US2005182252A1PendingUtilityA1
Novel 2'-C-methyl nucleoside derivatives
Priority: Feb 13, 2004Filed: Jul 29, 2004Published: Aug 18, 2005
Est. expiryFeb 13, 2024(expired)· nominal 20-yr term from priority
A61P 31/12C07H 19/04A61P 31/14A61P 31/18C07H 19/20
57
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Claims
Abstract
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:
Claims
exact text as granted — not AI-modified1 . A compound of Formula I:
wherein:
B is selected from the group consisting of
V is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl;
W and W′ are independently selected from the group consisting of —R 2 , optionally substituted monocyclic aryl, and optionally substituted monocyclic heteroaryl;
Z is selected from the group consisting of halogen, —CN, —COR 5 , —CONR 4 2 , —CO 2 R 5 —SO 2 R 5 —SO 2 NR 4 2 , —OR 4 , —SR 4 , —R 4 , —NR 4 2 , —OCOR 5 , —OCO 2 R 5 , —SCOR 5 , —SCO 2 R 5 , —NHCOR 4 , —NHCO 2 R 5 , —(CH 2 ) p —OR 6 , and —(CH 2 ) p —SR 6 ; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 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, optionally containing one heteroatom; or
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms;
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 selected from the group consisting of R 3 and hydrogen;
R 5 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
R 6 is selected from the group consisting of hydrogen, and lower acyl;
R 12 is selected from the group consisting of hydrogen, and lower acyl; and
p is an integer 2 or 3;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 wherein:
B is
3 . The compound of claim 1 wherein:
B is
4 . The compound of claim 1 wherein:
B is
5 . 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 optionally substituted monocyclic heteroaryl;
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 ) n —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, optionally containing 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, optionally containing one heteroatom; or
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group;
R 4 is C—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;
R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 4 acyl, C 1 -C 4 alkoxycarbonyl, and a naturally-occurring L-amino acid connected via its carbonyl group to form an ester; or
together R 7 and R 8 form a cyclic carbonate;
R 9 is selected from the group consisting of amino, azido, —N═CHN(R 4 ) 2 , —NHC(O)R 4 , and —NHC(O)OR 4 ; and
R 10 is selected from the group consisting of OR 6 , halogen, and H;
or a pharmaceutically acceptable salt thereof.
6 . 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 22 , —SR 3 , —SO 2 R 3 , —SO 2 NR 22 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, optionally containing 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.
7 . The compound of claim 6 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.
8 . The compound of claim 7 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 .
9 . The compound of claim 8 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.
10 . The compound of claim 9 wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
11 . The compound of claim 1 wherein 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 ;
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.
12 . The compound of claim 11 wherein Z is selected from the group consisting of —H, —OMe, —OEt, and phenyl.
13 . The compound of claim 1 wherein:
W and W′ are independently selected from the group consisting of —H, C 1 -C 6 alkyl, and phenyl; or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group.
14 . The compound of claim 1 wherein 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.
15 . The compound of claim 1 wherein:
V is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl; 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, optionally containing 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, optionally containing one heteroatom; or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group; and 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.
16 . The compound of claim 15 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, optionally containing 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.
17 . The compound of claim 16 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.
18 . The compound of claim 17 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 .
19 . The compound of claim 1 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; and Z is selected from the group consisting of —H, OMe, OEt, and phenyl; and W and W′ are independently selected from the group consisting of —H and phenyl, or W and W′ are each methyl.
20 . The compound of claim 1 wherein Z, W, and W′ are each —H.
21 . The compound of claim 1 wherein V and W are the same and each is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl.
22 . The compound of claim 1 wherein:
B is V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl; and Z, W, and W′ are each —H.
23 . The compound of claim 22 wherein said compound is:
24 . The compound of claim 1 wherein:
B is V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl; and Z, W, and W′ are each —H.
25 . The compound of claim 24 wherein said compound is:
26 . The compound of claim 1 wherein:
B is V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl; and Z, W, and W′ are each —H.
