Aza-peptide macrocyclic hepatitis c serine protease inhibitors

Abstract

The present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt, ester, or prodrug, thereof, which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 A is selected from: 
 (a) hydrogen;  
 (b) —(C═O)—O—R 1 , where R 1  is selected from: 
 1. hydrogen,  
 2. C 1 -C 6  alkyl,  
 3. C 3 -C 12  cycloalkyl,  
 4. substituted C 3 -C 12  cycloalkyl,  
 5. aryl,  
 6. substituted aryl,  
 7. heteroaryl,  
 8. substituted heteroaryl,  
 9. heterocycloalkyl,  
 10. substituted heterocycloalkyl, or  
 11. —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 
 (c) —(C═O)—R 2 , where R 2  is selected from: 
 1. —R 1 , where R 1  is as previously defined,  
 2. alkylamino,  
 3. dialkyl amino,  
 4. arylamino, or  
 5. diarylamino;  
 
 (d) —C(═O)—NH—R 2 , where R 2  is as previously defined;  
 (e) —C(═S)—NH—R 2 , where R 2  is as previously defined;  
 (f) —S(O) 2 —R 2 , where R 2  is as previously defined;  
 
 B is hydrogen or C 1 -C 6  alkyl;  
 G is 
 (a) —OH;  
 (b) —O—(C 1 -C 12  alkyl);  
 (c) —NH—R 2 , where R 2  is as previously defined;  
 (d) —NHS(O) 2 —R 1 , where R 1  as previously defined;  
 (e) —(C═O)—R 2 , where R 2  as previously defined;  
 (f) —(C═O)—O—R 1 , where R 1  as previously defined; or  
 (g) —(C═O)—NH—R 2 , where R 2  as previously defined;  
 
 M is absent or selected from: 
 (a) —O—;  
 (b) —S—;  
 (c) —NH—; or  
 (d) —NR 1 —, wherein R 1  is previously defined;  
 
 Q is selected from: 
 (a) aryl;  
 (b) substituted aryl;  
 (c) heteroaryl;  
 (d) substituted heteroaryl;  
 (e) heterocycloalkyl; or  
 (f) substituted heterocycloalkyl;  
 
 j=0, 1, 2, 3, or 4;  
 n=0, 1, or 2; and  
 s=0, 1, or 2.  
 
     
     
         2 . A compound of formula I, wherein M is absent and Q is  
       
         
           
           
               
               
           
         
       
       wherein X and Y are each independently selected from: 
 a) —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 b) —C 2 -C 6  alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 c) —C 2 -C 6  alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 d) aryl;  
 e) substituted aryl;  
 f) heteroaryl;  
 g) substituted heteroaryl;  
 h) heterocycloalkyl; or  
 i) substituted heterocycloalkyl;  
 or in the alternative, X and Y are taken together with the carbons to which they are attached to for a cyclic moiety selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 
     
     
         3 . A compound of formula I, wherein M is absent and Q is  
       
         
           
           
               
               
           
         
       
       wherein Y is selected from: 
 a) —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 b) —C 2 -C 6  alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 c) —C 2 -C 6  alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 d) aryl;  
 e) substituted aryl;  
 f) heteroayl;  
 g) substituted heteroaryl;  
 h) heterocycloalkyl; or  
 i) substituted heterocycloalkyl;  
 
     
     
         4 . A compound of formula I, wherein M is absent and Q is  
       
         
           
           
               
               
           
         
       
       wherein X, Y, and Z are each independently selected from: 
 a) —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 b) —C 2 -C 6  alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 c) —C 2 -C 6  alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 d) aryl;  
 e) substituted aryl;  
 f) heteroaryl;  
 g) substituted heteroaryl;  
 h) heterocycloalkyl; or  
 i) substituted heterocycloalkyl;  
 or in the alternative, X and Y or Y and Z are taken together with the carbons to which they are attached to for a cyclic moiety selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 
     
     
         5 . A compound of formula I, wherein M is absent and Q is  
       
         
           
           
               
               
           
         
       
       wherein W, X, Y, and Z are each independently selected from: 
 a) —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 b) —C 2 -C 6  alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 c) —C 2 -C 6  alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 d) aryl;  
 e) substituted aryl;  
 f) heteroaryl;  
 g) substituted heteroaryl;  
 h) heterocycloalkyl; or  
 i) substituted heterocycloalkyl;  
 or in the alternative, W and X, X and Y, or Y and Z are taken together with the carbons to which they are attached to for a cyclic moiety selected from:  
 aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 
     
     
         6 . A compound of formula I, wherein M is absent and Q is  
       
         
           
           
               
               
           
         
       
       wherein X, Y, and Z are each independently selected from: 
 a) —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 b) —C 2 -C 6  alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 c) —C 2 -C 6  alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 d) aryl;  
 e) substituted aryl;  
 f) heteroaryl;  
 g) substituted heteroaryl;  
 h) heterocycloalkyl; or  
 i) substituted heterocycloalkyl;  
 or in the alternative, Y and Z are taken together with the carbons to which they are attached to for a cyclic moiety selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 
     
     
         7 . A compound of formula I, wherein M is —O— and Q is  
       
         
           
           
               
               
           
         
       
       wherein 
 L is M, where M is as previously defined;  
 X, Y, and Z are each independently selected from: 
 a) —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 b) —C 2 -C 6  alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 c) —C 2 -C 6  alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 d) aryl;  
 e) substituted aryl;  
 f) heteroaryl;  
 g) substituted heteroaryl;  
 h) heterocycloalkyl; or  
 i) substituted heterocycloalkyl;  
 or in the alternative, X and Y are taken together with the carbons to which they are attached to for a cyclic moiety selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 
 
