Benzimidazole-imidazole derivatives

Abstract

Inhibitors of HCV replication of formula I including stereochemically isomeric forms, and salts, solvates thereof, wherein R and R′ are, each independently, —CR 1 R 2 R 3 , aryl, heteroaryl or heteroC 4-6 cycloalkyl, whereby aryl and heteroaryl may optionally be substituted with 1 or 2 substituents selected from halo and methyl. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       or a stereoisomeric form thereof, wherein:
 A is phenylene optionally substituted with 1, 2 or 3 substituents selected from halo or C 1-3 alkyl; 
 R and R′ are, each independently, —CR 1 R 2 R 3 , aryl, heteroaryl or heteroC 4-6 cycloalkyl, whereby aryl and heteroaryl may optionally be substituted with 1 or 2 substituents selected from halo and methyl; and wherein
 R 1  is hydrogen;
 C 1-4 alkyl optionally substituted with methoxy, hydroxy or dimethylamino; 
 phenyl optionally substituted with 1, 2 or 3 substituents independently selected from halo, C 1-4 alkoxy, and trifluoromethoxy; 
 1,3-benzodioxolanyl; 
 benzyl optionally substituted with 1, 2 or 3 substituents independently selected from halo or methoxy; 
 C 3-6 cycloalkyl; 
 heteroaryl; 
 heteroC 4-6 cycloalkyl; or 
 heteroarylmethyl; 
 
 R 2  is hydrogen, hydroxyl, amino, mono- or di-C 1-4 alkylamino, C 1-4 alkylcarbonylamino, C 1-4 alkyloxycarbonylamino, C 1-4 alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; 
 R 3  is hydrogen, 
 or R 1  and R 3  together form a cyclopropyl group; 
 or R 2  and R 3  form oxo; 
 
 
       or a pharmaceutically acceptable salt or a solvate thereof. 
     
     
         2 . The compound according to  claim 1 , wherein
 R 1  is hydrogen;
 C 1-4 alkyl optionally substituted with methoxy or dimethylamino; 
 phenyl optionally substituted with 1, 2 or 3 substituents independently selected from halo, C 1-4  alkoxy and trifluoromethoxy; 
 1,3-benzodioxolanyl; 
 benzyl optionally substituted with 1, 2 or 3 substituents independently selected from halo or methoxy; 
 C 3-6 cycloalkyl; 
 heteroaryl; 
 heteroC 4-6 cycloalkyl; or 
 heteroarylmethyl. 
   
     
     
         3 . The compound according to  claim 1 , wherein R and R′ are different from one another. 
     
     
         4 . The compound according to  claim 1 , wherein R and R′ are the same. 
     
     
         5 . The compound according to  claim 1 , wherein R and R′ each independently are —CR 1 R 2 R 3 . 
     
     
         6 . The compound according to  claim 5 , wherein each R 2  independently is C 1-4 alkylcarbonylamino or C 1-4 alkyloxycarbonylamino. 
     
     
         7 . The compound according  claim 5 , wherein each R 2  independently is methoxycarbonylamino. 
     
     
         8 . The compound according to  claim 5 , wherein each R 1  independently is branched C 3-4 alkyl, methoxyC 2-3 alkyl, cyclopentyl, or phenyl. 
     
     
         9 . The compound according to  claim 5 , wherein R 1  in R is 1-methylpropyl, 2-methylpropyl, 2-methoxyethyl, cyclopentyl, or phenyl; and R 1  in R′ is 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1-methoxyethyl, cyclopentyl, or phenyl. 
     
     
         10 . The compound according to  claim 5 , wherein both the carbon atoms in R and R′ bearing the R 1 , R 2  and R 3  substituent have the S-configuration. 
     
     
         11 . The compound according to  claim 1 , wherein the compound is of formula Ia 
       
         
           
           
               
               
           
         
       
     
     
         12 . The pharmaceutically acceptable salt or a solvate of a compound according to  claim 1 . 
     
     
         13 . The compound according to  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         14 . The compound according to  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         15 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         16 . A method for treating an HCV infection in a mammal comprising administering to the mammal a compound according to  claim 1 . 
     
     
         17 . A product comprising (a) a compound according to  claim 1 , and (b) another HCV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections. 
     
     
         18 . A product according to  claim 17  wherein the other HCV inhibitor is a HCV protease inhibitor. 
     
     
         19 . A product according to  claim 18  wherein the HCV protease inhibitor is selected from the group consisting of telaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-900518), ITMN-191 (R-7227), TMC435350 (TMC435), MK-7009, BI-201335, BI-2061 (ciluprevir), BMS-650032, ACH-1625, ACH-1095, GS 9256, VX-985, IDX-375 (HCV NS4A protease co-factor inhibitor), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450, EP-013420 (and congeners) and VBY-376. 
     
     
         20 . A product according to  claim 18  wherein the HCV protease inhibitor is selected from the group consisting of TMC435350 (TMC435), MK-7009 or ITMN-191 (R-7227). 
     
     
         21 . A product according to  claim 17  wherein the other HCV inhibitor is a HCV nucleoside or non-nucleoside polymerase inhibitor. 
     
     
         22 . A product according to  claim 21  wherein the HCV polymerase inhibitor is selected from the group consisting of R7128, PSI-7851, PSI 7977, IDX-189, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728, GL-60667, ABT-072, AZD-2795 and 13-cyclohexyl-3-methoxy-17,23-dimethyl-7H-10,6-(methanoiminothioiminoethanooxyethanoiminomethano)indolo[2,1-a][2]benzazepine-14,24-dione 16,16-dioxide. 
     
     
         23 . A product according to  claim 21  wherein the HCV polymerase inhibitor is PSI-6130 or a prodrug thereof. 
     
     
         24 . A product according to  claim 21  wherein the HCV polymerase inhibitor is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         25 . A product comprising (a) a compound according to  claim 1 , and (b) an immunomodulatory agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections.