CH 2 ) m OR7, —NR9(CH 2 ) m NR7R8; (1-6C)alkylcarbonyl; (3-6C)cycloalkylcarbonyl; —C(O)NR7R8; —C(O)NR9(CH 2 ) m NR7R8, —C(O)NR9(CH 2 ) m OR7, —C(O)OR7, —SO 2 (1-6C)alkyl), —SO 2 (3-6C)cycloalkyl); —O(1-6C)alkyl)O— where the oxygens are attached to the (1-12C)heteroaryl or (6-10C)aryl ring on two neighboring carbons; phenyl or (1-12C)heteroaryl; 
         R5 is hydrogen (3-6C)cycloalkyl; or (1-6C)alkyl; 
         R6 is hydrogen; (3-6C)cycloalkyl; (1-6C)alkyl; or (1-6C)alkylcarbonyl; 
         R7 is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; 
         R8 is hydrogen; (3-6C)cycloalkyl; (1-6C)alkyl; or (1-6C)alkylcarbonyl; or 
         R7 and R8 together with the nitrogen to which they are bonded in NR7R8 can form a 5-7-membered at least one nitrogen containing (4-6C)heterocyclyl ring which optionally contains one additional heteroatom selected from N, O or S; 
         R9 is hydrogen; (1-6C)alkyl or (3-6)cycloalkyl; and 
         m is 2 or 3. 
       
     
     
         2 . The compound according to  claim 1  wherein
 V is —(CH 2 )— or O, with the proviso that if V is O, X is —CH 2 CH 2 —; 
 R4 is taken from halogen; OH; NH 2 ; (3-6C)cycloalkyl or (1-6C)alkyl, both optionally substituted with one or more halogen; (3-6C)cycloalkoxy; (1-6C)alkoxy; phenoxy; —NR7R8; (1-6C)alkylcarbonyl; (3-6C)cycloalkylcarbonyl; —C(O)NR7R8; —O(1-6C)alkyl)O— where the oxygens are attached to the (1-12C)heteroaryl or (6-10C)aryl ring on two neighboring carbons; phenyl or (1-5C)heteroaryl. 
 
     
     
         3 . The compound according to  claims 1 - 2  wherein V is —CH 2 —. 
     
     
         4 . The compound according to  claims 1 - 3  wherein W is —CH 2 —. 
     
     
         5 . The compound according to  claims 1 - 4  wherein X is —CH 2 —. 
     
     
         6 . The compound according to  claims 1 - 5  wherein R2 is (1-5C)heteroaryl optionally substituted with one or more groups independently selected from R4 wherein R4 is selected from —NR7R8; NH 2  or (1-6C)alkoxy. 
     
     
         7 . The compound according to  claims 1 - 6  wherein R2 is phenyl optionally substituted with one or more groups independently selected from R4 wherein R4 is taken from halogen; OH; (3-6C)cycloalkyl or (1-6C)alkyl, both optionally substituted with one or more halogen; (1-6C)alkoxy; phenoxy; (1-6C)alkylcarbonyl; (3-6C)cycloalkylcarbonyl; —C(O)NR7R8; —O(1-6C)alkyl)O— where the oxygens are attached to the (hetero)aryl ring on two neighboring carbons or phenyl. 
     
     
         8 . The compound according to  claims 1 - 7  wherein R3 is hydrogen; —(CH 2 ) m NR5R6, or —C(O)CH 2 NR5R6. 
     
     
         9 . The compound according to  claim 8  wherein R3 is hydrogen. 
     
     
         10 . The compound according to  claims 1 - 7  wherein R3 is methyl, and Y=—C(O)NH—. 
     
     
         11 . The compound according to  claims 1 - 9  wherein Y is a bond. 
     
     
         12 . A pharmaceutical composition which comprises a compound of formula I according to any of  claims 1  to  11  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 
     
     
         13 . The compound according to anyone of  claims 1  to  11  for use in the treatment or prophylaxis of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases and proliferative diseases. 
     
     
         14 . The compound of anyone of  claims 1 - 11  for use in therapy. 
     
     
         15 . The compound according to anyone of  claims 1 - 11  for use in the treatment of immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases or proliferative diseases. 
     
     
         16 . Use of a compound of formula I according to any of  claims 1  to  11  or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases or proliferative diseases.