US2007179114A1PendingUtilityA1
Novel 2'-C methyl nucleoside derivatives
Est. expiryFeb 13, 2024(expired)· nominal 20-yr term from priority
A61P 31/14C07H 19/04C07H 19/20A61P 31/18A61P 31/12
60
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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 . (canceled)
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 ) 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;
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 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.
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 - 28 . (canceled)
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 - 101 . (canceled)
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 - 104 . (canceled)
105 . The compound of claim 102 wherein B is:
106 . The compound of claim 105 wherein X is NH 2 .Join the waitlist — get patent alerts
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