Novel macrocyclic inhibitors of hepatitis c virus replication

Abstract

The embodiments provide compounds of the general Formulae I, II, III, IV, V, VI, VII, and X, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a 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 having the structure of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof wherein: 
         (a) R 1  is —(CR 5 R 6 ) n R 4 ; 
         (b) n is 0; 
         (c) R 2  is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, C 1-6  alkoxy, —(CH 2 ) q C 3-7 cycloalkyl, C 3-6  heterocycloalkyl, aryl, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , —C(O)OR 2a , —O[(CH 2 ) p NR 3a R 3b ], —(CH 2 ) p NR 3a R 3b , and C 1-6  alkyl optionally substituted with up to 5 fluoro or cyano; 
         (d) R 4  is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, C 1-6  alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro, —(CH 2 ) q C 3-7 cycloalkyl, aryl, C 1-6  alkylthio, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , and —C(O)OR 2a ; 
         (e) R 1a  and R 1b  are each separately a hydrogen atom, or separately selected from the group consisting of C 1-6  alkyl, C 3-7  cycloalkyl, and phenyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, —(CH 2 ) q C 3-7 cycloalkyl, C 1-6  alkyl, and C 1-6  alkoxy; or R 1a  and R 1b  are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; 
         (f) each R 2a  is separately selected from the group consisting of C 1-6  alkyl and C 6 or 10  aryl; 
         (g) R 3a  and R 3b  are each separately selected from the group consisting of hydrogen and C 1-6  alkyl; 
         (h) each m is separately 0, 1 or 2; 
         (i) each p is separately an integer selected from 1-6; 
         (j) each q is separately 0, 1 or 2; 
         (k) R 3  is —C(O)NHS(O) 2 R 9 , where R 9  is selected from the group consisting of C 1-6  alkyl, —(CH 2 ) q C 3-7 cycloalkyl, —(CH 2 ) q C 6 or 10  aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, C 1-6  alkyl, —(CH 2 ) t C 3-7 cycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl optionally substituted with up to 5 fluoro, alkoxy optionally substituted with up to 5 fluoro, and C 1-6  arylalkyl, or R 9  is —NR 9a R 9b ; 
         wherein R 9a  and R 9b  are each separately a hydrogen atom, or separately selected from the group consisting of C 1-6  alkyl, —(CH 2 ) q C 3-7 cycloalkyl, and C 6 or 10  aryl, each optionally substituted with one or more substituents each independently selected from the group consisting of —(CH 2 ) t C 3-7 cycloalkyl and phenyl, 
         or R 9a  and R 9b  are each separately selected from the group consisting of a hydrogen atom and a heterocycle, 
         or —NR 9a R 9b  is a three- to six-membered alkyl cyclic secondary amine, which optionally has one to three additional hetero atoms incorporated in the ring, 
         or R 9a  and R 9b  are taken together with the nitrogen to which they are attached to form a heteroaryl; 
         (l) each t is separately 0, 1 or 2; 
         (m) R 5  and R 6  are each hydrogen; 
         (n) Z is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         (o) R 19  is hydrogen, C 1-6  alkyl optionally substituted with up to 5 fluoro, or —SO m R 2a ; 
         (p) R 20  is hydrogen; 
         (q) R 21  and R 22  are each hydrogen or together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl; and 
         (r) the dashed line represents an optional double bond; 
         with the proviso that the compound of formula I is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , with the proviso that if R 4  is a six-membered substituted aryl or heteroaryl, then all substituents on the ring other than fluoro are in the meta and/or para position relative to the ring's point of attachment to the parent molecular moiety. 
     
     
         3 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of aryl, heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, C 1-6  alkoxy, —(CH 2 ) q C 3-7 cycloalkyl, C 3-6  heterocycloalkyl, aryl, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , —C(O)OR 2a , —O[(CH 2 ) p NR 3a R 3b ], —(CH 2 ) p NR 3a R 3b , and C 1-6  alkyl. 
     
