Benzimidazole analogues for the treatment or prevention of flavivirus infections

Abstract

Compounds represented by formula I: or pharmaceutically acceptable salts and solvates thereof, wherein A, B, B′, X, Y, R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 5 , R 5 ′, R 6 , m, n, or p are as defined herein, are useful for treating flaviviridae viral infections.

1 . (canceled) 
     
     
         2 . A compound of formula (IIIA′): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein 
         each A is independently C 6-14  aryl, 4-12 membered heterocycle, C 3-10  cycloalkyl, or 5-12 membered heteroaryl; 
         B and B′ are each independently absent or —(C≡C)—; 
         R 1  is halogen, —OR a , —NR a R b , —C(═O)OR a , —C(O)NR a R b , —C(═O)OH, —C(═O)R a , —C(═NOR c )R a , —C(═NR c )NR a R b , —NR d C(═O)NR a R b , —NR b C(═O)OR a , —NR d C(═NR c )NR a R b , —NR b C(═O)OR a , —OC(═O)NR a R b , —OC(═O)R a , —OC(═O)OR a , hydroxyl, nitro, azido, cyano, —S(O) 0-3 R a , —SO 2 NR a R b , —NR b SO 2 R a , —NR b SO 2 NR a R b , —P(═O)OR a OR b , C 1-6  alkyl which is unsubstituted or substituted one or more times by R 10 , C 2-6  alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2-6  alkynyl which is unsubstituted or substituted one or more times by R 10 , or any two occurrences of R 1  can be taken together with the atoms to which they are attached to form a 5-7 cycloalkyl which is unsubstituted or substituted one or more times by R 11  or a 5-7 membered heterocycle which is unsubstituted or substituted one or more times by R 12 ; 
         R a -R d  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 7-16  aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl; 
         R 2′  and R 2  are each independently halogen, C 1-10  alkyl, C 1-6  halogenated alkyl, —(CH 2 ) 1-6 OH, —OR a , —C(═O)OR a , NR a R b , —NR b C(═O)R a , —C(O)NR a R b , —S(O) 0-3 R a , C 6-12  aryl, or 5-12 membered heteroaryl; 
         R 3  and R 3 ′ are each independently H, C 1-18  alkyl which is unsubstituted or substituted one or more times by R 10 , C 2-12  alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2-12  alkynyl which is unsubstituted or substituted one or more times by R 10 , C 6-14  aryl which is unsubstituted or substituted one or more times by R 11 , C 2-16  aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-12 membered heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-18 membered heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-12 membered heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 membered heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ; 
         X and Y are each independently 
       
       
         
           
           
               
               
           
         
       
       or a bond;
 wherein the asterisk (*) indicates the point of attachment to the nitrogen of ring C or C′; 
 R 4  is H, C 1-6  alkyl, or halogenated C 1-6  alkyl; 
 R 5  and R 5 ′ are each independently halogen, —C(O)NR a R b , —(CH 2 ) 1-6 OH, C 1-6  alkyl, C 1-6  halogenated alkyl, C 6-14  aryl, or C 1-6  alkoxy; wherein two occurrence of R 4  can be taken together with the atoms to which they are attached to form a C 1-6  alkenyl which is unsubstituted or substituted one or more times by R 10 , a 3-7 cycloalkyl which is unsubstituted or substituted one or more times by R 11  or a 4-7 membered heterocycle which is unsubstituted or substituted one or more times by R 12 ; wherein two occurrence of R 4 ′ can be taken together with the atoms to which they are attached to form a C 1-6  alkenyl which is unsubstituted or substituted one or more times by R 10 , a 3-7 cycloalkyl which is unsubstituted or substituted one or more times by R 11  or a 4-7 membered heterocycle which is unsubstituted or substituted one or more times by R 12 , wherein R a -R b  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 7-16  aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl; 
 R 6  and R 6 ′ are each independently H, C 1-6  alkyl, —(CH 2 ) 1-6 OH, C 2-6  alkenyl, or C 2-6  alkynyl; 
 m and n, combined are 1, 2, 3 or 4; 
 p is 0, 1, 2, 3 or 4; 
 q′ is 0, 1 or 2; 
 q and r are each independently 0, 1, 2, 3 or 4; 
 R 10  is halogen, —OR a , oxo, —NR a R b , ═NO—R c , —C(═O)OR a , —C(O)NR a R b , —C(═O)OH, —C(═O)R a , —C(═NOR c )R a , —C(═NR c )NR a R b , —NR d C(═O)NR a R b , —NR b C(═O)R a , —NR d C(═NR c )NR a R b , —NR b C(═O)OR a , —OC(═O)NR a R b , —OC(═O)R a , —OC(═O)OR a , hydroxyl, nitro, azido, cyano, —S(O) 0-3 R a , —SO 2 NR a R b , —NR b SO 2 R a , —NR b SO 2 NR a R b , or —P(═O)OR a OR b ; 
 R 11  is halogen, —OR a , —NR a R b , —C(═O)OR a , —C(O)NR a R b , —C(═O)OH, —C(═O)R a , —C(═NOR c )R a , —C(═NR c )NR a R b , —NR d C(═O)NR a R b , —NR b C(═O)R a , —NR d C(═NR c )NR a R b , —NR b C(═O)OR a , —OC(═O)NR a R b , —OC(═O)R a , —OC(═O)OR a , hydroxyl, nitro, azido, cyano, —S(O) 0-3 R a , SO 2 NR a R b , —NR b SO 2 R a , —NR b SO 2 NR a R b , or —P(═O)OR a OR b , C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 7-16  aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl; and 
 R 12  is halogen, —OR a , oxo, NR a R b , ═NO—R c , —C(═O)OR a , —C(O)NR a R b , —C(═O)OH, —C(═O)R a , —C(═NOR c )R a , —C(═NR c )NR a R b , —NR d C(═O)NR a R b , —NR b C(═O)R a , —NR d C(═NR c )NR a R b , —NR b C(═O)OR a , —OC(═O)NR a R b , —OC(═O)R a , —OC(═O)OR a , hydroxyl, nitro, azido, cyano, —S(O) 0-3 R a , —SO 2 NR a R b , —NR b SO 2 R a , —NR b SO 2 NR a R b , or —P(═O)OR a OR b , C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 7-16  aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl. 
 
