Potent and selective inhibitors of hepatitis c virus

A compound of Formula (II)

• each R1 and R1′ are independently present or absent if present are independently selected from the group consisting of hydroxy, hydroxyalkyl, alkoxy(C1-6), alkoxyalkyl(C2-8), alkoxycarbonyl, alkyl(C1-8), arylalkoxycarbonyl, lower alkenyl (C2-6), lower alkynyl (C2-6), carboxy, halogen, CF3, haloalkyl, N3, CN, N(R′)2, SR′, OCOR′, N(COR′)R′, N(COR′)COR′, SCOR′, and S(O)2NR′2, S(O)2R′;
• each R′ is independently H, a lower alkyl (C1-6), lower haloalkyl (C1-6), lower alkoxy (C1-6), lower alkenyl (C2-6), lower alkynyl (C2-6), lower cycloalkyl (C3-6), aryl, heteroaryl, alkylaryl, or arylalkyl, or if two R′ reside on the same nitrogen atom they can come together to form an alkyl ring (C3-6) containing none or one heteroatom independently selected from N, O, and S;
• wherein the R′ groups can optionally be substituted with one or more substituents as defined above;
• u and v are independently 0, 1, 2, 3, or 4;
• A is selected from the group consisting of phenyl and six-membered heteroaromatic rings containing one, two, or three nitrogen atoms;
• B is selected from the group consisting of phenyl, a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a six-membered ring or a six-membered bridged or spiro-fused ring containing none, one, or two heteroatoms independently selected from the group consisting of N, O, and S, a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from the group consisting of N, O, and S, a five-membered ring containing none, one, or two heteroatoms independently selected from the group consisting of N, O, and S;
• a four-membered ring containing none, one, or two heteroatoms independently selected from the group consisting of N, O, and S;
• alkylheteroaryl, and alkylaryl;
• L is selected from the group consisting of O, S, S(O), S(O)2, and C═NCN, or selected from the group consisting of phenyl, a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a six-membered ring or a six-membered bridged ring containing none, one, or two heteroatoms independently selected from the group consisting of N, O, and S, a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from the group consisting of N, O, and S, a five-membered ring containing none, one, or two heteroatoms independently selected from the group consisting of N, O, and S;
• C and D are independently a five-membered heteroaromatic ring containing one, two or three heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• when R2 and R2′ are attached to a carbon they are independently selected from the group consisting of hydrogen, halogen, CF3, hydroxy, N(R′)S(O)2R′, S(O)2R′, S(O)2N(R′)2, alkoxy (C1-6), cyano, alkynyl (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, heterocyclylalkyl, and hydroxyalkyl;
• when R2 and R2′ are attached to a nitrogen they are independently selected from the group consisting of hydrogen, alkoxy (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, carbonylalkyl, carbonyl aryl, alkyl, heterocyclylalkyl, hydroxyalkyl (C2-6), and S(O)2R′;
• R3 and R3′ are independently
• each m is independently 0, 1, or 2;
• each o is independently 1, 2, or 3;
• each s is independently 0, 1, 2, or 3;
• each X is independently selected from the group consisting of O, S, S(O), SO2, CH2, CHR5, and C(R5)2;
• provided that when m is 0, X is selected from CH2, CHR5, and C(R5)2;
• each R5 is independently selected from the group consisting of CF3, N3, and haloalkyl, and C(R5)2 can also be C(O),
• each R6 is independently selected from the group consisting of —C(O)—, —C(S)— and —C(NRz)—;
• R7 is selected from the group consisting of hydrogen and alkyl;
• R8 and R9 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and hydroxyalkyl;
• or,
• R8 and R9, together with the carbon atom to which they are attached, form a five- or six-membered saturated ring optionally containing one or two heteroatoms selected from the group consisting of NRz, O, and S;
• wherein Rz is selected from the group consisting of hydrogen and alkyl;
• each R10 and R11 are independently selected from the group consisting of H, alkylcarboxy amino, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylamino, alkylguanasyl, alkylaryl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, cycloakylamino, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, alkylheterocyclyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, and hydroxyalkyl, wherein the groups can optionally be substituted with one or more substituents as defined above;
• each R12 and R16 are independently selected from the group consisting of hydrogen, R13—C(O)—, R13—C(S)—, and R′;
• wherein each R′ is as defined above;
• and
• each R13 is independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, and —N(R′)2, wherein each R′ is as defined above;
• and pharmaceutically acceptable salts and prodrugs thereof,
• wherein the compounds can be in the form of the R- or S-configuration, or a mixture thereof, including a racemic or diastereomeric mixture thereof.

A compound of Formula (III)

• each R1 and R1′ is present or absent if present is independently selected from the group consisting of hydroxy, hydroxyalkyl, alkoxy(C1-6), alkoxyalkyl(C2-8), alkoxycarbonyl, alkyl(C1-8), arylalkoxycarbonyl, lower alkenyl (C2-6), lower alkynyl (C2-6), carboxy, halogen, CF3, haloalkyl, N3, CN, N(R′)2, SR′, OCOR′, N(COR′)R′, N(COR′)COR′, SCOR′, S(O)2NR′2, S(O)2R′, wherein each R′ is independently H, a lower alkyl (C1-C6), lower haloalkyl (C1-C6), lower alkoxy (C1-6), lower alkenyl (C2-6), lower alkynyl (C2-6), lower cycloalkyl (C3-6), aryl, heteroaryl, alkylaryl, or arylalkyl, or if two R′ reside on the same nitrogen atom they can come together to form an alkyl ring (C3-6) containing none or one heteroatom independently selected from the group consisting of N, O, and S;
• wherein the R′ groups can optionally be substituted with one or more substituents as defined above;
• u and v are independently 0, 1, 2, 3, or 4;
• A is selected from the group consisting of phenyl and six-membered heteroaromatic rings containing one, two, or three nitrogen atoms;
• B is selected from the group consisting of phenyl, a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a six-membered ring or a six-membered bridged or spiro-fused ring containing none, one, or two heteroatoms independently selected from the group consisting of N, O, and S, a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from the group consisting of N, O, and S, a five-membered ring containing none, one, or two heteroatoms independently selected from the group consisting of N, O, and S;
• a four-membered ring containing none, one, or two heteroatoms independently selected from the group consisting of N, O, and S;
• alkylheteroaryl, and alkylaryl;
• R3 is
• each m is independently 0, 1, or 2;
• each o is independently 1, 2, or 3;
• each s is independently 0, 1, 2, or 3;
• each X is independently selected from the group consisting of O, S, S(O), SO2, CH2, CHR5, and C(R5)2;
• provided that when m is 0, X is selected from the group consisting of CH2, CHR5, and C(R5)2;
• each R5 is independently selected from the group consisting of CF3, N3, and haloalkyl, and C(R5)2 can also be C(O),
• each R6 is independently selected from the group consisting of —C(O)—, —C(S)— and —C(NRz)—;
• R7 is selected from the group consisting of hydrogen and alkyl;
• R8 and R9 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and hydroxyalkyl;
• or,
• R8 and R9, together with the carbon atom to which they are attached, form a five- or six-membered saturated ring optionally containing one or two heteroatoms selected from NRz, O, and S;
• wherein Rz is selected from the group consisting of hydrogen and alkyl;
• each R10 and R11 are independently selected from the group consisting of H, alkylcarboxy amino, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylamino, alkylguanasyl, alkylaryl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, cycloakylamino, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, alkylheterocyclyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, and hydroxyalkyl, wherein the groups can optionally be substituted with one or more substituents as defined above;
• each R12 and R16 are independently selected from the group consisting of hydrogen, R13—C(O)—, R13—C(S)—, and R′;
• wherein each R′ is as defined above;
• each R13 is independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, and —N(R′)2, wherein each R′ is as defined above;
• R14 and R14′ are independently selected from the group consisting of halogen, CF3, hydroxy, alkoxy (C1-6), cyano, alkynyl (C2-6), alkoxyalkyl (C3-6), alkoxycarbonylalkyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, heterocyclylalkyl, hydroxyalkyl;
• and
• R15 and R15′ are independently selected from the group consisting of hydrogen, alkoxy (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, carbonylalkyl, carbonyl aryl, alkyl, heterocyclylalkyl, hydroxyalkyl (C2-6), and pharmaceutically acceptable salts and prodrugs thereof,
• wherein the compounds can be in the form of the R- or S-configuration, or a mixture thereof, including a racemic or diastereomeric mixture thereof.

