MACROCYCLIC PROLINE DERIVED HCV SERINE PROTEASE INHIBITORS

摘要

The present invention discloses compounds of Formula I 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 the compounds of the present invention.

主权项

1. A compound of Formula I:wherein
A is absent, —(C═O)—, —S(O)2−, —C(═N—OR1)— or —C(═N—CN)—; {circle around (B)} is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl; or {circle around (B)} iswherein R7 and R8 are each independently C1-C8 alkyl or C2-C8 alkenyl and are each independently optionally substituted with one or more halo;
M1 and M2 are each independently selected from O or NR1; each R1 is independently selected at each occurrence from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; or 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, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; L1 and L2 are each independently selected from —C1-C8 alkylene, —C2-C8 alkenylene, or —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkylene, substituted —C2-C8 alkenylene, or substituted —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkenylene, and substituted —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-; X and Y taken together with the carbon atoms to which they are attached to form a cyclic moiety which selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocylic, carbocyclic, and substituted carbocyclic; X′ is N or —C(R2)—, where R2 is selected from the group consisting of: (i) hydrogen, halogen, CN, CF3, NO2, OR3, SR3, —NHS(O)2—R3, —NH(SO2)NR4R5, NR4R5, CO2R3, COR3, CONR4R5, N(R1)COR3; aryl; substituted aryl; heteroaryl; or 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, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; each R3 is independently selected from 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; and —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; or substituted heteroaryl; each R4 and R5 are independently selected from H and R3, or R4 and R5 combined together with the N they are attached to form a heterocyclic ring; R and R′ are each independently selected from the group consisting of: —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, r substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) hydrogenor deuterium; G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and R″ is selected from hydrogen, methyl, ethyl, and allyl.