Novel peptides as NS3-serine protease inhibitors of hepatitis C virus

Abstract

The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

1 . A compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y maybe optionally substituted with X 11  or X 12 ;  
 X 11  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X 11  may be additionally optionally substituted with X 12 ;  
 X 12  is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X 12 ;  
 R 1  is COR 5 , wherein R 5  is COOR 8 , CONR 9 R 10 CF 3 , C 2 F 5 , C 3 F 7 , CF 2 R 6 , R 6 , wherein R 6 , R 8 , R 9  and R 10  are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R 1′ )] p COOR 11 , [CH(R 1′ )] p CONR 12 R 13 , [CH(R 1′ )] p SO 2 R 11 , [CH(R 1′ )] p COR 11 , [CH(R 1′ )] p CH(OH)R 11 , CH(R 1′ )CONHCH(R 2′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )R′, CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ )COOR 11  and CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ ) CONR 12 R 13 , wherein R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 11 , R 12 , R 13 , and R′ are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl;  
 Z is selected from O, N, CH or CR;  
 W may be present or absent, and if W is present, W is selected from C═O, C═S, C(═N—CN), or SO 2 ;  
 Q may be present or absent, and when Q is present, Q is CH, N, P, (CH 2 ) p , (CHR) p , (CRR′) p , O, NR, S, or SO 2 ; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L;  
 A is O, CH 2 , (CHR) p, (CHR—CHR′) p, (CRR′) p, NR, S, or SO 2 ;  
 E is CH, N, CR, or a double bond towards A, L or G;  
 G may be present or absent, and when G is present, G is (CH 2 ) p , (CHR) p, or (CRR′) p ; and when G is absent, J is present and E is directly connected to the carbon atom in Formula I as G is linked to;  
 J may be present or absent, and when J is present, J is (CH 2 ) p , (CHR) p, or (CRR′) p , SO 2 , NH, NR or O; and when J is absent, G is present and E is directly linked to N shown in Formula I as linked to J;  
 L may be present or absent, and when L is present, L is CH, CR, O, S or NR; and when L is absent, then M may be present or absent; and if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E;  
 M may be present or absent, and when M is present, M is O, NR, S, SO 2 , (CH 2 ) p, (CHR) p (CHR—CHR′) p , or (CRR′) p;  
 p is a number from 0 to 6; and  
 R, R′, R 2 , R 3  and R 4  are independently selected from the group consisting of H; C 1 -C 10  alkyl; C 2 -C 10  alkenyl; C 3 -C 8  cycloalkyl; C 3 -C 8  heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino other than for R 2 , amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate;  
 further wherein said unit N-C-G-E-L-J-N represents a five-membered or six-membered cyclic ring structure with the proviso that when said unit N-C-G-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, G, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring;  
 provided that in Formula I when W is C═O and the moiety:  
                     
 represents the structure:  
                     
 where R 30  and R 31  are independently H, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryalkyl, with R 30  and R 31  being optionally substituted with 1-3 R 33  substituents selected from alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocycylalkyl, keto, hydroxy, amino, alkylamino, alkanoylamino, aroylalmino, aralkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, formyl, acetyl, sulfonyl, or sulfonamido, wherein said R 33  substituents can be optionally substituted with alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, amino, alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, fomryl, sulfonyl or sulfonamido;  
 α is a bond, —C(H)(R 34 )—, —O—, —S—, or —N(R 35 )—, where R 34  is H, alkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl and is optionally substituted with 1-3 R 33  substituents, and R 35  is H, alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkanoyl, —C(O)R 36 , —SO 2 R 36 , or carboxamido and is optionally substituted with 1-3 R 33  substituents, or R 35  and y together with the atoms to which they are bound, form a nitrogen containing mono- or bicyclic ring system optionally substituted with 1-3 R 33  substituents, and R 36  is alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl;  
 β is a bond, —CH2-, —C(O)—, —C(O)C(O)—, —S(O)—, —S(O) 2 —, OR—S(O)R 34 ;  
 γ is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —OR 37  or —N(R 37 ) 2 , wherein any carbon atom is optionally substituted with R 33 , wherein R 37  is independently H, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroaralkyl, wherein any carbon of R 37  is optionally substituted with R 33 ;  
 then R 10  is H and R 8  and R 9  are independently selected from the group consisting of CH(R 1′ )CONHCH(R 2′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )R′, CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ )COOR 11  and CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ )CONR 12 R 13 ; and  
 provided that the proline at the P2 position is modified, wherein the P2 position is the position corresponding to the second amino acid from the keto amide group.  
 