     
     
         8 . A compound of formula I, wherein M is —O— and Q is  
       
         
           
           
               
               
           
         
       
       wherein 
 L is M, where M is as previously defined;  
 X, Y, and Z are each independently selected from: 
 a) —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 b) —C 2 -C 6  alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 c) —C 2 -C 6  alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 d) aryl;  
 e) substituted aryl;  
 f) heteroaryl;  
 g) substituted heteroaryl;  
 h) heterocycloalkyl; or  
 
 i) substituted heterocycloalkyl;  
 or in the alternative, X and Y are taken together with the carbons to which they are attached to for a cyclic moiety selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; or  
 
     
     
         9 . A compound of formula I, wherein M is —O— and Q is  
       
         
           
           
               
               
           
         
       
       wherein 
 L is M, where M is as previously defined;  
 X, Y, and Z are each independently selected from: 
 a) —C 1 -C 6  alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 b) —C 2 -C 6  alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 c) —C 2 -C 6  alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 d) aryl;  
 e) substituted aryl;  
 f) heteroaryl;  
 g) substituted heteroaryl;  
 h) heterocycloalkyl; or  
 i) substituted heterocycloalkyl;  
 or in the alternative, X and Y are taken together with the carbons to which they are attached to for a cyclic moiety selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl.  
 
 
     
     
         10 . A compound according to  claim 1  represented by formula I selected from: 
 Compound of formula I, wherein A=Boc, B=hydrogen, G=OEt, M=—O—, Q=hydrogen, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OEt, M=—O—, Q=—S(O) 2 CH 3 , and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G—OEt, M=—O—, Q=2-thiophenyl-quinolin-4-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=2-thiophenyl-quinolin-4-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OEt, M is absent, Q=4,5-diphenyltriazol-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=4,5-di-thiophenyltriazol-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=4-(thiophen-3-yl)-5-(p-methoxyphenyl)triazol-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=4-(n-butyl)-5-phenyltriazol-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=5-(3-methoxyphenyl)tetrazol-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=5-(4-pyridyl)tetrazol-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=5-(3,4-dichlorophenyl)tetrazol-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=5-(3-bromo-4-methoxy-phenyl)tetrazol-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=4-(4-fluoro-phenyl)-6-phenyl-1H-pyridazin-3-on-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M is absent, Q=6-phenyl-5-piperidin-1-yl-1H-pyridazin-3-on-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=7-Methoxy-2-phenyl-quinolin-4-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=7-Methoxy-2-thiazolyl-quinolin-4-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=7-Methoxy-2-thiophenyl-quinolin-4-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=7-Methoxy-3-(thiophen-2-yl)-1H-quinoxalin-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=6-Methoxy-3-(thiophen-2-yl)-1H-quinoxalin-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=7-Methoxy-3-[2-(thiophen-2-yl)vinyl]-1H-quinoxalin-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=6-Methoxy-3-[2-(thiophen-2-yl)vinyl]-1H-quinoxalin-2-yl, and j=n=s=1;    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=7-Methoxy-3-[2-(pyridin-2-yl)vinyl]-1H-quinoxalin-2-yl, and j=n=s=1; or    Compound of formula I, wherein A=Boc, B=hydrogen, G=OH, M=—O—, Q=7-methoxy-3-[2-(pyridin-2-yl)vinyl]-1H-quinoxalin-2-yl, and j=n=s=1    
     
     
         11 . A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.  
     
     
         12 . A method of treating a hepatitis C viral infection in a mammal, comprising administering to the mammal an anti-hepatitis C virally effective amount of a pharmaceutical composition according to  claim 11 .  
     
     
         13 . A method of inhibiting the replication of hepatitis C virus, the method comprising supplying a hepatitis C viral NS3 protease inhibitory amount of the pharmaceutical composition of  claim 11 .  
     
     
         14 . The method of  claim 13  further comprising administering concurrently an additional anti-hepatitis C virus agent.  
     
     
         15 . The method of  claim 14 , wherein said additional anti-hepatitis C virus agent is selected from the group consisting of: α-interferon, β-interferon, ribavarin, and adamantine.  
     
     
         16 . The method of  claim 14 , wherein said additional anti-hepatitis C virus agent is an inhibitor of another target in the hepatitis C virus life cycle, which is selected from the group consisting of: helicase, polymerase, metalloprotease, and IRES.  
     
     
         17 . A process of making compounds of formula I:  
       
         
           
           
               
               
           
         
         wherein A, B, G, M, Q, j, n, and s are as defined in  claim 1 , comprising the steps of:  
         (a) reacting a compound of formula (A):  
         
           
             
             
                 
                 
             
           
         
          wherein A, B, and j is as defined in  claim 1  with a hydroxyproline ethyl ester derivative of formula (B): in the presence of a base to form a compound of formula (C):  
         
           
             
             
                 
                 
             
           
         
          wherein A, B, and j are as defined in  claim 1  and T is selected from OH, OMe, or OEt;  
         (b) reacting a compound of formula B with a compound of formula (D):  
         
           
             
             
                 
                 
             
           
         
          wherein G is as defined in  claim 1 , under standard amide formation conditions to form a compound of formula (E):  
         
           
             
             
                 
                 
             
           
         
          wherein A, B, G, M, Q, and j are as defined in  claim 1;  and  
         (c) reacting compound of formula E with a Ruthenium-based catalyst.