Novel 2'-c-methyl and 4'c-methyl nucleoside derivatives
Novel 2′-C-methyl nucleoside 5′-monophosphate and 4′-C-methyl nucleoside 5′-monophosphate derivatives, 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 (IX):
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 —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 . A compound of Formula (X):
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 ), —OR 6 , —(CH 2 ), —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;
R 6 is C 1 -C 4 acyl; and
R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 22 acyl, C 1 -C 22 alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroaryloxycarbonyl, and a naturally-occurring L-amino acid connected via its carbonyl group to form an ester; or
together R 7 at the 3′-carbon and R 8 form a cyclic carbonate;
or a pharmaceutically acceptable salt thereof.
3 . (canceled)
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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.
5 - 6 . (canceled)
7 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 3-pyridyl, and 4-pyridyl.
8 . (canceled)
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of —H, —OMe, —OEt, and phenyl.
10 . (canceled)
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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 31 —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,
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 3 is C 1 -C 6 alkyl
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.
13 - 19 . (canceled)
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is:
21 . (canceled)
22 . The compound of claim 1 wherein said compound is a compound of Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein:
V and the 5′oxymethylene group of the ribose sugar moiety are cis to one another.
23 . The compound of claim 2 wherein said compound is a compound of Formula (XII):
or a pharmaceutically acceptable salt thereof wherein:
V and the 5′oxymethylene group of the ribose sugar moiety are cis to one another.
24 - 28 . (canceled)
29 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein said compound is:
30 - 37 . (canceled)
38 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
39 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
40 - 43 . (canceled)
44 . A method of treating an HCV infection in a human patient comprising administering to said human patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
45 . A method of treating an HCV infection in a human patient comprising administering to said human patient a therapeutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof.
46 - 50 . (canceled)
51 . A compound of Formula (XIII):
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 —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.
52 . A compound of Formula (XIV):
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 ), —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;
R 6 is C 1 -C 4 acyl; and
R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 22 acyl, C 1 -C 22 alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroaryloxycarbonyl, and a naturally-occurring L-amino acid connected via its carbonyl group to form an ester; or
together R 7 at the 3′-oxygen and R 8 at the 2′-oxygen form a cyclic carbonate;
or a pharmaceutically acceptable salt thereof.
53 - 69 . (canceled)
70 . The compound of claim 51 , or a pharmaceutically acceptable salt thereof, wherein said compound is:
71 . (canceled)
72 . The compound of claim 51 wherein said compound is a compound of Formula (XV):
or a pharmaceutically acceptable salt thereof, wherein:
V and the 5′oxymethylene group of the ribose sugar moiety are cis to one another.
73 . The compound of claim 52 wherein said compound is a compound of Formula (XVI):
or a pharmaceutically acceptable salt thereof, wherein:
V and the 5′oxymethylene group of the ribose sugar moiety are cis to one another.
74 - 78 . (canceled)
79 . The compound of claim 73 or a pharmaceutically acceptable salt thereof, wherein said compound is:
80 - 87 . (canceled)
88 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 51 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
89 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 52 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
90 - 93 . (canceled)
94 . A method of treating an HCV infection a in a human patient comprising administering to said human patient a therapeutically effective amount of a compound of claim 51 , or a pharmaceutically acceptable salt thereof.
95 . A method of treating an HCV infection in a human patient comprising administering to said human patient a therapeutically effective amount of a compound of claim 52 , or a pharmaceutically acceptable salt thereof.
96 - 111 . (canceled)
112 . The compound of claim 20 , which is a compound of formula XIX:
which has the (R)-stereochemical configuration at the stereogenic carbon atom marked with an * and the (S)-stereochemical configuration at the stereogenic phosphorus center;
or a compound of formula XVII:
which has the (S)-stereochemical configuration at the stereogenic carbon atom marked with an * and the (R)-stereochemical configuration at the stereogenic phosphorus center;
or a pharmaceutically acceptable salt thereof.
113 - 119 . (canceled)