Modified 2' and 3' nucleoside prodrugs for treating flaviviridae infections

Abstract

2′ and/or 3′ prodrugs of 1′, 2′, 3′ or 4′-branched nucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

1 .- 43 . (canceled) 
     
     
         44 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Base is selected from the group consisting of adenine, N 6 -alkylpurine, N 6 -acylpurine, N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -alkylaminopurine, N 6 -thioalkyl purine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, C 5 -iodopyrimidine, C 6 -iodo-pyrimidine, C 5 -Br-vinyl pyrimidine, C 6 -Br-vinyl pyrimidine, C 5 -nitropyrimidine, C 5 -amino-pyrimidine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine; 
 R 7  is halo, F, Cl, Br or I; 
 R 1  is H; phosphate; monophosphate, diphosphate; triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1  is H or phosphate; 
 R 2  is phosphate; monophosphate; diphosphate; triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 2  is H or phosphate; and 
 Y 3  is independently H, F, Cl, Br or I. 
 
       
     
     
         45 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Base is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           each R′, R″ and R 1  is independently selected from the group consisting of H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl, β-cycloalkyl, NH 2 , NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH 2 , CO 2 -alkyl, CONH-alkyl, CON-dialkyl, OH, CF 3 , CH 2 OH, (CH 2 ) m OH, (CH 2 ) m NH 2 , (CH 2 ) m COOH, (CH 2 ) m CN, (CH 2 ) m NO 2  and (CH 2 ) m CONH 2 ; 
           m is 0 or 1; 
           W is C or N; 
           T and V independently are CH or N; 
           Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH 2 , or N; 
           Q 1  and Q 2  independently are N or C—R; 
           Q 3 , Q 4 , Q 5  and Q 6  independently are N or CH; 
           X is O; 
           R 7  is halo, F, Cl, Br or I; 
           R 1  is H; phosphate; monophosphate, diphosphate; triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1  is H or phosphate; 
           R 2  is phosphate; monophosphate; diphosphate; triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 2  is H or phosphate; and 
           Y 3  is independently H, F, Cl, Br or I. 
         
       
     
     
         46 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein:
 Base is selected from the group consisting of adenine, N 6 -alkylpurine, N 6 -acylpurine, N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -alkylaminopurine, N 6 -thioalkyl purine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, C 5 -iodopyrimidine, C 6 -iodo-pyrimidine, C 5 -Br-vinyl pyrimidine, C 6 -Br-vinyl pyrimidine, C 5 -nitropyrimidine, C 5 -amino-pyrimidine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine; 
 X is O; 
 R 1  is H or phosphate; 
 R 6  is alkyl; 
 R 7  is halo, F, Cl, Br or I; 
 each R 8  and R 11  is independently hydrogen, optionally substituted alkyl, optionally substituted lower alkyl, CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, halogenated lower alkyl, CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, —CH 2 C(O)OH, —CH 2 C(O)OR 4 , —CH 2 C(O)O(lower alkyl), —CH 2 C(O)NH 2 , —CH 2 C(O)NHR 4 , —CH 2 C(O)NH(lower alkyl), —CH 2 C(O)N(R 4 ) 2 , —CH 2 C(O)N(lower alkyl) 2 , —(CH 2 ) m C(O)OH, —(CH 2 ) m C(O)OR 4 , —(CH 2 ) m C(O)O(lower alkyl), —(CH 2 ) m C(O)NH 2 , —(CH 2 ) m C(O)NHR 4 , —(CH 2 ) m C(O)NH(lower alkyl), —(CH 2 ) m C(O)N(R 4 ) 2 , —(CH 2 ) m C(O)N(lower alkyl) 2 , —C(O)OH, —C(O)OR 4 , —C(O)O(lower alkyl), —C(O)NH 2 , —C(O)NHR 4 , —C(O)NH(lower alkyl), —C(O)N(R 4 ) 2 , —C(O)N(lower alkyl) 2 , cyano, NH-acyl or N(acyl) 2 ; 
 each R 9  and R 10  is independently hydrogen, OH, OR 2 , optionally substituted alkyl, optionally substituted lower alkyl, CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, halogenated lower alkyl, CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, —CH 2 C(O)OH, —CH 2 C(O)OR 4 , —CH 2 C(O)O(lower alkyl), —CH 2 C(O)SH, —CH 2 C(O)SR 4 , —CH 2 C(O)S(lower alkyl), —CH 2 C(O)NH 2 , —CH 2 C(O)NHR 4 , —CH 2 C(O)NH(lower alkyl), —CH 2 C(O)N(R 4 ) 2 , —CH 2 C(O)N(lower alkyl) 2 , —(CH 2 ) m C(O)OH, —(CH 2 ) m C(O)OR 4 , —(CH 2 ) m C(O)O(lower alkyl), —(CH 2 ) m C(O)SH, —(CH 2 ) m C(O)SR 4 , —(CH 2 ) m C(O)S(lower alkyl), —(CH 2 ) m (O)NH 2 , —(CH 2 ) m C(O)NHR 4 , —(CH 2 ) m C(O)NH(lower alkyl), —(CH 2 ) m C(O)N(R 4 ) 2 , —(CH 2 ) m C(O)N(lower alkyl) 2 , —C(O)OH, —C(O)OR 4 , —C(O)O(lower alkyl), —C(O)SH, —C(O)SR 4 , —C(O)S(lower alkyl), —C(O)NH 2 , —C(O)NHR 4 , —C(O)NH(lower alkyl), —C(O)N(R 4 ) 2 , —C(O)N(lower alkyl) 2 , —O(acyl), —O(lower acyl), —O(R 4 ), —O(alkyl), —O(lower alkyl), —O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl), —S(lower acyl), —S(R 4 ), —S(lower alkyl), —S(alkenyl), —S(alkynyl), —S(aralkyl), —S(cycloalkyl), NO 2 , NH 2 , —NH(lower alkyl), —NHR 4 , —NR 4 R 5 , —NH(acyl), —N(lower alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(aralkyl), —NH(cycloalkyl), —N(acyl) 2 , azido, cyano, SCN, OCN, NCO or halo; 
 R 2  is phosphate; monophosphate; diphosphate; triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 2  is H or phosphate; 
 Y 3  is independently H, F, Cl, Br or I; 
 each R 4  and R 5  is independently hydrogen, acyl, lower acyl, alkyl, methyl, ethyl, propyl, cyclopropyl, lower alkyl, alkenyl, alkynyl or cycloalkyl; and 
 each n is independently 0, 1 or 2. 
 
       
     
