Compounds and methods for the treatment or prevention of flavivirus infections

Abstract

The present invention provides novel compounds represented by formula I: or pharmaceutically acceptable salts thereof useful for treating flaviviridae viral infection.

1 .- 97 . (canceled) 
     
     
         98 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein, 
         X is 
       
       
         
           
           
               
               
           
         
         M is 
       
       
         
           
           
               
               
           
         
         J is 
       
       
         
           
           
               
               
           
         
         Y 1  is a bond; 
         Y is COOH; 
         R 1  is C 2-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-14  aryl, C 3-12  heterocycle, C 3-18  heteroaralkyl or C 6-18  aralkyl; 
         R 2  is C 2-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-14  aryl, C 3-12  heterocycle, C 3-18  heteroaralkyl, or C 6-18  aralkyl; 
         R 3  is H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-14  aryl, C 3-12  heterocycle, C 3-18  heteroaralkyl or C 6-18  aralkyl; and 
         Z is H, halogen, or C 1-6  alkyl; 
         with the proviso that: when X is Benzamide and R 1  is phenyl, then R 3  is other than hydrogen; 
         wherein
 alkyl in R 1 , R 2 , R 3 , and Z is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido; 
 alkenyl in R 1 , R 2 , and R 3  is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido; 
 alkynyl in R 1 , R 2 , and R 3  is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido; 
 aryl in R 1 , R 2 , and R 3  is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido; 
 aralkyl in R 1 , R 2 , and R 3  is in each case an aryl group attached to the adjacent atom by a C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, and the aryl group is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido; 
 heterocycle in R 1 , R 2 , and R 3  is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido; 
 heteroaralkyl in R 1 , R 2 , and R 3  in each case an heterocycle group attached to the adjacent atom by a C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl, and the heterocycle group is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido; and 
 R 12 , R c , R d , R 13  and R 14 , are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-14  aryl, C 3-12  heterocycle, C 3-18  heteroaralkyl, or C 6-18  aralkyl, or R c  and R d  are taken together with the oxygens to form a 5 to 10 membered heterocycle, or R 13  and R 14  are taken together with the nitrogen to form a 3 to 10 membered heterocycle, 
 in each case above alkyl groups include alkyls in which one or more hydrogen atoms are each replaced by a halogen, and 
 sulfur atoms are in the form of S, SO, or SO 2 . 
 
       
     
     
         99 . A compound according to  claim 98 , wherein said compound is of formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         100 . A compound according to  claim 98 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         101 . A compound according to  claim 98 , wherein Z is H. 
     
     
         102 . A compound according to  claim 98 , wherein R 1  is C 2-12  alkyl, C 6-14  aryl, or C 3-12  heterocycle, which in each case is substituted or unsubstituted. 
     
     
         103 . A compound according to  claim 98 , wherein R 3  is H, C 1-12  alkyl, C 6-18  aralkyl, C 3-12  heterocycle, or C 3-18  heteroaralkyl, which in each case is substituted or unsubstituted. 
     
     
         104 . A compound according to  claim 98 , wherein
 R 3  is H, or R 3  is methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, azepanyl or benzyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido; and   R 12 , R c , R d , R 13  and R 14  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-14  aryl, C 3-12  heterocycle, C 3-18  heteroaralkyl, or C 6-18  aralkyl,   or R c  and R d , taken together with the oxygens, form a 5 to 10 membered heterocycle,   or R 13  and R 14 , taken together with the nitrogen, form a 3 to 10 membered heterocycle.   
     
     
         105 . A compound according to  claim 104 , wherein R 3  is isopropyl or cyclohexyl, which in each case is substituted or unsubstituted. 
     
     
         106 . A compound according to  claim 98 , wherein R 2  is C 2-12  alkyl, C 6-14  aryl, or C 3-12  heterocycle, which in each case is substituted or unsubstituted. 
     
