HCV NS3 protease inhibitors
View Patent ↗The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
1. A compound of formula (I), or a pharmaceutical acceptable salt thereof:
wherein:
is selected from the group consisting of:
each L is independently selected from the group consisting of N and CH, provided that the total number of L that are N is from 1 to 4,
R 1 is selected from the group consisting of —CO 2 H, —CONHSO 2 (cyclopropyl) and —CONHSO 2 (1-methylcyclopropyl);
R 2 is selected from the group consisting of ethyl and ethenyl;
R 3 is selected from the group consisting of cyclopentyl, cyclohexyl, and —C(CH 3 ) 3 ;
each R 4 is independently selected from the group consisting of halogen atoms, C 1 -C 4 alkoxy, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, —CN, —CF 3 , —OCF 3 , SCH 3 , —SO 2 (CH 3 ), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, phenyl, naphthyl and heteroaryl groups, wherein
each said R 4 heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 4 heteroaryl is attached through a ring atom selected from C or N,
each said R 4 phenyl, naphthyl and heteroaryl groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, —OR 5 , —SR 5 , —N(R 5 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 1 -C 6 haloalkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 5 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 5 , —C(O)R 5 and —CON(R 5 ) 2 , and 2 adjacent substituents of said R 4 phenyl, naphthyl and heteroaryl groups may be taken together to form a 3- to 6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S;
Y is selected from the group consisting of —C(O)—, —C(O)O— and —C(O)NH—;
each R 5 is independently H or C 1 -C 6 alkyl;
each R 6 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, or heterocyclyl(C 1 -C 8 alkyl);
M is selected from the group consisting of C 4 -C 7 alkylene and C 4 -C 7 alkenylene, wherein said M is substituted with 0 to 3 substituents independently selected C 1 -C 8 alkyl, provided that two adjacent substituents can together form a 3 to 6 membered ring.
2. The compound according to claim 1 ,
wherein
is selected from the group consisting of:
3. The compound according to claim 2 , wherein 0 or 1 R 4 is present and, if present, is selected from the group consisting of —Br, —Cl, —CN, phenyl, —O-phenyl, —OCF 3 , —OCH 3 , —C(O)OH, —CH 3 and —C(O)CH 3 .
4. The compound according to claim 3 , wherein R 1 is —C(O)OH.
5. The compound according to claim 3 , wherein R 1 is —C(O)NHSO 2 cyclopropyl.
6. The compound according to claim 3 , wherein R 1 is —CONHSO 2 (1-methylcyclopropyl).
7. The compound according to claim 3 , wherein R 2 is —CH 2 CH 3 .
8. The compound according to claim 3 , wherein R 2 is —CH═CH 2 .
9. The compound according to claim 3 , wherein R 3 is cyclopentyl.
10. The compound according to claim 3 , wherein R 3 is cyclohexyl.
11. The compound according to claim 3 , wherein R 3 is —C(CH 3 ) 3 .
12. The compound according claim 3 , wherein M is selected from the group consisting of
where Z is
13. The compound according to claim 1 , wherein said compound has the following structure or a pharmaceutical acceptable salt thereof:
wherein “a” is an optionally present bond and R 4 if present is selected from the group consisting of —Br, —Cl, —CN, phenyl, —O-phenyl, —OCF 3 , —OCH 3 , —C(O)OH, —CH 3 and —C(O)CH 3 .
14. The compound according to claim 1 , wherein said compound has the following structure or a pharmaceutically acceptable salt thereof:
wherein “a” is an optionally present bond and R 4 if present is selected from the group consisting of —Br, —Cl, —CN, phenyl, —O-phenyl, —OCF 3 , —OCH 3 , —C(O)OH, —CH 3 and —C(O)CH 3 .
15. The compound according to claim 1 , wherein said compound has the following structure or a pharmaceutical acceptable salt thereof:
wherein “a” is an optionally present bond and R 4 if present is selected from the group consisting of —Br, —Cl, —CN, phenyl, —O-phenyl, —OCF 3 , —OCH 3 , —C(O)OH, —CH 3 and —C(O)CH 3 .
16. The compound according to claim 1 , wherein said compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
17. A compound selected from the group consisting of:
and pharmaceutical acceptable salts thereof.
18. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. The pharmaceutical composition according to claim 18 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
20. The pharmaceutical composition according to claim 18 , further comprising a second therapeutic agent selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
21. A method of treating a patient infected with HCV comprising the step of administering to said patient a therapeutically effective amount of the compound according to claim 1 .
22. A compound wherein said compound is
or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising an effective amount of the compound according to claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
24. The pharmaceutical composition according to claim 23 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
25. The pharmaceutical composition according to claim 23 , further comprising a second therapeutic agent selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
26. A method of treating a patient infected with HCV comprising the step of administering to said patient a therapeutically effective amount of the compound according to claim 22 .