     
         4 . The compound of  claim 1 , wherein R 4  is selected from the group consisting of phenyl and heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, C 1-6  alkyl, C 1-6  alkoxy, —(CH 2 ) q C 3-7 cycloalkyl, aryl, C 1-6  alkylthio, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , and —C(O)OR 2a . 
     
     
         5 . The compound of  claim 1 , wherein R 9  is selected from the group consisting of C 1-6  alkyl, —(CH 2 ) q C 3-7 cycloalkyl, —(CH 2 ) q C 6 or 10  aryl, and a heteroaromatic ring, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, C 1-6  alkyl, —(CH 2 ) t C 3-7 cycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl optionally substituted with up to 5 fluoro, and C 1-6  alkoxy optionally substituted with up to 5 fluoro, or R 9  is —NR 9a R 9b . 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9  is selected from C 1-6  alkyl and —(CH 2 ) q C 3-7 cycloalkyl, wherein the —(CH 2 ) q C 3-7 cycloalkyl is optionally substituted with one substituent selected from the group consisting of halo, C 1-6  alkyl, C 2-6  alkenyl, and C 1-6  alkoxy. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is selected from heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, C 1-6  alkoxy, —(CH 2 ) q C 3-7 cycloalkyl, C 3-6  heterocycloalkyl, aryl, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , —C(O)OR 2a , —O[(CH 2 ) p NR 3a R 3b ], —(CH 2 ) p NR 3a R 3b , and C 1-6  alkyl optionally substituted with up to 5 fluoro or cyano. 
     
     
         8 . The compound of  claim 7 , wherein R 2  is selected from heteroaryl and polycyclic moiety, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, C 1-6  alkoxy, —(CH 2 ) q C 3-7 cycloalkyl, C 3-6  heterocycloalkyl, aryl, —S(O) 2 NR 1a R 1b , —C(O)N 1a R 1b , —NR 1a R 1b , —C(O)R 2a , —C(O)OR 2a , —O[(CH 2 ) p NR 3a R 3b ], —(CH 2 ) p NR 3a R 3b , and C 1-6  alkyl. 
     
     
         9 . The compound of  claim 7 , wherein R 2  is selected from heteroaryl and polycyclic moiety. 
     
     
         10 . The compound of  claim 9 , wherein the heteroaryl is isoquinolinyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, C 1-6  alkoxy, —(CH 2 ) q C 3-7 cycloalkyl, C 3-6  heterocycloalkyl, aryl, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , —C(O)OR 2a , —O[(CH 2 ) p NR 3a R 3b ], —(CH 2 ) p NR 3a R 3b , and C 1-6  alkyl optionally substituted with up to 5 fluoro or cyano. 
     
     
         11 . The compound of  claim 10 , wherein the isoquinolinyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, C 1-6  alkoxy, —(CH 2 ) q C 3-7 cycloalkyl, C 3-6  heterocycloalkyl, aryl, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , —C(O)OR 2a , —O[(CH 2 ) p NR 3a R 3b ], —(CH 2 ) p NR 3a R 3b , and C 1-6  alkyl. 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is 
       
         
           
           
               
               
           
         
       
       and the dashed line represents a double bond. 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is 
       
         
           
           
               
               
           