     
         107 . A compound according to  claim 98 , wherein
 R 2  is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, 2-(cyclopentyl)-ethyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl isobutyl, pentyl, neopentyl or t-butyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido; and   R 12 , R c , R d , R 13  and R 14  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-14  aryl, C 3-12  heterocycle, C 3-18  heteroaralkyl, or C 6-18  aralkyl,   or R c  and R d , taken together with the oxygens, form a 5 to 10 membered heterocycle,   or R 13  and R 14 , taken together with the nitrogen, form a 3 to 10 membered heterocycle.   
     
     
         108 . A compound according to  claim 99 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         109 . A compound according to  claim 99 , wherein Z is H. 
     
     
         110 . A compound according to  claim 99 , wherein R 1  is C 2-12  alkyl, C 6-14  aryl, or C 3-12  heterocycle, which in each case is substituted or unsubstituted. 
     
     
         111 . A compound according to  claim 99 , wherein R 3  is H, or R 3  is C 1-12  alkyl, C 6-18  aralkyl, C 3-12  heterocycle, or C 3-18  heteroaralkyl, which in each case is substituted or unsubstituted. 
     
     
         112 . A compound according to  claim 99 , wherein
 R 3  is H, or R 3  is methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, azepanyl or benzyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido; and   R 12 , R c , R d , R 13  and R 14  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-14  aryl, C 3-12  heterocycle, C 3-18  heteroaralkyl, or C 6-18  aralkyl,   or R c  and R d , taken together with the oxygens, form a 5 to 10 membered heterocycle,   or R 13  and R 14 , taken together with the nitrogen, form a 3 to 10 membered heterocycle.   
     
     
         113 . A compound according to  claim 99 , wherein R 3  is H, or R 3  is methyl, isopropyl, piperidinyl, piperidinylmethyl, dioxolanyl or cyclohexyl, which in each case is substituted or unsubstituted. 
     
     
         114 . A compound according to  claim 99 , wherein R 2  is C 2-12  alkyl, C 6-14  aryl, or C 3-12  heterocycle, which in each case is substituted or unsubstituted. 
     
     
         115 . A compound according to  claim 99 , wherein Z is H and X is 
       
         
           
           
               
               
           
         
       
     
     
         116 . A compound according to  claim 115 , wherein
 R 1  is C 2-12  alkyl, C 6-14  aryl, or C 3-12  heterocycle, which in each case is substituted or unsubstituted;   R 3  is H, or R 3  is C 1-12  alkyl, C 6-18  aralkyl, C 3-12  heterocycle, or C 3-18  heteroaralkyl, which in each case is substituted or unsubstituted; and   R 2  is C 2-12  alkyl, C 6-14  aryl, or C 3-12  heterocycle, which in each case is substituted or unsubstituted.   
     
     
         117 . A compound according to  claim 115 , wherein
 R 3  is H, or R 3  is methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, azepanyl or benzyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido;   R 2  is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl cyclohexyl, cycloheptyl, 2-(cyclopentyl)-ethyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl isobutyl, pentyl, neopentyl or t-butyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aralkyl, C 6-12  aryl, C 1-6  alkyloxy, C 2-6  alkenyloxy, C 2-6  alkynyloxy, C 6-12  aryloxy, C(O)C 1-6  alkyl, C(O)C 2-6  alkenyl, C(O)C 2-6  alkynyl, C(O)C 6-12  aryl, C(O)C 6-12  aralkyl, C 3-10  heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido; and   R 12 , R c , R d , R 13  and R 14  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-14  aryl, C 3-12  heterocycle, C 3-18  heteroaralkyl, or C 6-18  aralkyl,   or R c  and R d , taken together with the oxygens, form a 5 to 10 membered heterocycle,   or R 13  and R 14 , taken together with the nitrogen, form a 3 to 10 membered heterocycle.   
     
     
         118 . A method for treating a Hepatitis C virus (HCV) infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to  claim 98 .