Inhibitors of hepatitis C virus replication
The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5A inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5A activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
1. A compound having structural formula (I):
and/or a pharmaceutically acceptable salt thereof, wherein:
is chosen from the group consisting of 9-membered bicyclic aryl ring systems that contain from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and that are substituted on C or N atoms by u substituents R 1 ,
each R 1 is independently chosen from the group consisting of hydrogen, halogen, —OR 3a , —CN, —(CH 2 ) 0-6 C(O)R 3 , —CO 2 R 3a , —C(O)N(R 3a ) 2 , —SR 3a , —S(O)R 3a , —S(O 2 )R 3a , —(CH 2 ) 0-6 N(R 3a ) 2 , —N(R 3a )SO 2 R 3a , —N(R 3a )CO 2 R 3a , —N(R 3a )C(O)R 3 , —N(R 3a )COR 3a , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, C 3-8 carbocycle containing from 0 to 3 heteroatoms chosen from N, O and S, and phenyl, and the C 1-6 alkyl, C 3-8 carbocycle and phenyl are substituted by from 0 to 3 substitutents independently chosen from the group consisting of hydrogen, halogen, —OR 3a , —CN, —CO 2 R 3a , —C(O)N(R 3a ) 2 , —N(R 3a ) 2 , —N(R 3a )CO 2 R 3a , —SR 3a , —S(O)R 3a , —S(O 2 )R 3a , —N(R 3a )SO 2 R 3a , —N(R 3a )CO 2 R 3a , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and C 3-8 cycloalkyl,
u is from 0 to 4,
each R 3 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl, —OH, —O—C 1-6 alkyl and C 3-8 cycloalkyl, and
each R 3a is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl;
is a group chosen from 8- to 10-membered bicyclic ring systems, containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by v substituents R 2 ,
each R 2 is independently chosen from the group consisting of hydrogen, halogen, —OR 4a , —CN, —CO 2 R 4a , —C(O)R 4a , —C(O)N(R 4a ) 2 , —N(R 4a ) 2 , —N(R 4a )COR 4 , —N(R 4a )CO 2 R 4a , —N(R 4a )C(O)N(R 4a ), —N(R 4a )SO 2 R 4a , —SR 4a , —S(O)R 4a , —S(O 2 )R 4a , C 1-6 alkyl substituted by from 0 to 4 R 4 and C 3-8 cycloalkyl substituted by from 0 to 4 R 4 ,
v is from 0 to 4,
each R 4 is independently chosen from the group consisting of hydrogen, —OH, C 1-6 alkyl and C 3-8 cycloalkyl;
each R 4a is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl;
such that said
and said
are taken together with one said substituent R 1 and one said substituent R 2 to form a 5- to 9-membered carbocyclic ring system represented by a group chosen from the group consisting of:
where
W is chosen from the group consisting of —(CH 2 ) 1-3 —, —(CH 2 ) 0-2 NH(CH 2 ) 0-2 —, —(CH 2 ) 0-2 N(C 1-6 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 0-2 O(CH 2 ) 0-2 — and —(CH 2 ) 0-2 C(O)(CH 2 ) 0-2 —, where W is substituted by from 0 to 4 R w , where each R w is independently selected from C 1-6 alkyl and C 3-8 cycloalkyl;
each D is a group independently chosen from the group consisting of:
a single bond, or —N(R 5 )C(O)—
each R 5 is hydrogen, and C 1-6 alkyl and
each E is a group independently chosen from the group consisting of:
a single bond, or
(c) a pyrrolidinyl derivative chosen from the group consisting of:
I is a bivalent group chosen from —C(O)—, and —CO 2 —,
each R 8a is independently chosen from the group consisting of hydrogen, halogen, —OH, —OC 1-6 alkyl and C 1-6 alkyl, or two R 8a may be taken together to form oxo,
each R 8b is independently chosen from the group consisting of hydrogen, halogen, —OH, —OC 1-6 alkyl and C 1-6 alkyl, or two R 8b may be taken together to form oxo,
each R 8c is independently chosen from the group consisting of hydrogen and C 1-6 alkyl,
or any two groups selected from R 8a , R 8b and R 8c may be taken together to form a spiro-bicyclic or bridged bicyclic ring;
each R 9 is independently chosen from the group consisting of hydrogen, halogen, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NH—C 1-6 alkyl and —NHC(O)—C 1-6 alkyl,
each R 7 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and phenyl, and the C 1-6 alkyl and phenyl are substituted by from 0 to 3 substituents independently chosen from the group consisting of hydrogen, halogen, C 1-6 alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl; and
each G is independently chosen from the group consisting of:
hydrogen, and C 1-6 alkyl having 0 to 4 substituents R 11 ,
each R 11 is independently chosen from the group consisting of:
—N(R 10 ) 2 ,
(o) aryl ring systems G′ chosen from the group consisting of:
5- to 7-membered monocyclic ring systems and;
each R 10 is independently chosen from the group consisting of
hydrogen,
C 1-6 alkyl,
—C(O)R 14 ,
—CO 2 R 14 , and
3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S,
each R 14 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl, —(CH 2 ) 0-3 C 3-8 cycloalkyl and phenyl.
