HCV Protease Inhibitors and Uses Thereof

Abstract

This invention relates to: (a) compounds of formula I and salts thereof that, inter alia, are useful as hepatitis C virus (HCV) inhibitors; (b) intermediates useful for the preparation of such compounds and salts; (c) pharmaceutical compositions comprising such compounds and salts; and (d) methods of use of such compounds, salts, and compositions.

We claim: 
     
         1 . A compound or salt thereof, wherein:
 the compound corresponds in structure to formula I:   
       
         
           
           
               
               
           
         
         A is a carbocyclyl optionally substituted with one or more independently selected R A  substituents; 
         each R A  is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, aminocarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, aminoalkylcarbonyl, carbocyclylaminocarbonyl, heterocyclylaminocarbonyl, carbocyclylalkylcarbonyl, heterocyclylalkylcarbonyl, carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, carbocyclylsulfonyl, heterocyclylsulfonyl, alkylcarbocyclylsulfonyl, alkenylcarbocyclylsulfonyl, alkynylcarbonylsulfonyl, alkylheterocyclylsulfonyl, alkenylheterocyclylsulfonyl, alkynylheterocyclysulfonyl, amino, alkylamino, carbocyclylamino, heterocyclylamino, alkylcarbocyclylamino, and alkylheterocyclylamino, wherein:
 the amino portion of the aminoalkylcarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyloxycarbonyl, carbocyclylalkyloxycarbonyl, and heterocyclylalkyloxycarbonyl; 
 
         R 1  is selected from the group consisting of optionally substituted carbocyclyl and optionally substituted heterocyclyl; 
         R 2  is selected from the group consisting of optionally substituted carbocyclyl and optionally substituted heterocyclyl; 
         R 3  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, carbocyclyl, and heterocyclyl; 
         R 4  is selected from the group consisting hydrogen, alkyl, alkenyl, and alkynyl; 
         R 5  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, carbocyclyl, and heterocyclyl; 
         R 6  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclyl, heterocyclyl, amino, carbocyclylalkyl, and heterocyclylalkyl; 
         R 7  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclyl, heterocyclyl, amino, carbocyclylalkyl, and heterocyclylalkyl; 
         R 8  is aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of R B  and R C ; 
         each R B  is independently selected from the group consisting of aminocarbonylalkyl, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclyl, and heterocyclyl, wherein:
 the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: 
 the alkyl, alkenyl, and alkynyl optionally are substituted one or more substituents independently selected from the group consisting of hydroxy, alkyloxy, carbocyclyloxy, heterocyclyloxy, carbocyclyl, heterocyclyl, and aminocarbonyl, wherein:
 the carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkenyl, alkynyl, hydroxy, alkyloxy, alkenyloxy, and alkynyloxy, and 
 the aminocarbonyl optionally is substituted with one or two independently selected alkyl; and 
 
 
         each R C  is independently selected from the group consisting of alkyl, alkenyl, and alkynyl. 
       
     
     
         2 . The compound or salt of  claim 1 , wherein the compound corresponds in structure to formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound or salt of  claim 1 , wherein each R A  is independently selected from the group consisting of carbocyclyl, heterocyclyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, aminoalkylcarbonyl, carbocyclylaminocarbonyl, heterocyclylaminocarbonyl, carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl, alkylcarbocyclylsulfonyl, and alkylheterocyclylsulfonyl, wherein:
 the amino portion of the aminoalkylcarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyloxycarbonyl, carbocyclylalkyloxycarbonyl, and heterocyclylalkyloxycarbonyl.   
     
     
         4 . The compound or salt of  claim 1 , wherein each R A  is independently selected from the group consisting of carbocyclyl, heterocyclyl, alkylcarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, carbocyclyloxycarbonyl, aminoalkylcarbonyl, heterocyclylaminocarbonyl, carbocyclylalkyloxycarbonyl, and alkylcarbocyclylsulfonyl, wherein:
 the amino portion of the aminoalkylcarbonyl optionally is substituted with one or two independently selected carbocyclylalkyloxycarbonyl.   
     
     
         5 . The compound or salt of  claim 1 , wherein:
 R 8  is aminocarbonyl substituted with R B ; and   R B  is selected from the group consisting of aminocarbonylalkyl, carbocyclyl, and heterocyclyl, wherein:
 the amino portion of the aminocarbonylalkyl optionally is substituted with a substituent selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: 
 the alkyl, alkenyl, and alkynyl optionally are substituted one or two substituents independently selected from the group consisting of hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and aminocarbonyl, wherein:
 the carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, and alkyloxy, and 
 the aminocarbonyl optionally is substituted with one or two independently selected alkyl. 
 
