Thiophene carboxamides as inhibitors of the enzyme ikk-2

Abstract

The invention relates to thiophene carboxamides of formula (I), wherein Ar, R 1 , R 2 , R 3 , R 4 , R 5 , m and n 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) 
     
       
         
         
             
             
         
       
       in which: 
       R 1  represents H or CH 3 ; 
       R 2  represents H, halogen, cyano, C1 to 2 alkyl, trifluoromethyl or C1 to 2 alkoxy; 
       n represents an integer 1, 2 or 3; 
       m represents an integer 0, 1, 2 or 3; 
       R 3  represents H, C2 to 4 alkenyl or C1 to 4 alkyl; said alkyl group being optionally further substituted by CN, C1 to 4 alkoxy, C1 to 4 alkyl-SO 2 — or one or more fluoro atoms; 
       or R 3  represents a C1 to 4 alkylene group that forms a 4 to 7 membered azacyclic ring by virtue of being additionally bonded to either the aromatic ring, Ar, or to the linker group, 
       —CR 4 R 5 —(CR 4 R 5 ) n —; 
       R 4  and R 5  independently represent H or C1 to 2 alkyl; or the group CR 4 R 5  together represents a 3 to 6 membered carbocyclic ring that optionally incorporates one heteroatom selected from O or S; and each R 4 , each R 5  and each group CR 4 R 5  is selected independently; 
       Ar represents a 5- or 6-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; or where the group CR 4 R 5  together represents a 3 to 6 membered carbocyclic ring that optionally incorporates one heteroatom selected from O or S, Ar may additionally be phenyl; said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, C1 to 2 alkyl, trifluoromethyl, C1 to 2 alkoxy, NR 6 R 7 , —CONR 6 R 7 , 
       —COOR 6 , —NR 6 COR 7 , —S(O) p R 6 , —SO 2 NR 6 R 7  and —NR 6 SO 2 R 7 ; 
       R 6  and R 7  independently represent H, C2 to 4 alkenyl or C1 to 4 alkyl; said alkyl or alkenyl groups being optionally further substituted by one or more halogen atoms; 
       p represents an integer 0, 1 or 2; 
       and pharmaceutically acceptable salts thereof. 
     
   
   
       2 . A compound of formula (I), according to  claim 1 , wherein n represents the integer 1. 
   
   
       3 . A compound of formula (I), according to  claim 1 , wherein R 1  represents H. 
   
   
       4 . A compound of formula (I), according to  claim 1 , in which Ar represents optionally substituted phenyl or optionally substituted pyridyl. 
   
   
       5 . (canceled) 
   
   
       6 . A compound of formula (I), according to  claim 1 , in which m represents the integer 1. 
   
   
       7 . 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 R 1 , R 2 , R 3 , R 4 , R 5 , Ar, m and n are as defined in  claim 1 , with an isocyanate; or 
       (b) reaction of a compound of formula (III) 
     
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 4 , R 5  and n are as defined in  claim 1  and LG represents a leaving group, with an amine (R 3 NH(CR 4 R 5 ) m —Ar) wherein R 3 , R 4 , R 5 , Ar and m are as defined in  claim 1 ; or 
       (c) reaction of a compound of formula (IV) 
     
     
       
         
         
             
             
         
       
       wherein R 2 , R 3 , R 4 , R 5 , m, n and Ar are as defined in  claim 1 , 
       with a compound of formula (V) 
     
     
       
         
         
             
             
         
       
       wherein R 1  is as defined in  claim 1  and LG represents a leaving group; or 
       (d) reaction of a compound of formula (VI) 
     
     
       
         
         
             
             
         
       
       wherein R 2 , R 3 , R 4 , R 5 , m, n and Ar are as defined in  claim 1  and LG represents a leaving group, 
       with a compound of formula (VII) 
     
     
       
         
         
             
             
         
       
       wherein R 1  is as defined in  claim 1 ; 
       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. 
     
   
   
       8 . 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. 
   
   
       9 . 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. 
   
   
       10 . 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. 
   
   
       11 . (canceled) 
   
   
       12 . (canceled) 
   
   
       13 . A method or the treatment or prophylaxis of inflammatory disease comprising administering to a person suffering from or at risk of said inflammatory disease a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 . 
   
   
       14 . The method as claimed in  claim 13  wherein the disease is rheumatoid arthritis. 
   
   
       15 . The method as claimed in  claim 13  wherein the disease is chronic obstructive pulmonary disease. 
   
   
       16 . (canceled) 
   
   
       17 . A method of treating, or reducing the risk of, a disease or a 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 . 
   
   
       18 . The method as claimed in  claim 17 , wherein the disease is cancer.