Prevention and/or treatment of cns disorders

Abstract

Adenosine receptor (e.g., A2A and/or A1 receptor) antagonist compounds and compositions including said compounds are disclosed. The present disclosure also provides methods of using said compounds and compositions for modulating (e.g., inhibiting or antagonizing) A2A and/or A1 receptor in a biological system. The compounds and compositions find use in various therapeutic applications including the treatment of central nervous system or neurodegenerative diseases, such as Parkinson's disease. The compounds and compositions may also find use in various therapeutic applications including the treatment of cancer and in immuno-oncology.

1 . A method of treating a parkinsonism in a subject in need thereof or for ameliorating a symptom of parkinsonism of a subject in need thereof, comprising administering an effective amount of a compound of formula (II): 
       
         
           
           
               
               
           
         
         R 1  is selected from (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, substituted (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, substituted (C 2 -C 8 )alkynyl, (C 1 -C 3 )haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )alkoxy, —CONH 2 , substituted amido, —NH 2 , substituted amino, —CO 2 H, cyano, halogen, hydroxyl, —NO 2 , —SO 3 H, —SO 2 NH 2 , substituted sulfonamide, and thiol; 
         R 2  to R 9  are independently selected from H, (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, substituted (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, substituted (C 2 -C 8 )alkynyl, (C 1 -C 3 )haloalkyl, (C 1 -C 8 )alkoxy, substituted (C 1 -C 8 )alkoxy, —CONH 2 , substituted amido, —NH 2 , substituted amino, —CO 2 H, cyano, halogen, hydroxyl, —NO 2 , —SO 3 H, —SO 2 NH 2 , substituted sulfonamide, and thiol, 
         or a solvate, a hydrate, a prodrug, and/or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 
         to the subject. 
       
     
     
         2 . The method of  claim 1 , wherein R 1  is (C 1 -C 5 )alkyl, substituted (C 1 -C 5 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 )alkoxy, —NH 2 , substituted amino, halogen, and hydroxyl; and
 R 2  to R 9  are independently selected from H, (C 1 -C 5 )alkyl, substituted (C 1 -C 5 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 )alkoxy, —NH 2 , substituted amino, halogen, and hydroxyl. 
 
     
     
         3 . The method of  claim 2 , wherein R 1  is selected from NH 2 , F, CH 3 , and CF 3 ; and
 R 2  to R 9  are independently selected from H, NH 2 , F, CH 3 , and CF 3 .   
     
     
         4 . The method of  claim 1 , wherein the compound is of formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 R 21  and R 22  are independently selected from H, (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl, SO 2 R 30 , and COR 30 , wherein R 30  is (C 1 -C 8 )alkyl, or substituted (C 1 -C 8 )alkyl. 
 
       
     
     
         5 . The method of  claim 1 , wherein
 R 21  and R 22  are each H;   R 5 , R 6 , R 8  and R 9  are independently selected from H, (C 1 -C 5 )alkyl, substituted (C 1 -C 5 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 8 )alkoxy, halogen, and hydroxyl.   R 2  to R 4  are each H; and   R 1  is selected from (C 1 -C 5 )alkyl, substituted (C 1 -C 5 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 5 )alkoxy, substituted (C 1 -C 5 )alkoxy, halogen, and hydroxyl.   
     
     
         6 . The method of  claim 5 , wherein R 1  is selected from F, CH 3 , and CF 3 . 
     
     
         7 . The method of  claim 1 , wherein the compound of formula (II) is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the subject suffers from an adenosine receptor associated disorder. 
     
     
         9 . The method of  claim 1 , wherein the symptom of parkinsonism is selected from the group consisting of bradykinesia, dystonia, tremor, myoclonus and startle, ataxia, dyskinesia, and gait disorders. 
     
     
         10 . The method of  claim 1 , wherein the subject has Parkinson's disease. 
     
     
         11 . The method of  claim 1 , wherein the subject has depression, epilepsy, or a combination thereof.