2. The compound according to claim 1 , wherein W is chosen from the group consisting of —CH 2 —, —NH—, —N(C 1-6 alkyl)-, —C(O)—, —CH 2 NH—, —CH 2 N(C 1-6 alkyl)-, —CH 2 CH 2 —, —C(O)CH 2 —, —CH 2 C(O)—, —CH 2 O—, —CH 2 CH 2 CH 2 —, —C(O)CH 2 CH 2 —, —CH 2 C(O)CH 2 —, —CH 2 OCH 2 —, —CH 2 CH 2 C(O)—, —CH 2 CH 2 O—, —CH 2 CH 2 NH—, —CH 2 CH 2 N(C 1-6 alkyl)-, —CH 2 NHCH 2 —, —CH 2 N(C 1-6 alkyl)CH 2 —, —NHCH 2 CH 2 —, and —N(C 1-6 alkyl)CH 2 CH 2 —.
3. The compound according to claim 1 , wherein each E is
4. The compound according to claim 1 , wherein each G is independently chosen from the group consisting of:
(a) C 1-6 alkyl having 0 to 4 substituents R 11 ,
(b) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 10 on N or C atoms; and
(c) aryl ring systems G′ chosen from the group consisting of:
(i) 5- to 7-membered monocyclic ring systems.
5. The compound according to claim 1 , wherein each G is independently chosen from the group consisting of
hydrogen, or
(c) C 1-5 alkyl having 1 to 3 substituents R 11 .
6. The compound according to claim 5 , wherein each G is independently chosen from the group consisting of C 1-4 alkyl having 1 to 2 substituents R 11 , wherein each R 11 is independently chosen from the group consisting of —NH 2 , —NCH 3 H, —N(CH 3 ) 2 , and phenyl.
7. The compound according to claim 1 , wherein
W is chosen from the group consisting of —(CH 2 ) 1-3 —, —(CH 2 ) 0-2 NH(CH 2 ) 0-2 —, —(CH 2 ) 0-2 N(C 1-6 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 0-2 O(CH 2 ) 0-2 — and —(CH 2 ) 0-2 C(O)(CH 2 ) 0-2 —, where W is substituted by from 0 to 4 R w , where each R w is independently selected from C 1-6 alkyl and C 3-8 cycloalkyl; and
each R 1 is hydrogen, or halogen,
wherein each D is independently chosen from the group consisting of a single bond, and —NR 5 C(O)—, where
R 5 is hydrogen,
wherein each E is independently chosen from the group consisting of a single bond,
where one of R 8a and R 8b is —OH or fluorine;
wherein each G is independently chosen from the group consisting of hydrogen or C 1-5 alkyl.
8. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition according to claim 8 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
10. The pharmaceutical composition according to claim 9 , wherein said second therapeutic agent is selected from the group consisting of HCV protease inhibitors and HCV NSSB polymerase inhibitors.
11. A method of treating a patient infected with HCV comprising the step of administering a compound according to claim 1 , in an amount effective to infection by HCV in a subject in need thereof.
12. A method of treating a patient infected with HCV comprising the step of administering a compound according to claim 1 , in an amount effective to inhibit HCV viral replication and/or viral production.