     
     
         3 . (canceled) 
     
     
         4 . The compound according to  claim 2 , wherein each A is independently cyclopropyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, piperadinyl, phenyl, naphthalenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, dihydrobenzodioxinyl, thienofuranyl, thienothienyl, thienopyrrolyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or triazolyl; and wherein each A is independently substituted with (R 1 ) p . 
     
     
         5 - 7 . (canceled) 
     
     
         8 . The compound according to  claim 4 , wherein each A is independently piperazinyl, piperadinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, dihydrobenzodioxinyl, thienofuranyl, thienothienyl, quinolinyl, or triazolyl, each of which is substituted with (R 1 ) p . 
     
     
         9 .- 10 . (canceled) 
     
     
         11 . The compound according to  claim 2 , wherein each A is independently a 5-12 membered heteroaryl wherein the heteroatom(s) are selected from the group consisting of oxygen and sulphur; wherein each A is independently substituted with (R 1 ) p . 
     
     
         12 . The compound according to  claim 2 , wherein B and B′ are independently absent, C 1-6  alkyl or C 2-6  alkynyl. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . The compound according to  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and
 t1+t2=p. 
 
     
     
         17 - 26 . (canceled) 
     
     
         27 . The compound according to  claim 16 , wherein R 1  is halogen, C 1-4  alkyl which is unsubstituted or substituted one or more times by R 10 , —C(═O)OR a , —C(O)NR a R b , hydroxyl, cyano, or C 1-3  alkoxy. 
     
     
         28 . The compound according to  claim 27 , wherein R 1  is chloro, fluoro, bromo, methyl, ethyl, propyl, butyl, —CH 2 OH, difluoromethyl, trifluoromethyl, hydroxyl, cyano, or methoxy. 
     
     
         29 . The compound according to  claim 2 , wherein each R 2 ′ are independently fluoro or methyl. 
     
     
         30 . The compound according to any one of  claim 29 , wherein q is 0. 
     
     
         31 . The compound according to  claim 2 , wherein each R 2  are independently fluoro or methyl. 
     
     
         32 . The compound according to  claim 31 , wherein r is 0. 
     
     
         33 . The compound according to  claim 2 , wherein R 6  and R 6 ′ are H or methyl. 
     
     
         34 . The compound according to  claim 2 , wherein R 5  and R 5 ′ in formulas (IIB), (VIII), (IX), (X) and (XI), are each independently halogen, methyl, ethyl, isopropyl, di-fluoromethyl, di-fluoroethyl, trifluoromethyl, tri-fluoroethyl, —CH 2 OH, —NR a N b , t-butoxy-, or hydroxyl; or two R 5  groups together with the atoms to which they are attached form fused cyclopropyl, spiro cyclopropyl or 
       
         
           
           
               
               
           
         
       
       two R 5 ′ groups together with the atoms to which they are attached form fused cyclopropyl, spiro cyclopropyl or 
       
         
           
           
               
               
           
         
       
       and R 5  and R 5 ′ in formulas (IIIA), (IIIA′), (IVA) and (VA), are each independently halogen, methyl, ethyl, isopropyl, di-fluoromethyl, di-fluoroethyl, trifluoromethyl, tri-fluoroethyl, —CH 2 OH, —NR a N b , or t-butoxy-; or two R 5  groups together with the atoms to which they are attached form fused cyclopropyl, spiro cyclopropyl or 
       
         
           
           
               
               
           
         
       
       two R 5 ′ groups together with the atoms to which they are attached form fused cyclopropyl, spiro cyclopropyl or 
       
         
           
           
               
               
           
         
       
     
     
         35 - 36 . (canceled) 
     
     
         37 . The compound according to  claim 2 , wherein m and n are independently 1 or 2. 
     