   
   
       2 . The compound of  claim 1 , wherein R 1  is COCONR 9 R 10 , and R 9  is H, R 10  is H, R 4 , CH(R 1′ )COOR 11 , CH(R 1′ )CH(R 1′ )COOR 11 , CH(R 1′ )CONR 12 R 13 , CH(R 1′ )CH(R 1′ )CONR 12 R 13 , CH(R 1′ )CH(R 1′ )SO 2 R 11 , CH(R 1′ )CH(R 1′ )SO 2 NR 12 R 13 , CH(R 1′ )CH(R 1′ )COR 11 , CH(R 1′ )CONHCH(R 2′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ ) CONR 12 R 13 , or CH(R 1′ )CONHCH(R 2′ )(R 1′ ), wherein R 14  is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl; wherein R 1  is H or alkyl, and R 2′  is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, piperidyl or pyridyl; and 
 wherein R 11  is H, methyl, ethyl, allyl, tert-butyl, benzyl, α-methylbenzyl, α,α-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl;    R′ is hydroxymethyl or CH 2 CONR 12 R 13 ;    R 2′  is independently selected from the group consisting of:                          wherein:    U 1  and U 2  maybe same or different and are selected from H, F, CH 2 COOH, CH 2 COOMe, CH 2 CONH 2 , CH 2 CONHMe, CH 2 CONMe 2 , azido, amino, hydroxyl, substituted amino, substituted hydroxyl;    U 3  and U 4  maybe same or different and are selected from O and S;    U 5  is selected from the moieties consisting of alkyl sulfonyl, aryl sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or a combination thereof;    and NR 12 R 13  is selected from the group consisting of:                          wherein U 6  is H, OH, or CH 2 OH, and    R 14  is selected from the group consisting of: H, Me, Et, n-propyl, methoxy, cyclopropyl, n-butyl, 1-but-3-ynyl, benzyl, α-methylbenzyl, phenethyl, allyl, 1-but-3-enyl, OMe, cyclopropylmethyl.    
   
   
       3 . The compound of  claim 2 , wherein R 2  is selected from the group consisting of the following moieties:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       4 . The compound of  claim 3 , wherein R 3  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 31 =OH or O-alkyl; 
 Y 19  is selected from the following moieties:  
                     
 and Y 20  is selected from the following moieties:  
                     
 
   
   
       5 . The compound of  claim 4 , wherein R 3  is selected from the group consisting of the following moieties:  
     
       
         
         
             
             
         
       
     
   
   
       6 . The compound of  claim 5 , wherein Z is N and R 4  is H.  
   
   
       7 . The compound of  claim 6 , wherein W is C═O.  
   
   
       8 . The compound of  claim 7 , wherein Y is selected from the following moieties:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: 
 Y 11  is selected from H, COOH, COOEt, OMe, Ph, OPh; NHMe, NHAc, NHPh, CH(Me) 2 , 1-triazolyl, 1-imidazolyl, and NHCH 2 COOH;  
 Y 12  is selected from H, COOH, COOMe, OMe, F, Cl, or Br;  
 Y 13  is selected from the following moieties:  
                     
 Y 14  is selected from MeSO 2 , Ac, Boc, iBoc, Cbz, or Alloc;  
 Y 15  and Y 16  are independently selected from alkyl, aryl, heteroalkyl, and heteroaryl;  
 Y 17  is CF 3 , NO 2 , CONH 2 , OH, COOCH 3 , OCH 3 , OC 6 H 5 , C 6 H 5 , COC 6 H 5 , NH 2 , or COOH; and  
 Y 18  is COOCH 3 , NO 2 , N(CH 3 ) 2 , F, OCH 3 , CH 2 COOH, COOH, SO 2 NH 2 , or NHCOCH 3 .  
 
