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 method for treating Hepatitis B virus (HBV) infection and related conditions, said method comprising administering to a subject an effective amount of at least one compound having formula (I): 
       
         
           
           
               
               
           
         
         R 1  is hydrogen; 
         R 2  is selected from a group consisting of hydrogen, methyl, trifluoromethyl, fluorine, and chlorine; 
         R 3  is selected from a group consisting of hydrogen, methyl, fluorine, and chlorine; 
         R 4  is selected from a group consisting of hydrogen, fluorine, chlorine, and methyl; 
         R 5  is selected from a group consisting of hydrogen and chlorine; 
         R 7  is selected from a group consisting of hydrogen, chlorine, fluorine, and bromine; 
         R 9  is selected from a group consisting of hydrogen methyl fluorine and chlorine; 
         R x  is selected from a group consisting of NH 2 , 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof. 
     
     
         2 . The method of  claim 1 , wherein the at least one compound is at least one member 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;   5-sec-Butylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Diethylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-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-(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-benzylsulfamoyl)-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   
       and pharmaceutically acceptable forms thereof. 
     
     
         3 . The method of  claim 1 , wherein the at least one compound is administered in a composition further comprising at least one excipient. 
     
     
         4 . The method of  claim 3 , wherein the at least one compound is at least one member 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;   5-sec-Butylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Diethylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-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-(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-benzylsulfamoyl)-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   
       and pharmaceutically acceptable forms thereof. 
     
     
         5 . A method for treating Hepatitis B virus (HBV) infection and related conditions, said method comprising administering to a subject an effective amount of at least one compound having formula (II): 
       
         
           
           
               
               
           
         
         Including hydrates, solvates, pharmaceutically acceptable salts, pro-drugs and complexes thereof, wherein: 
         R x  is selected from a group consisting of 
       
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof. 
     
     
         6 . The method of  claim 5 , wherein the at least one compound is at least one member selected from the group consisting of
 5-sec-Butylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Diethylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-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-(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-benzylsulfamoyl)-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   
       and pharmaceutically acceptable forms thereof. 
     
     
         7 . The method of  claim 5 , wherein the at least one compound is administered in a composition further comprising at least one excipient. 
     
     
         8 . The method of  claim 7 , wherein the at least one compound is at least one member selected from the group consisting of
 5-sec-Butylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   5-Diethylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-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-(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-benzylsulfamoyl)-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide;   
       and pharmaceutically acceptable forms thereof. 
     
     
         9 . A method for treating Hepatitis B virus (HBV) infection and related conditions, said method comprising administering to a subject an effective amount of at least one compound having formula (III): 
       
         
           
           
               
               
           
         
         Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: 
         R 10  is selected from a group consisting of hydrogen, methyl, chlorine and bromine; 
         R y  is selected from a group consisting of, 
       
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof. 
     
     
         10 . The method of  claim 9 , wherein the at least one compound is at least one member selected from the group consisting of
 3-(Azepane-1-sulfonyl)-N-benzyl-4-chloro-benzamide;   N-Benzyl-4-chloro-3-(piperidine-1-sulfonyl)-benzamide;   N-Benzyl-4-methyl-3-(4-methyl-piperidine-1-sulfonyl)-benzamide,   N-Benzyl-3-benzylsulfamoyl-4-methyl-benzamide;   3-(3-Benzylcarbamoyl-benzenesulfonylamino)-benzoic acid;   N-Benzyl-4-bromo-3-diethylsulfamoyl-benzamide;   and pharmaceutically acceptable forms thereof.   
     
     
         11 . The method of  claim 9 , wherein the at least one compound is administered in a composition further comprising at least one excipient. 
     
     
         12 . The method of  claim 11 , wherein the at least one compound is at least one member selected from the group consisting of
 3-(Azepane-1-sulfonyl)-N-benzyl-4-chloro-benzamide;   N-Benzyl-4-chloro-3-(piperidine-1-sulfonyl)-benzamide;   N-Benzyl-4-methyl-3-(4-methyl-piperidine-1-sulfonyl)-benzamide;   N-Benzyl-3-benzylsulfamoyl-4-methyl-benzamide;   3-(3-Benzylcarbamoyl-benzenesulfonylamino)-benzoic acid;   N-Benzyl-4-bromo-3-diethylsulfamoyl-benzamide;   and pharmaceutically acceptable forms thereof.   
     
     
         13 . A method for treating Hepatitis B virus (HBV) infection and related conditions, said method comprising administering to a subject an effective amount of at least one compound having formula (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof. 
     
     
         14 . The method of  claim 13 , wherein the at least one compound is administered in a composition further comprising at least one excipient.