A compound having the formula:

• wherein:
• R3 is
• each m is independently 0, 1, or 2;
• n is 0, 1, 2, or 3,
• each s is independently 0, 1, 2, or 3;
• each X is independently selected from the group consisting of O, S, S(O), SO2, CH2, CHR5, and C(R5)2;
• provided that when m is 0, X is selected from the group consisting of CH2, CHR5, and C(R5)2;
• each R5 is independently selected from the group consisting of 5-membered heteroaryl, halo substituted 5-membered heteroaryl, thioalkyl, thioaryl, SCH3, SCF3, sulfoxide alkyl, sulfoxide aryl, S(O)CH3, S(O)CF3, sulfone alkyl, sulfone aryl, S(O)2CH3, S(O)2CF3, haloalkyl, CF3, N3, and CN, with the proviso that —C(R5)2 can be —C(O),
• each R′ is a defined above;
• with the proviso that C(R5)z cannot be C(alkoxy)2, C(OH)2, C(alkoxy)(OH), or C(halo)(OH), and with the further proviso that C(R5)2 can also be C(═O),
• each R6 is independently selected from the group consisting of —C(O)—, —C(S)— and —C(NRz)—;
• each R10 and R11 are independently selected from the group consisting of H, alkylcarboxy amino, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylamino, alkylguanasyl, alkylaryl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, cycloakylamino, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, alkylheterocyclyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, and hydroxyalkyl, wherein the groups can be substituted with one or more substituents as defined above;
• each R12 and R16 are independently selected from the group consisting of hydrogen, R13—C(O)—, R13—C(S)—, and R′;
• wherein each R′ is as defined above;
• each R13 is independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, and —N(R′)2, wherein each R′ is as defined above;
• R14 and R14′ are independently selected from the group consisting of halogen, CF3, hydroxy, alkoxy (C1-6), aryl, 5-membered heteroaryl, lower alkyl (C1-6) or halo substituted aryl, aryl or halo substituted 5-membered heteroaryl, cyano, alkynyl (C2-6), alkoxyalkyl (C3-6), alkoxycarbonylalkyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, heterocyclylalkyl, and hydroxyalkyl;
• and
• R15 and R15′ are independently selected from the group consisting of hydrogen, alkoxy (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, carbonylalkyl, carbonyl aryl, alkyl, heterocyclylalkyl, and hydroxyalkyl (C2-6), and pharmaceutically acceptable salts and prodrugs thereof,
• Z is selected from the group consisting of C1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF3, —CN, —NO2, —C2R′, —SR', —N3, —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)O R″, —SO2R′, —SO2NR′R″, and —NR′SO2R″, where R′ and R″ are individually hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and
• j is an integer of from 0 to 3,
• wherein the compounds can be in the form of the R- or S-configuration, or a mixture thereof, including a racemic or diastereomeric mixture thereof.

A compound having the formula:

• wherein:
• R3 is
• each m is independently 0, 1, or 2;
• each s is independently 0, 1, 2, or 3;
• each X is independently selected from the group consisting of O, S, S(O), SO2, CH2, CHR5, and C(R5)2;
• provided that when m is 0, X is selected from CH2, CHR5, and C(R5)2;
• each R5 is independently selected from the group consisting of 5-membered heteroaryl, halo substituted 5-membered heteroaryl, thioalkyl, thioaryl, SCH3, SCF3, sulfoxide alkyl, sulfoxide aryl, S(O)CH3, S(O)CF3, sulfone alkyl, sulfone aryl, S(O)2CH3, S(O)2CF3, haloalkyl, CF3, N3, and CN, with the proviso —C(R5)2 can be —C(O),
• each R6 is independently selected from the group consisting of —C(O)—, —C(S)— and —C(NRz)—;
• each R10 and R11 are independently selected from the group consisting of H, alkylcarboxy amino, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylamino, alkylguanasyl, alkylaryl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, cycloakylamino, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, alkylheterocyclyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, and hydroxyalkyl, wherein the groups can be substituted with one or more substituents as defined above;
• each R12 and R16 are independently selected from the group consisting of hydrogen, R13—C(O)—, R13—C(S)—, and R′;
• wherein each R′ is as defined above;
• each R13 is independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, and —N(R′)2, wherein each R′ is as defined above;
• R14 and R14′ are independently selected from the group consisting of halogen, CF3, hydroxy, alkoxy (C1-6), aryl, 5-membered heteroaryl, lower alkyl (C1-6) or halo substituted aryl, aryl or halo substituted 5-membered heteroaryl, cyano, alkynyl (C2-6), alkoxyalkyl (C3-6), alkoxycarbonylalkyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, heterocyclylalkyl, and hydroxyalkyl;
• and
• R15 and R15′ are independently selected from the group consisting of hydrogen, alkoxy (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, carbonylalkyl, carbonyl aryl, alkyl, heterocyclylalkyl, and hydroxyalkyl (C2-6), and pharmaceutically acceptable salts and prodrugs thereof,
• wherein the compounds can be in the form of the R- or S-configuration, or a mixture thereof, including a racemic or diastereomeric mixture thereof.