Hcv ns-3 serine protease inhibitors

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.

1 - 57 . (canceled) 
   
   
       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)OR 1 , or C(═O)NHSO 2 R 2 , wherein; 
       R 1  is hydrogen, or C 1 -C 6 alkyl; 
       R 2  is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl; 
       wherein R 2  is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSO p Rb, Y—S(═O) p Rb, Y—S(═O) p NRaRb, Y—C(═O)ORb and Y—NRaC(═O)ORb; 
       Y is independently a bond or C 1 -C 3 alkylene; 
       Ra is independently H or C 1 -C 3 alkyl; 
       Rb is independently H, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl or C 0 -C 3 alkylheterocyclyl; 
       p is independently 1 or 2; 
       M is CR 7 R 7 ; 
       R 7 ′ taken together with R 7  forms a C 3 -C 6 cycloalkyl 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 C 1 -C 6 alkyl; 
       W is —O— or —S—; 
       R 8  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 C 1 -C 3 alkyl group; any of which R8 groups can be optionally mono, di, or tri substituted with R 9 , wherein 
       R 9  is independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSO p Rb, Y—S(═O) p Rb, Y—S(═O) p NRaRb, Y—C(═O)ORb and Y—NRaC(═O)ORb; wherein said carbocyclyl or heterocyclyl moiety is optionally substituted with R 10 ; wherein 
       R 10  is C 1 -C6alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, amino, sulfonyl, (C 1 -C 3  alkyl)sulfonyl, NO 2 , OH, SH, halo, haloalkyl, carboxyl, amido; 
       J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R 7 /R 7 ′ cycloalkyl and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from: —O—, —S— or —NR 12 —, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R 14 ; wherein; 
       R 12  is H, C 1 -C 6  alkyl, C 3 -C 6 cycloalkyl, or COR 13 ; 
       R 13  is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl; 
       R 14  is independently selected from H, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, halo, amino, oxo, thio, or C 1 -C 6  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; 
       R 16  is H; or R 16  is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 CO—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSO p Rb, Y—S(═O) p Rb, Y—S(═O) p NRaRb, Y—C(═O)ORb, Y—NRaC(═O)ORb; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       59 . The method according to  claim 58 , wherein R 2  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 0 -C 0 alkylaryl, optionally substituted C 3 -C 7 cycloalkyl, or optionally substituted phenyl. 
   
   
       60 . The method according to  claim 59 , wherein R 2  is methyl. 
   
   
       61 . The method according to  claim 59 , wherein R 2  is cyclopropyl. 
   
   
       62 . The method according to  claim 58 , wherein said compound has the partial structure selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       63 . The method according to  claim 62 , wherein Rq is C 1 -C 3  alkyl. 
   
   
       64 . The method according to  claim 62 , wherein Rq is methyl. 
   
   
       65 . The method according to  claim 58 , wherein A is C(═O)OR 1 , wherein R 1  is H or C 1 -C 6  alkyl. 
   
   
       66 . The method according to  claim 58 , wherein W is —O—. 
   
   
       67 . The method according to  claim 66  wherein R 8  is optionally substituted C 0 -C 3 alkylcarbocyclyl or optionally substituted C 0 -C 3 alkylheterocyclyl. 
   
   
       68 . The method according to  claim 67 , wherein the C 0 -C 3  alkyl moiety is methylene. 
   
   
       69 . The method according to  claim 68 , wherein R 8  is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-napthyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R 9  as defined. 
   
   
       70 . The method according to  claim 69  wherein R 8  is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R 9  as defined. 
   
   
       71 . The method according to  claim 70  wherein R 8  is: 
     
       
         
         
             
             
         
       
       wherein R 9a  is C 1 -C 6  alkyl; C 1 -C 6 alkoxy; thioC 1 -C 3 alkyl; amino optionally substituted with C 1 -C 6 alkyl; C 0 -C 3 alkylaryl; or C 0 -C 3 alkylheteroaryl, C 0 -C 3 alkylheterocyclyl, said aryl, heteroaryl or heterocycle being optionally substituted with R 19  wherein 
       R 10  is C 1 -C 6 alkyl, C 0 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, amino optionally mono- or di-substituted with C 1 -C 6 alkyl, amido, C 1 -C 3 alkyl amide; and R 9b  is C 1 -C 6  alkyl, C 1 -C 6 -alkoxy, amino, di(C 1 -C 3 alkyl)amino, (C 1 -C 3 alkyl) amide, NO 2 , OH, halo, trifluoromethyl, carboxyl. 
     
