Sulfamoylbenzamide derivatives as antiviral agents against hbv infection

Abstract

The present invention provides sulfamoylbenzamide derivatives, and pharmaceutical compositions thereof. In certain embodiments, the compounds and pharmaceutical compositions of the invention inhibit pregenomic RNA encapsidation. In other embodiments, the compounds and pharmaceutical compositions of the invention are useful for treating Hepatitis B virus (HBV) infection.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H; 
 R 2  is selected from the group consisting of H, CH 3 , CF 3 , F and Cl; 
 R 3  is selected from the group consisting of H, CH 3 , F and Cl; 
 R 4  is selected from the group consisting of H, F, Cl and CH 3 ; 
 R 5  is selected from the group consisting of H and Cl; 
 R 7  is selected from the group consisting of H, Cl, F and Br; 
 R 9  is selected from the group consisting of H, CH 3 , F and Cl; 
 R x  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the at least one compound is selected from the group consisting of:
 2-Chloro-5-sulfamoyl-N-3-methylphenyl-benzamide;   4-Fluoro-3-sulfamoyl-N-(3-trifluoromethyl-phenyl)-benzamide;   N-(2-Chloro-5-trifluoromethyl-phenyl)-4-fluoro-3-sulfamoyl-benzamide;   N-Phenyl-3-sulfamoyl-benzamide;   5-sec-Butylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   3-Diethylsulfamoyl-N-phenyl-benzamide;   5-Diethylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   2-Chloro-5-diethylsulfamoyl-N-m-tolyl-benzamide;   N-(4-Chloro-phenyl)-3-diethylsulfamoyl-benzamide;   5-Allylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   N-(3,4-Difluoro-phenyl)-5-dipropylsulfamoyl-2-fluoro-benzamide;   5-Cycloheptylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Cycloheptylsulfamoyl-2-fluoro-N-p-tolyl-benzamide;   5-Cyclohexylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   2-Bromo-5-cyclohexylsulfamoyl-N-phenyl-benzamide;   4-Chloro-3-cyclohexylsulfamoyl-N-(4-fluoro-phenyl)-benzamide;   3-Cyclohexylsulfamoyl-4-methyl-N-phenyl-benzamide;   N-(3,4-Difluoro-phenyl)-4-fluoro-3-(2-methyl-cyclohexylsulfamoyl)-benzamide;   3-Cyclopentylsulfamoyl-N-phenyl-benzamide;   5-Cyclopentylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Cyclopentylsulfamoyl-2-fluoro-N-(4-fluoro-phenyl)-benzamide;   5-Cyclopentylsulfamoyl-N-(3,5-dimethyl-phenyl)-2-fluoro-benzamide;   3-Cyclopentylsulfamoyl-4-fluoro-N-3-methylphenyl-benzamide;   5-Cyclopentylsulfamoyl-N-(3,5-dichloro-phenyl)-2-fluoro-benzamide;   3-[(Furan-2-ylmethyl)-sulfamoyl]-N-phenyl-benzamide;   N-(3-Chloro-4-fluoro-phenyl)-5-[(furan-2-ylmethyl)-sulfamoyl]-2-methyl-benzamide;   2-Fluoro-N-(3-fluoro-phenyl)-5-[(furan-2-ylmethyl)-sulfamoyl]-benzamide;   N-(3,5-Dichloro-phenyl)-2-fluoro-5-[(furan-2-ylmethyl)-sulfamoyl]-benzamide;   4-Fluoro-3-[(furan-2-ylmethyl)-sulfamoyl]-N-3-methylphenyl-benzamide;   5-[(4-Chloro-3-phenylcarbamoyl-benzenesulfonylamino)-methyl]-furan-2-carboxylic acid methyl ester;   N-(3-Chloro-phenyl)-5-(2-cyclohex-1-enyl-ethylsulfamoyl)-2-fluoro-benzamide;   5-(2-Cyclohex-1-enyl-ethylsulfamoyl)-N-(3,5-dimethyl-phenyl)-2-fluoro-benzamide;   5-(2-Cyclohex-1-enyl-ethylsulfamoyl)-N-(3,5-dimethyl-phenyl)-2-fluoro-benzamide;   N-(3-Chloro-phenyl)-4-fluoro-3-[(pyridin-3-ylmethyl)-sulfamoyl]-benzamide;   N-(3,4-Difluoro-phenyl)-2-fluoro-5-phenethylsulfamoyl-benzamide;   N-(3-Chloro-phenyl)-2-fluoro-5-phenethylsulfamoyl-benzamide;   5-Benzylsulfamoyl-N-(3-chloro-4-fluoro-phenyl)-2-fluoro-benzamide;   5-Benzylsulfamoyl-2-chloro-N-phenyl-benzamide;   N-(4-Chloro-phenyl)-5-[2-(3,4-dimethoxy-phenyl)-ethylsulfamoyl]-2-fluoro-benzamide;   5-(2-Chloro-benzylsulfamoyl)-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   3-(2-Chloro-benzylsulfamoyl)-N-(4-chloro-phenyl)-4-fluoro-benzamide;   2-Fluoro-5-(4-methoxy-phenylsulfamoyl)-N-3-methylphenyl-benzamide;   2-Fluoro-5-(4-fluoro-phenylsulfamoyl)-N-3-methylphenyl-benzamide;   N-(4-Chloro-phenyl)-3-(3-fluoro-phenylsulfamoyl)-benzamide;   N-(4-Chloro-phenyl)-3-2-methylphenylsulfamoyl-benzamide;   N-Phenyl-3-m-tolylsulfamoyl-benzamide;   N-Phenyl-3-o-tolylsulfamoyl-benzamide;   3-(Benzyl-ethyl-sulfamoyl)-N-(3,4-difluoro-phenyl)-4-fluoro-benzamide;   5-(Azepane-1-sulfonyl)-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   4-Methyl-N-phenyl-3-(piperidine-1-sulfonyl)-benzamide;   4-Methyl-N-phenyl-3-(piperidine-1-sulfonyl)-benzamide;   4-Chloro-N-(3-fluoro-phenyl)-3-(morpholine-4-sulfonyl)-benzamide;   4-Chloro-N-phenyl-3-(thiomorpholine-4-sulfonyl)-benzamide;   any pharmaceutically acceptable salt thereof, and any mixtures thereof.   
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the compound of formula (I) is the compound of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 R x  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the at least one compound is selected from the group consisting of:
 5-sec-Butyl sulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Diethyl sulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Allylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   N-(3,4-Difluoro-phenyl)-5-dipropyl sulfamoyl-2-fluoro-benzamide;   5-Cycloheptylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-(Azepane-1-sulfonyl)-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Cyclohexylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Cyclopentylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   N-(3,4-Difluoro-phenyl)-2-fluoro-5-phenethylsulfamoyl-benzamide;   5-(2-Chloro-benzyl sulfamoyl)-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   any pharmaceutically acceptable salt thereof, and any mixtures thereof.