2-nh-heteroarylimidazoles with antibacterial activity

Abstract

A method of inhibiting MetRS activity comprises administering to a patient in need thereof a MetRS inhibiting effective amount of a compound of the formula (I). A method of treating a resistant or multiply-resistant E. faecalis infection, a resistant or multiply-resistant S. aureus infection, and/or a resistant or multiply-resistant S. epidermidis infection comprises administering to a patient in need thereof an antibacterially effective amount of a compound of the formula (I).

1 . A method of inhibiting MetRS activity comprising administering to a patient in need thereof a MetRS inhibiting effective amount of a compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     in which: 
 R 1  is an optionally substituted aryl or an optionally substituted heteroaryl ring;  
 R 2  is a 5 or 6-membered heteroaryl ring which is optionally substituted with from 1 to 3 substituents selected from halo, cyano, hydroxy, (C 1-6 )alkyl (optionally substituted by 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;  
 X is CH 2  or CHR 3  in which R 3  is C (1-6) alkyl or is linked to the ortho position of an aryl or heteroaryl ring of R 1  to form a 5 to 7 membered ring optionally including oxygen or nitrogen as a ring atom;  
 Y is C (1-3) alkylene or C (4-6) cycloalkylene;  
 including tautomeric forms of the imidazole ring; and  
 salts thereof and  
 excluding 8-[2-(benzylamino)ethylamino]theophylline.  
 
   
   
       2 . A method of inhibiting metRS activity according to  claim 1 , wherein said compound is selected from the group consisting of N-(3,5-dibromobenzyl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine; 
 N-(4,6-dichloro-1H-indol-2-ylmethyl)-N′-(H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine;    N-(6,8-dibromo-1,2,3,4,-tetrahydroquinolin-4-yl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine dihydrochloride;    N-(4,5-dibromothien-2-ylmethyl)-N′-(H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine;    N-(3,5-dibromobenzyl)-N′-(1H-imidazo[4,5-c]pyridin-2-yl)-propane-1,3-diamine;    N-(4,6-dichloro-1H-indol-2-ylmethyl)-N′-(1H-imidazo[4,5-b]pyrazin-2-yl)-propane-1,3-diamine dihydrochloride;    N-(4,6-dichloro-1H-indol-2-ylmethyl)-N′-(9H-purin-8-yl)-propane-1,3-diamine dihydrochloride;    N-(4,5-dibromothien-2-ylmethyl)-N′-(9H-purin-8-yl)-propane-1,3-diamine dihydrochloride;    N-(3-bromo-5-methoxy-1H-indol-7-ylmethyl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine;    N-(6-Ethyl-8-iodo-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine dihydrochloride;    N-(6,8-dibromo-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine dihydrochloride;    N-(3-chloro-5-methoxy-1H-indol-7-ylmethyl)-N′-(H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine;    N-(4,5-dibromo-3-methylthiophen-2-ylmethyl)-N′-(H-imidazo[4,5-c]pyridin-2-yl)propane-1,3-diamine;    N-(4,5-dibromo-3-methylthiophen-2-ylmethyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine dihydrochloride;    N-(4,5-dibromo-3-methylthiophen-2-ylmethyl)-N′-(H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-vinylthiophen-2-ylmethyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)-propane-1,3-diamine;    N-(4-bromo-3-methyl-5-vinylthiophen-2-ylmethyl)-N′(1H-imidazo[4,5-b]pyridin-2-yl)-propane-1,3-diamine;    N-(4-bromo-3-methyl-5-vinylthiophen-2-ylmethyl)-N′(1H-imidazo[4,5-c]pyridin-2-yl)-propane-1,3-diamine;    N-(3-bromo-2-ethoxy-5-methylsulfanybenzyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine dihydrochloride;    N-(6-chloro-8-iodochroman-4-yl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine;    N-(3-chloro-5-methoxy-1H-indol-7-ylmethyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine dihydrochloride;    N-(4,5-dibromo-3-methylthiophen-2-ylmethyl)-N′-(1H-thieno[3,4-d]imidazol-2-yl)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-vinylthiophen-2-ylmethyl)-N′-(1H-thieno[3,4-d]imidazol-2-yl)propane-1,3-diamine;    N-(3-chloro-5-methoxy-1H-indol-7-ylmethyl)-N′-(1H-thieno[3,4-d]imidazol-2-yl)propane-1,3-diamine;    N-(4-bromo-5-difluoromethyl-3-methylthiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine dihydrochloride;    N-(4-bromo-5-difluoromethyl-3-methylthiophen-2-ylmethyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine dihydrochloride;    N-(4-bromo-5-difluoromethyl-3-methylthiophen-2-ylmethyl)-N′-(1H-thieno[3,4-d]imidazol-2-yl)propane-1,3-diamine dihydrochloride;    N-(4-bromo-3-methyl-5-trifluoromethylthiophen-2-ylmethyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine dihydrochloride;    N-(4-bromo-3-methyl-5-trifluoromethylthiophen-2-ylmethyl)-N′-(1H-thieno[3,4-d]imidazol-2-yl)propane-1,3-diamine dihydrochloride;    N-(4-bromo-3-methyl-5-trifluoromethylthiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine dihydrochloride;    N-(4-bromo-3-methyl-5-trifluoromethylthiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-c]pyridin-2-yl)propane-1,3-diamine dihydrochloride;    N-(4-bromo-5-(1-fluorovinyl)-3-methylthiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine hydrochloride;    N-(4-bromo-5-(1-fluorovinyl)-3-methylthiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-c]pyridin-2-yl)propane-1,3-diamine;    N-(4-bromo-5-(1-fluorovinyl)-3-methylthiophen-2-ylmethyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine;    N-(4-bromo-5-(1-fluorovinyl)-3-methylthiophen-2-ylmethyl)-N′-(1H-thieno[3,4-d]imidazol-2-yl)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-ethynylthiophen-2-ylmethyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-ethynylthiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-ethynylthiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-c]pyridin-2-yl)propane-1,3-diamine;    N-(4-bromo-3-methyl-5-ethynylthiophen-2-ylmethyl)-N′-(1H-thieno[3,4-d]imidazol-2-yl)propane-1,3-diamine;    N-(4-bromo-5-ethyl-3-(1-propynyl)thiophen-2-ylmethyl)-N′-(5H-imidazo[4,5-c]pyridazin-6-yl)propane-1,3-diamine dihydrochloride;    N-(4-bromo-5-ethyl-3-(1-propynyl)thiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-c]pyridin-2-yl)propane-1,3-diamine;    N-(4-bromo-5-ethyl-3-(1-propynyl)thiophen-2-ylmethyl)-N′-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine;    and N-(4-bromo-5-ethyl-3-(1-propynyl)thiophen-2-ylmethyl)-N′-(1H-thieno[3,4-d]imidazol-2-yl)propane-1,3-diamine.    
   
