Tetrazolyl macrocyclic hepatitis C serine protease inhibitors

摘要

The present invention relates to compounds of Formula I, II, III or IV, or pharmaceutically acceptable salts, esters, or prodrugs thereof:;
which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising a compound of the present invention.

主权项

1. A compound represented by Formula I, II, III or IV:or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of R1, —(C═O)—O—R1, —(C═O)—R2, —C(═O)—NH—R2, —S(O)2—R1, and —S(O)2NHR2; R1 is selected from the group consisting of:
(i) aryl; substituted aryl; heteroaryl; substituted heteroaryl;(ii) heterocycloalkyl or substituted heterocycloalkyl; and(iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; R2 is independently selected from the group consisting of:
(i) hydrogen;(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;(iii) heterocycloalkyl or substituted heterocycloalkyl; and(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; G is selected from the group consisting of —NHS(O)2—R3 and —NH(SO2)NR4R5; R3 is selected from the group consisting of: (i) heteroaryl; substituted heteroaryl; and (ii) heterocycloalkyl or substituted heterocycloalkyl; R4 and R5 are independently selected from: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; L is selected from the group consisting of —CH2—, —O—, —S—, and —S(O)2—; X is selected from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; and (v) —W—R6, where W is absent, or selected from —O—, —S—, —NH—, —N(Me)—, —C(O)NH—, and —C(O)N(Me)-; R6 is selected from the group consisting of:
(a) hydrogen;(b) aryl; substituted aryl; heteroaryl; substituted heteroaryl(c) heterocyclic or substituted heterocyclic; and(d) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; denotes a carbon-carbon single or double bond j=0, 1, 2, 3, or 4; k=1, 2, or 3; m=0, 1, or 2; and n=1, 2 or 3.