Inhibitors of hepatitis C virus polymerase
The present invention provides, among other things, compounds represented by the general Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, R 2 , and R 3 are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.
1. A compound according to Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X is —CH 2 — and Y is —NR 1 —;
R 1 is —C 5-6 hydroxyalkyl, —S(O) 2 —C 0-4 alkyl-R O , —C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R O ;
wherein:
R M and R N are independently hydrogen, —C 1-4 alkyl, or R M and R N together with the atoms to which they are attached can form a 4- to 6-membered ring; and
R O is (a) a 5- to 7-membered cycloalkyl, substituted with a —C 1-3 alkyl, aryl, —O-aryl, or —NR M R N moiety, (b) a 7-membered cycloalkyl optionally substituted with a hydroxyl, or (c) a 6- to 10-membered aryl, monocyclic or bicyclic, and substituted with one to three moieties independently selected from —C 1-4 alkyl, halogen, —NR M R N , —C 1-4 haloalkyl, —C 1-4 alkoxy, —C 1-4 hydroxyalkyl, cyano, —O-aryl, and aryl, provided that at least one such substitution is —C 1-4 alkoxy, —C 1-4 hydroxyalkyl, cyano, or —O-aryl;
R 2 is —C 1-5 alkyl optionally substituted with 1-5 halogens, —C 1-5 alkoxy, —C 5-7 cycloalkyl-C 0-3 alkyl in which the alkyl is optionally substituted with 1-3 halogens, —C 1-4 alkyl-C 3-5 cycloalkyl, or phenyl optionally substituted with 1 or 2 halogens or —C 1-3 alkyl groups optionally substituted with 1-3 halogens;
R 3 is —R A —R B ;
wherein R A is a phenyl moiety optionally substituted with one or two Z, in which each Z is independently halogen, —C 1-3 alkyl, —C 1-3 haloalkyl, —C 1-3 alkoxy, or cyano; and
wherein R B is —N(R U )C(O)—R Q ;
wherein R Q is a thiazolyl, optionally substituted with one or two R Z , in which each R Z is independently —C 1-3 alkyl, —C 1-3 alkoxy, or —NR M R N ;
R S and R T are each independently hydrogen or —C 1-4 alkyl, or one of R S and R T is hydrogen and the other is —C(O)-5- to 9-membered aryl; and
R U is hydrogen or —C 1-4 alkyl;
provided that, when R A is phenyl, then R B appears at the para or meta position relative to the thiophene moiety; and
R 4 is hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 1-4 alkyl, —C 1-4 alkyl-OC(O)—C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 3-6 cycloalkyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C 0-3 alkyl-C 5-6 aryl, or —C 1-4 alkyl-NR V R W ; and
R V and R W are independently hydrogen or —C 1-4 alkyl.
2. A compound according to claim 1 , wherein R A is phenyl substituted with one or two Z.
3. A compound according to claim 2 , wherein R B appears at the para position relative to the thiophene moiety.
4. A compound according to claim 3 , wherein R B is —NHC(O)—R Q .
5. A compound according to claim 1 , wherein R 2 is —C 5-6 cycloalkyl-C 1-3 alkyl.
6. A compound according to claim 1 , wherein:
R 1 is hydrogen, —C 1-4 alkyl, —C 1-3 alkyl-C 3-6 cycloalkyl, —C 1-4 hydroxyalkyl, —C 2-4 alkyl-NR M R N , —C 1-4 alkyl ester, or —C 1-3 alkyl-C 6-10 aryl; and
R M and R N are independently hydrogen or —C 1-4 alkyl.
7. A compound according to claim 1 , wherein R 1 is —C 1-4 alkyl, —C 1-3 alkyl-C 3-6 cycloalkyl, —C 1-4 hydroxyalkyl, or —C 2-4 alkyl-NR M R N .
8. A compound according to claim 1 , wherein R 4 is hydrogen.