Modulators of virus assembly as antiviral agents

Abstract

In addition to containing and protecting the viral genome, the capsid (protein shell) of hepatitis B virus (HBV) plays critical roles in the viral life cycle including regulation of intracellular trafficking and nucleic acid metabolism. Substituted pyrimidine modulators of the assembly of the HBV capsid structure and methods for their use are described.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 Ar 1  is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; 
 R 1  is hydrogen or pro-drug forming group; 
 Ak is alkylene; 
 Z is 
 
       
         
           
           
               
               
           
         
         where X is CHN 3 , C═O, C═NR 5 , —C(O)N(R N )—, or NR N , where R 5  is hydroxy or a derivative thereof or amino or a derivative thereof, and R N  is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, arylalkyl, heteroarylalkyl, alkyl-C(O), heteroalkyl-C(O), alkoxyl-C(O), alkynyl-C(O), alkylacylamino-C(O), and heteroalkylacylamino-C(O), each of which is optionally substituted; 
         R 4  is alkyl, heteroalkyl, alkenyl, or alkynyl, each of which is optionally substituted; 
         Y is O, or HN; 
         R A  represents from 0 to 3 substituents independently selected in each instance from the group consisting of halo, and alkyl, heteroalkyl, aryl, heteroaryl, amino and derivatives thereof, and hydroxyl and derivatives thereof, each of which is optionally substituted; 
         R B  represents from 0 to 3 substituents independently selected in each instance from the group consisting of halo, and alkyl, heteroalkyl, aryl, heteroaryl, amino and derivatives thereof, and hydroxyl and derivatives thereof, each of which is optionally substituted; and where the compound is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1  wherein R A  represents 2-cholor-4-fluoro. 
     
     
         3 . The compound of  claim 1  wherein Ar 1  is 2-pyridyl. 
     
     
         4 . The compound of  claim 1  wherein R B  represents 0 substituents. 
     
     
         5 . The compound of  claim 1  wherein Y is O. 
     
     
         6 . The compound of  claim 1  wherein R 4  is methyl. 
     
     
         7 . The compound of  claim 1  wherein Ak is methylene. 
     
     
         8 . The compound of  claim 7  wherein X is C═O, —C(O)N(R N )—, or NR N . 
     
     
         9 . The compound of  claim 8  wherein X is C═O. 
     
     
         10 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein;
 Ar 2  is aryl or heteroaryl; 
 R 1  is hydrogen or a pro-drug forming group; 
 R 4  is alkyl, heteroalkyl, alkenyl, or alkynyl, each of which is optionally substituted; 
 Y is O, or HN; 
 R 6  is in each instance independently selected from the group consisting of hydrogen and Ak-Z 1 , where Ak is alkylene, and Z 1  is hydrogen or NR 2 R 3 ; where R 2  and R 3  are independently in each instance selected from the group consisting of hydrogen, and alkyl, cycloalkyl, heteroalkyl and heterocycloalkyl, each of which is optionally substituted, or 
 R 2  and R 3  are taken together with the attached nitrogen to form 
 
       
         
           
           
               
               
           
         
         wherein X is CHN 3 , C═O, —C(O)N(R Na )—, C═NR 5 , or NR Na ; where R 5  is hydroxy or a derivative thereof or amino or a derivative thereof; and R Na  is selected from the group consisting of hydrogen, and alkyl, alkenyl, alkynyl, heteroalkyl, arylalkyl, heteroarylalkyl, alkyl-C(O), heteroalkyl-C(O), alkoxyl-C(O), alkynyl-C(O), alkylacylamino-C(O), and heteroalkylacylamino-C(O), each of which is optionally substituted; 
         Ak 1  is (CH 2 )n, where n is 1 to 4; 
         R A  represents from 0 to 3 substituents independently selected in each instance from the group consisting of halo, and alkyl, heteroalkyl, aryl, heteroaryl, amino and derivatives thereof, and hydroxyl and derivatives thereof, each of which is optionally substituted; and 
         R B  represents from 0 to 3 substituents independently selected in each instance from the group consisting of halo, and alkyl, heteroalkyl, aryl, heteroaryl, amino and derivatives thereof, and hydroxyl and derivatives thereof, each of which is optionally substituted. 
       
     
     
         11 . The compound of  claim 10  wherein R 6  is methyl. 
     
     
         12 . The compound of  claim 10  wherein R 6  is 
       
         
           
           
               
               
           
         
         where X is CHN 3 , C=0, —C(O)N(R Na )—, C═NR 5 , or NR Na ; where R 5  is hydroxy or a derivative thereof or amino or a derivative thereof, and R Na  is hydrogen or alkyl, alkenyl, alkynyl, heteroalkyl, arylalkyl, heteroarylalkyl, alkyl-C(O), heteroalkyl-C(O), alkoxyl-C(O), alkynyl-C(O), alkylacylamino-C(O), or heteroalkylacylamino-C(O), each of which is optionally substituted. 
       
     
     
         13 . The compound of  claim 12  wherein X is C═O, —C(O)N(R Na )—, or NR Na , where R Na  is hydrogen or alkyl, alkenyl, alkynyl, heteroalkyl, arylalkyl, heteroarylalkyl, alkyl-C(O), heteroallcyl-C(O), alkylacylamino-C(O), and heteroalkylacylamino-C(O), each of which is optionally substituted. 
     
     
         14 . The compound of  claim 13  wherein X is C═O. 
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of  claim 1  for treating hepatitis B. 
     
     
         16 . (canceled) 
     
     
         17 . A method for treating a patient in need of relief from infection by hepatitis B virus, the method comprising the step of administering to the patient a therapeutically effective amount of one or more compounds of  claim 1 , wherein the method for treating ameliorates at least one symptom of infection of hepatitis B virus in the patient or inhibits chronic infection by hepatitis B virus in the patient. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 17  wherein the infection is a chronic infection or an acute infection. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 17  wherein the compound activates assembly of a virus core, disrupting the normal timing of virus production in an infected cell, and/or stabilizes existing capsids in an infected cell, inhibiting dissociation of the virus core and release of a viral genome in the cell's nucleus. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 17  wherein the compound affects the viral lifecycle by inducing assembly of the viral core lowering the concentration of unassembled hepatitis B virus capsin protein and inhibiting a non-structural activity of the capsid protein. 
     
     
         24 . The method of  claim 17  wherein the compound acts on the viral lifecycle by binding to free capsid protein dimer inhibiting a capsid protein non-structural activity.