   
     
     
         6 . The compound or salt of  claim 1 , wherein:
 R 8  is aminocarbonyl substituted with R B ; and   R B  is selected from the group consisting of aminocarbonylalkyl, carbocyclyl, and heterocyclyl, wherein:   the amino portion of the aminocarbonylalkyl optionally is substituted with alkyl, wherein:
 the alkyl optionally is substituted two substituents independently selected from the group consisting of alkyloxy, carbocyclyl, heterocyclyl, and aminocarbonyl, wherein:
 the carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, and alkyloxy, and 
 the aminocarbonyl optionally is substituted with two independently selected alkyl. 
 
   
     
     
         7 . The compound or salt of  claim 1 , wherein R 1  is 6-membered nitrogen-containing heterocyclyl. 
     
     
         8 . The compound or salt of  claim 1 , wherein R 2  is C 5 -C 6 -cycloalkyl. 
     
     
         9 . The compound or salt of  claim 1 , wherein R 3  is alkyl. 
     
     
         10 . The compound or salt of  claim 1 , wherein R 4  is hydrogen. 
     
     
         11 . The compound or salt of  claim 1 , wherein R 5  is alkyl. 
     
     
         12 . The compound or salt of  claim 1 , wherein R 6  is hydrogen. 
     
     
         13 . The compound or salt of  claim 1 , wherein R 7  is hydrogen. 
     
     
         14 . The compound or salt of  claim 1 , wherein:
 A is selected from the group consisting of C 5 -C 7 -carbocyclyl, wherein:
 the carbocyclyl is optionally substituted with one, two, or three independently selected R A  substituents; 
   each R A  is independently selected from the group consisting of carbocyclyl, heterocyclyl, alkylcarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, carbocyclyloxycarbonyl, aminoalkylcarbonyl, heterocyclylaminocarbonyl, carbocyclylalkyloxycarbonyl, and alkylcarbocyclylsulfonyl, wherein:
 the amino portion of the aminoalkylcarbonyl optionally is substituted with carbocyclylalkyloxycarbonyl; 
   R 1  is 5-6-membered heterocyclyl;   R 2  is C 5 -C 6 -carbocyclyl;   R 3  is selected from the group consisting of hydrogen, alkyl, carbocyclylalkyl, carbocyclyl, and aminocarbonylalkyl;   R 4  is selected from the group consisting of hydrogen and alkyl;   R 5  is selected from the group consisting of alkyl and carbocyclylalkyl;   R 6  is selected from the group consisting of hydrogen and alkyl;   R 7  is selected from the group consisting of hydrogen and alkyl;   R 8  is aminocarbonyl optionally substituted with R B ; and   R B  is independently selected from the group consisting of aminocarbonylalkyl and carbocyclyl, wherein:
 the amino portion of the aminocarbonylalkyl is substituted with alkyl, wherein:
 the alkyl optionally is substituted with one or more substituents independently selected from the group consisting of carbocyclyl and aminocarbonyl, wherein:
 the carbocyclyl optionally is substituted with one or more substituents selected from the group consisting of halo and alkyloxy, and 
 the aminocarbonyl optionally is substituted with one or two independently selected alkyl. 
 
 
   
     
     
         15 . The compound or salt of  claim 1 , wherein:
 A is selected from the group consisting of C 5 -C 6 -single-ring carbocyclyl and C 7 -bridged carbocyclyl, wherein:
 each such substituent optionally is substituted with R A ; 
   R A  is selected from the group consisting of carbocyclyl, heterocyclyl, alkylcarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, carbocyclyloxycarbonyl, aminoalkylcarbonyl, heterocyclylaminocarbonyl, carbocyclylalkyloxycarbonyl, and alkylcarbocyclylsulfonyl, wherein:
 the amino portion of the aminoalkylcarbonyl optionally is substituted with carbocyclylalkyloxycarbonyl; 
   R 1  is 5-6-membered nitrogen-containing heterocyclyl;   R 2  is C 5 -C 6 -cycloalkyl;   R 3  is selected from the group consisting of hydrogen, alkyl, aminocarbonylalkyl, cycloalkyl, arylalkyl, and cycloalkylalkyl;   R 4  is hydrogen;   R 5  is selected from the group consisting of alkyl and cycloalkylalkyl;   R 6  is hydrogen;   R 7  is hydrogen;   R 8  is aminocarbonyl substituted with R B ; and   R B  is independently selected from the group consisting of aminocarbonylalkyl and cycloalkyl, wherein:   the amino portion of the aminocarbonylalkyl optionally is substituted with alkyl, wherein:
 the alkyl optionally is substituted with aminocarbonyl, wherein:
 the aminocarbonyl optionally is substituted with one or two independently selected alkyl. 
 
   
     
     
         16 . A pharmaceutical composition comprising one or more compounds and/or salts recited in  claim 1 . 
     
     
         17 . A method for treating hepatitis C in a mammal in need of such treatment, wherein the method comprises administering to the mammal one or more compounds and/or salts recited in  claim 1 .