Macrocyclic peptides as inhibitors of viral replication

摘要

The invention provides 4-amino-4-oxobutanoyl peptide compounds of Formula I;
and the pharmaceutically salts and hydrates thereof.
;The variables R1-R9, R16, R18, R19, n, M, n, M, and Z are defined herein. Certain compounds of Formula I are useful as antiviral agents. Certain 4-amino-4-oxobutanoyl peptide compounds disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more 4-amino-4-oxobutanoyl peptide compounds and one or more pharmaceutically acceptable carriers. Such pharmaceutical compositions may contain 4-amino-4-oxobutanoyl peptide compound as the only active agent or may contain a combination of 4-amino-4-oxobutanoyl peptide containing peptides compound and one or more other pharmaceutically active agents. The invention also provides methods for treating viral infections, including Hepatitis C infections, in mammals.

主权项

1. A compound of the formula: or a pharmaceutically acceptable salt thereof, where R1 is —(C═O)R12, or —(C═O)OR12, and R2 is hydrogen, or R1 and R2 are joined to form a 5- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently chosen from N, O, and S which ring is optionally fused to a phenyl or 5- or 6-membered heteroaryl to form a bicyclic ring system, each of which 5- to 7-membered heterocycloalkyl ring or bicyclic ring system is optionally substituted; R3, R4, R6, and R8 are independently hydrogen or methyl; R5 is a C7-C11 saturated or unsaturated hydrocarbon chain that is (i) covalently bound to R7, where R7 is a methylene group or R5 is a C7-C11 saturated or unsaturated hydrocarbon chain that is (ii) covalently bound to an optionally substituted cycloalkyl ring formed by R7 and R8 being joined to from a 3- to 7-membered optionally substituted cycloalkyl ring; and R6 is hydrogen, C1-C6alkyl, or (C3-C7cycloalkyl)C0-C2alkyl; R9 is hydroxyl, amino, —COOH, —NR10R11, —OR12, —SR12, —NR10(S═O)R11, or —NR10SO2R11, R10, R11, and R12 are independently at each occurrence hydrogen, or C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (aryl)C0-C2alkyl, (C3-C7cycloalkyl)C0-C2alkyl, (C3-C7cycloalkenyl)C0-C2alkyl, (heterocycloalkyl)C0-C2alkyl, or (5- to 10-membered heteroaryl)C0-C2alkyl, each of which substituted with 0 to 3 substituents independently chosen from halogen, hydroxyl, oxo, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, and trifluoromethoxy; n is 0, 1, or 2; M is hydrogen; halogen, hydroxyl, C1-C2alkyl, or C1-C2alkoxy; Y is O, —O(C═O)(NR20)—, or —O(C═O)—; Z is R21 represents from 0 to 3 groups independently chosen from halogen, hydroxyl, amino, cyano, —CONH2, —COOH, C1-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, C1-C4alkylthio, mono- and di-C1-C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy; R22 is hydrogen, halogen, hydroxyl, amino, cyano, —CONH2, —COOH, C1-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, C1-C4alkylthio, mono- and di-C1-C4alkylamino, C1-C4alkylester, C1-C2haloalkyl, and C1-C2haloalkoxy, or R22 is (C3-C7cycloalkyl)C0-C2alkyl, (phenyl)C0-C2alkyl, (phenyl)C0-C2alkoxy, (5- or 6-membered heteroaryl)C0-C2alkyl, (5- or 6-membered heteroaryl)C0-C2alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl)C0-C2alkyl, or 9- or 10 membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently chosen from (i) halogen, hydroxyl, amino, cyano, nitro, —COOH, —CONH2, CH3(C═O)NH—, C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxyalkyl, mono- and di-C1-C4alkylamino, —NR8SO2R11, —C(O)OR11, —NR8COR11, —NR8C(O)OR11, trifluoromethyl, trifluoromethoxy, and (ii) phenyl and 5- or 6-membered heteroaryl, each of which is substituted with 0 or 1 or more of halogen, hydroxyl, C1-C4alkyl, C1-C2alkoxy; and R16 represents 0 to 4 substituents is independently chosen at from halogen, C1-C2alkyl, and C1-C2alkoxy; R18 and R19 are independently hydrogen, hydroxyl, halogen, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, or C1-C2haloalkoxy; and R20 is hydrogen, C1-C2alkyl, C1-C2haloalkyl, or C1-C2haloalkoxy.