Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase

• US 20040110717A1
• Filed: 01/16/2004
• Published: 06/10/2004
• Est. Priority Date: 01/22/2001
• Status: Active Grant

• Current Assignee: ISIS Pharmaceuticals Incorporated, Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Hall, Dawn L., Himmelberger, Amy L., Tomassini, Joanne E., Bhat, Balkrishen, MacCoss, Malcolm, Olsen, David B., Prakash, Thazha P., Cook, Phillip Dan, Eldrup, Anne B., An, Haoyun, Prhavc, Marija, LaFemina, Robert L., Guinosso, Charles J., Carroll, Steven S., Kuo, Lawrence C., Bhat, Neelima, Rutkowski, Carrie A.
• Granted Patent: US 7,105,499 B2
• Time in Patent Office: Days
• US Class Current: 514/45
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/2292 Thymosin; Related peptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

The present invention provides nucleoside derivatives which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside derivatives alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside derivatives of the present invention.

Claims

1. A method of inhibiting RNA-dependent RNA viral polymerase or inhibiting RNA-dependent RNA viral replication comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of structural formula I which is of the stereochemical configuration:

2. A method of treating RNA-dependent RNA viral infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of claim 1.

3. The method of claim 1 wherein the compound is of structural formula II of the indicated stereochemical configuration:

4. The method of claim 2 wherein the compound is of the structural formula II of the indicated stereochemical configuration:

5. The method of claim 3 wherein the compound is of the structural formula III of the indicated stereochemical configuration:

6. The method of claim 4 wherein the compound is of the structural formula III of the indicated stereochemical configuration:

7. The method of claim 5 wherein B is

8. The method of claim 6 wherein B is

9. The method of claim 5 wherein B is

10. The method of claim 6 wherein B is

11. The method of claim 6 wherein the compound is selected from the group consisting of:

2′

-O-methyl-cytidine,

2′

-C-methyl-cytidine,

3′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

3′

-O-octanoyl-2′

-O-methyl-cytidine,

2′

-C-methyl-adenosine,

2′

-C-methyl-8-amino-adenosine,

4-amino-5-cyano-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-(aminocarbonyl)-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

3′

-deoxy-3′

-methyl-cytidine,

4-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxarmide,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

3′

-amino-3′

-deoxyadenosine,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide, 2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-ethyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

6-amino-1-(β

-D-ribofuranosyl)-1H-inidazo[4,5-c]pyridin-4(5H)-one,

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2′

-O-methylguanosine,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one,

7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-3,4-dihydro-4-oxo-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

8-azidoguanosine,

8-aminoguanosine,

8-bromoadenosine,

8-aminoadenosine,

8-bromoguanosine,

4-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-4-chloro-5-ethyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-thione,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(3H)-one,

4-amino-1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

2-amino-6-chloro-9-(β

-D-ribofuranosyl)-9H-purine,

2-amino-4-chloro-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

6-methyl-9-(β

-D-ribofuranosyl)-9H-purine,

2-amino-7-(2-deoxy-2-fluoro-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-4-chloro-7-(2-deoxy-2-fluoro-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(β

-D-arabinofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-methyl-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

9-(β

-D-arabinofuranosyl)-9H-purin-6(1H)-one,

1-(β

-D-arabinofuranosyl)-1H-cytosine,

2-amino-4-chloro-5-methyl-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

3′

-deoxy-3′

-(fluoromethyl)-guanosine,

2′

-amino-2′

-deoxycytidine,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2′

-O-methyladenosine,

4-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

3′

-amino-3′

-deoxy-2′

-O-methyl -adenosine,

3′

-deoxy-3′

-methyl-uridine,

6-amino-1-(3-deoxy-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(3H)-one,

2-amino-7-(2-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]-pyrimidin-5-carbonitrile,

3′

-deoxy-2′

-O-(2-methoxyethyl)-3′

-methyl-5-methyluridine,

2′

-amino-2′

-deoxy-uridine,

2-amino-9-(β

-D-arabinofuranosyl)-9H-purin-6(1H)-one,

3′

-deoxy-3′

-methylguanosine,

2′

-O-[4-(imidazolyl-1)butyl]guanosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxyguanosine,

2-amino-7-(2-deoxy-2-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-iodo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(2-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