   
   
       72 . The method according to  claim 71 , wherein R 9a  is aryl or heteroaryl, either of which is optionally substituted with R 10  as defined. 
   
   
       73 . The method according to  claim 72 , wherein R 9a  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       wherein R 10  is H, C 1 -C 6 alkyl, or C 0 -C 3 alkylcycloalkyl, amino optionally mono- or di-substituted with C 1 -C 6 alkyl, amido, (C 1 -C 3 alkyl)amide. 
     
   
   
       74 . The method according to  claim 72 , wherein R 9a  is optionally substituted phenyl, preferably phenyl substituted with C 1 -C 6 alkyl; C 1 -C 6 alkoxy; or halo. 
   
   
       75 . The method according to  claim 71 , wherein R 8  is: 
     
       
         
         
             
             
         
       
       and wherein R 10a  is H, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, amino optionally mono- or di-substituted with C 1 -C 6 alkyl, amido, (C 1 -C 3  alkyl)amide, heteroaryl or heterocyclyl; and R 9b  is C 1 -C 6  alkyl, C 1 -C 6 -alkoxy, amino, di(C 1 -C 3  alkyl)amino, (C 1 -C 3  alkyl)amide, NO 2 , OH, halo, trifluoromethyl, or carboxyl. 
     
   
   
       76 . The method according to  claim 71 , wherein R 9b  is C 1 -C 6 -alkoxy, preferably methoxy. 
   
   
       77 . The method according to  claim 58 , wherein R 7  and R 7 ′ together define a spiro-cyclopropyl or spiro-cyclobutyl ring. 
   
   
       78 . 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 —NR 12 —, wherein R 12  is H, C 1 -C 6  alkyl, or —C(═O)C 1 -C 6  alkyl. 
   
   
       79 . The method according to  claim 78 , wherein J is saturated or mono-unsaturated. 
   
   
       80 . The method according to  claim 78 , wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain. 
   
   
       81 . The method according to  claim 78 , wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms. 
   
   
       82 . The method according to  claim 58 , wherein R 16  is H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl. 
   
   
       83 . The method according to  claim 82 , wherein R 16  is H or methyl. 
   
   
       84 . The method according to  claim 58 , wherein the flavivirus infection is HCV infection. 
   
   
       85 . 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. 
   
   
       86 . 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. 
   
   
       87 . 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. 
   
   
       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)NHSO 2 R 2 , or C(═O)OR 1  wherein; 
       R 1  is H or C 1 -C 6  alkyl; 
       R 2  is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl; 
       wherein R 2 , is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSO p Rb, Y—S(═O) p Rb, Y—S(═O) p NRaRb, Y—C(═O)ORb and Y—NRaC(═O)ORb; 
       Y is independently a bond or C 1 -C 3 alkylene; 
       Ra is independently H or C 1 -C 3 alkyl; 
       Rb is independently H, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl or C 0 -C 3 alkylheterocyclyl; 
       p is independently 1 or 2; 
       M is CR 7 R 7 ′; 
       R 7 ′ taken together with R 7  forms a C 3 -C 6 cycloalkyl 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 C 1 -C 6  alkyl; 
       W is —O—, or —S—; 
       J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R 7 /R 7 ′ cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from: —O—, —S— or —NR 12 —, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R 14 ; wherein; 
       R 12  is H, C 1 -C 6  alkyl, C 3 -C 6 cycloalkyl, or COR 13 ; 
       R 13  is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl; 
       R 14  is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, halo, amino, oxo, thio, or C 1 -C 6  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; 
       R 16  is H; or R 16  is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 CO—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSO p Rb, Y—S(═O) p Rb, Y—S(═O) p NRaRb, Y—C(═O)ORb, Y—NRaC(═O)ORb; 
       wherein R 8  is C 0 -C 3 alkylaryl, or C 0 -C 3 alkylheteroaryl, either of which is optionally mono, di, or tri substituted with R 9 , wherein; 
       R 9  is C 1 -C 6  alkyl, C 1 -C 6 alkoxy, NO 2 , OH, halo, trifluoromethyl, amino or amido optionally mono- or di-substituted with C 1 -C 6 alkyl, carboxy, C 0 -C 3 alkylaryl, or C 0 -C 3 alkylheteroaryl, the aryl or heteroaryl being optionally substituted with R 10 ; 
       wherein 
       R 10  is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 aloxy, amino optionally mono- or di-substituted with C 1 -C 6 alkyl, C 1 -C 3  alkyl amide, sulfonylC 1 -C 3 alkyl, NO 2 , OH, halo, trifluoromethyl, carboxyl, or heteroaryl; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       89 . The method according to  claim 88 , wherein R 2  is optionally substituted C 3 -C 7 cycloalkyl, 
   
