US 7,608,590 B2 · HCV NS-3 serine protease inhibitors

Abstract

Compounds of the formula where the variables are as defined in the specification inhibit the NS3 protease of flavivirus such as hepatitis C virus (HCV). The compounds comprise a novel linkage between a heterocyclic P2 unit and those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

A compound of formula I′:

wherein
A is C(═O)OR1, or C(═O)NHSO2R2,wherein;
R1 is hydrogen, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
R2 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
wherein
R2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb, Y—NRaC(═O)ORb;
Y is independently a bond or C1-C3alkyl;
Ra is independently H or C1-C3alkyl;
Rb is independently H, C1-C6alkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl;
p is independently 1 or 2;
M is CR7R7′;
R7 taken together with R7′ forms a C3-C6cycloalkyl ring substituted with J;
q is 1 and k is 1;
W is —CH2—, —O—, —OC(═O)NH, —OC(═O), —S—, —NH—, —NRa, —NHSO2—, —NHC(═O)NH— or —NHC(═O)—, —NHC(═S)NH— or a bond;
R8 is a ring system containing 1 or 2 saturated, partially saturated or unsaturated rings each of which has 4-7 ring atoms and each of which has 0 to 4 hetero atoms independently selected from S, O and N, the ring system being optionally spaced from W by a C1-C3 alkylene group;
any of which R8 groups can be optionally mono-, di-, or tri-substituted with R9, wherein
R9 is independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb, Y—NRaC(═O)ORb;
wherein said carbocyclyl or heterocyclyl is optionally substituted with R10;
wherein
R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino, amido, sulfonyl, (C1-C3 alkyl)sulfonyl, NO2, OH, SH, halo, haloalkyl, carboxyl;
E is —C(═O)—, —C(═S)—, —S(═O)2−, —S(═O)—, —C(═N—Rf)—;
Rf is H, —CN, —C(═O)NRaRb;
—C(═O)C1-C3alkyl;
J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R7/R7′ cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from:
—O—, —S— or —NR12—, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R14;
wherein;
R12 is H, C1-C6alkyl, C3-C6cycloalkyl, or C(═O)R13;
R13 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
R14 is independently selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, hydroxy, halo, amino, oxo, thio and C1-C6thioalkyl;
m is 0 ;
n is 0;
G is —NRy-;
Ry is J;
R16 is H;
or C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb, Y—NRac(═O)ORb;
or a pharmaceutically acceptable salt thereof.

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HCV NS-3 serine protease inhibitors

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HCV NS-3 serine protease inhibitors

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Abstract

Claims47