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 sych 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.

1 - 56 . (canceled) 
   
   
       57 . 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 I′: 
     
       
         
         
             
             
         
       
       wherein 
       A is C(═O)OR 1 , or C(═O)NHSO 2 R 2 , wherein;
 R 1  is hydrogen, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl; 
 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 CO—, Y—NRaRb, Y—O—R b , 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; 
 Y is independently a bond or C 1 -C 3 alkyl; 
 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 1 and k is 1; 
 W is —CH 2 —, —O—, —OC(═O)NH, —OC(═O), —S—, —NH—, —NRa, —NHSO 2 —, —NHC(═O)NH— or —NHC(═O)—, —NHC(═S)NH— or a bond; 
 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 hereto atoms independently selected from S, O and N, the ring system being optionally spaced from W by a C 1 -C 3  alkylene group; any of which R 8  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, Y—NRaC(═O)ORb; wherein said carbocyclyl or heterocyclyl is optionally substituted with R 10 ; wherein
 R 10  is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, amino, amido, sulfonyl, (C 1 -C 3 alkyl)sulfonyl, NO 2 , 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)C 1 -C 3 alkyl; 
 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 C(═O)R 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 the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, halo, amino, oxo, thio and C 1 -C 6 thioalkyl; 
 m is 0; n is 0; 
 Ry is J; 
 R 16  is H; or 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. 
     
   
   
       58 . The method according to  claim 57 , wherein said compound has the partial structure Ia′, Ib′ or Iaa′: 
     
       
         
         
             
             
         
       
       where e is 1 or 2. 
     
   
   
       59 . The method according to  claim 57 , wherein E is —C(═O)—. 
   
   
       60 . The method according to  claim 57 , wherein R 16  is H, C 1 -C 3  alkyl or C 3 -C 6  cycloalkyl. 
   
   
       61 . The method according to  claim 57 , wherein W is —OC(═O)—, —NRa—, NHS(O) 2 —; —NHC(═O)—; —OC(═O)NH—; —S—, a bond or —O—. 
   
   
       62 . The method according to  claim 61  wherein R 8  is optionally substituted C 0 -C 3 alkylcarbocyclyl or optionally substituted C 0 -C 3 -alkylheterocyclyl. 
   
   
       63 . The method according to  claim 62 , wherein the C 0 -C 3  alkyl moiety is methylene or a bond. 
   
   
       64 . The method according to  claim 63 , wherein R 8  is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-naphthyl, or quinolinyl any of which is unsubstituted, mono, or distributed with R 9 . 
   
   
       65 . The method according to  claim 64 , wherein R 8  is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or distributed with R 9 . 
   
   
       66 . The method according to  claim 65  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 10  wherein
 R 10  is C 1 -C 6 alkyl, C 0 -C 3 alkylC 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, amino optionally mono- or di-substituted with C1-C6alkyl, amido, C1-C3 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. 
     
   
   
       67 . The method according to  claim 66 , wherein R 9a  is aryl or heteroaryl, either of which is optionally substituted with R 10 . 
   
   
       68 . The method according to  claim 67 , wherein R 9a  is selected from the group consisted 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. 
     
   
   
       69 . The method according to  claim 67 , wherein R 9a  is phenyl, optionally substituted with C 1 -C 6 alkyl; C 1 -C 6 alkoxy; or halo. 
   
   
       70 . The method according to  claim 66 , wherein R 8  is: 
     
       
         
         
             
             
         
       
       wherein R 10a  is H, C 1 -C 6 alkyl, or C 0 -C 3 alkylcarbocyclyl, amino optionally mono- or di-substituted with C 1 -C 6 alkyl, amido, 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, amide, NO 2 , OH, halo, trifluoromethyl, or carboxyl. 
     
   
   
       71 . The method according to  claim 66 , wherein R 9b  is C 1 -C 6 -alkoxy. 
   
   
       72 . The method according to  claim 57 , wherein A is C(═O)NHSO 2 R 2 . 
   
   
       73 . The method according to  claim 72 , wherein R 2  is optionally substituted C 1 -C 6  alkyl. 
   
   
       74 . The method according to  claim 72 , wherein R 2  is optionally substituted C 3 -C 7 cycloalkyl. 
   
   
       75 . The method according to  claim 72 , wherein R 2  is optionally substituted C 0 -C 6 alkylary. 
   
   
       76 . The method according to  claim 57 , wherein A is C(═O)OR 1 . 
   
   
       77 . The method according to  claim 76 , wherein R 1  is H or C 1 -C 6  alkyl. 
   
   
       78 . The method according to  claim 57 , wherein R 7  and R7′ together define a spiro-cyclopropyl. 
   
   
       79 . The method according to  claim 57 , 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. 
   
   
       80 . The method according to  claim 79 , wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain. 
   
   
       81 . The method according to  claim 79 , wherein J is saturated or mono-unsaturated. 
   
   
       82 . The method according to  claim 79 , wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms. 
   
   
       83 . The method according to  claim 57  wherein said compound has formula Ihe′: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 R 16  is H, or C 1 -C 6 alkyl; 
 J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain; 
 
       q is 1 and k is 1;
 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; 
 W is —O— or —OC(═O)NH—; 
 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, C 0 -C 3 alkylaryl, C 0 -C 3 alkylheteroaryl, carboxyl, said 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 alkoxy, 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. 
     
   
   
       84 . The method according to  claim 83 , wherein J is a single 5-8 membered saturated or partially unsaturated alkylene chain. 
   
   
       85 . The method according to  claims 83 , wherein J is monounsaturated. 
   
