# US 2010/0166706 A1 · Hcv ns-3 serine protease inhibitors

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- Number: US 2010/0166706 A1
- Document ID: US20100166706A1
- Status: Published application
- Kind: A1
- Application number: 12/642,984
- Filed: 2009-12-21
- Published: 2010-07-01
- Earliest claimed: 2004-01-30
- Assignees: Medivir AB
- Inventors: Asa Rosenquist; Fredrik Thorstensson; Per-Ola Johansson; Ingemar Kvarnstrom; Bertil Samuelsson; Hans Wallberg
- Web page: https://patentgrep.com/patent/US20100166706A1

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 235/40: having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C 237/04: the carbon skeleton being acyclic and saturated
- C07C 237/10: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 247/04: being saturated
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 281/02: Compounds containing any of the groups [IMAGE cpc-sch-C07C-0972.gif], e.g. carbazates
- C07C 309/73: to carbon atoms of non-condensed six-membered aromatic rings
- C07C 311/51: Y being a hydrogen or a carbon atom
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 215/20: Oxygen atoms
- C07D 215/233: only one oxygen atom which is attached in position 4
- C07D 245/04: condensed with carbocyclic rings or ring systems
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07K 5/0205: {containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof}
- C07K 5/06034: {the side chain containing 2 to 4 carbon atoms}
- C07K 5/06052: {Val-amino acid}
- C07C 2601/02: with a three-membered ring
- C07C 2601/08: the ring being saturated
- C07C 2601/10: the ring being unsaturated
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Methods drawn to peptidomimetic compounds which inhibit the NS3 protease of the hepatitis C virus (HCV), are described. The compounds have the formula (VI) where the variable definitions are as provided in the specification. The compounds comprise a carbocyclic P2 unit in conjunction with a novel linkage to 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.

## Claims

### Claim at position 1

1-57. (canceled)

### Claim 58

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.

### Claim 59 (depends on 58)

The method according to claim 58, wherein R2 is optionally substituted C1-C6 alkyl, optionally substituted C0-C0alkylaryl, optionally substituted C3-C7cycloalkyl, or optionally substituted phenyl.

### Claim 60 (depends on 59)

The method according to claim 59, wherein R2 is methyl.

### Claim 61 (depends on 59)

The method according to claim 59, wherein R2 is cyclopropyl.

### Claim 62 (depends on 58)

The method according to claim 58, wherein said compound has the partial structure selected from the group consisting of:

### Claim 63 (depends on 62)

The method according to claim 62, wherein Rq is C1-C3 alkyl.

### Claim 64 (depends on 62)

The method according to claim 62, wherein Rq is methyl.

### Claim 65 (depends on 58)

The method according to claim 58, wherein A is C(═O)OR1, wherein R1 is H or C1-C6 alkyl.

### Claim 66 (depends on 58)

The method according to claim 58, wherein W is —O—.

### Claim 67 (depends on 66)

The method according to claim 66 wherein R8 is optionally substituted C0-C3alkylcarbocyclyl or optionally substituted C0-C3alkylheterocyclyl.

### Claim 68 (depends on 67)

The method according to claim 67, wherein the C0-C3 alkyl moiety is methylene.

### Claim 69 (depends on 68)

The method according to claim 68, wherein R8 is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-napthyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9 as defined.

### Claim 70 (depends on 69)

The method according to claim 69 wherein R8 is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9 as defined.

### Claim 71 (depends on 70)

The method according to claim 70 wherein R8 is:
wherein R9a is C1-C6 alkyl; C1-C6alkoxy; thioC1-C3alkyl; amino optionally substituted with C1-C6alkyl; C0-C3alkylaryl; or C0-C3alkylheteroaryl, C0-C3alkylheterocyclyl, said aryl, heteroaryl or heterocycle being optionally substituted with R19 wherein
R10 is C1-C6alkyl, C0-C3alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino optionally mono- or di-substituted with C1-C6alkyl, amido, C1-C3alkyl amide; and R9b is C1-C6 alkyl, C1-C6-alkoxy, amino, di(C1-C3alkyl)amino, (C1-C3alkyl) amide, NO2, OH, halo, trifluoromethyl, carboxyl.

### Claim 72 (depends on 71)

The method according to claim 71, wherein R9a is aryl or heteroaryl, either of which is optionally substituted with R10 as defined.

### Claim 73 (depends on 72)

The method according to claim 72, wherein R9a is selected from the group consisting of:
wherein R10 is H, C1-C6alkyl, or C0-C3alkylcycloalkyl, amino optionally mono- or di-substituted with C1-C6alkyl, amido, (C1-C3alkyl)amide.

### Claim 74 (depends on 72)

The method according to claim 72, wherein R9a is optionally substituted phenyl, preferably phenyl substituted with C1-C6alkyl; C1-C6alkoxy; or halo.

### Claim 75 (depends on 71)

The method according to claim 71, wherein R8 is:
and wherein R10a is H, C1-C6alkyl, C0-C3alkylcarbocyclyl, amino optionally mono- or di-substituted with C1-C6alkyl, amido, (C1-C3 alkyl)amide, heteroaryl or heterocyclyl; and R9b is C1-C6 alkyl, C1-C6-alkoxy, amino, di(C1-C3 alkyl)amino, (C1-C3 alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl.

### Claim 76 (depends on 71)

The method according to claim 71, wherein R9b is C1-C6-alkoxy, preferably methoxy.

### Claim 77 (depends on 58)

The method according to claim 58, wherein R7 and R7′ together define a spiro-cyclopropyl or spiro-cyclobutyl ring.

