Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease

Abstract

The present invention relates to compounds, methods and pharmaceutical compositions for inhibiting proteases, particularly serine proteases, and more particularly HCV NS3 proteases. The compounds, and the compositions and methods that utilize them, can be used, either alone or in combination to inhibit viruses, particularly HCV virus.

1 - 37 . (canceled) 
     
     
         38 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         G 1  is thiol, hydroxyl, thiomethyl, alkenyl, alkynyl, trifluoromethyl, C 1-2  alkoxy, C 1-2  alkylthio, or C 1-3  alkyl, wherein the C 1-3  alkyl group is optionally substituted with thiol, hydroxyl, thiomethyl, alkenyl, alkynyl, trifluoromethyl, C 1-2  alkoxy, or C 1-2  alkylthio; 
         W 1  is: 
       
       
         
           
           
               
               
           
         
         G 2  is alkyl, aryl, aralkyl, or a mono-, bi- or tricyclic heterocycle, optionally substituted with 1-3 groups selected from alkyl, alkenyl, alkynyl, aralkyl, alkoxy, alkenoxy, aryloxy, heterocyclyl, heterocyclylalkyl, aralkoxy, heterocyclylalkoxy, oxo, hydroxy, amino, alkanoylamino, alkoxycarbonylamino, ureido, carboxy, heterocyclyloxyalkyl, aryloxyalkyl, heterocyclylcaronyl, aroyl, arylsulfonyl, heterocyclylsulfonyl, heterocyclylsulfonylamino, arylsulfonamido, aralkylsulfonamido, heterocyclylalkanoyl, carboxyalkyl, carboxyamidoalkyl, alkanesulfonyl, sulfonamido, halo, cyano, or haloalkyl; 
         G 4  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, or heterocyclylthioalkyl; 
         Q 1  is hydroxy, alkoxy, or aryloxy, an oxygen atom and together with the boron to which they are bound, form a 5-7 membered ring, wherein the ring atoms are carbon, nitrogen or oxygen. 
         U is hydrogen, G 9 -C(O)—, G 9 -SO 2 —, G 9 -C(O)—C(O)—, (G 9 ) 2 -N—C(O)—C(O)—, (G 9 ) 2 -N—SO 2 —, (G 9 ) 2 N—C(O)—, or G 9 -O—C(O)—; 
         G 9  is hydrogen, alkyl, carboxyalkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, or heterocyclyalkenyl optionally substituted with 1-3 groups selected from alkyl, alkenyl, aralkyl, alkoxy, alkenoxy, aryloxy, heterocyclyl, carboxyalkyl, carboxyamidoalkyl, alkylsulfonyl, or sulfonamido; or two G 9  groups, together with the nitrogen atom to which they are bound, form a 4-10 membered nitrogen containing monocyclic or bicyclic saturated or partially unsaturated ring system, wherein 1-2 of the atoms forming the ring are N, S, or O and the other atoms forming the ring are C; wherein the ring system is optionally substituted by one or two groups selected from alkyl, alkenyl, aralkyl, alkoxy, alkenoxy, aryloxy, aralkoxy, heterocyclyl, keto, hydroxy, amino, alkanoyl amino, carboxy, carboxyalkyl, carboxamidoalkyl, sulfonyl, or sulfonamide; 
         E 4  is a bond; 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
         G 13  is cycloalkylalkyl, aralkyl, heterocycylalkyl, aralkoxyalkyl, heterocycylalkoxyalkyl, aralkylthioalkyl, or heterocycylalkylthioalkyl, optionally substituted by 1-2 alkyl, alkenyl, aralkyl, alkoxy, alkenoxy, aryloxy, aralkoxy, heterocyclyl, oxo, hydroxy, amino, alkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl, sulfonyl, or sulfonamido groups. 
         G 14  is hydrogen, alkyl, alkenyl, hydroxy, alkoxy, or —CH 2 -G 8 , wherein G 8  is aryl, aralkyl, carbocyclyl or heterocyclyl, where the ring portion each aryl, aralkyl, or heterocycle is optionally substituted with 1-3 groups selected from alkyl, alkenyl, aralkyl, alkoxy, alkenoxy, aryloxy, heterocyclyl, heterocyclylalkyl, aralkoxy, heterocyclylalkoxy, oxo, hydroxy, amino, alkanoylamino, alkoxycarbonylamino, ureido, carboxy, carboxyalkyl, carboxyamidoalkyl, alkanesulfonyl, sulfonamido, halo, cyano, or haloalkyl; or 
         when E 4  is: 
       
       
         
           
           
               
               
           
         
