Novel hydroxamates as therapeutic agents

Abstract

The present invention is directed to certain hydroxamate derivatives that are useful in the treatment of hepatitis C. These compounds are also inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.

1 - 37 . (canceled)  
     
     
         38 . A method for producing a compound of Formula (I):  
       
         
           
           
               
               
           
         
         comprising reacting a compound of Formula (III):  
         
           
             
             
                 
                 
             
           
         
         with a hydroxylamine of formula NH 2 OR″;  
         to give a compound of Formula (V):  
         
           
             
             
                 
                 
             
           
         
         wherein Z is O, S, or NH;  
         Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxyl, or optionally substituted phenoxy;  
         R is one or two optional substituents independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylalkyloxy, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-S(O) n R a  (where n is 0 to 2 and R a  is hydroxyalkyl or optionally substituted phenyl), -alkylene-NR e -alkyleneCONR c R d  (where R c  is hydroxyl and R d  and R e  are independently hydrogen or alkyl), or carboxyalkylaminoalkyl;  
         R 51  is hydroxy, alkoxy, halo, or succinimido ester; and  
         R″ is hydrogen, alkyl, or an oxygen protecting group; and  
         removing the R″ group in the compound of Formula (V), when R″ is alkyl or an oxygen protecting group, to give a compound of Formula (I).  
       
     
     
         39 . A method for producing a compound of Formula (I):  
       
         
           
           
               
               
           
         
         comprising treating a compound of Formula (IV):  
         
           
             
             
                 
                 
             
           
         
         with an acid; followed by treatment with NH 2 OR″;  
         to give a compound of Formula (V):  
         
           
             
             
                 
                 
             
           
         
         wherein Z is O, S, or NH;  
         Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxyl, or optionally substituted phenoxy;  
         R is one or two optional substituents independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylalkyloxy, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-S(O) n R a  (where n is 0 to 2 and R a  is hydroxyalkyl or optionally substituted phenyl), -alkylene-NR c -alkyleneCONR c R d  (where R c  is hydroxyl and R d  and R e  are independently hydrogen or alkyl), or carboxyalkylaminoalkyl;  
         M +  is an alkali metal; and  
         R″ is hydrogen, alkyl, or an oxygen protecting group;  
         and removing the R″ group in the compound of Formula (V), when R″ is alkyl or an oxygen protecting group, to give a compound of Formula (I).  
       
     
     
         40 . The method of either  claim 38  or  39 , wherein Z is O.  
     
     
         41 . The method of either  claim 38  or  39 , wherein Z is NH.  
     
     
         42 . The method of either  claim 38  or  39 , wherein Z is S.  
     
     
         43 . The method of either  claim 38  or  39 , wherein Y is —CH 2 CH 2 —.  
     
     
         44 . The method of  claim 40 , wherein the benzofuranyl group is monosubstituted.  
     
     
         45 . The method of  claim 41 , wherein the indolyl group is monosubstituted.  
     
     
         46 . The method of  claim 42 , wherein the benzothiofuranyl is monosubstituted.  
     
     
         47 . The method of  claim 44 , wherein the substituent is N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, hydroxyl-4-yloxymethyl, 2,4,6-trifluorophenoxy-methyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxy-methyl, 4-[1.2.4]-triazin-1-yl-phenoxymethyl, 2-phenylethyl, 3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropyl-thiomethyl, 3-hydroxypropylsulfinyl-methyl, 3-hydroxypropylsulfonylmethyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 2-carboxyethylaminomethyl.  
     
     
         49 . The method of  claim 44 , wherein the compound of Formula (1) has the structure:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         52 . A pharmaceutical composition comprising a therapeutically effective amount of a compound prepared by the method of either  claim 38  or  claim 39  or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.  
     
     
         53 . A method for producing the compound of Formula (V) in  claim 38 , wherein R 51  is alkyl, comprising reacting a compound of Formula 4:  
       
         
           
           
               
               
           
         
         with a compound of formula:  
         
           
             
             
                 
                 
             
           
         
         wherein Z is O, S, or NH;  
         Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted. phenylalkylsulfonyl, hydroxyl, or optionally substituted phenoxy;  
         R is one or two optional substituents independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylalkyloxy, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyioxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-S(O) n R a  (where n is 0 to 2 and R a  is hydroxyalkyl or optionally substituted phenyl), -alkylene-NR e -alkyleneCONR c R d  (where R c  is hydroxyl and R d  and R e  are independently hydrogen or alkyl), or carboxyalkylaminoalkyl; and  
         Z′ is —OH or halo.