   
       86 . The method according to  claim 85 , wherein J has one double bond spaced one carbon atom from the cyclopropyl group depicted in the formula Ihe′. 
   
   
       87 . The method according to  claim 83 , wherein R 8  is the group 
     
       
         
         
             
             
         
       
       wherein R 9a  is C 0 -C 3 alkylaryl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocyclyl; said aryl, heteroaryl or heterocyclyl being optionally substituted with R 10  wherein R 10  is C 1 -C 6 alkyl, amino, amino mono- or disubstituted with C 1 -C 6 alkyl or NHC(═O)C 1 -C 6 alkyl; and 
       R 9b  is C 1 -C 6 alkoxy; or 
       R 8  is C 0 -C 3 alkylaryl wherein the aryl group is optionally substituted with 1-2 substituents selected from C 0 -C 3 alkylheterocyclyl and trifluoC 1 -C 6 alkyl; and wherein the C 0 -C 3 alkylheterocyclyl is optionally substituted with R 10 . 
     
   
   
       88 . The method according to  claim 87 , wherein R 9a  is phenyl, 
     
       
         
         
             
             
         
       
       wherein R 10  is H, C 1 -C 6 alkyl, amino, amino mono or disubstituted with C 1 -C 3 alkyl. 
     
   
   
       89 . The method according to  claim 83 , wherein A is C(═O)NHS(═O) 2 R 2 . 
   
   
       90 . The method according to  claim 89 , wherein R 2  is optionally substituted cycloalkyl. 
   
   
       91 . The method according to  claim 90  wherein R 2  is optionally substituted cyclopropyl. 
   
   
       92 . The method according to  claim 60 , wherein R 16  is methyl. 
   
   
       93 . The method according to  claim 57  wherein the flavivirus infection is HCV infection. 
   
   
       94 . The method according to  claim 57  further comprising sequential or simultaneous administration of an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon. 
   
   
       95 . The method according to  claim 57  wherein said administering further comprises administering said compound in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier. 
   
   
       96 . The method of  claim 95 , wherein said pharmaceutical composition further comprises an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon. 
   
   
       97 . 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 I′: 
     
       
         
         
             
             
         
       
       wherein 
       A is C(═O)OR 1 , or C(═O)NHSO 2 R 2 , wherein;
 R 1  is hydrogen, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl; 
 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 CO—, Y—NRaRb, Y—O—R b , 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; 
 
 Y is independently a bond or C 1 -C 3 alkyl; 
 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 1 and k is 1; 
 W is —O—, —OC(═O)NH, —OC(═O), —S—, —NRa, —NHSO 2 —, —NHC(═O)—, or a bond; 
 
       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, amido optionally mono- or di-substituted with C 1 -C 6 alkyl, C 0 -C 3 alkylaryl, C 0 -C 3 alkylheteroaryl, carboxyl, 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 alkoxy, amino optionally mono- or di-substituted with C 1 -C 6 alkyl, amido, sulfonylC 1 -C 6 alkyl, NO 2 , OH, halo, trifluoromethyl, carboxyl, or heteroaryl; 
 E is —C(═O)—, —C(═S)—, —S(═O) 2 —, —S(═O)—, —C(═N—Rf)-; 
 Rf is H, —CN, —C(═O)NRaRb; —C(═O)C 1 -C 3 alkyl; 
 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 C(═O)R 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 the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, halo, amino, oxo, thio and C 1 -C 6 thioalkyl; 
 m is 0; n is 0; 
 
       G is —NRy-;
 Ry is J; 
 R 16  is H; or 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. 
     
   
   
       98 . The method according to  claim 97  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 ; 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, halo, trifluoromethyl, or heteroaryl.   
   
   
       99 . The method according to  claim 98 , 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. 
   
   
       100 . The method according to  claim 99  wherein R 10  is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with C 1 -C 3  alkyl, amido, or C 1 -C 3 alkyl thiazolyl. 
   
   
       101 . The method according to  claim 97 , wherein W is —O—. 
   
   
       102 . The method according to  claim 97  wherein the flavivirus infection is HCV infection. 
   
   
       103 . The method according to  claim 97  further comprising sequential or simultaneous administration of an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon. 
   
   
       104 . The method according to  claim 97  wherein said administering further comprises administering said compound in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier. 
   
   
       105 . The method of  claim 104 , wherein said pharmaceutical composition further comprises an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon. 
   
   
       106 . 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:
 19-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-4,14-dicarboxylic acid 4-ethyl ester 14-methyl ester;   19-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-3,14-dicarboxylic acid 3-ethyl ester;   14-[(Cyclohexyl-methylcarbamoyl-methyl)-19-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-4-carboxylic acid 3-ethyl ester;   14-[(Cyclohexyl-methylcarbamoyl-methyl)-19-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-4-carboxylic acid;   [14-Cyclopropanesulfonylaminocarbonyl-17(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.0*4,6*]octadec-7-en-13-yl]-carbamic acid ter.butyl ester;   17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13,15-triaza-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-3,13,15-triaza-tricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid;   or a pharmaceutically acceptable salt thereof.   
   
   
       107 . The method according to  claim 106  wherein the flavivirus infection is HCV infection. 
   
   
       108 . The method according to  claim 106  further comprising sequential or simultaneous administration of an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon. 
   
   
       109 . The method according to  claim 106  wherein said administering further comprises administering said compound in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier. 
   
   
       110 . The method of  claim 109 , wherein said pharmaceutical composition further comprises an additional HCV antiviral selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin, and interferon.