     
         38 . The compound according to  claim 37 , wherein m and n are 1. 
     
     
         39 . The compound according to  claim 2 , wherein X and Y are 
       
         
           
           
               
               
           
         
       
     
     
         40 . The compound according to  claim 2 , wherein R 3  and R 3 ′ are each independently, C 1-8  alkyl which is unsubstituted or substituted one or more times by R 10 , C 2-8  alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2-8  alkynyl which is unsubstituted or substituted one or more times by R 10 , phenyl which is unsubstituted or substituted one or more times by R 11 , C 7-8  aralkyl which is unsubstituted or substituted one or more times by R 11 , 5-6 membered heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-8 membered heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-6 membered heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-8 membered heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 . 
     
     
         41 - 45 . (canceled) 
     
     
         46 . The compound according to  claim 2 , wherein R 10  is halogen, —OR a , oxo, —NR a R b , ═NO—R c , —C(═O)OR a , —C(O)NR a R b , —C(═O)OH, —C(═O)R a , —C(═NOR c )R a , —C(═NR c )NR a R b , —NR d C(═O)NR a R b , —NR b C(═O)R a , —NR d C(═NR c )NR a R b , —NR b C(═O)OR a , —OC(═O)NR a R b , —OC(═O)R a , —OC(═O)OR a , hydroxyl, nitro, azido, cyano, —S(O) 0-3 R a , —SO 2 NR a R b , —NR b SO 2 R a , or —NR b SO 2 NR a R b , wherein R a -R d  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 7-16  aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl 
     
     
         47 - 48 . (canceled) 
     
     
         49 . The compound according to  claim 2 , wherein R a -R d  are each independently H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, phenyl, C 7-8  aralkyl, 5-6 membered heteroaryl, 6-8 membered heteroaralkyl, 5-6 membered heterocycle, or 6-8 membered heterocycle-alkyl. 
     
     
         50 - 51 . (canceled) 
     
     
         52 . The compound according to  claim 2 , wherein the compound is of formula (IVA): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein 
         R 7  and R 7 ′ are each independently C 1-8  alkyl which is unsubstituted or substituted one or more times by R 10 , C 2-8  alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2-8  alkynyl which is unsubstituted or substituted one or more times by R 10 , phenyl which is unsubstituted or substituted one or more times by R 11 , benzyl which is unsubstituted or substituted one or more times by R 11 , 5-6 membered heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-7 membered heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-6 membered heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-7 membered heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ; 
         R 8  and R 8 ′ are each independently —NR a R b , —NR d C(═O)NR a R b , —NR b C(═O)OR a , —NR d C(═NR c )NR a R b , —NR b C(═O)OR a , —NR b SO 2 R a , or —NR b SO 2 NR a R b , wherein R a -R d  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 7-16  aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl; and 
         m and n combined are 0, 1, 2, 3 or 4. 
       
     
     
         53 - 58 . (canceled) 
     
     
         59 . The compound according to  claim 2 , wherein the compound is of formula (VA): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         60 . (canceled) 
     
     
         61 . The compound of  claim 59 , wherein the compound is of formula (V): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         62 . The compound according to  claim 61 , wherein the compound is of formula (VI): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         63 - 65 . (canceled) 
     
     
         66 . The compound according to  claim 2 , wherein the compound is of formula (VII): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof; 
         wherein 
         R 7  and R 7 ′ are each independently C 1-8  alkyl which is unsubstituted or substituted one or more times by R 10 , C 2-8  alkenyl which is unsubstituted or substituted one or more times by R 10 , C 2-8  alkynyl which is unsubstituted or substituted one or more times by R 10 , phenyl which is unsubstituted or substituted one or more times by R 11 , benzyl which is unsubstituted or substituted one or more times by R 11 , 5-6 membered heteroaryl which is unsubstituted or substituted one or more times by R 11 , 6-7 membered heteroaralkyl which is unsubstituted or substituted one or more times by R 11 , 3-6 membered heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-7 membered heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ; 
         R 8  and R 8 ′ are each independently —NR a R b , —NR d C(═O)NR a R b , —NR b C(═O)OR a , —NR d C(═NR c )NR a R b , —NR b C(═O)OR a , —NR b SO 2 R a , or —NR b SO 2 NR a R b , wherein R a -R d  are each independently H, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 6-12  aryl, C 2-16  aralkyl, 5-12 membered heteroaryl, 6-18 membered heteroaralkyl, 3-12 membered heterocycle, or 4-18 membered heterocycle-alkyl. 
       
     
     
         67 - 162 . (canceled) 
     
     
         163 . A pharmaceutical composition comprising at least one compound according to  claim 2  and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         164 - 168 . (canceled)