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 III:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of CO 2 R 10 and CONHSO 2 R 6 ;
R 2 is selected from the group consisting of C 1 -C 4 alkyl and C 2 -C 4 alkenyl;
R 3 is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and CON(R 10 ) 2 ;
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, and aryl(C 1 -C 8 )alkyl; wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and CON(R 10 ) 2 ;
R 5 is selected from the group consisting of CO 2 R 4 , aryl, and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 7 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and CON(R 10 ) 2 ;
each R 6 is independently selected from the group consisting of 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, and heterocyclyl(C 1 -C 8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents or P(O)R 11 R 12 , and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S, attached through a ring carbon or nitrogen;
W is selected from the group consisting of H and C 1 -C 6 alkoxyl;
X is O;
Y is selected from the group consisting of C═O and SO 2 ;
Z is selected from the group consisting of O, CH 2 and N(R 4 ), and wherein R 4 is H or methyl;
M is selected from the group consisting of unsubstituted C 1 -C 5 alkylene and unsubstituted C 2 -C 5 alkenylene;
L is a direct bond;
each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl; and
each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl.
2. A compound is selected from the group consisting of compounds III-1 to 111-98:
3. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , and a pharmaceutically acceptable carrier.
4. The pharmaceutical composition of claim 3 , further comprising a second therapeutic agent selected from the group consisting of a hepatitis C virus (HCV) antiviral agent, an immunomodulator, and an anti-infective agent.
5. The pharmaceutical composition of claim 4 , wherein the HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.
6. A method of inhibiting HCV NS3 protease activity in a subject in need thereof, said method comprising administering to said subject a medicament comprising a compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of CO 2 R 10 and CONHSO 2 R 6 ;
R 2 is selected from the group consisting of C 1 -C 4 alkyl and C 2 -C 4 alkenyl;
R 3 is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), NR 10 SO 7 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and CON(R 10 ) 2 ;
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, and aryl(C 1 -C 8 )alkyl; wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 SR 10 , N(R 10 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NO 2 CN CF 3 , SO 2 (C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and CON(R 10 ) 2 ;
R 5 is selected from the group consisting of CO 2 R 4 , aryl, and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 7 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C6 cycloalkoxy, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and CON(R 10 ) 2 ;
each R 6 is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkl, aryl, aryl (C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents or P(O)R 11 R 12 , and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S, attached through a ring carbon or nitrogen;
W is selected from the group consisting of H and C 1 -C 6 alkoxy;
X is O;
Y is selected from the group consisting of C═O and SO 2 ;
Z is selected from the group consisting of O, CH 2 and N(R 4 ), and wherein R 4 is H or methyl;
M is selected from the group consisting of unsubstituted C 1 -C 5 alkylene and unsubstituted C 2 -C 5 alkenylene;
L is a direct bond;
each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl; and
each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl.
7. A method of or treating infection by HCV in a subject in need thereof, said method comprising administering to said subject a medicament comprising a compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
Ris selected from the group consisting of CO 2 R 10 and CONHSO 2 R 6 ;
R 2 is selected from the group consisting of C 1 -C 4 alkyl and C 2 -C 4 alkenyl;
R 3 is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NO 2 , CN, CF 3 SO 2 (C 1 -C 6 alkyl), NR 10 SO 2 R 6 SO 2 N(R 6 NHCOOR 6 NHCOR 6 , NHCONHR 5 CO 2 R 10 , and CON(R 10 ) 2 ;
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, and aryl(C 1 -C 8 )alkyl; wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and CON(R 10 ) 2 ;
R 5 is selected from the group consisting of CO 2 R 4 , aryl, and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 7 ) 2 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C6 cycloalkoxy, NO 2 , CN, CF 3 , SO 2 C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and CON(R 10 ) 2 ;
each R 6 is independently selected from the group consisting of 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, and heterocyclyl(C 1 -C 8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents or P(O)R 11 R 12 , and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S, attached through a ring carbon or nitrogen;
W is selected from the group consisting of H and C 1 -C 6 alkoxy;
X is O;
Y is selected from the group consisting of C═O and SO 2 ;
Z is selected from the group consisting of O, CH 2 and N(R 4 ), and wherein R 4 is H or methyl;
M is selected from the group consisting of unsubstituted C 1 -C 5 alkylene and unsubstituted C 2 -C 5 alkenylene;
L is a direct bond;
each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl; and
each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl.
8. The method of claim 7 , wherein said medicament further comprises at least one second therapeutic agent selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent.
9. The method of claim 8 , wherein the HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.
10. A pharmaceutical composition comprising an effective amount of a compound of claim 2 , and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10 , further comprising a second therapeutic agent selected from the group consisting of a hepatitis C virus (HCV) antiviral agent, an immunomodulator, and an anti-infective agent.
12. The pharmaceutical composition of claim 10 , wherein the HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.
13. A method of inhibiting HCV NS3 protease activity in a subject in need thereof, said method comprising administering to said subject a medicament comprising a compound of claim 2 .
14. A method of or treating infection by HCV in a subject in need thereof, said method comprising administering to said subject a medicament comprising a compound of claim 2 .
15. The method of claim 14 , wherein said medicament further comprises at least one second therapeutic agent selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent.
16. The method of claim 15 , wherein the HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.