2′-C-methyl nucleoside derivatives
View Patent ↗Compounds of Formula I, stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof, their preparation, and their uses for the treatment of hepatitis C viral infection are described:
1. A compound of Formula II:
wherein:
B is selected from the group consisting of
V is selected from the group consisting of optionally substituted monocyclic aryl and unsubstituted or substituted monocyclic heteroaryl wherein said substituted monocyclic aryl and said substituted monocyclic heteroaryl are substituted with 1-6 substituents selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halogen, hydroxy, cyano, amino, —OR 3 , —OR 12 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , and —SO 2 NR 2 2 ;
W and W′ are independently selected from the group consisting of —H, methyl, and V, or W and W′ are each methyl, with the proviso that when W is V, then W′ is H;
Z is selected from the group consisting of —H, —OMe, —OEt, phenyl, C 1 -C 3 alkyl, —NR 4 2 , —SR 4 , —(CH 2 ) p —OR 6 , —(CH 2 ) p —SR 6 and —OCOR 5 ; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, containing 0-1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus; or
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, containing 0-1 heteroatom; or
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group;
R 2 is selected from the group consisting of R 3 and hydrogen;
R 3 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
R 4 is C 1 -C 4 alkyl;
R 5 is selected from the group consisting of C 1 -C 4 alkyl, monocyclic aryl, and monocyclic aralkyl; and
R 6 is C 1 -C 4 acyl; and
together R 7 and R 8 form a cyclic carbonate; and
R 10 is selected from the group consisting of OR 4 , OR 6 , NH 2 , NHR 4 , halogen, and H;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein:
V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, —CF 3 , —OR 3 , —OR 12 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , —SO 2 NR 2 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, —CF 3 , —OR 3 , —OR 12 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , —SO 2 NR 2 2 and —CN, and wherein said monocyclic heteroaryl and substituted monocyclic heteroaryl has 1-2 heteroatoms that are independently selected from the group consisting of N, O, and S with the provisos that
a) when there are two heteroatoms and one is O, then the other can not be O or S, and
b) when there are two heteroatoms and one is S, then the other can not be O or S; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, containing 0-1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus; and
R 3 is C 1 -C 6 alkyl.
3. The compound of claim 2 wherein:
V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 NH 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 NH 2 and —CN and wherein said monocyclic heteroaryl and substituted monocyclic heteroaryl has 1-2 heteroatoms that are independently selected from the group consisting of N, O, and S with the provisos that
a) when there are two heteroatoms and one is O, then the other can not be O or S, and
b) when there are two heteroatoms and one is S, then the other can not be O or S; or
together V and Z are connected via an additional 4 atoms to form a 6-membered ring that is fused to a phenyl or substituted phenyl at the beta and gamma position to the O attached to the phosphorus, wherein said substituted phenyl is substituted with 1-6 substituents selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halogen, hydroxy, cyano, amino, —OR 3 , —OR 12 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , and —SO 2 NR 2 2 .
4. The compound of claim 1 wherein V is selected from the group consisting of phenyl; substituted phenyl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; pyridyl; substituted pyridyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and
—CF 3 ; furanyl; substituted furanyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; thienyl; and substituted thienyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ;
and wherein Z, W, and W′ are each —H.
5. The compound of claim 4 wherein V is selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
6. The compound of claim 5 wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
7. The compound of claim 1 , wherein said compound is a compound of Formula III:
wherein:
V and the 5′oxymethylene group of the ribose sugar moiety are cis to one another and wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
8. The compound of claim 7 , wherein said compound has R-stereochemistry at the V-attached carbon and has S-stereochemistry at the phosphorus center.
9. The compound of claim 7 wherein said compound has S-stereochemistry at the V-attached carbon and has R-stereochemistry at the phosphorus center.
10. A compound of Formula I:
wherein:
B is
V is phenyl optionally substituted by one or two halogen atoms, or V is pyridyl;
and W, W′ and Z are all —H;
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , wherein V is selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
12. The compound of claim 11 , wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, and 4-pyridyl.
13. The compound of claim 12 , wherein V and the 5′oxymethylene group of the ribose sugar moiety are cis to one another.
14. The compound of claim 13 , wherein said compound has R-stereochemistry at the V-attached carbon and has S-stereochemistry at the phosphorus center.
15. The compound of claim 13 , wherein said compound has S-stereochemistry at the V-attached carbon and has R-stereochemistry at the phosphorus center.
16. The compound of claim 10 wherein said compound is:
17. The compound of claim 10 , wherein said compound is:
18. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 10 and a pharmaceutically acceptable carrier.
20. A method of inhibiting viral replication in a human patient comprising administering to said human patient a therapeutically effective amount of a compound of claim 1 .
21. The method of claim 20 , wherein said viral replication is RNA-dependent RNA viral replication.
22. The method of claim 20 , wherein said viral replication is HCV replication.
23. A method of inhibiting viral replication in a human patient comprising administering to said human patient a therapeutically effective amount of a compound of claim 10 .
24. The method of claim 23 , wherein said viral replication is RNA-dependent RNA viral replication.
25. The method of claim 23 , wherein said viral replication is HCV replication.
26. A method of treating a viral infection in a human patient comprising administering to said human patient a therapeutically effective amount of a compound of claim 1 .
27. The method of claim 26 , wherein said viral infection is RNA-dependent RNA viral infection.
28. The method of claim 26 , wherein said viral infection is HCV infection.
29. The method of claim 26 , wherein said compound is used in combination with a therapeutically effective amount of a second agent active against HCV.
30. The method of claim 29 , wherein said second agent active against HCV is ribavirin; levovirin; viramidine; thymosin alpha-1; interferon-β; 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.
31. The method of claim 30 , wherein said second agent active against HCV is interferon-α or pegylated interferon-α, alone or in combination with ribavirin or levovirin.
32. A method of treating a viral infection in a human patient comprising administering to said human patient a therapeutically effective amount of a compound of claim 10 .
33. The method of claim 32 , wherein said viral infection is RNA-dependent RNA viral infection.
34. The method of claim 32 , wherein said viral infection is HCV infection.
35. The method of claim 34 , wherein said compound of Formula I is used in combination with a therapeutically effective amount of a second agent active against HCV.
36. The method of claim 35 , wherein said second agent active against HCV is ribavirin; levovirin; viramidine; thymosin alpha-1; interferon-β; 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.
37. The method of claim 36 , wherein said second agent active against HCV is interferon-α or pegylated interferon-α, alone or in combination with ribavirin or levovirin.