         
       
       and the dashed line represents a double bond;
 R 2  is heteroaryl wherein the heteroaryl is isoquinolinyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, C 1-6  alkoxy, —(CH 2 ) q C 3-7 cycloalkyl, C 3-6  heterocycloalkyl, aryl, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , —C(O)OR 2a , —O[(CH 2 ) p NR 3a R 3b ], —(CH 2 ) p NR 3a R 3b , and C 1-6  alkyl optionally substituted with up to 5 fluoro or cyano; and 
 R 3  is —C(O)NHS(O) 2 R 9 , where R 9  is selected from C 1-6  alkyl and —(CH 2 ) q C 3-7 cycloalkyl, each optionally substituted with one substituent selected from the group consisting of halo, C 1-6  alkyl, C 2-6  alkenyl, and C 1-6  alkoxy; and 
 R 4  is heteroaryl containing one nitrogen atom, and the heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, C 1-6  alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro, —(CH 2 ) q C 3-7 cycloalkyl, aryl, C 1-6  alkylthio, —S(O) 2 NR 1a R 1b , —C(O)NR 1a R 1b , —NR 1a R 1b , —C(O)R 2a , and —C(O)OR 2a . 
 
     
     
         14 . A compound having the structure of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         (a) R 1  is —(CR 5 R 6 ) n R 4 ; 
         (b) n is 0; 
         (c) R 2  is heteroaryl optionally substituted with one or more substituents each independently selected from halo and C 1-6  alkoxy; 
         (d) R 4  is heteroaryl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6  alkoxy and optionally substituted aryl; 
         (e) q is 0; 
         (f) R 3  is —C(O)NHS(O) 2 R 9 , where R 9  is —(CH 2 ) q C 3-7 cycloalkyl, and the C 3-7 cycloalkyl is cyclopropyl; 
         (g) R 5  and R 6  are each separately hydrogen; 
         (h) Z is 
       
       
         
           
           
               
               
           
         
         (i) R 20  is hydrogen; 
         (j) R 21  and R 22  are each hydrogen; and 
         (k) the dashed line represents a double bond. 
       
     
     
         15 . The compound of  claim 14 , wherein:
 R 2  is isoquinolinyl optionally substituted with one or more substituents each independently selected from halo and C 1-6  alkoxy; and   R 4  is pyridinyl or thiazolyl, each optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6  alkoxy and optionally substituted aryl.   
     
     
         16 . The compound of  claim 15 , wherein:
 R 2  is 6-methoxy-isoquinolinyl and R 4  is 2-methoxy-pyridin-4-yl; or   R 2  is 4-methoxy-7-chloro-isoquinolinyl and R 4  is 2-methoxy-pyridin-5-yl; or   R 2  is 6-methoxy-isoquinolinyl and R 4  is 4-(4-trifluoromethoxyphenyl)-thiazolyl; or   R 2  is 6-methoxy-isoquinolinyl and R 4  is 4-(2,4-difluorophenyl)-thiazolyl; or   R 2  is 6-methoxy-isoquinolinyl and R 4  is 4-phenylthiazolyl; or   R 2  is 4-methoxy-7-chloro-isoquinolinyl and R 4  is 4-(4-trifluoromethoxyphenyl)-thiazolyl.   
     
     
         17 . A composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         18 . The composition of  claim 17  further comprising at least one additional compound having anti-HCV activity. 
     
     
         19 . The composition of  claim 18  wherein at least one of the additional compounds is an interferon or a ribavirin. 
     
     
         20 . The composition of  claim 19  wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, and interferon alpha 2A. 
     
     
         21 . The composition of  claim 18  wherein at least one of the additional compounds is selected from ribavirin and an inosine 5′-monophospate dehydrogenase inhibitor. 
     
     
         22 . The composition of  claim 18  wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, and HCV NS5A protein for the treatment of an HCV infection. 
     
     
         23 . A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of  claim 23  further comprising administering at least one additional compounds having anti-HCV activity prior to, after, or simultaneously with the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method of  claim 24  wherein at least one of the additional compounds is an interferon or a ribavirin. 
     
     
         26 . The method of  claim 25  wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, and interferon alpha 2A. 
     
     
         27 . The method of  claim 24  wherein at least one of the additional compounds is selected from ribavirin and an inosine 5′-monophospate dehydrogenase inhibitor. 
     
     
         28 . The method of  claim 24  wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, and HCV NS5A protein for the treatment of an HCV infection.