6-amino-1-(2-O-methyl-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(2-deoxy-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(2-deoxy-2-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(β

-D-arabinofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

2′

-O-[2-(N,N-diethylaminooxy)ethyl]-5-methyluridine,

5-ethynyl-2′

-O-(2-methoxyethyl)-cytidine,

1-(2-C-methyl-β

-D-arabinofuranosyl)uracil,

2-amino-2′

-O-methyladenosine,

2′

-deoxy-2′

-fluoroadenosine,

3′

-deoxy-3′

-methyladenosine,

2-amino-7-(2-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-1-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

4-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (tubercidin),

4,6-diamino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carboxamide,

4-amino-1-(3-deoxy-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

4-amino-1-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

4-amino-1-(β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

4-amino-1-(2-C-methyl-β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

4-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine; and

the corresponding 5′

-triphosphates, 5′

-[bis(isopropyloxycarbonyloxymethyl)]monophosphates, 5′

-mono-(S-C_1-4 alkanoyl-2-thioethyl)monophosphates, and 5′

-bis-(S-C_1-4 alkanoyl-2-thioethyl)monophosphates thereof;

or a pharmaceutically acceptable salt thereof.

12. The method of claim 2 wherein the compound is selected from the group consisting of:

2′

-O-methyl-cytidine,

2′

-C-methyl-cytidine,

3 ′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

3′

-O-octanoyl-2′

-O-methyl-cytidine,

2′

-C-methyl-adenosine,

2′

-C-methyl-8-amino-adenosine,

4-amino-5-cyano-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-(aminocarbonyl)-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

3′

-deoxy-3′

-methyl-cytidine,

4-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(3-deoxy- -β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

3′

-amino-3′

-deoxyadenosine,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-ethyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

6-amino-1-(β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2′

-O-methylguanosine,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one,

7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-3,4-dihydro4oxo-7-(2-O-methyl-3-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

8-azidoguanosine,

8-aminoguanosine,

8-bromoadenosine,

8-aminoadenosine,

8-bromoguanosine,

4-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-4-chloro-5-ethyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-thione,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino4-chloro-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(3H)-one,

4-amino-1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

2-amino-6-chloro-9-(β

-D-ribofuranosyl)-9H-purine,

2-amino-4-chloro-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

6-methyl-9-(β

-D-ribofuranosyl)-9H-purine,

2-amino-7-(2-deoxy-2-fluoro-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-4-chloro-7-(2-deoxy-2-fluoro-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(β

-D-arabinofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-methyl-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

9-(β

-D-arabinofuranosyl)-9H-purin-6(1H)-one,

1-(β

-D-arabinofuranosyl)-1H-cytosine,

2-amino-4-chloro-5-methyl-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

3′

-deoxy-3′

-(fluoromethyl)-guanosine,

2′

-amino-2′

-deoxycytidine,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2′

-O-methyladenosine,

4-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

3′

-amino-3′

-deoxy-2′

-O-methyl-adenosine,

3′

-deoxy-3′

-methyl-uridine,

6-amino-1-(3-deoxy-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(3H)-one,

2-amino-7-(2-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]-pyrimidin-5-carbonitrile,

3′

-deoxy-2′

-O-(2-methoxyethyl)-3′

-methyl-5-methyluridine,

2′

-amino-2′

-deoxy-uridine,

2-amino-9-(β

-D-arabinofuranosyl)-9H-purin-6(1H)-one,

3′

-deoxy-3′

-methylguanosine,

2′

-O-[4-(imidazolyl-1)butyl]guanosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxyguanosine,

2-amino-7-(2-deoxy-2-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-iodo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(2-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

6-amino-1-(2-O-methyl-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(2-deoxy-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5R)-one,

6-amino-1-(3-deoxy-3-methyl-1β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(2-deoxy-2-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(β

-D-arabinofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

2′

-O-[2-(N,N-diethylaminooxy)ethyl]-5-methyluridine,

5-ethynyl-2′

-O-(2-methoxyethyl)-cytidine,

1-(2-C-methyl-β

-D-arabinofuranosyl)uracil,

2-amino-2′

-O-methyladenosine,

2′

-deoxy-2′

-fluoroadenosine,

3′

-deoxy-3′

-methyladenosine,

2-amino-7-(2-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-1-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

4-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (tubercidin),

4,6-diamino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carboxamide,

4-amino-1-(3-deoxy-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

4-amino-1-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

4-amino-1-(β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

4-amino-1-(2-C-methyl-β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

4-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine; and

the corresponding 5′

-triphosphates, 5′

-[bis(isopropyloxycarbonyloxymethyl)]monophosphates, 5′

-mono-(S-C_1-4 alkanoyl-2-thioethyl)monophosphates, and 5′

-bis-(S-C_1-4 alkanoyl-2-thioethyl)monophosphates thereof;

or a pharmaceutically acceptable salt thereof.

