Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases
View Patent ↗The present invention relates to compounds of formula I that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system. (I)
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
X is
A is fluorophenyl;
B is a) hydrogen;
b) Ar;
c) C 1 -C 6 alkyl-Ar;
d) —CHR a —Ar; or
e) cyclopropyl;
Ar is a 5-6 membered monocyclic aromatic ring with 0 or 1 heteroatom ring atoms independently selected from N and S, optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkoxy, halo, and cyano;
D is H or NR 3 SO 2 R 4 ;
R 2 is C 1 -C 6 alkyl;
R 3 is C 1 -C 6 alkyl;
R 4 is C 1 -C 6 alkyl;
R a is C 1 -C 6 hydroxyalkyl, or alkylalkoxy;
R c is hydrogen, C 1 -C 6 alkyl, alkylalkoxy, or —CH 2 NHC(O)CH 3 ;
R d is hydrogen, F, Cl or C 1 -C 6 alkyl;
R e and R f are independently hydrogen or C 1 -C 6 alkyl; and
R g is hydrogen or C 1 -C 6 alkoxy.
2. The compound of claim 1 , wherein R 2 , R 3 and R 4 are methyl.
3. The compound of any one of claims 1 to 2 , wherein D is N(CH 3 )SO 2 CH 3 .
4. The compound of any one of claims 1 to 3 , wherein each halo is F.
5. The compound of any one of claims 1 to 4 , wherein B is —CH 2 —Ar, —CH 2 CH 2 —Ar, —CH(CH 3 )—Ar, or —C(CH 3 ) 2 —Ar.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula:
or a pharmaceutically acceptable salt thereof.
7. The compound of any one of claims 1 to 6 , wherein X is
8. The compound of any one of claims 1 to 7 , wherein R c is hydrogen or methyl and R g is hydrogen.
9. The compound of any one of claims 1 to 4 or 6 to 8 , wherein B is
hydrogen;
phenyl;
fluorophenyl;
—(CH 2 ) 1-2 -phenyl;
—CH 2 -fluorophenyl;
—CH(CH 3 )-fluorophenyl;
—C(CH 3 ) 2 -fluorophenyl;
—CH 2 -chlorophenyl;
—CH 2 -phenyl-OCH 3 ;
—CH 2 -phenyl-cyano;
—CH 2 -fluoropyridine;
thiophene;
cyclopropyl;
—CH(CH 2 OCH 3 )-fluorophenyl;
—CH(CH 2 OH)-phenyl;
—CH(CH 2 OH)-fluorophenyl;
—CH(CH 2 CH 2 OH)-fluorophenyl;
—CH 2 -4-fluoro-2-methoxyphenyl; or
—CH 2 -difluorophenyl.
10. The compound of claim 1 which is any one of
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) an effective amount of the compound of any one of claims 1 - 10 or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition of claim 11 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
13. The pharmaceutical composition of claim 12 , wherein the second therapeutic agent is selected from the group consisting of HCV NS3 and NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
14. A method of treating a patient infected with HCV, the method comprising administering to the patient the compound of any one of claims 1 to 10 , or a pharmaceutically acceptable salt thereof, in an amount effective to prevent and/or treat infection by HCV in the patient.
15. The method of claim 14 , further comprising administering to said patient an effective amount of at least one second therapeutic agent selected from the group consisting of HCV NS3 and NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.