1,2,5-Oxadiazoles As Inhibitors Of Indoleamine 2,3- Dioxygenase

Abstract

The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.

1 .- 174 . (canceled) 
     
     
         175 . A process for preparing a compound of Formula F15: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein R 2  is Cl, Br, CF 3 , CH 3 , or CN; R 3  is H or F; and n is 1 or 2, comprising:
 a) reacting a compound of Formula F13: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein Pg 1  is an amino protecting group, with an amino deprotecting agent to afford a compound of Formula F14: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; and
 b) reacting said compound of Formula F14 with a base to afford said compound of Formula F15. 
 
     
     
         176 . The process of  claim 175 , wherein R 2  is Br, R 3  is F, and n is 1. 
     
     
         177 . The process of  claim 175 , wherein:
 said Pg 1  is tert-butoxycarbonyl;   said amino deprotecting agent is trifluoroacetic acid or hydrochloric acid;   said reacting is performed in a solvent comprising dioxane and/or isopropanol; and   said base is sodium hydroxide.   
     
     
         178 . The process of  claim 175 , wherein said compound of Formula F13 is obtained by treating a compound of Formula F12: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, with Pg 1 -NH-sulfonyl chloride followed by treatment with an organic base to afford said compound of Formula F13. 
     
     
         179 . The process of  claim 178 , wherein:
 said Pg 1  comprises tert-butoxycarbonyl;   said treating is performed in dichloromethane; and   said organic base is triethylamine.   
     
     
         180 . The process of  claim 178 , wherein said compound of Formula F12 is obtained by reducing a compound of Formula F11: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         181 . The process of  claim 180 , wherein said reducing is carried out in the presence of sodium iodide, chlorotrimethylsilane, and methanol. 
     
     
         182 . The process of  claim 180 , further comprising purifying said compound of Formula F12 by:
 a) reacting said compound of Formula F12 with an amino protecting agent to afford a compound of Formula F12′:   
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein Pg 2 N is a protected amine;
 b) purifying said compound of Formula F12′ to provide a purified compound of Formula F12′; and 
 c) reacting said purified compound of Formula F12′ with an amino deprotecting agent to provide a purified compound of Formula F12. 
 
     
     
         183 . The process of  claim 182 , wherein:
 said amino protecting agent is di-t-butyl dicarbonate;   said purifying is performed by chromatography on silica gel;   said amino deprotecting agent is hydrochloric acid; and   said reacting is performed in a solvent comprising dioxane and/or isopropanol.   
     
     
         184 . The process of  claim 180 , wherein said compound of Formula F11 is obtained by treating a compound of Formula F10: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein L 1  is selected from alkylsulfonyl, haloalkylsulfonyl, and arylsulfonyl; with an azide reagent to afford said compound of Formula F11. 
     
     
         185 . The process of  claim 184 , wherein:
 L 1  is methanesulfonyl; and   said azide reagent is sodium azide.   
     
     
         186 . The process of  claim 178 , wherein said compound of Formula F12 is obtained by reacting a compound of Formula F24: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein Pg 3 N is a protected amine; with an amino deprotecting agent to afford said compound of Formula F12. 
     
     
         187 . The process of  claim 186 , wherein said protected amine is (C 6 H 5 ) 3 C—NH or (C 6 H 5 ) 2 C═N. 
     
     
         188 . The process of  claim 186 , wherein said deprotecting agent comprises:
 a) an organic acid; or   b) an organic acid and an organosilane.   
     
     
         189 . The process of  claim 188 , wherein said organosilane is tri(isopropyl)silane. 
     
     
         190 . The process of  claim 188 , wherein said organic acid is trifluoroacetic acid. 
     
     
         191 . The process of  claim 186 , wherein said compound of Formula F24 is obtained by treating a compound of Formula F22: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, with a compound of Formula F25: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein Pg 3 N is a protected amine; and a coupling reagent to provide said compound of Formula F24. 
     
     
         192 . The process of  claim 191 , wherein said protected amine is (C 6 H 5 ) 3 C—NH or (C 6 H 5 ) 2 C═N. 
     
     
         193 . The process of  claim 191 , wherein said compound of Formula F22 is obtained by
 a) treating a compound of Formula F21:   
       
         
           
           
               
               
           
         
       
       or a salt thereof, with carbonyl diimidazole to afford a compound of Formula F26: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; and
 b) treating said compound of Formula F26 with trifluoroacetic anhydride to afford said compound of Formula F22. 
 
     
     
         194 . A process for preparing a compound of Formula F15: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein R 2  is Cl, Br, CF 3 , CH 3 , or CN; R 3  is H or F; and n is 1 or 2, comprising:
 a) reacting a compound of Formula F12: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof, with sulfamide and an organic base to afford a compound of Formula F14: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, and
 b) reacting said compound of Formula F14, or a salt thereof, with a base to afford said compound of Formula F15. 
 
     
     
         195 . The process of  claim 194 , wherein:
 said organic base is pyridine;   said reacting of a compound of Formula F12 further comprises heating the reaction; and   said base is sodium hydroxide.   
     
     
         196 . A compound of Formula F12: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein R 2  is Cl, Br, CF 3 , CH 3 , or CN; R 3  is H or F; and n is 1 or 2. 
     
     
         197 . The compound of  claim 196 , wherein R 2  is Br, R 3  is F, and n is 1. 
     
     
         198 . A compound of Formula F14: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein R 2  is Cl, Br, CF 3 , CH 3 , or CN; R 3  is H or F; and n is 1 or 2. 
     
     
         199 . The compound of  claim 198 , wherein R 2  is Br, R 3  is F, and n is 1.