   
       90 . The method according to  claim 89 , wherein R 2  is cyclopropyl. 
   
   
       91 . The method according to  claim 88 , wherein W is —O—. 
   
   
       92 . The method according to  claim 88 , wherein R 9  is C 1 -C 6  alkyl, C 1 -C 6 alkoxy, amino, di-(C 1 -C 3  alkyl)amino, C 1 -C 3 alkylamide, aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with R 10 ; and wherein
 R 10  is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, amino, mono- or di-C 1 -C 3  alkylamino, amido, C 1 -C 3  alkylamide, halo, trifluoromethyl, or heteroaryl.   
   
   
       93 . The method according to  claim 92 , wherein, R 10  is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino optionally mono- or di-substituted with C 1 -C 3  alkyl, amido, C 1 -C 3 -alkylamide, halo, or heteroaryl. 
   
   
       94 . The method according to  claim 93 , wherein R 10  is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with C 1 -C 3  alkyl, amido, C 1 -C 3 alkylamide, or C 1 -C 3 alkyl thiazolyl. 
   
   
       95 . The method according to  claim 88 , with the partial structure selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       96 . The method according to  claim 95 , wherein Rq is C 1 -C 3  alkyl. 
   
   
       97 . The method according to  claim 96 , wherein Rq is methyl. 
   
   
       98 . The method according to  claim 88 , wherein the C 0 -C 3  alkyl moiety of R 8  is a bond. 
   
   
       99 . The method according to  claim 88 , wherein R 16  is H or methyl. 
   
   
       100 . 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 —NR 12 —, wherein R 12  is H, or C 1 -C 6  alkyl. 
   
   
       101 . The method according to  claim 100 , wherein J is saturated or mono-unsaturated. 
   
   
       102 . The method according to  claim 100 , wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain. 
   
   
       103 . The method according to  claim 100 , wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms. 
   
   
       104 . The method according to  claim 88 , wherein
 A is C(═O)NHSO 2 R 2 ;   R 2  is C 0 -C 3 alkylcarbocyclyl;   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 R 7 /R 7 ′ cycloalkyl to G and forms a macrocycle;   G is —NRy —;   Ry is J;   R 16  is C 1 -C 6 alkyl;   R 8  is heteroaryl, which is optionally mono, di, or tri substituted with R 9 , wherein;   R 9  is C 1 -C 6  alkyl, C 1 -C 6 alkoxy, or heteroaryl, the heteroaryl being optionally substituted with R 10 ; wherein R 10  is C 1 -C 6 alkyl.   
   
   
       105 . The method according to  claim 88 , wherein
 R 2  is cyclopropyl;   Rz is H;   Rq is H;   W is —O—; and   J is a single mono-unsaturated alkylene chain that extends from the R 7 /R 7 ′ cyclopropyl to G and forms a macrocycle dimensioned to provide a macrocycle of 14 or 15 ring atoms.   
   
   
       106 . The method according to  claim 88 , wherein the flavivirus infection is HCV infection. 
   
   
       107 . 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. 
   
   
       108 . 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. 
   
   
       109 . 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. 
   
   
       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.   
   
   
       111 . The method according to  claim 110 , wherein A is C(═O)OR 1 , wherein R 1  is methyl, ethyl, or tert-butyl. 
   
   
       112 . The method according to  claim 110 , wherein the flavivirus infection is HCV infection. 
   
   
       113 . 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. 
   
   
       114 . 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. 
   
   
       115 . 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.