Hcv ns-3 serine protease inhibitors

A method for treatment or prophylaxis of flavivirus infection comprising administering to an individual afflicted with or at risk of flavivirus infection an effective amount of a compound of formula VI:

• wherein
• A is C(═O)OR1, or C(═O)NHSO2R2, wherein;
• R1 is hydrogen, or C1-C6alkyl;
• 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, 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 and Y—NRaC(═O)ORb;
• Y is independently a bond or C1-C3alkylene;
• 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 0 and k is 1;
• Rz is H, or together with the asterisked carbon forms an olefinic bond;
• Rq is H or C1-C6alkyl;
• W is —O— or —S—;
• 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 selected from S, O and N, the ring system being optionally spaced from W by a C1-C3alkyl 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 and Y—NRaC(═O)ORb;
• wherein said carbocyclyl or heterocyclyl moiety is optionally substituted with R10;
• wherein
• R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino, sulfonyl, (C1-C3 alkyl)sulfonyl, NO2, OH, SH, halo, haloalkyl, carboxyl, amido;
• J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R7/R7′ cycloalkyl 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-C6 alkyl, C3-C6cycloalkyl, or COR13;
• R13 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
• R14 is independently selected from H, C1-C6haloalkyl, C1-C6alkoxy, hydroxyl, halo, amino, oxo, thio, or C1-C6 thioalkyl;
• m is 0;
• n is 0;
• G is —NRy-, or —NRjNRj-;
• Ry is J;
• one Rj is H and the other Rj is J;
• R16 is H;
• or R16 is 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.

A method for treatment or prophylaxis of flavivirus infection comprising administering to an individual afflicted with or at risk of flavivirus infection an effective amount of a compound of formula VI:

• wherein
• A is C(═O)NHSO2R2, or C(═O)OR1 wherein;
• R1 is H or C1-C6 alkyl;
• 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, 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 and Y—NRaC(═O)ORb;
• Y is independently a bond or C1-C3alkylene;
• 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 0 and k is 1;
• Rz is H or together with the asterisked carbon forms an olefinic bond;
• Rq is H or C1-C6 alkyl;
• W is —O—, or —S—;
• 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-C6 alkyl, C3-C6cycloalkyl, or COR13;
• R13 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
• R14 is independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, hydroxy, halo, amino, oxo, thio, or C1-C6 thioalkyl;
• m is 0;
• n is 0;
• G is —NRy — or —NRjNRj—;
• Ry is J;
• one Rj is H and the other Rj is H or J;
• R16 is H;
• or R16 is 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;
• wherein R8 is C0-C3alkylaryl, or C0-C3alkylheteroaryl, either of which is optionally mono, di, or tri substituted with R9, wherein;
• R9 is C1-C6 alkyl, C1-C6alkoxy, NO2, OH, halo, trifluoromethyl, amino or amido optionally mono- or di-substituted with C1-C6alkyl, carboxy, C0-C3alkylaryl, or C0-C3alkylheteroaryl, the aryl or heteroaryl being optionally substituted with R10;
• wherein
• R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6aloxy, amino optionally mono- or di-substituted with C1-C6alkyl, C1-C3 alkyl amide, sulfonylC1-C3alkyl, NO2, OH, halo, trifluoromethyl, carboxyl, or heteroaryl;
• or a pharmaceutically acceptable salt thereof.

A method for treatment or prophylaxis of flavivirus infection comprising administering to an individual afflicted with or at risk of flavivirus infection an effective amount of a compound selected from the group consisting of:

• (Z)-(1R,4R,6S,16R,18R)-14-tert-Butoxycarbonylamino-18-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,15-dioxo-3,14-diaza-tricyclo[14.3.0.0.4.6]nonadec-7-ene-4-carboxylic acid ethyl ester;
• (Z)-(1R,4R,6S,16R,18R)-14-tert-Butoxycarbonylamino-18-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,15-dioxo-3,14-diaza-tricyclo[14.3.0.0.4.6]nonadec-7-ene-4-carboxylic acid;
• 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carboxylic acid ethyl ester;
• 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carboxylic acid;
• Cyclopropanesulphonic acid [17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*octadec-7-ene-4-carbonyl]-amide;
• 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carboxylic acid ethyl ester;
• 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carboxylic acid ethyl ester;
• Cyclopropanesulphonic acid [17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*octadec-7-ene-4-carbonyl]-amide;
• [4-Cyclopropanesulphonylaminocarbonyl-17-(7-methoxy-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-en-13-yl]-carbamic acid tert.butyl ester;
• Cyclopropanesulphonic acid[13-amino-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carbonyl]amide trifluoroacetic acid salt;
• Cyclopropanesulphonic acid {17-[2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carbonyl)-amide;
• N-{4-[4-(4-Cyclopropanesulphonylaminocarbonyl-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6]octadec-7-en-17-yloxy)-7-methoxy-quinoli-2-yl]-thiazol-2-yl}-3,3-dimethylbutyramide;
• 17-[2-(2-Isopropylamino-thiazol-4-yl)-7-methoxy-quionlin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carboxylic acid ethyl ester;
• 17-[2-(2-Isopropylamino-thiazol-4-yl)-7-methoxy-quionlin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carboxylic acid;
• and
• Cyclopropanesulphonic acid {17-[2-(2-isopropylamino-thiazol-4-yl)-7-methoxy-quionlin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-4-carbonyl}-amide;
• or a pharmaceutically acceptable salt thereof.