     
         47 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein:
 Base is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           each R′, R″ and R′″ is independently selected from the group consisting of H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl, O-cycloalkyl, NH 2 , NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH 2 , CO 2 -alkyl, CONH-alkyl, CON-dialkyl, OH, CF 3 , CH 2 OH, (CH 2 ) m OH, (CH 2 ) m NH 2 , (CH 2 ) m COOH, (CH 2 ) m CN, (CH 2 ) m NO 2  and (CH 2 ) m CONH 2 ; 
           m is 0 or 1; 
           W is C or N; 
           T and V independently are CH or N; 
           Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH 2 , or N; 
           Q 1  and Q 2  independently are N or C—R; 
           Q 3 , Q 4 , Q 5  and Q 6  independently are N or CH; 
           X is O; 
           R 1  is H or phosphate; 
           R 6  is alkyl; 
           R 7  is halo, F, Cl, Br or I; 
           each R 8  and R 11  is independently hydrogen, optionally substituted alkyl, optionally substituted lower alkyl, CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, halogenated lower alkyl, CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, —CH 2 C(O)OH, —CH 2 C(O)OR 4 , —CH 2 C(O)O(lower alkyl), —CH 2 C(O)NH 2 , —CH 2 C(O)NHR 4 , —CH 2 C(O)NH(lower alkyl), —CH 2 C(O)N(R 4 ) 2 , —CH 2 C(O)N(lower alkyl) 2 , —(CH 2 ) m C(O)OH, —(CH 2 ) m C(O)OR 4 , —(CH 2 ) m C(O)O(lower alkyl), —(CH 2 ) m C(O)NH 2 , —(CH 2 ) m C(O)NHR 4 , —(CH 2 ) m C(O)NH(lower alkyl), —(CH 2 ) m C(O)N(R 4 ) 2 , —(CH 2 ) m C(O)N(lower alkyl) 2 , —C(O)OH, —C(O)OR 4 , —C(O)O(lower alkyl), —C(O)NH 2 , —C(O)NHR 4 , —C(O)NH(lower alkyl), —C(O)N(R 4 ) 2 , —C(O)N(lower alkyl) 2 , cyano, NH-acyl or N(acyl) 2 ; 
           each R 9  and R 10  is independently hydrogen, OH, OR 2 , optionally substituted alkyl, optionally substituted lower alkyl, CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, halogenated lower alkyl, CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, —CH 2 C(O)OH, —CH 2 C(O)OR 4 , —CH 2 C(O)O(lower alkyl), —CH 2 C(O)SH, —CH 2 C(O)SR 4 , —CH 2 C(O)S(lower alkyl), —CH 2 C(O)NH 2 , —CH 2 C(O)NHR 4 , —CH 2 C(O)NH(lower alkyl), —CH 2 C(O)N(R 4 ) 2 , —CH 2 C(O)N(lower alkyl) 2 , —(CH 2 ) n C(O)OH, —(CH 2 ) n C(O)OR 4 , —(CH 2 ) n C(O)O(lower alkyl), —(CH 2 ) n C(O)SH, —(CH 2 ) n C(O)SR 4 , —(CH 2 ) n C(O)S(lower alkyl), —(CH 2 ) n C(O)NH 2 , —(CH 2 ) n C(O)NHR 4 , —(CH 2 ) n C(O)NH(lower alkyl), —(CH 2 ) n C(O)N(R 4 ) 2 , —(CH 2 ) n C(O)N(lower alkyl) 2 , —C(O)OH, —C(O)OR 4 , —C(O)O(lower alkyl), —C(O)SH, —C(O)SR 4 , —C(O)S(lower alkyl), —C(O)NH 2 , —C(O)NHR 4 , —C(O)NH(lower alkyl), —C(O)N(R 4 ) 2 , —C(O)N(lower alkyl) 2 , —O(acyl), —O(lower acyl), —O(R 4 ), —O(alkyl), —O(lower alkyl), —O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl), —S(lower acyl), —S(R 4 ), —S(lower alkyl), —S(alkenyl), —S(alkynyl), —S(aralkyl), —S(cycloalkyl), NO 2 , NH 2 , —NH(lower alkyl), —NHR 4 , —NR 4 R 5 , —N(lower alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(aralkyl), —NH(cycloalkyl), —N(acyl) 2 , azido, cyano, SCN, OCN, NCO or halo; 
           R 2  is phosphate; monophosphate; diphosphate; triphosphate; stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 2  is H or phosphate; and 
           Y 3  is independently H, F, Cl, Br or I; 
           each R 4  and R 5  is independently hydrogen, acyl, lower acyl, alkyl, methyl, ethyl, propyl, cyclopropyl, lower alkyl, alkenyl, alkynyl or cycloalkyl; and 
           each n is independently 0, 1 or 2. 
         
       
     
     
         48 . The compound of  claim 45 , wherein Base is 
       
         
           
           
               
               
           
         
       
     
     
         49 . The compound of  claim 47 , wherein Base is 
       
         
           
           
               
               
           
         
       
     
     
         50 . The compound of  claim 45 , wherein Base is 
       
         
           
           
               
               
           
         
       
     
     
         51 . The compound of  claim 47 , wherein Base is 
       
         
           
           
               
               
           
         
       
     
     
         52 . The compound of  claim 44  wherein R 1  is H or phosphate. 
     
     
         53 . The compound of  claim 45  wherein R 1  is H or phosphate. 
     
     
         54 . The compound of  claim 46  wherein R 1  is H or phosphate. 
     
     
         55 . The compound of  claim 46  wherein R 8  and R 11  are each H. 
     
     
         56 . The compound of  claim 47  wherein R 8  and R 11  are each H. 
     
     
         57 . The compound of  claim 44 , or a pharmaceutically acceptable salt thereof, wherein
 R 2  is acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 2  is H.   
     
     
         58 . The compound of  claim 45 , or a pharmaceutically acceptable salt thereof, wherein
 R 2  is acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 2  is H.   
     
     
         59 . The compound of  claim 44 , wherein R 7  is F. 
     
     
         60 . The compound of  claim 45 , wherein R 7  is F. 
     
     
         61 . The compound of  claim 46 , wherein R 7  is F. 
     
     
         62 . The compound of  claim 47 , wherein R 7  is F. 
     
     
         63 . The compound of  claim 44 , wherein each Y 3  is H. 
     
     
         64 . The compound of  claim 45 , wherein each Y 3  is H. 
     
     
         65 . The compound of  claim 44 , wherein R 1  and R 2  are each acyl. 
     
     
         66 . The compound of  claim 45 , wherein R 1  and R 2  are each acyl. 
     
     
         67 . The compound of  claim 65 , wherein acyl is of the formula C(O)R′, wherein R 1  is a straight, branched or cyclic alkyl. 
     
     
         68 . The compound of  claim 66 , wherein acyl is of the formula C(O)R′, wherein R 1  is a straight, branched or cyclic alkyl. 
     
     
         69 . The compound of  claim 67 , wherein R 1  and R 2  are each butyryl. 
     
     
         70 . The compound of  claim 68 , wherein R 1  and R 2  are each butyryl. 
     
     
         71 . The compound of  claim 44 , wherein Base is selected from the group consisting of adenine, guanine and hypoxanthine. 
     
     
         72 . The compound of  claim 44 , wherein Base is selected from the group consisting of cytosine, thymine, uracil, pyrrolopyrimidine and pyrazolopyrimidine. 
     
     
         73 . The compound of  claim 46 , wherein Base is selected from the group consisting of adenine, guanine and hypoxanthine. 
     
     
         74 . The compound of  claim 46 , wherein Base is selected from the group consisting of cytosine, thymine, uracil, pyrrolopyrimidine and pyrazolopyrimidine. 
     
     
         75 . The compound of  claim 44 , wherein Base is adenine. 
     
     
         76 . The compound of  claim 44 , wherein Base is guanine. 
     
     
         77 . The compound of  claim 44 , wherein Base is hypoxanthine. 
     
     
         78 . The compound of  claim 44 , wherein Base is cytosine. 
     
     
         79 . The compound of  claim 44 , wherein Base is thymine. 
     
     
         80 . The compound of  claim 44 , wherein Base is uracil. 
     
     
         81 . The compound of  claim 44 , wherein Base is pyrrolopyrimidine. 
     
     
         82 . The compound of  claim 44 , wherein Base is pyrazolopyrimidine. 
     
     
         83 . The compound of  claim 46 , wherein Base is adenine. 
     
     
         84 . The compound of  claim 46 , wherein Base is guanine. 
     
     
         85 . The compound of  claim 46 , wherein Base is hypoxanthine. 
     
     
         86 . The compound of  claim 46 , wherein Base is cytosine. 
     
     
         87 . The compound of  claim 46 , wherein Base is thymine. 
     
     
         88 . The compound of  claim 46 , wherein Base is uracil. 
     
     
         89 . The compound of  claim 46 , wherein Base is pyrrolopyrimidine. 
     
     
         90 . The compound of  claim 46 , wherein Base is pyrazolopyrimidine. 
     
     
         91 . A pharmaceutical composition comprising a compound of  claim 44 , or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. 
     
     
         92 . A pharmaceutical composition comprising a compound of  claim 45 , or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. 
     
     
         93 . A pharmaceutical composition comprising a compound of  claim 46 , or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. 
     
     
         94 . A pharmaceutical composition comprising a compound of  claim 47 , or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. 
     
     
         95 . The composition of  claim 91 , wherein the compound or pharmaceutically acceptable salt thereof is in the form of an oral dosage. 
     