13. The method of claim 11 wherein the compound is selected from the group consisting of:

2′

-O-′

methyl-cytidine,

2′

-C-methyl-cytidine,

3 ′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

3′

-O-octanoyl-2′

-O-methyl-cytidine,

4-amino-1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

4-amino-5-cyano-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-(aminocarbonyl)-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2′

-C-methyladenosine,

2′

-C-methyl-8-amino-adenosine,

3′

-deoxy-3′

-methyl-cytidine,

4-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

3′

-amino-3′

-deoxyadenosine,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-ethyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

6-amino-1-(β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3d]pyrimidin-4(3H)-one,

2′

-O-methylguanosine,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one,

7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-3,4-dihydro-4-oxo-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrinidine-5-carbonitrile,

2-amino-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

8-azidoguanosine,

8-aminoguanosine,

8-bromoadenosine,

8-aminoadenosine,

8-bromoguanosine,

4-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrinidin-5-carboxamide,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-4-chloro-5-ethyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3- d]pyrimidine,

2-amino-4-chloro-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine,

2-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(2-deoxy-2-fluoro-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

4-amino-1-(2-C-methyl-β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine, and

2-amino-7-(β

-D-arabinofuranosyl)-3,4-dihydro4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile; and

the corresponding 5′

-triphosphates, 5′

-[bis(isopropyloxycarbonyloxymethyl)]monophosphates, 5′

-mono-(S-pivaloyl-2-thioethyl)monophosphates, and 5′

-bis-(S-pivaloyl-2-thioethyl)monophosphates thereof;

or a pharmaceutically acceptable salt thereof.

14. The method of claim 12 wherein the compound is selected from the group consisting of:

2′

-O-methyl-cytidine,

2′

-C-methyl-cytidine,

3′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

3′

-O-octanoyl-2′

-O-methyl-cytidine,

4-amino-1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4d]pyrimidine,

4-amino-5-cyano-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-(aminocarbonyl)-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2′

-C-methyladenosine,

2′

-C-methyl-8-amino-adenosine,

3′

-deoxy-3′

-methyl-cytidine,

4-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

3′

-amino-3′

-deoxyadenosine,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrinidin-5-carboxamide,

4-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-pyrimidin-5-carboxamide,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-ethyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

6-amino-1-(β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

2-amino-7-(3-deoxy-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2′

-O-methylguanosine,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidin-4-(3H)-one,

7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-3,4-dihydro4-oxo-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine-5-carbonitrile,

2-amino-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

8-azidoguanosine,

8-aminoguanosine,

8-bromoadenosine,

8-aminoadenosine,

8-bromoguanosine,

4-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-carboxamide,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-4chloro-5-ethyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine,

2-amino-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(2-deoxy-2-fluoro-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

4-amino-1-(2-C-methyl-β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

2-amino-7-(β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one, and

2-amino-7-(β

-D-arabinofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrinidin-5-carbonitrile; and

the corresponding 5′

-triphosphates, 5′

-t[bis(isopropyloxycarbonyloxymethyl)]monophosphates, 5′

-mono-(S-pivaloyl-2-hioethyl)monophosphates, and 5′

-bis-(S-pivaloyl-2-thioethyl)monophosphates thereof;

or a pharmaceutically acceptable salt thereof.

