Nucleoside aryl phosphoramidates for the treatment of RNA-dependent RNA viral infection

1. A compound of the structural formula I:

or a pharmaceutically acceptable salts thereof; wherein

n is 0, 1, or 2;

Ar is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, or isoquinolinyl, wherein Ar is optionally substituted with one to five substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyano, nitro, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, and C 1-4 alkyloxycarbonyl;

R 1 is hydrogen or fluoro;

R 2 is fluoro, methoxy, or OR 10 ;

R 3 is selected from the group consisting of hydrogen, C 1-16 alkylcarbonyl, C 2-18 alkenylcarbonyl,

C 1-10 alkyloxycarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 cycloalkyloxycarbonyl, and an amino acyl residue of structural formula:

R 10 is selected from the group consisting of hydrogen, C 1-16 alkylcarbonyl, C 2-18 alkenylcarbonyl, C 1-10 alkyloxycarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 cycloalkyloxycarbonyl, and an amino acyl residue of structural formula:

or R 3 and R 10 together with the oxygen atoms to which they are attached form a five-membered cyclic carbonate;

R 4 is hydrogen, C 1-5 alkyl, phenyl, or benzyl;

wherein alkyl is optionally substituted with one substituent selected from the group consisting of fluorine, hydroxy, methoxy, amino, carboxy, carbamoyl, guanidino, mercapto, methylthio, 1H-imidazolyl, and 1H-indol-3-yl; and wherein phenyl and benzyl are optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, and methoxy;

R 5 is hydrogen or methyl;

or R 4 and R 5 together with the carbon atom to which they attached form a 3- to 6-membered aliphatic spirocyclic ring system;

R 6 is hydrogen, C 1-16 alkyl, C 2-20 alkenyl, (CH 2 ) n C 3-6 cycloalkyl, phenyl, benzyl, or adamantyl;

wherein alkyl, alkenyl, cycloalkyl, and adamantyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkoxy;

and wherein phenyl and benzyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, cyano, C 1-4 alkoxy, trifluoromethyl, and trifluoromethoxy;

R 7 is hydrogen, C 1-5 alkyl, or phenyl C 0-2 alkyl;

R 8 is hydrogen, C 1-4 alkyl, C 1-4 acyl, benzoyl, C 1-4 alkyloxycarbonyl, phenyl C 0-2 alkyloxycarbonyl, C 1-4 alkylaminocarbonyl, phenyl C 0-2 alkylaminocarbonyl, C 1-4 alkylsulfonyl, or phenyl C 0-2 alkylsulfonyl; and

R 9 is hydrogen, C 1-8 alkylcarbonyl, or C 1-8 alkyloxycarbonyl.

2. The compound of claim 1 wherein R 1 is hydrogen or fluoro, R 2 is hydroxy, and R 3 is hydrogen.

3. The compound of claim 1 wherein R 1 is hydrogen or fluoro, R 2 is fluoro, and R 3 is hydrogen.

4. The compound of claim 1 wherein Ar is phenyl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyano, nitro, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, and C 1-4 alkyloxycarbonyl.

5. The compound of claim 4 wherein Ar is phenyl substituted with three to five substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyano, nitro, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, and C 1-4 alkyloxycarbonyl.

6. The compound of claim 5 wherein Ar is phenyl substituted with three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyano, nitro, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, and C 1-4 alkyloxycarbonyl.

7. The compound of claim 1 wherein Ar is indolyl.

8. The compound of claim 1 wherein R 5 is hydrogen and R 4 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, 2-methyl-1-propyl, hydroxymethyl, fluoromethyl, mercaptomethyl, carboxymethyl, carbamoylmethyl, 1-hydroxyethyl, 2-carboxyethyl, 2-carbamoylethyl, 2-methylthioethyl, 4-amino-1-butyl, 3-amino-1-propyl, 3-guanidino-1-propyl, 1H-imidazol-4-ylmethyl, phenyl, benzyl, 4-hydroxybenzyl, and 1H-indol-3-ylmethyl.

9. The compound of claim 8 wherein R 4 is methyl or benzyl.

10. The compound of claim 9 wherein R 4 is methyl.

11. The compound of claim 1 wherein R 6 is C 7-16 alkyl.

12. The compound of claim 11 wherein R 6 is C 8-12 alkyl.

13. The compound of claim 12 wherein R 6 is C 8 alkyl.

14. The compound of claim 1 wherein Ar is phenyl or indolyl each of which is optionally substituted with one to three substituents selected from halogen and C 1-4 alkyl; R 4 is methyl; R 6 is ethyl or butyl; and R 5 is hydrogen.

15. The compound of claim 1 wherein Ar is unsubstituted phenyl and R 6 is C 8 alkyl.

16. The compound of claim 1 which is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

18. A method for treating hepatitis C virus infection in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.