Activating pyruvate kinase r and mutants thereof

Abstract

The disclosure provides chemical compounds useful as activators of PKR. PKR activating compounds are useful in the treatment of disease and disorders associated with modulation of PKR and/or PKM2, such as pyruvate kinase deficiency (PKD).

We claim: 
     
         1 . A method of making Compound 1 comprising the step of reacting 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (Intermediate B) with (R)-2-hydroxy-2-phenylacetic acid in a reaction mixture to obtain Compound 1: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , further comprising the step of preparing a HCl salt of Intermediate B by reacting tert-butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate A) in a reaction mixture comprising HCl/dioxane and dichloromethane to obtain the 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole HCl. 
     
     
         3 . The method of  claim 2 , further comprising the step of preparing Intermediate A by reacting tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate HCl in a reaction mixture comprising pyridine-2-sulfonyl chloride and TEA to obtain tert-butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate HCl. 
     
     
         4 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         5 . The compound of  claim 4 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         6 . The compound of  claim 4 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         7 . The compound of  claim 6 , comprising the hydrochlorate salt of Intermediate B. 
     
     
         8 . A composition comprising the compound tert-Butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate A) or a salt thereof. 
     
     
         9 . The composition of  claim 8 , wherein the composition is a reaction mixture comprising tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate or a salt thereof, pyridine-2-sulfonyl chloride, TEA and tert-butyl 5-(pyridine-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate A) or a salt thereof. 
     
     
         10 . The composition of  claim 8 , wherein the composition is a reaction mixture comprising tert-butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate A) or a salt thereof, HCl/dioxane, dichloromethane and 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (Intermediate B) or a salt thereof. 
     
     
         11 . A composition comprising the compound 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (Intermediate B) or a salt thereof. 
     
     
         12 . The composition of  claim 12 , wherein the composition is a reaction mixture comprising 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (Intermediate B) or a salt thereof, (R)-2-hydroxy-2-phenylacetic acid and Compound 1