Methods and compositions for treating flaviviruses and pestiviruses using 4'-modified nucleoside

A method for the treatment or prophylaxis of a flaviviruses and pestiviruses infection in a host, comprising administering an anti-virally effective amount of a compound of Formula II:

• 20
• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• R1, R2 and R3 are independently H, mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug;
• acyl;
• alkyl;
• sulfonate ester;
• 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 R1, R2 and R3 are independently H or phosphate;
• Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4, NR4R5 or SR4;
• X1 is selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR4;
• and
• R4 and R5 are independently hydrogen, acyl, or alkyl.

A method for the treatment or prophylaxis of a flaviviruses and pestiviruses infection in a host, comprising administering an anti-virally effective amount of a compound selected from Formulas III, IV and V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:

• 21
• wherein:
• Base is a purine or pyrimidine base;
• R1, R2 and R3 are independently H;
• mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug;
• acyl;
• alkyl;
• sulfonate ester;
• 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 R1, R2 or R3 is independently H or phosphate;
• R6 is hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), CF3, chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
• and
• X is O, S, SO2 or CH2.

A method for the treatment or prophylaxis of a flaviviruses and pestiviruses infection in a host, comprising administering an anti-virally effective amount of a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof:

• 22
• wherein:
• Base is a purine or pyrimidine base;
• R1, R2 and R3 are independently H;
• mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug;
• acyl;
• alkyl;
• sulfonate ester;
• 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 R1, R2 or R3 is independently H or phosphate;
• R6 is hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), CF3, chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
• and
• X is O, S, SO2 or CH2.

A method for the treatment or prophylaxis of a flaviviruses and pestiviruses infection in a host, comprising administering an anti-virally effective amount of a compound of Formula I:

• 29
• or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other antivirally effective agents, wherein:
• R1, R2 and R3 are independently H, mono-phosphate, di-phosphate, tri-phosphate;
• a stabilized phosphate prodrug;
• acyl;
• alkyl;
• sulfonate ester;
• 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 R1, R2 and R3 are independently H or phosphate;
• Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
• X1 and X2 are independently selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR4;
• and
• R4 and R5 are independently hydrogen, acyl, or alkyl.

A method for the treatment or prophylaxis of a flaviviruses and pestiviruses infection in a host, comprising administering an anti-virally effective amount of a compound of Formula II:

• 30
• or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other antivirally effective agents, wherein:
• R1, R2 and R3 are independently H, mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug;
• acyl;
• alkyl;
• sulfonate ester;
• 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 R1, R2 and R3 are independently H or phosphate;
• Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
• X1 is selected from the group consisting of H, alkyl CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR4;
• and
• R4 and R5 are independently hydrogen, acyl, or alkyl.

A method for the treatment or prophylaxis of a flaviviruses and pestiviruses infection in a host, comprising administering an anti-virally effective amount of a compound selected from Formulas III, IV and V:

• 31
• or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other antivirally effective agents, wherein:
• Base is a purine or pyrimidine base;
• R1, R2 and R3 are independently H;
• mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug;
• acyl;
• alkyl;
• sulfonate ester;
• 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 R1, R2 or R3 is independently H or phosphate;
• R6 is hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), CF3, chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
• and
• X is O, S, SO2 or CH2.

A method for the treatment or prophylaxis of a flaviviruses and pestiviruses infection in a host, comprising administering an anti-virally effective amount of a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof:

• 32
• or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other antivirally effective agents, wherein:
• Base is a purine or pyrimidine base;
• R1, R2 and R3 are independently H;
• mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug;
• acyl;
• alkyl;
• sulfonate ester;
• 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 R1, R2 or R3 is independently H or phosphate;
• R6 is hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), CF3, chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
• X is O, S, SO2 or CH2.
• R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
• R8 and R10 are independently H, alkyl, chlorine, bromine or iodine;
• alternatively, R7 and R9, R7 and R10, R8 and R9, or R8 and R10 can come together to form a pi bond;
• and
• X is O, S, SO2 or CH2.