Process for making hepatitis b core protein modulators

Abstract

The present disclosure provides, in part, a process for preparing compounds (I) having allosteric effector properties against Hepatitis B virus Cp.

What is claimed is: 
     
         1 .- 17 . (canceled) 
     
     
         18 . A process for preparing a compound represented by Formula VIII: 
       
         
           
           
               
               
           
         
         wherein w is 0, 1 or 2; 
         A is a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms each independently selected from the group consisting of S, N, and O; wherein said heteroaryl may optionally be substituted with one or more substituents selected from R f ; 
         R f  is independently selected, for each occurrence, from the group consisting of hydrogen, halogen, hydroxyl, cyano, R a R b N—, R a R b N-carbonyl-, R a R b N—SO 2 —, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) w —, (wherein w is 0, 1 or 2), C 1-6 alkylcarbonyl-N(R a )— and C 1-6 alkoxycarbonyl-N(R a )—; wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) w —, C 1-6 alkylcarbonyl-N(R a )—, C 1-6 alkoxycarbonyl-N(R a )— may be optimally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, and C 1-6 alkoxy; 
         R a  and R b  are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by me or more substituents selected from fluorine, hydroxyl, C 1-3 alkoxy; or R a  and R b , together with the nitrogen to which they are attached, may form a 4-6 membered heterocyclic ring; 
       
       comprising: 
       coupling a compound of Formula IX: 
       
         
           
           
               
               
           
         
       
       with a compound of Formula X: 
       
         
           
           
               
               
           
         
       
       to provide a compound of Formula XI: 
       
         
           
           
               
               
           
         
       
       optionally oxidizing the compound of Formula XI to provide a compound of Formula XII: 
       
         
           
           
               
               
           
         
         wherein w is 1 or 2; 
       
       reducing the compound of Formula XII to provide a compound of Formula XIII: 
       
         
           
           
               
               
           
         
         wherein w is 1 or 2; 
       
       hydrolyzing the compound of Formula XIII to provide a compound of Formula XIV: 
       
         
           
           
               
               
           
         
       
       cyclizing the compound of Formula XIV to provide a tricyclic compound of Formula VII: 
       
         
           
           
               
               
           
         
       
       and 
       amidating the compound of Formula VII to provide the compound of Formula VIII. 
     
     
         19 . The process of  claim 18 , wherein coupling the compound of Formula IX with the compound of Formula X is conducted in the presence of a base. 
     
     
         20 . The process of  claim 18 , wherein the base is cesium carbonate. 
     
     
         21 . The process of  claim 18 , wherein oxidizing the compound of Formula XI comprises contacting the compound of Formula XI with aqueous hydrogen peroxide. 
     
     
         22 . The process of  claim 18 , wherein oxidizing the compound of Formula XI comprises contacting the compound of Formula XI with sodium metaperiodate and catalytic ruthenium (III) chloride. 
     
     
         23 . The process of  claim 18 , wherein reducing the compound of Formula XII comprises contacting the compound of Formula XII with Pd/C under hydrogen gas. 
     
     
         24 . The process of  claim 18 , wherein hydrolyzing the compound of Formula XIII comprises contacting the compound of Formula XIII with an aqueous base. 
     
     
         25 . The process of  claim 24 , wherein the aqueous base is aqueous lithium hydroxide. 
     
     
         26 . The process of  claim 18 , wherein cyclizing the compound of Formula XIV comprises contacting the compound of Formula XIV with carbodiimidazole. 
     
     
         27 . The process of  claim 18 , wherein amidating the compound of Formula VII comprises contacting the compound of Formula VII with a primary amine represented by A-CH 2 —NH 2  in the presence of a coupling agent. 
     
     
         28 . The process of  claim 27 , wherein the coupling agent is hydroxy benzotriazole/ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochloride. 
     
     
         29 . The process of  claim 27 , wherein the primary amine is represented by: 
       
         
           
           
               
               
           
         
       
       wherein R f  is C 1-6 alkyl optionally substituted by one or more fluorine atoms. 
     
     
         30 . The process of  claim 27 , wherein the primary amine is: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The process of  claim 18 , wherein the compound of Formula VII is: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The process of  claim 18 , wherein the compound of Formula VIII is: 
       
         
           
           
               
               
           
         
       
     
     
         33 . A compound or pharmaceutically acceptable salt thereof, represented by: 
       
         
           
           
               
               
           
         
       
       prepared by the process of  claim 18 .