   
       3 . The method of  claim 1 , wherein the metRS is a metRS from a Gram positive organism.  
   
   
       4 . The method of  claim 3 , wherein the Gram positive organism is selected from the group consisting of  S. aureus, S. epidermidis, S. pyogenes, S. pneumoniae , and  Ent. faecalis.    
   
   
       5 . The method of  claim 1 , wherein the metRS is a metRS from a Gram negative organism.  
   
   
       6 . The method of  claim 5 , wherein the Gram negative organism is selected from the group consisting of  H. influenzae, M. catarrhalis , and  E. coli.    
   
   
       7 . The method of  claim 1 , wherein the patient has a bacterial infection selected from the group consisting of respiratory tract infections, otitis media, meningitis, endocarditis, skin and soft tissue infections, and mastitis.  
   
   
       8 . The method of  claim 1 , wherein the patient is a human or a non-human mammal.  
   
   
       9 . The method of  claim 8 , wherein the patient is human and the compound is administered in an amount of a least about 50 to about 3000 mg per day.  
   
   
       10 . The method of  claim 9 , wherein the patient is human and the compound is administered in an amount of about 1500 mg per day.  
   
   
       11 . The method of  claim 9 , wherein the patient is human and the compound is administered in an amount of at least about 5 to about 20 mg per kg per day.  
   
   
       12 . The method of  claim 1 , wherein the compound is N-(4,5,-dibromothien-2-ylmethyl)-N′-(1H-imidazo[4,5-b]pyridine-2-yl)-propane-1,3-diamine.  
   
   
       13 . The method of  claim 1 , wherein the compound is an R-enantiomer.  
   
   
       14 . A method of treating a resistant or multiply-resistant  S. aureus  infection, the method comprising administering to a patient in need thereof an antibacterially effective amount of a compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     in which: 
 R 1  is an optionally substituted aryl or an optionally substituted heteroaryl ring;  
 R 2  is a 5 or 6-membered heteroaryl ring which is optionally substituted with from 1 to 3 substituents selected from halo, cyano, hydroxy, (C 1-6 )alkyl (optionally substituted by 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;  
 X is CH 2  or CHR 3  in which R 3  is C (1-6) alkyl or is linked to the ortho position of an aryl or heteroaryl ring of R 1  to form a 5 to 7 membered ring optionally including oxygen or nitrogen as a ring atom;  
 Y is C (1-3) alkylene or C (4-6) cycloalkylene;  
 including tautomeric forms of the imidazole ring; and  
 salts thereof and  
 excluding 8-[2-(benzylamino)ethylamino]theophylline.  
 
   
   
       15 . A method of treating a resistant or multiply-resistant  E. faecalis  infection, the method comprising administering to a patient in need thereof an antibacterially effective amount of a compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     in which: 
 R 1  is an optionally substituted aryl or an optionally substituted heteroaryl ring;  
 R 2  is a 5 or 6-membered heteroaryl ring which is optionally substituted with from 1 to 3 substituents selected from halo, cyano, hydroxy, (C 1-6 )alkyl (optionally substituted by 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;  
 X is CH 2  or CHR 3  in which R 3  is C (1-6) alkyl or is linked to the ortho position of an aryl or heteroaryl ring of R 1  to form a 5 to 7 membered ring optionally including oxygen or nitrogen as a ring atom;  
 Y is C (1-3) alkylene or C (4-6) cycloalkylene;  
 including tautomeric forms of the imidazole ring; and  
 salts thereof and  
 excluding 8-[2-(benzylamino)ethylamino]theophylline.  
 
   
   
       16 . A method of treating a resistant or multiply-resistant  S. epidermidis  infection, the method comprising administering to a patient in need thereof an antibacterially effective amount of a compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     in which: 
 R 1  is an optionally substituted aryl or an optionally substituted heteroaryl ring;  
 R 2  is a 5 or 6-membered heteroaryl ring which is optionally substituted with from 1 to 3 substituents selected from halo, cyano, hydroxy, (C 1-6 )alkyl (optionally substituted by 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;  
 X is CH 2  or CHR 3  in which R 3  is C (1-6) alkyl or is linked to the ortho position of an aryl or heteroaryl ring of R 1  to form a 5 to 7 membered ring optionally including oxygen or nitrogen as a ring atom;  
 Y is C (1-3) alkylene or C (4-6) cycloalkylene;  
 including tautomeric forms of the imidazole ring; and  
 salts thereof and  
 excluding 8-[2-(benzylamino)ethylamino]theophylline.