Derivatives of uridine 5′-cyclophosphate useful to treat hepatitis C viral infections

1. A compound of Formula IB:

and pharmaceutically acceptable salts thereof,

wherein:

R is an optionally substituted phenyl or an optionally substituted pyridyl;

R 1B is selected from:

C 1 -C 8 alkyl substituted with one or more R 1BA ,

C 1 -C 8 alkoxy optionally substituted with one or more R 1BA , and

—N(R 1C ) 2 ;

each R 1C is independently hydrogen or C 1 -C 8 alkyl;

each R 1BA is independently hydroxy, halo, —N(R 1CC ) 2 or —OR 1BB ;

R 1BB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl; and

each R 1CC is independently hydrogen or C 1 -C 8 alkyl.

2. The compound of claim 1 , wherein R is selected from the group consisting of:

3. The compound of claim 1 , wherein R is selected from the group consisting of

4. The compound of claim 1 , wherein R 1B is C 1 -C 6 haloalkyl.

5. The compound of claim 1 , wherein R 1B is C 1 -C 8 alkyl substituted with —N(R 1CC ) 2 .

6. The compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

7. A compound having the structure of Formula I-A:

and pharmaceutically acceptable salts thereof,

wherein:

R is an optionally substituted phenyl or an optionally substituted pyridyl;

R 1A is selected from hydroxyl, —O—C(═)CH 3 , and C 1 -C 8 alkyl optionally substituted with one or more R 1AA ;

each R 1AA is independently hydroxy, halo, or —O—C(═O)R 1AB ; and

R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

8. The compound of claim 7 , wherein R 1A is C 1 -C 8 alkyl substituted with one or more R 1AA ;

each R 1AA is independently hydroxy, or halo; and

R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

9. The compound of claim 7 , wherein R 1A is C 1 -C 8 alkyl substituted with one or more R 1AA ;

each R 1AA is independently —O—C(═O)R 1AB ; and

R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

10. The compound of claim 1 , wherein R 1B is C 1 -C 8 alkyl or C 1 -C 8 alkoxy each optionally substituted with one or more R 1BA ;

each R 1BA is independently hydroxy, halo, —N(R 1CC ) 2 or —OR 1BB ;

R 1BB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl; and

each R 1CC is independently hydrogen or C 1 -C 6 alkyl.

11. The compound of claim 1 , wherein R 1B is —N(R 1C ) 2 ; and

each R 1C is independently hydrogen or C 1 -C 6 alkyl.

12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

13. A method of treating a viral infection in a subject comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

14. The method of claim 13 , further comprising administering an effective amount of an additional therapeutic agent to the subject wherein the additional therapeutic agent is selected from the group consisting of thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, an inhibitor of HCV helicase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, ribavirin, interferon-α, and pegylated interferon-α.

15. The method of claim 13 , wherein the viral infection comprises hepatitis C (HCV).

16. A method of inhibiting viral replication in a cell comprising contacting the cell with the compound of claim 1 .

17. The method of claim 16 , wherein the viral replication is RNA-dependent.

18. The method of claim 16 , further comprising contacting the cell with an additional antiviral agent(s) selected from the group consisting of ribavirin, thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, ribavirin, interferon-α, and pegylated interferon-α.

19. The method of claim 16 , wherein the cell is a hepatocyte.

20. The compound of claim 7 selected from the group consisting of:

21. A method of treating a viral infection in a subject comprising administering an effective amount of a compound of claim 7 to a subject in need thereof.