27 . The compound of claim 26 wherein said compound is:
28 . The compound of claim 26 wherein said compound is:
29 . The compound of claim 1 wherein said compound is a compound of Formula V:
wherein:
V and the 5′oxymethylene group of the ribose sugar moiety are cis to one another.
30 . The compound of claim 5 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.
31 . The compound of claim 30 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.
32 . The compound of claim 31 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.
33 . The compound of claim 32 wherein said compound has R-stereochemistry at the V-attached carbon and has S-stereochemistry at the phosphorus center.
34 . The compound of claim 32 wherein said compound has S-stereochemistry at the V-attached carbon and has R-stereochemistry at the phosphorus center.
35 . The compound of claim 29 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; and R 3 is C 1 -C 6 alkyl.
36 . The compound of claim 35 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.
37 . The compound of claim 36 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 .
38 . The compound of claim 37 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.
39 . The compound of claim 38 wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
40 . The compound of claim 29 wherein said compound has R-stereochemistry at the V-attached carbon and has S-stereochemistry at the phosphorus center.
41 . The compound of claim 29 wherein said compound has S-stereochemistry at the V-attached carbon and has R-stereochemistry at the phosphorus center.
42 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
43 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 5 and a pharmaceutically acceptable carrier.
44 . 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 .
45 . 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 5 .
46 . The method of claim 44 wherein said viral replication is RNA-dependent RNA viral replication.
47 . The method of claim 44 wherein said viral replication is HCV replication.
48 . 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 .
49 . 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 5 .
50 . The method of claim 48 wherein said viral infection is RNA-dependent RNA viral infection.
51 . The method of claim 48 wherein said viral infection is HCV infection.
52 . The method of claim 51 wherein said compound of Formula I is used in combination with a therapeutically effective amount of a second agent active against HCV.
53 . The method of claim 52 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.
54 . The method of claim 53 wherein said second agent active against HCV is interferon-α or pegylated interferon-≢, alone or in combination with ribavirin or levovirin.
55 . A compound of Formula I:
wherein:
B is
V is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl;
W and W′ are independently selected from the group consisting of —R 2 , optionally substituted monocyclic aryl, and optionally substituted monocyclic heteroaryl;
Z is selected from the group consisting of halogen, —CN, —COR 5 , —CONR 4 2 , —CO 2 R 5 , —SO 2 R 5 , —SO 2 NR 4 2 , —OR 4 , —SR 4 , —R 4 , —NR 4 2 , —OCOR 5 , —OCO 2 R 5 , —SCOR 5 , —SCO 2 R 5 , —NHCOR 4 , —NHCO 2 R 5 , —(CH 2 ) p —OR 6 , and —(CH 2 ) p —SR 6 ; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 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, optionally containing one heteroatom; or
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms;
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 selected from the group consisting of R 5 and hydrogen;
R 5 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
R 6 is selected from the group consisting of hydrogen, and lower acyl;
R 12 is selected from the group consisting of hydrogen, and lower acyl; and
p is an integer 2 or 3;
or a pharmaceutically salt thereof.
56 . 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 optionally substituted monocyclic heteroaryl;
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, optionally containing 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, optionally containing one heteroatom; or
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group;
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;
R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 4 acyl, C 1 -C 4 alkoxycarbonyl, and a naturally-occurring L-amino acid connected via its carbonyl group to form an ester; or
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.
57 . The compound of claim 55 , 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, optionally containing 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.
58 . The compound of claim 57 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.
59 . The compound of claim 58 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 .
60 . The compound of claim 59 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.
61 . The compound of claim 60 wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
62 . The compound of claim 55 , wherein 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 ;
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.
63 . The compound of claim 62 wherein Z is selected from the group consisting of —H, —OMe, —OEt, and phenyl.
64 . The compound of claim 55 , wherein:
W and W′ are independently selected from the group consisting of —H, C 1 -C 6 alkyl, and phenyl; or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group.
65 . The compound of claim 55 , wherein 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.
66 . The compound of claim 55 , wherein:
V is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl; 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, optionally containing 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, optionally containing one heteroatom; or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group; and 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.
67 . The compound of claim 66 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 R3, —NR 2 , —NR 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, optionally containing 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.
