Inhibitor of indoleamine 2,3-dioxygenase-1 and methods of manufacture and use thereof

Abstract

Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other severe diseases such as Alzheimer's disease and arthritis. Small molecule inhibitors of IDO, syntheses, and uses thereof are provided.

1 - 7 . (canceled) 
     
     
         8 . A method of treating a disease associated with tryptophan metabolism in a subject, the method comprising administering a therapeutically effective amount to a subject of a compound, or a pharmaceutically acceptable salt thereof, of either of Formulas I: 
       
         
           
           
               
               
           
         
       
       wherein
 X is H, F, Cl, or Br; 
 R 1  is piperidin-2-yl, 1-phenylmethan-1 -yl-1-ol, pyrrol-2-yl, or 
 
       
         
           
           
               
               
           
         
         and R 2 , R 3 , R 4 , R 5 , and R 6  are each independently H, F, Cl, amino, hydroxy, alkoxy, cyano, trifluoromethyl, or phenyl. 
       
     
     
         9 . The method of  claim 8  in which the disease is cancer. 
     
     
         10 . The method of  claim 9  in which the disease is glioblastoma multiforme. 
     
     
         11 . The method of  claim 8  in which the disease is neurodegeneration. 
     
     
         12 . The method of  claim 11  in which the disease is Alzheimer's disease. 
     
     
         13 - 19 . (canceled) 
     
     
         20 . The method of  claim 8 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 20 , wherein R 4  is H, F, Cl, amino, hydroxy, alkoxy, cyano, trifluoromethyl, or phenyl; and R 2 , R 3 , R 5 , and R 6  are each independently H, F, Cl, amino, or hydroxy. 
     
     
         22 . The method of  claim 21 , wherein R 4  is H, F, Cl, amino, hydroxy, methoxy, or cyano. 
     
     
         23 . The method of  claim 22 , wherein the compound is of Formula Ia; X is Br; R 4  is H, methoxy, or cyano; R 2  is H, amino, or hydroxy; and R 3 , R 5 , and R 6  are each H. 
     
     
         24 . The method of  claim 22 , wherein the compound is of Formula Ib; X is F or Br; R 6  is H; R 5  is H, F, or Cl; R 3  and R 4  are each H, Cl, or hydroxy; and R 2  is H or hydroxy. 
     
     
         25 . The method of  claim 8 , wherein the compound is of Formula 1b, R 1  is pyrrol-2-yl, and X is F or Br.