Methods for treating hepatitis c

Abstract

The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IBES activity.

1 .- 75 . (canceled) 
     
     
         76 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is: (a) -nitro;
 (b) —COR a , wherein R a  is: (1) —C 1  to C 6  alkyl, (2) -cyclopropyl, (3) -cyclobutyl, (4) -cyclopentyl, (5) -cyclohexyl, (6) -aryl optionally substituted with an alkoxy or a halogen, or (7) -amino disubstituted with C 1  to C 6 alkyl or one C 1  to C 6 alkyl substituent and one cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent; 
 (c) —COOR x , wherein R x  is a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; 
 (d) -formyl; 
 (e) -aryl optionally substituted with an alkoxy; or, 
 (f) -hydrogen; 
 
 Y is: -aryl, optionally substituted with one or more of the following:
 (1) -alkoxy optionally substituted with: (i) -alkoxy, (ii) -hydroxy, (iii) -one or more halogen(s), (iv) -5 or 6 membered heterocycle, optionally substituted with: —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, or -hydroxy, (v) -amino optionally substituted with one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, (vi) —NR i SO 2 R x , wherein R x  is as defined above and R 1  is: -hydrogen, —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, —COR x , wherein R x  is as defined above, -haloalkyl, or -haloalkoxy, (vii) —NR j COR k , wherein R k  is: —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -hydrogen, or -amino optionally substituted with one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and R j  is: -hydrogen, —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, —COR x , wherein R x  is as defined above, -haloalkyl, or -haloalkoxy, (viii) —N═N + ═N − , or (ix) —COR l , wherein R l  is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, 
 (2) -amino optionally substituted with one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 
 (3) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, optionally substituted with: —NHSO 2 R x , wherein R x  is as defined above, or —NR x SO 2 R x , wherein R x  is as defined above, 
 (4) -haloalkoxy, 
 (5) -halogen, 
 (6) -hydroxy, 
 (7) —COOR x , wherein R x  is as defined above, 
 (8) —COR m , wherein R m  is: (i) -amino optionally substituted with one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl are optionally substituted with: -hydroxy, -5 or 6 membered heterocycle, -amino optionally substituted with one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or -alkoxy, (ii) -3 to 7 membered heterocycle, optionally substituted with a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with a disubstituted amino, wherein amino is disubstituted with C 1  to C 6 alkyl or one C 1  to C 6 alkyl substituent and one cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent, or (iii) —NHR n , wherein R n  is: —CH 2 CONH 2 , or -aryl optionally substituted with: —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -one or more halogen(s), -nitro, or -one or more alkoxy(s), 
 (9) —NR o COR p , wherein R p  is: (i) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, optionally substituted with: -halogen, -alkoxy, or -aryl, (ii) -5 or 6 membered heterocycle, (iii) -aryl, optionally substituted with a halogen, (iv) -5 or 6 membered heteroaryl optionally substituted with one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, (v) hydrogen, or 
 
 
       
         
           
           
               
               
           
         
       
       and wherein R o  is: (i) -hydrogen, (ii) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, (iii) —COR x , wherein R x  is as defined above, (iv) -haloalkyl, or (v) -haloalkoxy,
   (10) —NR q CONR q R r , wherein R q  is: (i) -hydrogen, (ii) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, (iii) -haloalkyl, (iv) -haloalkoxy, or (v) —COR x , wherein R x  is as defined above, and wherein R r  is: (1) -aryl optionally substituted with:   
 
       
         
           
           
               
               
           
         
       
       —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -haloalkyl, —OR s , wherein R s  is aryl, or —COOR x , wherein R x  is as defined above, (ii) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, optionally substituted with one or more of the following: -halogen, -alkenyl, -aryl, or —COOR x , wherein R x  is as defined above, (iii) —COOR x , wherein R x  is as defined above, (iv) -cyclopropyl, (v) -cyclobutyl, (vi) -cyclopentyl, (vii) -cyclohexyl or (viii) -cyclopropylmethyl,
   (11) —NR t COOR u , wherein R u  is: (i) —C 1  to C 12  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, wherein C 1  to C 12  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl are optionally substituted with: (a) -aryl optionally substituted with a C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, or an alkoxy, (b) -alkenyl, (c) -alkoxy, (d) -alkynyl, (e) -halogen, or (f) -5 or 6 membered heterocycle, (ii) aryl, optionally substituted with: -alkoxy, -halogen, —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, (iii) -5 or 6 membered heterocycle, (iv) -cyclopropyl, (v) -cyclobutyl, (vi) -cyclopentyl, (vii) -cyclohexyl, (viii) -cyclopropylmethyl, or (ix) -cyclopropylethyl, and R t  is: (i) -hydrogen, (ii) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, —COR x , wherein R x  is as defined above, (iv) -haloalkyl, or (v) -haloalkoxy,   (12) —NR v SO 2 R w , wherein R v  is: (i) -hydrogen, (ii) —COR x , wherein R x  is as defined above, or (iii) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, wherein C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl is optionally substituted with: -halogen, —COR x , wherein R x  is as defined above, —OCOR x , wherein R x  is as defined above, -hydroxy, or -alkoxy, and wherein R w  is: (i) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, wherein C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl is optionally substituted with: -halogen, -haloalkyl, -aryl, or -5 or 6 membered heterocycle, (ii) —C 2  to C 6  alkenyl, (iii) -mono-alkyl-amino or -dialkyl-amino optionally substituted on alkyl with a halogen, (iv) amino disubstituted with one C 1  to C 6 alkyl substituent and one cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent, (v) -5 or 6 membered heterocycle, or (vi) -5 or 6 membered heteroaryl optionally substituted with: —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, -5 or 6 membered heterocycle, of   
 
       
         
           
           
               
               
           
         
       
       optionally substituted with a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R y  is a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or hydrogen, 
       
         
           
           
               
               
           
         
       
       wherein R z  is hydrogen or a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with aryl,
   (20) —SR x , wherein R x  is as defined above,   (21) —SO 2 R aa , wherein R aa  is: (i) —C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, (ii) -amino, (iii) -mono-alkyl-amino or -dialkyl-amino optionally substituted on alkyl with a hydroxy or a —COOR x , wherein R x  is as defined above, (iv) amino disubstituted with one C 1  to C 6 alkyl substituent and one cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent; or (v) -5 or 6 membered heteroaryl,   (22) -aryl, or   (23) —NHR bb , wherein R bb  is:   
 
       
         
           
           
               
               
           
         
       
       (iii) —C(═S)NH 2 , or (iv) —PO(OR x ) 2 , wherein R x  is as defined above;
 Z is: (a) —COOR x , wherein R x  is as defined above;
 (b) -cyclopropyl; 
 (c) -cyclobutyl; 
 (d) -cyclopentyl; 
 (e) -cyclohexyl; 
 (f) -cyclopropylmethyl; 
 (g) -cyclobutylmethyl; or 
 (h) -cyclopentylmethyl; 
 
 R is: (a) -hydrogen;
 (b) -halogen; or 
 (c) -alkoxy; 
 
 R 1  is: (a) -hydrogen;
 (b) -hydroxy; 
 (c) -halogen; 
 (d) -haloalkyl; 
 (e) -nitro; 
 (f) -5 or 6 membered heteroaryl; 
 (g) -5 or 6 membered heterocycle; 
 (h) -alkoxy optionally substituted with: (1) -one or more halogen(s), (2) -aryl, or (3) -5 or 6 membered heterocycle; 
 (i) -aryl optionally substituted with an alkoxy; 
 (j) —COR x , wherein R x  is as defined above; 
 (k) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, optionally substituted with (i) a -dialkyl-amino (ii) amino disubstituted with one C 1  to C 6 alkyl substituent and one cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent; or (iii) a 5 or 6 membered heterocycle; or 
 R 1  joins together with R 2  to form: 
 
 
       
         
           
           
               
               
           
         
         R 2  is: (a) -nitro;
 (b) -hydrogen; 
 (c) -halogen; 
 (d) -hydroxy; 
 (e) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, optionally substituted with one or more halogen(s); 
 (f) -amino; 
 (g) -alkoxy optionally substituted with: (1) -one or more halogen(s), (2) —OCOR x , wherein R x  is as defined above, (3) -amino disubstituted with C 1  to C 6 alkyl and optionally substituted on alkyl with an alkoxy, (4) amino disubstituted with one C 1  to C 6 alkyl substituent and one cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent; (5) -5 or 6 membered heterocycle optionally substituted with a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, (6) -5 or 6 membered heteroaryl, or (7) -aryl; 
 (h) —COOR x , wherein R x  is as defined above; 
 (i) -haloalkyl; 
 (j) -amide optionally substituted with: (l) -hydroxy, or (2) -aryl; 
 (k) -5 or 6 membered heteroaryl; 
 (l) —OCOR x , wherein R x  is as defined above; 
 (m) —NHCOR jj , wherein R jj  is: (1) -alkoxy, or (2) -amino optionally substituted with one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; 
 (n) —OR kk , wherein R kk  is a 5 to 6 membered heteroaryl; 
 (o) —NHSO 2 R x , wherein R x  is as defined above; or 
 R 2  joins together with R 1  to form: 
 
       
       
         
           
           
               
               
           
         
         R 3  is:
 (a) -hydrogen; or 
 (b) —CH 2 OCOR x , and R x  is as defined above; 
 
         provided that when X is phenyl substituted with alkoxy, then R is hydrogen, R 1  is a halogen, R 2  is hydrogen, and R 3  is hydrogen. 
       
     
     
         77 . The compound of  claim 76 , wherein:
 Y is (a) aryl, optionally substituted with one or more of the following:
 (1) -amino optionally substituted with one or more C 1  to C 6  alkyl(s), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, 
 (2) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, optionally substituted with a —NHSO 2 R x , wherein R., is as defined above, 
 (3) —NR o COR p , wherein R y  is: (i) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, optionally substituted with: halogen, or -aryl, or (ii) -5 or 6 membered heterocycle, and wherein R o  is a hydrogen, 
 (4) —NR q CONR q R r , wherein R q  is: (1) -hydrogen, or (ii) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, and wherein R r  is a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with one or more of the following: (a) -halogen, (b) -alkenyl, or (c) -aryl, (iii) -cyclopropyl; (iv) -cyclobutyl; (v) -cyclopentyl; (vi) -cyclohexyl; or (vii) -cyclopropylmethyl; 
 (5) —NR t COOR u , wherein R u  is: (i) —C 1  to C 12  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, optionally substituted with: (a) -aryl optionally substituted with a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or an alkoxy, (b) -alkenyl, (c) -alkoxy, (d) -alkynyl, (e) -halogen, or (f) -5 or 6 membered heterocycle, (ii) -aryl, optionally substituted with an alkoxy, (iii) -5 or 6 membered heterocycle, (iv) -cyclopropyl, (v) -cyclobutyl, (vi) -cyclopentyl, (vii) -cyclohexyl, -cyclopropylmethyl, or (ix) -cyclopropylethyl, and wherein R t  is: (i) -hydrogen, or (ii) —C 1  to C 6  alkyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, or -cyclohexyl, 
 (6) —NR v SO 2 R w , wherein R v  is a hydrogen, and wherein R w  is a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with a halogen; 
   
       
         
           
           
               
               
           
         
       
       wherein R 1  is a C 1  to C 6  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or
   (13) —NHR bb , wherein R bb  is a —PO(OR x ) 2 .   
 
     
     
         78 . The compound of  claim 76 , wherein:
 Z is: (a) —COOR x , wherein R x  is as defined above;
 (b) -cyclopropylmethyl; 
 (c) -cyclobutylmethyl; or 
 (d) -cyclopentylmethyl. 
   
     
     
         79 . The compound of  claim 76 , wherein:
 Z is: (a) -cyclopropyl;
 (b) -cyclobutyl; 
 (c) -cyclopentyl; or 
 (d) -cyclohexyl. 
   
     
     
         80 . A pharmaceutical composition comprising the compound of  claim 76  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 
     
     
         81 . The pharmaceutical composition of  claim 80 , further comprising one or more additional anti-viral agent selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, an inosine monophosphate dehydrogenase inhibitor, synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a helicase inhibitor, a glycosidase inhibitor, a Toll-like receptor agonist and combinations thereof. 
     
     
         82 . A method for treating a viral infection in a subject in need thereof comprising administering an effective amount of the compound of  claim 76  or a pharmaceutically acceptable salt thereof to the subject, wherein said viral infection is a Hepatitis C viral infection. 
     
     
         83 . A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         84 . A pharmaceutical composition comprising the compound of  claim 83  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 
     
     
         85 . The pharmaceutical composition of  claim 84 , further comprising one or more additional anti-viral agent selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, an inosine monophosphate dehydrogenase inhibitor, synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a helicase inhibitor, a glycosidase inhibitor, a Toll-like receptor agonist and combinations thereof. 
     
     
         86 . A method for treating a viral infection in a subject in need thereof comprising administering an effective amount of the compound of  claim 83  or a pharmaceutically acceptable salt thereof to the subject, wherein said viral infection is a Hepatitis C viral infection.