     
         96 . The composition of  claim 92 , wherein the compound or pharmaceutically acceptable salt thereof is in the form of an oral dosage. 
     
     
         97 . The composition of  claim 93 , wherein the compound or pharmaceutically acceptable salt thereof is in the form of an oral dosage. 
     
     
         98 . The composition of  claim 94 , wherein the compound or pharmaceutically acceptable salt thereof is in the form of an oral dosage. 
     
     
         99 . The composition of  claim 95  wherein the oral dosage is 50 to 1000 mg. 
     
     
         100 . The composition of  claim 96  wherein the oral dosage is 50 to 1000 mg. 
     
     
         101 . The composition of  claim 97  wherein the oral dosage is 50 to 1000 mg. 
     
     
         102 . The composition of  claim 98  wherein the oral dosage is 50 to 1000 mg. 
     
     
         103 . The composition of  claim 95  wherein the dosage is in the form of a tablet or capsule. 
     
     
         104 . The composition of  claim 96  wherein the dosage is in the form of a tablet or capsule. 
     
     
         105 . The composition of  claim 97  wherein the dosage is in the form of a tablet or capsule. 
     
     
         106 . The composition of  claim 98  wherein the dosage is in the form of a tablet or capsule. 
     
     
         107 . A method for the treatment of a host infected with a hepatitis C virus, comprising administering to the host infected with a hepatitis C virus an effective amount of a compound of  claim 44  or a pharmaceutically acceptable salt thereof. 
     
     
         108 . A method for the treatment of a host infected with a hepatitis C virus, comprising administering to the host infected with a hepatitis C virus an effective amount of a compound of  claim 45  or a pharmaceutically acceptable salt thereof. 
     
     
         109 . A method for the treatment of a host infected with a hepatitis C virus, comprising administering to the host infected with a hepatitis C virus an effective amount of a compound of  claim 46  or a pharmaceutically acceptable salt thereof. 
     
     
         110 . A method for the treatment of a host infected with a hepatitis C virus, comprising administering to the host infected with a hepatitis C virus an effective amount of a compound of  claim 47  or a pharmaceutically acceptable salt thereof. 
     
     
         111 . The method of  claim 107 , wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with at least a second antiviral agent. 
     
     
         112 . The method of  claim 108 , wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with at least a second antiviral agent. 
     
     
         113 . The method of  claim 109 , wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with at least a second antiviral agent. 
     
     
         114 . The method of  claim 110 , wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with at least a second antiviral agent. 
     
     
         115 . The method of  claim 111 , wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenan-threnequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a phenanthrenequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation and a ribozyme. 
     
     
         116 . The method of  claim 112 , wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenan-threnequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a phenanthrenequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation and a ribozyme. 
     
     
         117 . The method of  claim 113 , wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenan-threnequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a phenanthrenequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation and a ribozyme. 
     
     
         118 . The method of  claim 114 , wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenan-threnequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a phenanthrenequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation and a ribozyme. 
     
     
         119 . The method of  claim 111 , wherein the second antiviral agent is an interferon. 
     
     
         120 . The method of  claim 112 , wherein the second antiviral agent is an interferon. 
     
     
         121 . The method of  claim 113 , wherein the second antiviral agent is an interferon. 
     
     
         122 . The method of  claim 114 , wherein the second antiviral agent is an interferon. 
     
     
         123 . The method of  claim 111 , wherein the second antiviral agent is ribavirin. 
     
     
         124 . The method of  claim 112 , wherein the second antiviral agent is ribavirin. 
     
     
         125 . The method of  claim 113 , wherein the second antiviral agent is ribavirin. 
     
     
         126 . The method of  claim 114 , wherein the second antiviral agent is ribavirin. 
     
     
         127 . The method of  claim 107  wherein the host is a human. 
     
     
         128 . The method of  claim 108  wherein the host is a human. 
     
     
         129 . The method of  claim 109  wherein the host is a human. 
     
     
         130 . The method of  claim 110  wherein the host is a human.