Benzimidazoles and Methods of Using Same

Abstract

The present disclosure is concerned with benzimidazole compounds and methods of using these compounds for the treatment of hepatitis (e.g., hepatitis C), RNA virus infections (e.g., Zika virus, dengue virus, Powassan virus, Chikungunya virus, Enterovirus, respiratory syntactical virus (RSV), Rift Valley fever, Influenza virus, Tacaribe virus, Mayaro virus, West Nile virus, yellow fever virus, and coronavirus), and disorders of uncontrolled cellular proliferation (e.g., cancer). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed is: 
     
         1 . A compound having a structure represented by a formula selected from: 
       
         
           
           
               
               
           
         
         wherein   is a single or a double covalent bond; 
         wherein n is 0 or 1; 
         wherein Z, when present, is selected from N and CR 10 ;
 wherein R 10 , when present, is selected from hydrogen and halogen; 
 
         wherein R 1  is selected from —(C1-C4 alkyl)OR 11 , —(C1-C4 alkyl)NR 12a R 12b , —CO 2 R 13 , and —C(O)NR 14a R 14b ;
 wherein each of R 11 , R 12a , and R 12b , when present, is independently selected from hydrogen, C1-C4 alkyl, —C(═NH)NH 2 , —CO 2 (C1-C4 alkyl), —(C1-C4 alkyl)OR 20 , —(C1-C4 alkyl)NR 21a R 21b , —(C1-C4 alkyl)Ar 1 , and Ar 1 ;
 wherein Ar 1 , when present, is selected from aryl and heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 
 
 wherein each of R 13 , R 14a , and R 14b , when present, is independently selected from hydrogen and C1-C4 alkyl; 
 
         wherein R 2 , when present, is selected from C1-C4 alkyl and —(C1-C4 alkyl)NR 15a R 15b ;
 wherein each of R 15a  and R 15b , when present, is independently selected from hydrogen and C1-C4 alkyl; 
 
         wherein R 3  is selected from hydrogen and C1-C4 alkyl; 
         or wherein each of R 2 , when present, and R 3  together comprise a 5- to 6-membered heterocycle substituted with a group selected from C1-C4 alkyl and —(C1-C4 alkyl)NR 16a R 16b ;
 wherein each of R 16a  and R 16b , when present, is independently selected from hydrogen and C1-C4 alkyl; and 
 
         wherein Ar 2  is a heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, 
         provided that when the compound has a structure represented by a formula: 
       
       
         
           
           
               
               
           
         
         then either   is a double bond, Z is CR 10 , or R 2  is C1-C4 alkyl, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein,   is a double covalent bond. 
     
     
         3 . The compound of  claim 1 , n is 0. 
     
     
         4 . The compound of  claim 1 , wherein Z is CR 10 . 
     
     
         5 . The compound of  claim 1 , wherein R 1  is selected from —(C1-C4 alkyl)NR 12a R 12b  and —C(O)NR 14a R 14b . 
     
     
         6 . The compound of  claim 1 , wherein R 1  is —(C1-C4 alkyl)NR 12a R 12b . 
     
     
         7 . The compound of  claim 1 , wherein R 1  is —CH 2 NR 12a R 12b . 
     
     
         8 . The compound of  claim 1 , wherein R 1  is —CH 2 NMe 2 . 
     
     
         9 . The compound of  claim 1 , wherein R 1  is selected from —CO 2 R 13  and —C(O)NR 14a R 14b . 
     
     
         10 . The compound of  claim 1 , wherein R 1  is selected from —CO 2 Me and —C(O)NMe 2 . 
     
     
         11 . The compound of  claim 1 , wherein R 2  is —(C1-C4 alkyl)NR 15a R 15b . 
     
     
         12 . The compound of  claim 1 , wherein R 2  is —(C1-C4 alkyl)NMe 2 . 
     
     
         13 . The compound of  claim 1 , wherein Ar 2  is 5-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
     
     
         14 . The compound of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A method for treating hepatitis in a subject, the method comprising administering to the subject an effective amount of the compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein hepatitis is hepatitis C. 
     
     
         18 . A method for treating a RNA virus infection in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula selected from: 
       
         
           
           
               
               
           
         
         wherein   is a single or a double covalent bond; 
         wherein n is 0 or 1; 
         wherein Z, when present, is selected from N and CR 10 ;
 wherein R 10 , when present, is selected from hydrogen and halogen; 
 
         wherein R 1  is selected from —(C1-C4 alkyl)OR 11 , —(C1-C4 alkyl)NR 12a R 12b , —CO 2 R 13 , and —C(O)NR 14a R 14b ;
 wherein each of R 11 , R 12a , and R 12b , when present, is independently selected from hydrogen, C1-C4 alkyl, —C(═NH)NH 2 , —CO 2 (C1-C4 alkyl), —(C1-C4 alkyl)OR 20 , —(C1-C4 alkyl)NR 21a R 21b , —(C1-C4 alkyl)Ar 1 , and Ar 1 ;
 wherein Ar 1 , when present, is selected from aryl and heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 
 
 wherein each of R 13 , R 14a , and R 14b , when present, is independently selected from hydrogen and C1-C4 alkyl; 
 
         wherein R 2 , when present, is selected from C1-C4 alkyl and —(C1-C4 alkyl)NR 15a R 15b ;
 wherein each of R 15a  and R 15b , when present, is independently selected from hydrogen and C1-C4 alkyl; 
 
         wherein R 3  is selected from hydrogen and C1-C4 alkyl; 
         or wherein each of R 2 , when present, and R 3  together comprise a 5- to 6-membered heterocycle substituted with a group selected from C1-C4 alkyl and —(C1-C4 alkyl)NR 16a R 16b ;
 wherein each of R 16a  and R 16b , when present, is independently selected from hydrogen and C1-C4 alkyl; 
 
         wherein each of R 4  and R 5  is hydrogen or together comprise a 5- to 6-membered heterocycle; and 
         wherein Ar 2  is a heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, 
         provided that when each of R 4  and R 5  is hydrogen, then R is —(C1-C4 alkyl)OR 11  or —(C1-C4 alkyl)NR 12a R 12b , 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . The method of  claim 18 , wherein the RNA virus is selected from Zika virus, dengue virus, Powassan virus, Chikungunya virus, Enterovirus, respiratory syntactical virus (RSV), Rift Valley fever, Influenza virus, Tacaribe virus, Mayaro virus, West Nile virus, yellow fever virus, and coronavirus. 
     
     
         20 . The method of  claim 19 , wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).