15. The method of claim 13 wherein the compound is selected from the group consisting of:

2′

-O-methyl-cytidine,

2′

-C-methyl-cytidine,

3′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

3′

-O-octanoyl-2′

-O-methyl-cytidine,

4-amino-1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

4-amino-5-cyano-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-(aminocarbonyl)-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2′

-C-methyladenosine,

2′

-C-methyl-8-amino-adenosine,

8-bromoguanosine,

8-aminoguanosine,

8-aminoadenosine,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3d]pyrimidine,

2-amino-4-chloro-5-ethyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

4-amino-1-(2-C-methyl-β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile;

and the corresponding 5′

-triphosphates thereof;

2′

-O-methylcytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

3′

-deoxyguanosine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate], and

3′

-deoxycytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate];

or a pharmaceutically acceptable salt thereof.

16. The method of claim 14 wherein the compound is selected from the group consisting of:

2′

-O-methyl-cytidine,

2′

-C-methyl-cytidine,

3 ′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

3′

-O-octanoyl-2′

-O-methyl-cytidine,

4-amino-1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

4-amino-5-cyano-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-(aminocarbonyl)-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2′

-C-methyladenosine,

2′

-C-methyl-8-amino-adenosine,

8-bromoguanosine,

8-aminoguanosine,

8-aminoadenosine,

4-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-5-ethyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-1-(2-C-methyl-β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

2-amino-3,4-dihydro-4-oxo-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

2-amino-4chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile;

and the corresponding 5′

-triphosphates thereof;

2′

-O-methylcytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4oxo-7H-pyrrolo[2,3-d]pyrimidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

3′

-deoxyguanosine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate], and

3′

-deoxycytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate];

or a pharmaceutically acceptable salt thereof.

17. The method of claim 15 wherein the compound is selected from the group consisting of:

2′

-O-methylcytidine,

2′

-C-methylcytidine,

3′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

3′

-O-octanoyl-2′

-O-methyl-cytidine,

4-amino-1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

4-amino-5-cyano-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-(aminocarbonyl)-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2′

-C-methyladenosine,

2′

-O-methylcytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4oxo-7H-pyrrolo[2,3-d]pyrimidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate], and

3′

-deoxycytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate];

or a pharmaceutically acceptable salt thereof.

18. The method of claim 16 wherein the compound is selected from the group consisting of:

2′

-O-methylcytidine,

2′

-C-methylcytidine,

3′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

3′

-O-octanoyl-2′

-O-methyl-cytidine,

4-amino-1-(β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

4-amino-5-cyano-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-(aminocarbonyl)-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2′

-C-methyladenosine,

2′

-O-methylcytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate], and

3′

-deoxycytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate];

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 wherein said RNA-dependent RNA viral polymerase is Flaviviridae viral polymerase or Piconzaviridae viral polymerase and said RNA-dependent RNA viral replication is Flaviviridae viral replication or Picomnaviridae viral replication.

20. The method of claim 19 wherein said Flaviviridae viral polymerase is selected from the group consisting of hepatitis C virus polymerase, yellow fever virus polymerase, dengue virus polymerase, West Nile virus polymerase, Japanese encephalitis virus polymerase, Banzi virus polymerase, and bovine viral diarrhea virus (BVDV) polymerase and said Flaviviridae viral replication is selected from the group consisting of hepatitis C virus replication, yellow fever virus replication, dengue virus replication, West Nile virus replication, Japanese encephalitis virus replication, Banzi virus replication, and bovine viral diarrhea virus replication.

21. The method of claim 20 wherein said Flaviviridae viral polymerase is hepatitis C virus polymerase and said Flaviviridae viral replication is hepatitis C virus replication.

22. The method of claim 2 wherein said RNA-dependent RNA viral infection is Flaviviridae viral infection or Picomnaviridae viral infection.

23. The method of claim 22 wherein said Flaviviridae viral infection is selected from the group consisting of hepatitis C virus infection, yellow fever virus infection, dengue virus infection, West Nile virus infection, Japanese encephalitis virus infection, Banzi virus infection, and bovine viral diarrhea virus infection.

24. The method of claim 23 wherein said Flaviviridae viral infection is hepatitis C virus infection.

34. A method of inhibiting HCV NS5B polymerase, inhibiting HCV replication, and/or treating HCV infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of claim 1 in combination with a therapeutically effective amount of another agent active against HCV.

35. The method of claim 34 wherein said agent active against HCV is ribavirin;

levovirin;

thymosin alpha-1;

an inhibitor of NS3 serine protease;

an inhibitor of inosine monophosphate dehydrogenase;

interferon-α

or pegylated interferon-α

, alone or in combination with ribavirin or levovirin.

