Tetrasubstituted Benzenes

Abstract

Tetrasubstituted benzenes that act as modulators of gamma secretase and their use in the treatment of one or more symptoms of treating neurodegenerative disorders, e.g., Alzheimer's disease, are described.

1 - 62 . (canceled) 
     
     
         63 . A method for making ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)acetate, the method comprising contacting the compound of formula 
       
         
           
           
               
               
           
         
       
       with a 4-trifluoromethylphenyl reagent to provide a compound of formula 
       
         
           
           
               
               
           
         
       
     
     
         64 . The method of  claim 63 , wherein the 4-trifluoromethylphenyl reagent is 4-trifluoromethylphenyl boronic acid. 
     
     
         65 . The method of  claim 63 , wherein the reaction is conducted in the presence of a catalyst. 
     
     
         66 . The method of  claim 65 , wherein the catalyst is a palladium(0) catalyst. 
     
     
         67 . The method of  claim 63 , wherein the reaction is conducted in a presence of a base. 
     
     
         68 . The method of  claim 67 , wherein the base is potassium carbonate. 
     
     
         69 . The method of  claim 63 , further comprising isolating the product. 
     
     
         70 . A method for making ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-3-cyclobutylpropanoate, the method comprising contacting the compound of formula 
       
         
           
           
               
               
           
         
       
       with a cyclobutylmethyl reagent to provide the compound of formula 
       
         
           
           
               
               
           
         
       
     
     
         71 . The method of  claim 70 , wherein the cyclobutylmethyl reagent is cyclobutylmethyl halide. 
     
     
         72 . The method of  claim 71 , wherein cyclobutylmethyl halide is cyclobutylmethyl bromide. 
     
     
         73 . The method of  claim 70 , wherein the reaction is conducted in the presence of a deprotonating base. 
     
     
         74 . The method of  claim 73 , wherein the deprotonating base is sodium hydride. 
     
     
         75 . The method of  claim 70 , further comprising isolating the product. 
     
     
         76 . A method for making 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-3-cyclobutylpropanoic acid, the method comprising contacting the compound of formula 
       
         
           
           
               
               
           
         
       
       with a hydrolyzing reagent followed by acidification to provide a compound of formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         77 . The method of  claim 76 , wherein the hydrolyzing reagent is a hydroxide reagent. 
     
     
         78 . The method of  claim 77 , wherein the hydroxide reagent is lithium hydroxide. 
     
     
         79 . The method of  claim 76 , wherein the reaction is conducted in the presence of methanol:tetrahydrofuran:water. 
     
     
         80 . The method of  claim 76 , wherein acidification comprises addition of an inorganic acid. 
     
     
         81 . The method of  claim 80 , wherein the inorganic acid is hydrochloric acid. 
     
     
         82 . The method of  claim 76 , further comprising isolating the product or a salt thereof.