Hcv protease inhibitors and uses thereof

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

1 - 47 . (canceled) 
     
     
         48 . A conjugate of the formula: Cys159-linker-inhibitor moiety, 
       wherein:
 the Cys159 is Cys159 of HCV protease; 
 the inhibitor moiety is a moiety that selectively binds HCV protease; 
 the linker is a bivalent group resulting from the reaction of Cys159 of HCV protease with a L-Y warhead group, wherein
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e  groups; and
 each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C 1-6  aliphatic substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a bivalent C 1-6  unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 Z is hydrogen or C 1-6  aliphatic substituted with oxo, halogen, NO 2 , or CN. 
 
 
 
 
     
     
         49 . The conjugate according to  claim 48 , wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by —C(O)—; and   Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.   
     
     
         50 . The conjugate according to  claim 48 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one additional methylene unit_of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. 
     
     
         51 . The conjugate according to  claim 49 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—. 
     
     
         52 . The conjugate according to  claim 48 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)C(═CH 2 )CH 2 —, or —CH 2 NRC(O)CH═CH—; wherein R is H or optionally substituted C 1-6  aliphatic; and Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
     
     
         53 . The conjugate according to  claim 52 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)C(═CH 2 )CH 2 —, or —CH 2 NHC(O)CH═CH—. 
     
     
         54 . The conjugate according to  claim 48 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by —C(O)—. 
     
     
         55 . The conjugate according to  claim 48 , wherein -L-Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         56 . A conjugate of the formula: Cys159-linker-inhibitor moiety, wherein:
 the Cys159 is Cys159 of HCV protease;   the inhibitor moiety is a moiety that selectively binds HCV protease;   the linker is a bivalent group resulting from the reaction of Cys159 of HCV protease with a L-Y warhead group, wherein   L-Y is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         57 . A conjugate of the formula: Cys16-linker-inhibitor moiety, wherein:
 the Cys16 is Cys16 of HCV protease;   the inhibitor moiety is a moiety that selectively binds HCV protease;   the linker is a bivalent group resulting from the reaction of Cys16 of HCV protease with a L-Y warhead group, wherein
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e  groups; and
 each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C 1-6  aliphatic substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a bivalent C 1-6  unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 Z is hydrogen or C 1-6  aliphatic substituted with oxo, halogen, NO 2 , or CN. 
 
 
   
     
     
         58 . The conjugate according to  claim 57 , wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by —C(O)—; and   Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.   
     
     
         59 . The conjugate according to  claim 57 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one additional methylene unit_of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. 
     
     
         60 . The conjugate according to  claim 58 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—. 
     
     
         61 . The conjugate according to  claim 57 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)C(═CH 2 )CH 2 —, or —CH 2 NRC(O)CH═CH—; wherein R is H or optionally substituted C 1-6  aliphatic; and Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
     
     
         62 . The conjugate according to  claim 61 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)C(═CH 2 )CH 2 —, or —CH 2 NHC(O)CH═CH—. 
     
     
         63 . The conjugate according to  claim 57 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by —C(O)—. 
     
     
         64 . The conjugate according to  claim 57 , wherein -L-Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         65 . A conjugate of the formula: Cys16-linker-inhibitor moiety, wherein:
 the Cys16 is Cys16 of HCV protease;   the inhibitor moiety is a moiety that selectively binds HCV protease;   the linker is a bivalent group resulting from the reaction of Cys16 of HCV protease with a L-Y warhead group, wherein   L-Y is selected from the group consisting of: