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

1. A compound of the structural formula I:

or a pharmaceutically acceptable salt thereof: wherein

B is

 wherein the asterisk denotes the point of attachment to the rest of the compound;

n is 0, 1, or 2;

R 1 is hydrogen, methyl, or fluoromethyl;

R 2 is fluoro or OR 3 ;

R 3 is selected from the group consisting of hydrogen, methyl, 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 4 is hydrogen, C 1-5 alkyl, or phenyl; 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 is 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, and C 1-8 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;

R 9 is hydrogen, C 1-8 alkylcarbonyl, C 1-8 alkyloxycarbonyl, or [(di-C 1-8 alkylamino)-C 1-8 alkoxy]carbonyl; and

R 10 is hydrogen, C 1-8 alkyl, or C 1-8 alkylcarbonyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-A:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B1:

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

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, and 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; and

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

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl or fluoromethyl, and R 2 is hydroxy.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl or fluoromethyl, and R 2 is fluoro.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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, 4-hydroxybenzyl, and 1H-indol-3-ylmethyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1-8 alkyl, cyclohexyl, cyclopentyl, cyclohexylmethyl, 2-cyclohexylethyl, or 3-cyclohexyl-n-propyl, each of which is optionally substituted with one to three substituents independently selected from fluorine, hydroxy, and C 1-6 alkoxy.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 6 is ethyl, butyl, or heptyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, R 5 is hydrogen, and R 6 is ethyl, butyl, or heptyl.

12. The compound of claim 1 , which is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R 4 is C 1-4 alkyl;

R 6 is C 1-8 alkyl, C 1-8 alkyl substituted with C 1-6 alkoxy, cyclohexyl, cyclopentyl, cyclohexylmethyl, 2-cyclohexylethyl, or 3-cyclohexyl-n-propyl; and

R 9 is H, C 1-8 alkylcarbonyl, or [(di-C 1-4 alkylamino)-C 1-4 alkoxy]carbonyl.

13. The compound of claim 1 , which is a compound of Formula III-A:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , which is a compound of Formula III-B:

or a pharmaceutically acceptable salt thereof.

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

n-butyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4-H-furo[3,2-d][1,2,3]dioxaphosphinin-2-yl]amino}propanoate;

ethyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4-H-furo[3,2-d][1,2,3]dioxaphosphinin-2-yl]amino}propanoate;

n-heptyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4-H-furo[3,2-d][1,2,3]dioxaphosphinin-2-yl]amino}propanoate;

tert-butyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

n-butyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

ethyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]dioxaphosphinin-2-yl]amino}butanoate;

ethyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-leucinate;

ethyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-norvalinate;

cyclopentyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]-dioxaphosphinin-2-yl]-L-alaninate;

ethyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2oxidotetrahydro-4H-furo[3,2-d][1,3,2]-dioxaphosphinin-2-yl]-L-alaninate;

n-heptyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2oxidotetrahydro-4Hfuro[3,2d][1,3,2]-dioxaphosphinin-2-yl]-L-alaninate;

cyclohexyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2oxidotetrahydro-4Hfuro[3,2d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

isopentyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]-dioxaphosphinin-2-yl]-L-alaninate;

3-methoxypropyl N[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

2-ethylbutyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

2-propylpentyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

2-(hexyloxy)ethyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

cycloheptyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

3-cyclohexylpropyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

ethyl (2S)-2-({(4aR,6R,7R,7aR)-7-hydroxy-7-methyl-2-oxido-6-[2-oxo-4-[(2-propylpentanoyl)amino]pyrimidin-1(2H)-yl]tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl}amino)butanoate;

ethyl N-{(4aR,6R,7R,7aR)-7-hydroxy-7-methyl-2-oxido-6-[2-oxo-4-[(2-propylpentanoyl)amino]pyrimidin-1(2H)-yl]tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl}-L-alaninate;

n-heptyl N-{(4aR,6R,7R,7aR)-7-hydroxy-7-methyl-6-[4-[(1-methylene-2-propylpentyl)amino]-2-oxopyrimidin-1(2H)-yl]-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl}-L-alaninate; and

n-heptyl N-{(4aR,6R,7R,7aR)-6-[4-({[3-(dimethylamino)propoxy]carbonyl}amino)-2-oxopyrimidin-1(2H)-yl]-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl}-L-alaninate;

and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method for the treatment of hepatitis C virus infection in a mammal in need thereof, which comprises administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal.