Macrocyclic compounds as inhibitors of viral replication

Abstract

The embodiments provide compounds of the general formulas I-XIX, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         (a) Z is a group configured to hydrogen bond to an NS3 protease His57 imidazole moiety and to hydrogen bond to a NS3 protease Gly137 nitrogen atom; 
         (b) P 1 ′ is a group configured to form a non-polar interaction with at least one NS3 protease S1′ pocket moiety selected from the group consisting of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42, and Phe43; 
         (c) L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur; 
         (d) P 2  is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; P 2  being positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81; 
         (e) the dashed line represents an optional double bond; 
         (f) R 5  is selected from the group consisting of H, C(O)NR 6 R 7  and C(O)OR 8 ; 
         (g) R 6  and R 7  are each independently H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, hydroxyl-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 6  and R 7  are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and 
         (h) R 8  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, or phenyl; or R 8  is C 6 or 10  aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 8  is C 1-6  alkyl optionally substituted with up to 5 fluoro groups; or R 8  is a tetrahydrofuran ring linked through the C 3  or C 4  position of the tetrahydrofuran ring; or R 8  is a tetrahydropyran ring linked through the C 4  position of the tetrahydropyran ring. 
       
     
     
         2 . The compound of  claim 1 , wherein the C 13 -C 14  double bond is cis. 
     
     
         3 . The compound of  claim 1 , wherein the C 13 -C 14  double bond is trans. 
     
     
         4 . The compound of  claim 1 , wherein P 2  is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 
     
     
         5 . The compound of  claim 1 , wherein P 2  is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein L consists of from 1 to 5 atoms selected from the group consisting of nitrogen, hydrogen and sulfur. 
     
     
         7 . The compound of  claim 1 , wherein L consists of from 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. 
     
     
         8 . The compound of  claim 7 , wherein L is selected from the group consisting of —OCH 2 — and —NHCH 2 —. 
     
     
         9 . The compound of  claim 7 , wherein L is selected from the group consisting of —CH═CH— and —C≡C—. 
     
     
         10 . The compound of  claim 7 , wherein L is selected from the group consisting of —SCH 2 —, —SO 2 —, and —CH 2 SO—. 
     
     
         11 . The compound of  claim 1 , wherein L comprises a —W—C(═V)— group, where V and W are each individually selected from O, S or NH. 
     
     
         12 . The compound of  claim 11 , wherein:
 L comprises a —OC(═O)— group or —NHC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and   Z consists of 5 atoms selected from oxygen, nitrogen, sulfur and hydrogen.   
     
     
         13 . The compound of  claim 12 , wherein:
 L is selected from the group consisting of —OC(═O)— and —NHC(═O)—;   P 2  is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and   Z is —NHSO 2 —.   
     
     
         14 . The compound of  claim 13 , wherein P 2  is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 12 , wherein:
 L comprises a —OC(═O)— group;   P 2  is substituted heterocyclic;   R 5  is C(O)OR 8 ; and   R 8  is C 1-6  alkyl.   
     
     
         16 . The compound of  claim 11 , wherein:
 L comprises a —OC(═O)— group or —NHC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and   P 1 ′ is alkyl, alkenyl, or aryl.   
     
     
         17 . The compound of  claim 11 , wherein:
 L comprises a —OC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and   P 1 ′ is methyl, propyl, butyl, cyclopropyl or phenyl.   
     
     
         18 . The compound of  claim 17 , wherein:
 L is —OC(═O)—;   P 2  is a substituted heterocyclic;   R 5  is C(O)OR 8 ; and   R 8  is C 1-6  alkyl.   
     
     
         19 . The compound of  claim 1 , wherein L is selected from the group consisting of ester, amide, carboxy, carbamate, thioester, and thioamide. 
     
     
         20 . The compound of  claim 1 , wherein P 2  is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81. 
     
     
         21 . The compound of  claim 20 , wherein L consists of from 1 to 5 atoms selected from the group consisting of carbon and oxygen. 
     
     
         22 . The compound of  claim 20 , wherein P 2  is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 
     
     
         23 . The compound of  claim 1  of the formula 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 23 , wherein L is selected from the group consisting of —WC(═V)—NH— and —WC(═V)—O—, where V and W are each individually selected from O, S or NH. 
     
     
         25 . The compound of  claim 23 , wherein the C 13 -C 14  double bond is cis. 
     
     
         26 . The compound of  claim 23 , wherein the C 13 -C 14  double bond is trans. 
     
     
         27 . The compound of  claim 23 , wherein P 2  is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 
     
     
         28 . The compound of  claim 23 , wherein L consists of from 1 to 5 atoms selected from the group consisting of carbon and oxygen. 
     
     
         29 . The compound of  claim 23 , wherein L consists of from 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. 
     
     
         30 . The compound of  claim 29 , wherein L is selected from the group consisting of —OCH 2 — and —NHCH 2 —. 
     
     
         31 . The compound of  claim 29 , wherein L is selected from the group consisting of —CH═CH— and —C≡C—. 
     
     
         32 . The compound of  claim 29 , wherein L is selected from the group consisting of —SCH 2 —, —SO 2 —, and —CH 2 SO—. 
     
     
         33 . The compound of  claim 23 , wherein L comprises a —W—C(═V)— group, where
 V and W are each individually selected from O, S, or NH.   
     
     
         34 . The compound of  claim 33 , wherein:
 L comprises a —OC(═O)— group or —NHC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and   Z consists of 5 atoms selected from the group consisting of oxygen, nitrogen, sulfur and hydrogen.   
     
     
         35 . The compound of  claim 34 , wherein:
 L is selected from the group consisting of —OC(═O)— and —NHC(═O)—;   P 2  is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and   Z is —NHSO 2 —.   
     
     
         36 . The compound of  claim 34 , wherein:
 L comprises a —OC(═O)— group;   P 2  is a substituted heterocyclic;   R 5  is C(O)OR 8 ; and   R 8  is C 1-6  alkyl.   
     
     
         37 . The compound of  claim 33 , wherein:
 L comprises a —OC(═O)— group or —NHC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and   P 1 ′ is alkyl, alkenyl, or aryl.   
     
     
         38 . The compound of  claim 37 , wherein:
 L comprises a —OC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and   P 1 ′ is methyl, propyl, butyl, cyclopropyl or phenyl.   
     
     
         39 . The compound of  claim 38 , wherein:
 L is —OC(═O)—;   P 2  is a substituted heterocyclic;   R 5  is C(O)OR 8 ; and   R 8  is C 1-6  alkyl.   
     
     
         40 . The compound of  claim 38 , wherein P 2  is 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 23 , wherein L is selected from the group consisting of ester, amide, carboxy, carbamate, thioester, and thioamide. 
     
     
         42 . The compound of  claim 23 , wherein P 2  is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81. 
     
     
         43 . The compound of  claim 42 , wherein L consists of from 1 to 5 atoms selected from the group consisting of carbon and oxygen. 
     
     
         44 . The compound of  claim 42 , wherein P 2  is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 
     
     
         45 . The compound of  claim 1  of the formula 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of  claim 45 , wherein L is selected from the group consisting of —WC(═V)—NH— and —WC(═V)—O—, where V and W are each individually selected from O, S or NH. 
     
     
         47 . The compound of  claim 45 , wherein the C 13 -C 14  double bond is cis. 
     
     
         48 . The compound of  claim 45 , wherein the C 13 -C 14  double bond is trans. 
     
     
         49 . The compound of  claim 45 , wherein P 2  is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 
     
     
         50 . The compound of  claim 49 , wherein P 2  is 
       
         
           
           
               
               
           
         
       
     
     
         51 . The compound of  claim 45 , wherein L consists of from 1 to 5 atoms selected from the group consisting of carbon and oxygen. 
     
     
         52 . The compound of  claim 45 , wherein L consists of from 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. 
     
     
         53 . The compound of  claim 52 , wherein L is selected from the group consisting of —OCH 2 — and —NHCH 2 —. 
     
     
         54 . The compound of  claim 52 , wherein L is selected from the group consisting of —CH═CH— and —C≡C—. 
     
     
         55 . The compound of  claim 52 , wherein L is selected from the group consisting of —SCH 2 —, —SO 2 —, and —CH 2 SO—. 
     
     
         56 . The compound of  claim 45 , wherein L comprises a —W—C(═V)— group, where V and W are each individually selected from O, S, or NH. 
     
     
         57 . The compound of  claim 56 , wherein:
 L comprises a —OC(═O)— group or —NHC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and   Z consists of 5 atoms selected from the group consisting of oxygen, nitrogen, sulfur and hydrogen.   
     
     
         58 . The compound of  claim 57 , wherein:
 L is selected from the group consisting of —OC(═O)— and —NHC(═O)—;   P 2  is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and   Z is —NHSO 2 —.   
     
     
         59 . The compound of  claim 57 , wherein:
 L comprises a —OC(═O)— group;   P 2  is a substituted heterocyclic;   R 5  is C(O)OR 8 ; and   R 8  is C 1-6  alkyl.   
     
     
         60 . The compound of  claim 56 , wherein:
 L comprises a —OC(═O)— group or —NHC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; and   P 1 ′ is alkyl, alkenyl, or aryl.   
     
     
         61 . The compound of  claim 60 , wherein;
 L comprises a —OC(═O)— group;   P 2  is selected from the group consisting of unsubstituted heterocyclic and substituted heterocyclic; and   P 1 ′ is methyl, propyl, butyl, cyclopropyl or phenyl.   
     
     
         62 . The compound of  claim 61 , wherein:
 L is —OC(═O)—;   P 2  is a substituted heterocyclic;   R 5  is C(O)OR 8 ; and   R 8  is C 1-6  alkyl.   
     
     
         63 . The compound of  claim 45 , wherein L is selected from the group consisting of ester, amide, carboxy, carbamate, thioester, and thioamide. 
     
     
         64 . The compound of  claim 45 , wherein P 2  is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81. 
     
     
         65 . The compound of  claim 64 , wherein L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon and oxygen. 
     
     
         66 . The compound of  claim 64 , wherein P 2  is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle.