Substituted thiophenes with antibacterial activity

Abstract

Novel substituted thiophenes that are inhibitors of bacterial methionyl t-RNA synthetase (MRS) are disclosed. Also disclosed are method for their preparation and their use in therapy as anti-bacterial agents.

1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  is selected from the group consisting of C (1-3) alkyl, C (2-3) alkenyl, C (2-3)  alkynyl;  
 R 2  is halogen;  
 R 3  is selected from the group consisting of Br, optionally fluoro-substituted C (1-3) alkyl, optionally fluoro-substituted C (2-3) alkenyl, and C (2-3) alkynyl;  
 R 4  is selected from the group consisting of H, and C (1-3) alkyl;  
 Y is C (1-3) alkyl; and  
 Z is selected from the group consisting of substituted or unsubstituted heteroaryl imidiazole, substituted or unsubstituted quinolone, substituted or unsubstituted benzimidazole, substituted or unsubstituted fused heteroaryl pyridone, substituted or unsubstituted fused aryl pyrimidone, or substituted or unsubstituted fused heteroaryl pyrimidone.  
 
     
     
         2 . A compound according to  claim 1 , wherein the compound is a compound of the formula (IV):  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1 , R 2 , R 3 , R 4  and Y are defined as in  claim 1;  and  
 R 6  is selected from the group consisting of halo, cyano, hydroxy, (C 1-6 )alkyl, optionally substituted by a member selected from the group consisting of halo, hydroxy, amino, mono to perfluoro(C 1-3 )alkyl, carboxy or (C 1-6 )alkoxycarbonyl). (C 3-7 )cycloalkyl, C (1-6) alkoxy, amino, mono- or di-(C 1-6 )alkylamino, acylamino, carboxy, (C 1-6 )alkoxycarbonyl, carboxy(C 1-6 )alkyloxy, (C 1-6 )alkylthio, (C 1-6 )alkylsulphinyl, (C 1-6 )alkylsulphonyl, sulphamoyl, mono- and di-(C 1-6 )alkylsulphamoyl, carbamoyl, mono- and di-(C 1-6 )alkylcarbamoyl, and heterocyclyl;  
 m is 0 or an integer from 1 to 3;  
 further including tautomeric forms of the imidazole ring.  
 
     
     
         3 . A compound according to any of claims  1 - 2 ,  
       in which: 
 R 1  is selected from the group consisting of methyl, allyl, propene, and propyne;  
 R 2  is Br;  
 R 3  is selected from the group consisting of Br, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl, vinyl, fluorovinyl, and ethyne;  
 R 4  is H;  
 Y is C 2  alkyl; and  
 Z is selected from the group consisting of quinoline, heteroaryl imidazole, benzimidazole, and heteroaryl pyrimidone.  
 
     
     
         4 . A salt of a compound according to any of claim  1 - 3 .  
     
     
         5 . The salt of  claim 4 , wherein the salt is a pharmaceutically acceptable salt.  
     
     
         6 . The compound of  claim 1 , wherein the compound is selected from the group consisting of N-(4,5-Dibromo-3-methylthiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine; 
 N-(4-bromo-5-ethynyl-3-methylthiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-vinylthiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-5-(1-fluorovinyl)-3-methylthiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-5-ethyl-3-methylthiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-5-cyclopropyl-3-methylthiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-5-difluoromethyl-3-methylthiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-trifluoromethyl thiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-3-(1-propynyl)-5-ethyl thiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-3-(1-propenyl)-5-ethyl thiophen-2-ylmethyl)-N′-(1H-quinolin-4-one)propane-1,3-diamine;    N-(4-bromo-5-(1-fluorovinyl)-3-methylthiophen-2-ylmethyl)-N′-(1H-benzimidazole)propane-1,3-diamine;    N-(4-bromo-5-difluoromethyl-3-methylthiophen-2-ylmethyl)-N′-(1H-benzimidazole)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-trifluoromethylthiophen-2-ylmethyl)-N′-(1H-benzimidazole)propane-1,3-diamine; and    N-(4,5-Dibromo-3-methylthiophen-2-ylmethyl)-N′-(1H-thieno[3,2-d]pyrimidin-4-one)propane-1,3-diamine.    
     
     
         7 . A compound according to any of claim  1 - 6  for use in the treatment of bacterial infections.  
     
     
         8 . A pharmaceutical composition comprising a compound or salt of any of claim  1 - 6  and a pharmaceutically acceptable carrier or excipient.