36. Use of a compound of any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, and 25-29 in the manufacture of a medicament for inhibition of RNA-dependent RNA viral polymerase or inhibition of RNA-dependent RNA viral replication in a mammal.

37. Use of a compound of any one of claims 2, 4, 6, 8, 10, 12, 14, 16, 18, and 25-29 in the manufacture of a medicament for treatment of RNA-dependent RNA viral infection in a mammal.

38. Use according to claim 36 for the manufacture of a medicament for inhibition of HCV polymerase or inhibition of HCV replication in a mammal.

39. Use according to claim 37 for the manufacture of a medicament for treating HCV infection in a mammal.

40. Use according to claim 39 in combination interferon-α

or pegylated interferon-α

, alone or in combination with ribavirin or levovirin.

25. A compound of structural formula IV of the indicated stereochemical configuration:

26. The compound of claim 25 of structural formula V of the indicated stereochemical configuration:

27. The compound of claim 26 of structural formula VI:

28. The compound of claim 27 selected from the group consisting of:

2′

-O-methylcytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

3′

-deoxyguanosine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

2′

-O-methylguanosine-5′

-[bis-(S-acetyl-2-thioethyl)phosphate],

2′

-O-methylguanosine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

8-bromo-2′

-O-methylguanosine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

2-amino-3,4-dihydro-7-(2-O-methyl-β

-D-ribofuranosyl)4-oxo-7H-pyrrolo[2,3-d]pyrimidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

2-amino-5-bromo-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine-5′

-bis-(S-pivaloyl-2-thioethyl)phosphate],

5-bromo-2′

-O-methylcytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate],

3′

-deoxycytidine-5′

-[bis-(S-pivaloyl-2-thioethyl)phosphate], and

2′

-O-methylcytidine-5′

-[bis(isopropyloxycarbonyloxymethyl)]phosphate.

29. A pharmaceutical composition comprising a compound of claim 27 and a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29 useful for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection.

31. The pharmaceutical composition of claim 31 wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase, said RNA-dependent RNA viral replication is HCV replication, and said RNA-dependent RNA viral infection is HCV infection.

32. The pharmaceutical composition of claim 31 in combination with a therapeutically effective amount of another agent active against HCV.

33. The pharmaceutical composition of claim 32 wherein said agent active against HCV is ribavirin;

levovirin;

thymosin alpha-1;

an inhibitor of NS3 serine protease;

an inhibitor of inosine monophosphate dehydrogenase;

interferon-α

or pegylated interferon-α

, alone or in combination with ribavirin or levovirin.

41. A compound selected from the group consisting of:

3′

,5′

-di-O-octanoyl-2′

-O-methyl-cytidine,

4-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,

2-amino-5-ethyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(2-O-methyl-β

-D-′

ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one,

7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-3,4-dihydro-4-oxo-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carbonitrile,

2-amino-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-4-chloro-5-ethyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-chloro-5-methyl-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-thione,

2-amino-4-chloro-7-(2-O-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4chloro-5-methyl-7-(β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(2-deoxy-2-fluoro-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-4-chloro-7-(2-deoxy-2-fluoro-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(β

-D-arabinofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

9-(β

-D-arabinofuranosyl)-9H-purin-6(1H)-one,

3′

-amino-3′

-deoxy-2′

-O-methyl-adenosine,

6-amino-1-(3-deoxy-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(3H)-one,

3′

-deoxy-2′

-O-(2-methoxyethyl)-3′

-methyl-5-methyluridine,

2-amino-7-(3-deoxy-β

-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,

2-amino-7-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

2-amino-7-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

6-amino-1-(2-O-methyl-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

6-amino-1-(2-deoxy-2-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,

1-(2-C-methyl-β

-D-arabinofuranosyl)uracil,

4-amino-1-(3-deoxy-3-fluoro-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,

2-amino-7-(-3-deoxy-3-fluoro-β

-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carboxamide,

4-amino-1-(2-C-methyl-β

-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,

4-amino-1-(3-deoxy-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine, and

4-amino-1-(3-deoxy-3-methyl-β

-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine;

and the corresponding 5′

-triphosphates;

or a pharmaceutically acceptable salt thereof.