   
   
       9 . The compound of  claim 8 , wherein Y is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein:  
       Y 17 =CF 3 , NO 2 , CONH 2 , OH, NH 2 , or COOH;  
       Y 18 =F, COOH,  
     
   
   
       10 . The compound of  claim 9 , wherein Y is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       11 . The compound of  claim 10 , wherein L and M are absent, and J is directly linked to E.  
   
   
       12 . The compound of  claim 10 , wherein L, J and M are absent and E is directly linked to N.  
   
   
       13 . The compound of  claim 10 , wherein G and M are absent.  
   
   
       14 . The compound of  claim 10 , wherein the moiety:  
     
       
         
         
             
             
         
       
     
   
   
       15 . The compound of  claim 14 , wherein structure a is selected from the following structures:  
     
       
         
         
             
             
         
       
     
   
   
       16 . The compound of  claim 14 , wherein structure a is:  
     
       
         
         
             
             
         
       
     
     wherein R 20  is selected from the following structures:  
     
       
         
         
             
             
         
       
     
   
   
       17 . The compound of  claim 14 , wherein structure a is:  
     
       
         
         
             
             
         
       
     
     wherein R 21  and R 22  may be the same or different and are independently selected from the following structures:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 14 , wherein structure a is selected from the following structures:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       19 . The compound of  claim 10 , wherein:  
     
       
         
         
             
             
         
       
     
     wherein Q may be present or absent, and if Q is absent, M is directly linked to A.  
   
   
       20 . The compound of  claim 19 , wherein structure b is selected from the following structures:  
     
       
         
         
             
             
         
       
     
   
   
       21 . The compound of  claim 10 , wherein:  
     
       
         
         
             
             
         
       
     
     wherein G and J are independently selected from the group consisting of (CH 2 ) p , (CHR) p , (CHR—CHR′) p , and (CRR′) p ; A and M are independently selected from the group consisting of O, S, SO 2 , NR, (CH 2 ) p, (CHR) p , (CHR—CHR′) p , and (CRR′) p ; and Q is CH 2 , CHR, CRR′, NH, NR, O, S, SO 2 , NR, (CH 2 ) p, (CHR) p , and (CRR′) p .  
   
   
       22 . The compound of  claim 21 , wherein structure c is selected from the following structures:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       23 . The compound of  claim 10 , wherein:  
     
       
         
         
             
             
         
       
     
     is selected from the following structures:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       24 . The compound of  claim 23 , wherein:  
     
       
         
         
             
             
         
       
     
     is selected from the following structures:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       25 . A pharmaceutical composition comprising as an active ingredient a compound of  claim 1 .  
   
   
       26 . The pharmaceutical composition of  claim 25  for use in treating disorders associated with HCV.  
   
   
       27 . The pharmaceutical composition of  claim 25  additionally comprising a pharmaceutically acceptable carrier.  
   
   
       28 . The pharmaceutical composition of  claim 27 , additionally containing an antiviral agent.  
   
   
       29 . The pharmaceutical composition of  claim 28 , still additionally containing an interferon.  
   
   
       30 . The pharmaceutical composition of  claim 29 , wherein said antiviral agent is ribavirin and said interferon is α-interferon or pegylated interferon.  
   
   
       31 . A method of treating disorders associated with the HCV, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of a compound of  claim 1 .  
   
   
       32 . The method of  claim 31 , wherein said administration is oral or subcutaneous.  
   
   
       33 . The use of a compound of  claim 1  for the manufacture of a medicament to treat disorders associated with the HCV.  
   
   
       34 . A method of preparing a pharmaceutical composition for treating the disorders associated with the HCV, said method comprising bringing into intimate contact a compound of  claim 1  and a pharmaceutically acceptable carrier.