Macrocyclic compounds as hepatitis C virus inhibitors

申请公布号：: US8936781(B2)
申请号：: US201012759132
申请日期：: 2010.04.13
申请公布日期：: 2015.01.20
申请人：: Enanta Pharmaceuticals, Inc.
发明人：: Gai Yonghua;Or Yat Sun;Wang Guoqiang
分类号：: A61K38/12;C07K5/083;A61P31/14;A61K38/21;A61P35/00;A61P31/04;A61P31/10;C07K5/087;A61K45/06;C07K5/062
主分类号：: A61K38/12
代理机构：: Elmore Patent Law Group, P.C.
代理人：: Harlan Edgar W.;Elmore, Esq. Carolyn S.;Elmore Patent Law Group, P.C.
地址：: Watertown MA US
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 the formula:or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A is absent or selected from —(C═O)—, —S(O)2, —C═N—OR1 and —C(═N—CN); Z201 is absent or 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 —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkenylene, each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; aryl, substituted aryl, heteroaryl, or substituted heteroaryl; M is absent or selected from O, S, SO, SO2 or NR1; L101 is absent or 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 —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkenylene, each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; V is absent or selected from O, S, S(O), S(O)2 or NR1; wherein R1 is selected at each occurrence 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; Z101 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R and R′ are each independently selected from the group consisting of: (i) —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; —C4-C12 alkylcycloalkyl, or substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) hydrogen; deuterium; G is selected from —OH, —NHS(O)2—R2, —NH(SO2)NR3R4, and NR3R4; R2 is selected from: (i) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (ii) heterocycloalkyl; 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; heterocylic; substituted heterocyclic; R3 and R4 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; heterocyclic, or substitututed heterocyclic; alternatively, R3 and R4 are taken together with the nitrogen they are attached to form a heterocyclic or substituted heterocyclic; Q1 is: (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 wherein each heteroatom is 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 wherein each heteroatom is O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; Q2 is: (i) hydrogen, halogen, CN, CF3, N3, NO2, OR1, SR1, SO2R2, —NHS(O)2—R2, —NH(SO2)NR3R4, NR3R4, CO2R1, COR1, CONR1R2, N(R1)COR2; where R1, R2, R3 and R4 are as previously defined;(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;(iii) heterocycloalkyl, substituted heterocycloalkyl;(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms wherein each heteroatom is 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 wherein each heteroatom is O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; or Q1 and Q2, together with the carbon atoms to which they are attached, form a carbocyclic moiety or a heterocyclic moiety; and Q3 and Q4 are each independently: (i) hydrogen, halogen, CN, CF3, N3, NO2, OR1, SR1, SO2R2, —NHS(O)2—R2, —NH(SO2)NR3R4, NR3R4, CO2R1, COR1, CONR1R2, N(R1)COR2; where R1, R2, R3 and R4 are as previously defined; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl, substituted heterocycloalkyl; (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms wherein each heteroatom is 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 wherein each heteroatom is O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; or Q3 and Q4, taken together with the carbon atoms to which they are attached, form a carbocyclic moiety or a heterocyclic moiety.