Substituted thiophene compounds

Abstract

The invention relates to heteroaromatic carboxamides of formula (I), wherein A, R 1 , R 2 , 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) 
     
       
         
         
             
             
         
       
     
     in which:
 A represents thiophene; 
 R 1  represents a 5- to 7-membered heteroaromatic ring containing one to three heteroatoms selected independently from oxygen, nitrogen or sulfur; said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, nitro, —NR 1 R 4 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —S(O) m R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10 , C 1 -C 6  alkyl, trifluoromethyl, —(CH 2 ) n R 11 , —O(CH 2 ) n R 11  or —OR 12 ; 
 R 2  represents hydrogen, halogen, cyano, nitro, —NR 13 R 14 , —CONR 15 R 16 , —COOR 17 , —NR 18 COR 19 , —S(O) m R 20 , —SO 2 NR 15 R 16 , —NR 18 SO 2 R 20 , C 1 -C 2  alkyl, trifluoromethyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, trifluoromethoxy, C 1 -C 2  alkoxy or C 1 -C 2  alkanoyl; 
 X represents oxygen or sulphur; 
 each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 12  independently represent a hydrogen atom or C 1 -C 6  alkyl; 
 R 11  represents NR 21 R 22  where R 21  and R 22  are independently hydrogen or C 1 -C 6  alkyl optionally substituted by C 1 -C 4  alkoxy; or R 21  and R 22  together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR 23  group where R 23  is hydrogen or C 1 -C 6  alkyl; or R 11  represents OR 24  where R 24  represents C 1 -C 6  alkyl; 
 each of R 13 R 14 , R 15 , R 16 , R 17 , R 18 , R 19  and R 20  independently represent a hydrogen atom or C 1 -C 2  alkyl; 
 m represents an integer 0, 1 or 2; 
 n represents an integer 2, 3 or 4; 
 and optical isomers, racemates and tautomers thereof and pharmaceutically acceptable salts or solvates thereof: 
 provided that: 
 when A represents thiophene, furan or pyrrole, then R 1  is not 4-pyridinyl or 3-pyrazolyl; and. 
 
   
   
       2 . A compound of formula (I), according to  claim 1 , wherein X represents oxygen. 
   
   
       3 . A compound of formula (I), according to  claim 1 , in which the group A is substituted as shown below in formula (Ia), where B and D are selected from CR 2 , S, O and NR 25 , where R 25  is as defined in  claim 1  and R 25  is hydrogen or C 1 -C 6  alkyl: 
     
       
         
         
             
             
         
       
     
   
   
       4 - 5 . (canceled) 
   
   
       6 . A compound according to  claim 1 , in which R 2  represents H or methyl. 
   
   
       7 . A compound according to  claim 6  in which R 2  represents H. 
   
   
       8 . A compound of formula (I), according to  claim 1 , selected from: 
     3-[(aminocarbonyl)amino]-5-(2-thienyl)-2-thiophenecarboxamide; 
     3-[(aminocarbonyl)amino]-5-(3-thienyl)-2-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-4-methyl-5-(2-pyridyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-[2-(5-methoxypyridyl)]-4-methyl-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-4-methyl-5-(4-pyrimidyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-4-methyl-5-(2-pyrazinyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-4-methyl-5-(2furyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-4-methyl-5-(2-(4-methylthiazolyl))-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-4-methyl-5-(3-methyl-isoxazol-5-yl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(2-pyridyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(3-pyridyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-[5-(2-methoxypridyl]-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-[5-(2,4-dimethoxypyrimidyl)]-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(2-(N-t-butoxycarbonyl)pyrrolyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(2-(5-cyanothienyl))-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(3,5-dimethyl-isoxazol-4-yl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(3-furyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(2-pyrrolyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(5-pyrimidinyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(2-(5-chlorothienyl))-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-[2-(5-trifluoromethylpyridyl)]-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-[2-(5-bromopyridyl)]-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(2-(5-cyanofuryl))-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(2-furyl)-3-thiophenecarboxamide; 
     2-[(aminocarbonyl)amino]-5-(2-(5-methylfuryl))-3-thiophenecarboxamide; 
     and pharmaceutically acceptable salts and solvates thereof. 
   
   
       9 . 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  and R 2  are as defined in  claim 1  with an isocyanate (X═O) or an isothiocyanate (X═S); or
 (b) reaction of compound of formula (III) with a compound of formula (IV) 
 
     
       
         
         
             
             
         
       
       wherein A, X, R 1  and R 2  are as defined in  claim 1  and LG represents a leaving group; or 
       (c) reaction of compound of formula (V) with a compound of formula (VI) 
     
     
       
         
         
             
             
         
       
     
     wherein A, X, R 1  and R 2  are as defined in  claim 1  and LG represents a leaving group;
 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. 
 
   
   
       10 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 , in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       11 . A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof which method comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 , with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       12 - 19 . (canceled) 
   
   
       20 . A method of treating an IKK2 mediated disease which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed  claim 1 . 
   
   
       21 . A method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1 . 
   
   
       22 . A method according to  claim 21 , wherein the disease is asthma. 
   
   
       23 . A method according to  claim 21 , wherein the disease is rheumatoid arthritis. 
   
   
       24 . A method according to  claim 21 , wherein the disease is multiple sclerosis. 
   
   
       25 . A method according to  claim 21 , wherein the disease is chronic obstructive pulmonary disease.