### Claim 78 (depends on 58)

The method according to claim 58, wherein J is a 3 to 8-membered saturated or unsaturated alkylene chain optionally containing one to two heteroatoms independently selected from: —O—, —S— or —NR12—, wherein R12 is H, C1-C6 alkyl, or —C(═O)C1-C6 alkyl.

### Claim 79 (depends on 78)

The method according to claim 78, wherein J is saturated or mono-unsaturated.

### Claim 80 (depends on 78)

The method according to claim 78, wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain.

### Claim 81 (depends on 78)

The method according to claim 78, wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms.

### Claim 82 (depends on 58)

The method according to claim 58, wherein R16 is H, C1-C6alkyl, or C3-C6cycloalkyl.

### Claim 83 (depends on 82)

The method according to claim 82, wherein R16 is H or methyl.

### Claim 84 (depends on 58)

The method according to claim 58, wherein the flavivirus infection is HCV infection.

### Claim 85 (depends on 58)

The method according to claim 58, further comprising sequential or simultaneous administration of an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon.

### Claim 86 (depends on 58)

The method according to claim 58, wherein said administering further comprises administering said compound in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.

### Claim 87 (depends on 86)

The method according to claim 86, wherein said pharmaceutical composition further comprises an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon.

### Claim 88

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.

### Claim 89 (depends on 88)

The method according to claim 88, wherein R2 is optionally substituted C3-C7cycloalkyl,

### Claim 90 (depends on 89)

The method according to claim 89, wherein R2 is cyclopropyl.

### Claim 91 (depends on 88)

The method according to claim 88, wherein W is —O—.

### Claim 92 (depends on 88)

The method according to claim 88, wherein R9 is C1-C6 alkyl, C1-C6alkoxy, amino, di-(C1-C3 alkyl)amino, C1-C3alkylamide, aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with R10; and wherein
R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino, mono- or di-C1-C3 alkylamino, amido, C1-C3 alkylamide, halo, trifluoromethyl, or heteroaryl.

### Claim 93 (depends on 92)

The method according to claim 92, wherein, R10 is C1-C6alkyl, C1-C6alkoxy, amino optionally mono- or di-substituted with C1-C3 alkyl, amido, C1-C3-alkylamide, halo, or heteroaryl.

### Claim 94 (depends on 93)

The method according to claim 93, wherein R10 is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with C1-C3 alkyl, amido, C1-C3alkylamide, or C1-C3alkyl thiazolyl.

### Claim 95 (depends on 88)

The method according to claim 88, with the partial structure selected from the group consisting of:

### Claim 96 (depends on 95)

The method according to claim 95, wherein Rq is C1-C3 alkyl.

### Claim 97 (depends on 96)

The method according to claim 96, wherein Rq is methyl.

### Claim 98 (depends on 88)

The method according to claim 88, wherein the C0-C3 alkyl moiety of R8 is a bond.

### Claim 99 (depends on 88)

The method according to claim 88, wherein R16 is H or methyl.

### Claim 100 (depends on 88)

The method according to claim 88, wherein J is a 3 to 8-membered saturated or unsaturated alkylene chain optionally containing one to two heteroatoms independently selected from: —O—, —S— or —NR12—, wherein R12 is H, or C1-C6 alkyl.

### Claim 101 (depends on 100)

The method according to claim 100, wherein J is saturated or mono-unsaturated.

### Claim 102 (depends on 100)

The method according to claim 100, wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain.

### Claim 103 (depends on 100)

The method according to claim 100, wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms.

### Claim 104 (depends on 88)

The method according to claim 88, wherein
A is C(═O)NHSO2R2;
R2 is C0-C3alkylcarbocyclyl;
Rz is H;
Rq is H;
W is —O—;
J is a single 4 to 7-membered mono-unsaturated alkylene chain that extends from the R7/R7′ cycloalkyl to G and forms a macrocycle;
G is —NRy —;
Ry is J;
R16 is C1-C6alkyl;
R8 is heteroaryl, which is optionally mono, di, or tri substituted with R9, wherein;
R9 is C1-C6 alkyl, C1-C6alkoxy, or heteroaryl, the heteroaryl being optionally substituted with R10; wherein R10 is C1-C6alkyl.

### Claim 105 (depends on 88)

The method according to claim 88, wherein
R2 is cyclopropyl;
Rz is H;
Rq is H;
W is —O—; and
J is a single mono-unsaturated alkylene chain that extends from the R7/R7′ cyclopropyl to G and forms a macrocycle dimensioned to provide a macrocycle of 14 or 15 ring atoms.

### Claim 106 (depends on 88)

The method according to claim 88, wherein the flavivirus infection is HCV infection.

### Claim 107 (depends on 88)

The method according to claim 88, further comprising sequential or simultaneous administration of an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon.

### Claim 108 (depends on 88)

The method according to claim 88, wherein said administering further comprises administering said compound in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.

### Claim 109 (depends on 108)

The method according to claim 108, wherein said pharmaceutical composition further comprises an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon.

### Claim 110

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.

### Claim 111 (depends on 110)

The method according to claim 110, wherein A is C(═O)OR1, wherein R1 is methyl, ethyl, or tert-butyl.

### Claim 112 (depends on 110)

The method according to claim 110, wherein the flavivirus infection is HCV infection.

### Claim 113 (depends on 110)

The method according to claim 110, further comprising sequential or simultaneous administration of an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon.

### Claim 114 (depends on 110)

The method according to claim 110, wherein said administering further comprises administering said compound in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.

### Claim 115 (depends on 114)

The method of claim 114, wherein said pharmaceutical composition further comprises an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon.