HCV Inhibitors And Methods Of Using Them

Abstract

The present invention comprises tetrazoloquinoline-compounds that are inhibitors of HCV. Compositions comprising the compounds in combination with a pharmaceutically acceptable carrier are also disclosed, as are methods of using the compounds and compositions to inhibit HCV infection of a cell, particular in the form of treating HCV infection in a mammal.

1 - 28 . (canceled)  
     
     
         29 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  and R 2  are independently hydrogen, C 1 -C 6 -alkyl, heterocyclic, C 1 -C 6 -alkyl-OH, aryl, heteroaryl, halogen, cyano, —CO—H, —CO—OH, —CO—OR 7 , —CO—NH 2 , —CO—NHR 7 , —CO—NR 7 R 7 , —CO—NH—OH, —CO—NH—OR 7 , —CO—N(R 7 )—OR 7 , —CO—R 7 , —SO 2 NH 2 , —SO 2 NHR 7 , —SO 2 NR 7 R 7 , —SO 2 -heteroaryl, —SO 2 -aryl, —NHR 7 , C 1 -C 6 -alkyl-NH(R 7 )-aryl, —NH(R 7 )-aryl, —CO-heteroaryl, —NH—CO—O—R 7 -aryl, —NH—CO—NH—SO 2 -aryl, —NH—CO—OR 7 , —NH—CO—NH—(C 1 -C 6 -alkyl) or —NH—CO—(C 1 -C 6 -alkyl), wherein each of the heteroaryl and aryl groups are optionally substituted with C 1 -C 6 -alkyl, nitro, hydroxy, C 1 -C 6 -alkoxy, —CO—O—(C 1 -C 6 -akyl), cyano, —O-halo(C 1 -C 6 -alkyl), halo(C 1 -C 6 -alkyl) or halogen; or  
 R 1  or R 2  is a group selected from  
                     
 wherein R 8  is hydrogen or hydroxy; X is ═NH or ═S—, Y is ═N, and R 9  is hydroxy, C 1 -C 6 -alkoxy or aryl optionally substituted with hydroxy or C 1 -C 6 -alkyl; or  
 R 1  and R 2  together with the carbon atoms to which they are attached form a mono or bicyclic aryl or heteroaryl;  
 R 3 , R 4 , R 5  and R 6  are independently hydrogen, nitro, C 1 -C 6 -alkyl, aryl, —O-halo(C 1 -C 6 -alkyl), halo(C 1 -C 6 -alkyl), —O—(C 3 -C 6 -cycloalkyl), —S—(C 1 -C 6 -alkyl), heterocyclyl, C 1 -C 6 -alkoxy, —(C 1 -C 6 -alkoxy)-aryl, azido, halogen, —OCF 3 , —CF 3 , —CO—H, —CO—OH, —CO—OR 7 , —CO—NH 2 , —CO—NHR 7 , —CO—NR 7 R 7 , —CO—N(R 7 )OR 7 , —CO—R 7 , —SO 2 —(C 1 -C 6 -alkyl), —SO 2 NH 2 , —SO 2 NHR 7 , —SO 2 NR 7 R 7 , —CO-heteroaryl, —NH 2 , —NHR 7 , —NR 7 R 7 , —OH, —N(R 7 )—CO—R 7 , —NHSO 2 R 7 , —N(R 7 )—CO—OR 7  or —N(R 7 )—CO—NR 7 R 7 ;  
 R 4  and R 5  together with the carbon atoms to which they are attached form a heteroaryl;  
 R 7  is a cation, C 0 -C 6 -alkyl, —(C 1 -C 6 -alkyl)—OH, —(C 1 -C 6 -alkyl)—O—(C 1 -C 6 -alkyl), —(C 1 -C 6 -alkyl)—CN, C 2 -C 6 -alkene, heterocyclyl, aryl, heteroaryl or —(C 1 -C 6 -alkyl)-aryl, wherein each of the aryl, heterocyclyl and heteroaryl groups are optionally substituted with C 1 -C 6 -alkyl, nitro, hydroxy, C 1 -C 6 -alkoxy, —CO—O—(C 1 -C 6 -alkyl), cyano, —O-halo(C 1 -C 6 -alkyl), halo(C 1 -C 6 -alkyl) or halogen;  
 A 1 , A 2  and A 3  are independently carbon or nitrogen each optionally substituted with halo or C 1 -C 6 -alkyl, wherein one of A 1 , A 2  and A 3  is carbon optionally substituted with halo or C 1 -C 6 -alkyl;  
 ring A optionally contains from 1 to 2 nitrogen atoms;  
 provided that  
 the compounds are not one of the following combinations  
                                                                         A 1     A 2     A 3     R 1     R 2     R 3     R 4     R 5     R 6                     C   N   N   -H   -CH 3     -H   -H   -H   -H         C   N   N   -H   -H   -H   -H   -H   -H                                              
 
     
     
         30 . The compound according to  claim 29  of the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 10  is hydrogen, halo, or C 1 -C 6 -alkyl.  
 
     
     
         31 . The compound according to  claim 30 , wherein R 1  is —CO—NHR 7  or —CO—NR 7 R 7 .  
     
     
         32 . The compound according to  claim 30 , which is 
 ethyl 7,9-dichloro-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate;    ethyl 8-fluoro-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate;    methyl 8-fluoro-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate;    ethyl 7-chloro-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate;    ethyl 7-chloro-1-methyl-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylate;    7,9-dichloro-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylic acid;    8-fluoro-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylic acid;    7-chloro-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylic acid;    7-chloro-1-methyl-[1,2,4]triazolo[4,3-a]quinoline-4-carboxylic acid;    7,9-dichloro-N-(tetrahydro-2H-pyran-2-yloxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide;    1-chloro-8-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide;    7-chloro-N-(tetrahydro-2H-pyran-2-yloxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide;    7-chloro-1-methyl-N-(tetrahydro-2H-pyran-2-yloxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide;    7,9-dichloro-N-hydroxy-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide;    1-chloro-8-fluoro-N-hydroxy-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide;    7-chloro-N-hydroxy-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide; or    7-chloro-N-hydroxy-1-methyl-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide;    or a pharmaceutically acceptable salt thereof.    
     
     
         33 . A composition comprising a compound of  claim 29  and a pharmaceutically acceptable carrier.  
     
     
         34 . A method of inhibiting HCV proliferation comprising contacting an HCV infected cell with a composition according to  claim 33 .  
     
     
         35 . A method of treating a mammal infected with an HCV infection, the method comprising administering to the mammal a therapeutically effective amount of a composition according to  claim 33 .  
     
     
         36 . The method according to  claim 35  wherein the mammal is a human.  
     
     
         37 . A composition comprising a compound of  claim 30  and a pharmaceutically acceptable carrier.  
     
     
         38 . A method of inhibiting HCV proliferation comprising contacting an HCV infected cell with a composition according to  claim 37 .  
     
     
         39 . A method of treating a mammal infected with an HCV infection, the method comprising administering to the mammal a therapeutically effective amount of a composition according to  claim 37 .  
     
     
         40 . The method according to  claim 39  wherein the mammal is a human.