         G 13  and G 14 , together with the atoms to which they are bound (carbon and nitrogen, respectively), form a nitrogen-containing heterocyclic ring system having 4-7 members, which optionally contains one to two additional heteroatoms, wherein the resulting ring system is optionally fused with an additional carbocyclic or heterocyclic ring system to form a bicyclic ring system comprising 7-11 atoms; and wherein the monocyclic or bicyclic ring system is optionally substituted by one or two groups selected from oxo, hydroxy, alkyl, alkenyl, aryl, aralkyl, alkyl, alkenoxy, aryloxy, aralkyloxy, halo, or nitro; 
         each Q 3  is halogen, nitro, cyano, alkyl, alkenyl, aralkyl, alkoxy, alkenoxy, aryloxy, aralkoxy, heterocyclyl, heterocyclylalkyl, hydroxy, amino, alkylamino, alkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonamido, arylsulfonamido, or aralkylsulfonamido, wherein any alkyl, alkenyl, aryl, or heterocyclyl groups is optionally substituted with 1-3 groups selected from keto, hydroxy, nitro, cyano, halo, amino, alkyl, alkoxy, or alkylthio; wherein Q 3 , when not bonded to a specific atom, may be bonded to any substitutable atom; 
         Q 4  is independently alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, alkanoyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, wherein any of said alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl groups is optionally substituted with one or more groups independently selected from keto, hydroxy, nitro, cyano, halo, amino, alkyl, alkoxy, or alkylthio.; 
         Q 5  is aryl or an aromatic heterocycle, wherein: 
         the aryl or aromatic heterocycle is monocyclic, bicyclic, or tricyclic having 5-14 atoms, and is optionally substituted with 1-3 groups selected from hydroxy, nitro, cyano, halo, amino, alkyl, alkoxy, alkanoyl, alkylamino, or alkylthio; 
         E 5  is a bond or 
       
       
         
           
           
               
               
           
         
         wherein G 15  is alkyl, alkenyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, carboxyalkyl, or carboxamidoalkyl, where the ring of any aralkyl or heterocyclylalkyl group is optionally substituted with 1-2 alkyl, alkenyl, aralkyl, alkoxy, alkenoxy, aryloxy, aralkoxy, heterocyclyl, oxo, hydroxy, amino, alkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl, sulfonyl, or sulfonamido groups; 
         E 6  is a bond or 
       
       
         
           
           
               
               
           
         
         wherein G 16  is hydrogen, alkyl, alkenyl, aralkyl, or cycloalkylalkylyl; 
         E 7  is a bond or 
       
       
         
           
           
               
               
           
         
         wherein G 17  is alkyl optionally substituted with carboxy; wherein the alkyl is preferably C 1-3  alkyl; 
         E 8  is a bond or 
       
       
         
           
           
               
               
           
         
         wherein G 18  is alkyl optionally substituted with carboxy; wherein the alkyl is preferably C 1-3  alkyl; and 
         each Z 1  is independently 0 or H 2  provided that no more than two Z 1  groups is H 2  in a given compound. 
       
     
     
         39 . The compound of  claim 38 , wherein at least one substituent is defined as follows:
 G 1  is vinyl, acetylenyl, —CH 3 , —CF 3 , —CH 2 CH 3 , —CH 2 CF 3 , —SCH 3 , —SH, —CH 2 SH, or —CH 2 OH;   G 13  is C 3-6  branched alkyl or G 13  and G 14 , together with the atoms to which they are bound (carbon and nitrogen, respectively), form a nitrogen-containing heterocyclic ring system having 4-7 members, which optionally contains one to two additional heteroatoms, wherein the monocyclic or bicyclic ring system is optionally substituted by one or two groups selected from oxo, hydroxy, alkyl, alkenyl, aryl, aralkyl, alkyl, alkenoxy, aryloxy, aralkyloxy, halo, or nitro; and;   Z 1  is O.   
     
     
         40 . The compound of  claim 39 , wherein G 1  is —SH, —CH 2 SH, —CF 3 , or —CF 2 CF 3 . 
     
     
         41 . The compound of  claim 40 , wherein G 1  is —SH or —CF 3 . 
     
     
         42 . The compound of  claim 38 , wherein W 1  is: 
       
         
           
           
               
               
           
         
       
       each R 1  is hydroxy, alkoxy, or aryloxy, or each
 R 1  is an oxygen atom and together with the boron, to which they are each bound, form a 5-7 membered ring, wherein the ring atoms are carbon, nitrogen, or oxygen; 
 each R 2  is independently hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroaralkyl, or two R 2  groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a 5-7 membered monocyclic heterocyclic ring system; wherein any R 2  carbon atom is optionally substituted with J; 
 J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, keto, hydroxy, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, formyl, acyl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J 1  groups; and 
 J 1  is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, amino, alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, formyl, sulfonyl, or sulfonamide. 
 
     
     
         43 . A pharmaceutically acceptable composition comprising:
 a) a compound according to  claims 38 - 42  in an amount effective to inhibit HCV NS3 protease; and   b) a pharmaceutically suitable carrier.   
     
     
         44 . A method of inhibiting serine protease activity in a patient, comprising the step of administering to said patient a compound according to  claims 38 - 42 . 
     
     
         45 . The method of  claim 44 , wherein the serine protease is HCV NS3 protease. 
     
     
         46 . A method of treating or preventing a hepatitis C viral infection in a patient, comprising the step of administering to said patient a compound according to  claims 38 - 42 . 
     
     
         47 . The method of  claim 46 , wherein the compound is formulated together with a pharmaceutically suitable carrier into a pharmaceutically acceptable composition.