Thiophene-carboxamide derivatives and their use as inhibitors of the enzyme ikk-2

Abstract

The invention relates to thiophene carboxamides of formula (I), wherein A, R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined in the specification, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.

1 . A compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
       R 1  represents H or CH 3 ; 
       R 2  represents hydrogen, halogen, cyano, C1 to 2 alkyl, trifluoromethyl or C1 to 2 alkoxy; 
       R 3  and R 4  independently represent H or CH 3 ; 
       or the group CR 3 R 4  together represents a C3 to 6 cycloalkyl ring; 
       A represents a six-membered aromatic ring optionally incorporating one or two nitrogen atoms; and the group —CR 3 R 4 —X—R 5  is bonded to ring A in the 4-position relative to the thiophene ring; 
       X represents NR 6 ; 
       R 5  represents H, C1 to 6 alkyl, C2 to 6 alkenyl or C3 to 6 cycloalkyl; said cycloalkyl group optionally incorporating one heteroatom selected from O, S(O) n  or NR 7 ; said alkyl group being optionally further substituted by one or more groups selected independently from CN, OH, C1 to 4 alkoxy, F, a C5 to 10 monocyclic or bicyclic aromatic ring system optionally incorporating one or two heteroatoms independently selected from O, S and N, and said ring system being optionally further substituted by one or more substituents selected independently from halogen, C1 to 2 alkyl, C1 to 2 alkoxy or CF 3 ; or said alkyl being optionally further substituted by a C5 to 6 cycloalkyl ring that optionally incorporates a heteroatom selected from O, S(O) m  or NR 8  and/or a carbonyl group and is optionally further substituted by OH; 
       R 6  represents H or C1 to 6 alkyl; said alkyl group being optionally further substituted by CN, OH, C1 to 4 alkoxy or one or more fluoro atoms; 
       n and m independently represent an integer 0, 1 or 2; 
       R 7  and R 8  independently represent H or C1 to 2 alkyl; 
       and pharmaceutically acceptable salts thereof. 
     
   
   
       2 . A compound of formula (I), according to  claim 1 , wherein R 1  represents H. 
   
   
       3 . A compound of formula (I), according to  claim 1 , in which A represents optionally substituted phenyl. 
   
   
       4 . A compound of formula (I), according to  claim 1 , in which R 3  and R 4  each represent H. 
   
   
       5 . A process for the preparation of a compound of formula (I), according to  claim 1 , which comprises:
 (a) reaction of a compound of formula (II):   
     
       
         
         
             
             
         
       
       wherein A, R 1 , R 2 , R 3 , R 4 , R 5  and X are as defined in  claim 1  with an isocyanate; or 
       (b) reaction of a compound of formula (III) 
     
     
       
         
         
             
             
         
       
       wherein A, R 2 , R 3 , R 4 , R 5  and X are as defined in  claim 1 , 
       with a compound of formula (IV) 
     
     
       
         
         
             
             
         
       
       wherein R 1  is as defined in  claim 1  and LG represents a leaving group; or 
       (c) reaction of a compound of formula (V) 
     
     
       
         
         
             
             
         
       
       wherein A, R 2 , R 3 , R 4 , R 5  and X are as defined in  claim 1  and LG represents a leaving group, 
       with a compound of formula (VI) 
     
     
       
         
         
             
             
         
       
       wherein R 1  is as defined in  claim 1 ; or 
       (d) reaction of a compound of formula (VII) 
     
     
       
         
         
             
             
         
       
       wherein A, R 1 , R 2 , R 3  and R 4  are as defined in  claim 1 , and LG represents a leaving group, 
       with an amine of formula R 5 R 6 NH, wherein R 5  and R 6  are as defined in  claim 1 ; or 
       (e) reaction of a compound of formula (VIII) 
     
     
       
         
         
             
             
         
       
       wherein A, R 1 , R 2  and R 3  are as defined in  claim 1 , 
       with an amine of formula R 5 R 6 NH wherein R 5  and R 6  are as defined in  claim 1 , under reductive amination conditions; or 
       (f) reaction of a compound of formula (IX) 
     
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5  and A are as defined in  claim 1 , 
       with an aldehyde or ketone under reductive amination conditions; 
       and where necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting the resultant compound of formula (I) into a further compound of formula (I); and where desired converting the resultant compound of formula (I) into an optical isomer thereof. 
     
   
   
       6 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       7 . A pharmaceutical composition adapted for administration by inhalation or insufflation comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       8 . A process for the preparation of a pharmaceutical composition which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       9 . A method for the treatment or prophylaxis of inflammatory disease, comprising administering to a person suffering from or at risk of said disease a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 . 
   
   
       10 . The method as claimed in  claim 9  wherein the disease is rheumatoid arthritis. 
   
   
       11 . The method as claimed in  claim 9  wherein the disease is chronic obstructive pulmonary disease. 
   
   
       12 . A method of treating, or reducing the risk of, a disease or condition in which inhibition of IKK-2 activity is beneficial which comprises administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 . 
   
   
       13 . A compound of formula (I), according to  claim 2 , in which A represents optionally substituted phenyl. 
   
   
       14 . A compound of formula (I), according to  claim 2 , in which R 3  and R 4  each represent H. 
   
   
       15 . A compound of formula (I), according to  claim 3 , in which R 3  and R 4  each represent H. 
   
   
       16 . A compound of formula (I), according to  claim 13 , in which R 3  and R 4  each represent H. 
   
   
       17 . The method as claimed in  claim 12  wherein the disease is cancer.