68 . The compound of claim 67 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.
69 . The compound of claim 68 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 .
70 . The compound of claim 55 , 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; and Z is selected from the group consisting of —H, —OMe, —OEt, and phenyl; and W and W′ are independently selected from the group consisting of —H and phenyl, or W and W′ are each methyl.
71 . The compound of claim 55 , wherein Z, W, and W′ are each —H.
72 . The compound as of claim 55 , wherein V and W are the same and each is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl.
73 . The compound of claim 55 wherein:
B is V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl; and Z, W, and W′ are each —H.
74 . The compound of claim 73 wherein said compound is:
75 . The compound of claim 55 wherein said compound is a compound of Formula V:
wherein:
V and the 5′oxymethylene group of the ribose sugar moiety are cis to one another.
76 . The compound of claim 56 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.
77 . The compound of claim 76 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.
78 . The compound of claim 77 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.
79 . The compound of claim 78 wherein said compound has R-stereochemistry at the V-attached carbon and has S-stereochemistry at the phosphorus center.
80 . The compound of claim 78 wherein said compound has S-stereochemistry at the V-attached carbon and has R-stereochemistry at the phosphorus center.
81 . The compound of claim 75 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 2 , —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 22 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; and R 3 is C 1 -C 6 alkyl.
82 . The compound of claim 81 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 , —S Me, —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.
83 . The compound of claim 82 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 .
84 . The compound of claim 83 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.
85 . The compound of claim 84 wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, and 4-pyridyl.
86 . The compound of claim 75 wherein said compound has R-stereochemistry at the V-attached carbon and has S-stereochemistry at the phosphorus center.
87 . The compound of claim 75 wherein said compound has S-stereochemistry at the V-attached carbon and has R-stereochemistry at the phosphorus center.
88 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 55 and a pharmaceutically acceptable carrier.
89 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 56 and a pharmaceutically acceptable carrier.
90 . 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 55 .
91 . 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 56 .
92 . The method of claim 90 wherein said viral replication is RNA-dependent RNA viral replication.
93 . The method of claim 90 wherein said viral replication is HCV replication.
94 . 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 55 .
95 . 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 56 .
96 . The method of claim 94 wherein said viral infection is RNA-dependent RNA viral infection.
97 . The method of claim 94 wherein said viral infection is HCV infection.
98 . The method of claim 97 wherein said compound of Formula I is used in combination with a therapeutically effective amount of a second agent active against HCV.
99 . The method of claim 98 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.
100 . The method of claim 99 wherein said second agent active against HCV is interferon-α or pegylated interferon-α, alone or in combination with ribavirin or levovirin.
101 . A compound of Formula VI:
wherein X is selected from the group consisting of NH 2 , NHCH 3 , N(CH 3 ) 2 , OCH 3 , and SCH 3 ;
Y and Y′ are independently O or NH;
V, W, and W′ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, each of which is optionally substituted; and
Z is hydrogen, CHWOH, CHWOCOW′, SW, or CH 2 aryl.
102 . A compound of Formula VII:
wherein B is selected from the group consisting of:
X is selected from the group consisting of NH 2 , NHCH 3 , N(CH 3 ) 2 , OCH 3 , SCH 3 , OH, and SH;
Y and Y′ are independently O or NH;
R 14 is independently selected from the group consisting of H and NH 2 ;
the heterocyclic base B may be further substituted at any position on the heterocyclic base B with a substituent of a molecular weight of less than 150 and selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, acyl, and alkoxy, and wherein said substituents may be coupled to the 6-position of the heterocyclic base via a carbon, sulfur, oxygen, or selenium;
V, W, and W′ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, each of which is optionally substituted; and
Z is hydrogen, CHWOH, CHWOCOW′, SW, or CH 2 aryl.
103 . The compound of claim 102 wherein B is selected from the group consisting of:
104 . The compound of claim 103 wherein X is NH 2 .
105 . The compound of claim 103 wherein B is selected from the groups consisting of:
106 . The compound of claim 105 wherein X is NH 2 .Join the waitlist — get patent alerts
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