Flavivirus inhibition by sultams and related compounds

Abstract

Disclosed herein are compounds, compositions and methods for treating or ameliorating flavivirus infections. This is particularly important because the present disclosure provides methods for treating flavivirus infections for which there is no effective vaccine.

1 . A method for inhibiting flavivirus replication, comprising contacting a virus with a compound of the formula 
       
         
           
           
               
               
           
         
         wherein X is —S—, —S(O)—, —SO 2 —, —CH 2 —, —N(R 3 )—, —C(O)— or —O—, 
         Y is —S—, —N(R 4 )—, —C(R 5 )(R 6 )—, or —O—; 
         Z is S, N or O; 
         J is N or C(R 7 ); 
         A is —N(R 8 )(R 9 ), —OR 8  or —CR 9 R 10 R 11 ; 
         G is N or CH; 
         R 1  is selected from H, lower alkyl, aralkyl, aryl, halogen and halo alkyl; 
         R 2  is selected from lower alkyl, aralkyl, aryl; 
         R 3 , R 4 , R 5 , R 6  and R 7  independently are selected from H, lower alkyl, heteroalkyl, heterocyclyl, aralkyl and aryl 
         R 8  and R 9  independently are selected from lower alkyl, heteroalkyl, heterocyclyl, aralkyl and aryl; and 
         R 10  and R 11  independently are selected from H, lower alkyl, heteroalkyl, heterocyclyl, aralkyl and aryl. 
       
     
     
         2 . The method of  claim 1 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
         wherein X is —S—, —S(O)—, —SO 2 —, —N— or —O—; 
         Y is —S—, —N— or —O—; 
         Z is S, N or O; 
         A is —N(R 8 )(R 9 ) or —OR 8 ; 
         R 1  is selected from H, lower alkyl, aralkyl, aryl, halogen and halo alkyl; 
         R 2  is selected from lower alkyl, aralkyl, aryl; and 
         R 8  and R 9  independently are selected from lower alkyl, heteroalkyl, heterocyclyl, aralkyl and aryl. 
       
     
     
         3 . The method of  claim 1 , wherein X is —S—, —S(O)— or —SO 2 —. 
     
     
         4 . The method of  claim 1 , wherein Y is —S—. 
     
     
         5 . The method of  claim 1 , wherein Z is S. 
     
     
         6 . The method of  claim 1 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
         wherein X is —S—, —S(O)—, —SO 2 —, —N— or —O—; 
         Y is —S—, —N— or —O—; 
         Z is S, N or O; 
         R 1  is selected from H, lower alkyl, aralkyl, aryl, halogen and halo alkyl; 
         R 2  is selected from lower alkyl, aralkyl, aryl; and 
         R 8  and R 9  independently are selected from lower alkyl, heteroalkyl, heterocyclyl, aralkyl and aryl. 
       
     
     
         7 . The method of  claim 1 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 ; R 2 ; R 8  and R 9  are as set forth above. 
     
     
         8 . The method of  claim 6 , wherein R 1  is selected from H, methyl, ethyl, propyl, isopropyl, benzyl and phenyl. 
     
     
         9 . The method of  claim 6 , wherein R 2  is selected from lower alkyl, lower haloalkyl, optionally substituted phenyl, optionally substituted benzyl and haloalkyl. 
     
     
         10 . The method of  claim 7 , wherein R 2  represents 
       
         
           
           
               
               
           
         
         wherein R 6  is independently selected for each n from aryl, halogen, haloalkyl, lower alkyl, alkoxy, hydroxy, and n is an integer of 0-5. 
       
     
     
         11 . The method of  claim 7 , wherein R 8  and R 9  are independently selected from lower alkyl, aryl and aralkyl. 
     
     
         12 . The method of  claim 7 , wherein R 8  and R 9  are independently selected from methyl, ethyl, isopropyl and t-butyl. 
     
     
         13 . The method of  claim 6 , wherein R 8  and R 9  are the same. 
     
     
         14 . The method of  claim 10 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
         wherein X, Y, Z, R 1  and n are as set forth above; 
         R 13  and R 14 , are for each m and p, independently selected from lower alkyl and halo; and 
         m and p independently are from 0-5. 
       
     
     
         15 . The method of  claim 10 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
         wherein R 12 , R 13  and R 14 , are for each m and p, independently selected from lower alkyl, halogen and haloalkyl; and 
         m and p independently are from 0-5. 
       
     
     
         16 . The method of  claim 15 , wherein n=m=p=0. 
     
     
         17 . The method of  claim 1 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 1 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 1 , wherein the compound is selected from the group consisting of N′-(1,1-dioxido-2-phenyl-1,4,2-dithiazolidin-3-ylidene)-N,N-diphenylthiourea; (2,5-dimethyl-1,1-dioxido-1,4,2-dithiazolidin-3-ylidene)bis(1-methylethyl)thiourea; [1,1-dioxido-2-(phenylmethyl)-1,4,2-dithiazolidin-3-ylidene]bis(1-methylethyl)-thiourea; (1,1-dioxido-2-phenyl-1,4,2-dithiazolidin-3-ylidene)-bis(phenylmethyl)-thiourea; and combinations thereof. 
     
     
         20 . A method of treating or ameliorating a viral infection in a subject, comprising
 identifying a subject either at risk of infection with or infected with a virus; and   administering to the subject an effective amount of a compound of the formula   
       
         
           
           
               
               
           
         
         wherein X is —S—, —S(O)—, —SO 2 —, —N— or —O—; 
         Y is —S—, —N— or —O—; 
         Z is S, N or O; 
         A is —N(R 3 )(R 4 ) or —OR 5 ; 
         R 1  is selected from H, lower alkyl, aralkyl, aryl, halogen and halo alkyl; 
         R 2  is selected from lower alkyl, aralkyl, aryl; and 
         R 3 , R 4  and R 5  independently are selected from lower alkyl, heteroalkyl, heterocyclyl, aralkyl and aryl.