Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

Abstract

This disclosure relates to nucleotide and nucleoside therapeutic compounds and uses in treating infectious diseases viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.

1 .- 257 . (canceled) 
     
     
         258 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof wherein, 
         X is OCMe 2 , OCHF, OCF 2 , or OCD 2 ; 
         W is N or CR 7 ; 
         Z is N or CR 8 ; 
         R 1  is selected from H or from one of the following formulae: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Y is O or S; 
         Y 1  is OH, OAryl, OAlkyl, or BH 3   − M + ; 
         Y 2  is OH or BH 3   − M + ; 
         Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; 
         R 2  is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl; 
         R 4  is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid substituent; 
         R 5  is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid substituent, C 1-22  alkoxy, C 1-22  alkyl, C 2-22  alkenyl, C 2-22  alkynyl, or substituted heteroaryl having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom; 
         R 6  is methyl, ethyl, tert-butyl, C 1-22  alkoxy, C 1-22  alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; 
         R 7  is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano; 
         R 8  is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano; 
         wherein the lipid substituent is selected from optionally substituted C 6-22  alkoxy; optionally substituted C 6-22  alkyl; optionally substituted aryl substituted with C 6-22  alkyl; or optionally substituted polyethylene glycol, wherein the lipid substituent optionally comprises an alcohol; amine; thiol; has one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur; or the lipid substituent is unsaturated or polyunsaturated. 
       
     
     
         259 . The compound of  claim 258 , wherein R 2  is selected from H, chloro, methyl, cyclopropyl, and fluoromethyl. 
     
     
         260 . The compound of  claim 258 , wherein X is selected from OCH 2 , OCD 2 , and OCHMe. 
     
     
         261 . The compound of  claim 258 , wherein W is N or CR 7 , and R 7  is selected from H, methyl, fluoro, chloro, bromo, and iodo. 
     
     
         262 . The compound of  claim 258 , wherein Z is N or CR 8 , and R 8  is selected from H and methyl. 
     
     
         263 . The compound of  claim 258 , wherein R 1  is selected from H, or a group having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         264 . The compound of  claim 258 , having the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         265 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof wherein, 
         X is OCHMe, OCMe 2 , OCHF, OCF 2 , or OCD 2 ; 
         W is N or CR 7 ; 
         Z is N or CR 8 ; 
         R 1  is selected from H or from one of the following formulae: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Y is O or S; 
         Y 1  is OH, OAryl, OAlkyl, or BH 3   − M + ; 
         Y 2  is OH or BH 3   — M + ; 
         Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; 
         R 2  is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl; 
         R 4  is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid substituent; 
         R 5  is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid substituent, C 1-22  alkoxy, C 1-22  alkyl, C 2-22  alkenyl, C 2-22  alkynyl, or substituted heteroaryl having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom; 
         R 6  is methyl, ethyl, tert-butyl, C 1-22  alkoxy, C 1-22  alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; 
         R 7  is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano; 
         R 8  is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano; 
         wherein the lipid substituent is selected from optionally substituted C 6-22  alkoxy; optionally substituted C 6-22  alkyl; optionally substituted aryl substituted with C 6-22  alkyl; or optionally substituted polyethylene glycol, wherein the lipid substituent optionally comprises an alcohol; amine; thiol; has one or more of its carbon units substituted with an oxygen. nitrogen, or sulfur; or the lipid substituent is unsaturated or polyunsaturated. 
       
     
     
         266 . The compound of  claim 265 , wherein R 2  is selected from H, chloro, methyl, cyclopropyl, and fluoromethyl. 
     
     
         267 . The compound of  claim 265 , wherein X is selected from OCH 2 , OCD 2 , and OCHMe. 
     
     
         268 . The compound of  claim 265 , wherein W is N or CR 7 , and R 7  is selected from H, methyl, fluoro, chloro, bromo, and iodo. 
     
     
         269 . The compound of  claim 265 , wherein Z is N or CR 8 , and R 8  is selected from H and methyl. 
     
     
         270 . The compound of  claim 265 , wherein R 1  is selected from H, or a group having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         271 . The compound of  claim 265 , having the formula 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         272 . A pharmaceutical composition comprising a compound of  claim 258  and a pharmaceutically acceptable carrier. 
     
     
         273 . The pharmaceutical composition of  claim 272 , further comprising at least one additional antiviral agent. 
     
     
         274 . A method of treating infections caused by RNA viruses comprising administering to a host in need an effective amount of a compound of  claim 258 . 
     
     
         275 . A pharmaceutical composition comprising a compound of  claim 265  and a pharmaceutically acceptable carrier. 
     
     
         276 . The pharmaceutical composition of  claim 275 , further comprising at least one additional antiviral agent. 
     
     
         277 . A method of treating infections caused by RNA viruses comprising administering to a host in need an effective amount of a compound of  claim 265 .