Neuroactive compounds and methods of using same

Abstract

The invention described herein relates generally to neuroactive compounds and compositions for the treatment psychotic disorders, methods for treating psychosis using these neuroactive compounds, and methods for screening for novel neuroactive compounds. Certain aspects are directed to a family of compounds called “finazines.” Certain aspects are directed to in vivo screening methods using high-throughput behavioral assays in zebrafish.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         L 1  is C 2  alkylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
 L 2  is a C 1 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
 R 1  is an aryl substituted with at least one halogen, nitro, alkyl or alkoxy; 
 R 2  is for each occurrence independently selected from the group consisting of C 1 -C 6  alkyl, halogen, alkyl, alkoxy, and cycloalkyl; 
 R 3  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; 
 m is 0, 1, 2, 3 or 4; and 
 n is 0, 1, 2, 3 or 4; or 
 
         (ii) L 1  is a bond, C 1 -C 6  alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
 L 2  is a bond, C 1 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
 R 1  is an heteroaryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
 R 2  is for each occurrence independently selected from the group consisting of C 1 -C 6  alkyl, halogen, alkyl, alkoxy, and cycloalkyl; 
 
         R 3  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
 m is 0, 1, 2, 3 or 4; and 
 n is 0, 1, 2, 3 or 4; or 
 
         (iii) L 1  is a bond, C 3 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
 L 2  is a bond, C 1 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
 R 1  is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
 R 2  is for each occurrence independently selected from the group consisting of C 1 -C 6  alkyl, halogen, alkyl, alkoxy, and cycloalkyl; 
 R 3  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; 
 m is 0, 1, 2, 3 or 4; and 
 n is 0, 1, 2, 3 or 4; or 
 
         (iv) L 1  is C 2  alkylene, which can be substituted with 1 or 2 independently selected substituents;
 L 2  is a C 1 -C 6  alkylene, which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
 R 1  is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
 R 2  is for each occurrence independently selected from the group consisting of C 1 -C 6  alkyl, halogen, alkyl, alkoxy, and cycloalkyl; 
 R 3  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; 
 m is 0, 1, 2, 3 or 4; and 
 n is 0, 1, 2, 3 or 4; or 
 
         (v) L 1  is C 2  alkylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
 L 2  is a bond, C 1 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
 R 1  is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
 R 2  is selected from the group consisting of C 1 -C 6  alkyl, halogen, alkyl, alkoxy, and cycloalkyl; 
 R 3  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; 
 m is 1; and 
 n is 0, 1, 2, 3 or 4; or 
 
         (vi) L 1  is a C 2  alkylene substituted with 1 or 2 independently selected substituents;
 L 2  is a bond, C 1 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
 R 1  is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
 R 2  is for each occurrence independently selected from the group consisting of C 1 -C 6  alkyl, halogen, alkyl, alkoxy, and cycloalkyl; 
 R 3  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; 
 m is 0, 1, 2, 3 or 4; and 
 n is 0, 1, 2, 3 or 4; or 
 
         (vii) L 1  is a bond, C 3 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
 L 2  is a C 3 -C 6  enone; 
 R 1  is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
 R 2  is for each occurrence independently selected from the group consisting of C 1 -C 6  alkyl, halogen, alkyl, alkoxy, and cycloalkyl; 
 R 3  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; 
 m is 0, 1, 2, 3 or 4; and 
 n is 0, 1, 2, 3 or 4. 
 
       
     
     
         2 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein:
 L 21  is a bond, C 3 -C 6  alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents; 
 L 22  is a bond, C 3 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
 R 21  is an aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
 R 23  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; and 
 p is 0, 1, 2, 3 or 4. 
 
       
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . An antipsychotic composition comprising a compound selected from the group consisting of:
 (i) compound of Formula I:   
       
         
           
           
               
               
           
         
         wherein: 
         L 1  is a bond, C 1 -C 6  alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents; 
         L 2  is a bond, C 1 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
         R 1  is aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
         R 2  is for each occurrence independently selected C 1 -C 6  alkyl, halogen, alkyl, alkoxy, and cycloalkyl; 
         R 3  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; 
         m is 0, 1, 2, 3 or 4; and 
         n is 0, 1, 2, 3 or 4; 
       
       (ii) compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         L 21  is a bond, C 3 -C 6  alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents; 
         L 22  is a bond, C 3 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
         R 21  is an aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents; 
         R 23  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; and 
         p is 0, 1, 2, 3 or 4; 
       
       (iii) compound of Formula III: 
       
         
           
           
               
               
           
         
         wherein: 
         L 31  is a bond, C 3 -C 6  alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents; 
         L 32  is a bond, C 3 -C 6  alkylene, C 2 -C 6  alkenylene or C 2 -C 6  alkynylene, each of which can be substituted with 1 or 2 independently selected substituents; 
         R 32  is for each occurrence independently selected from the group consisting of C 1 -C 6  alkyl, halogen, alkyl, alkoxy, cycloalkyl, and CO2R 34;    
         R 33  is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R 3  together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents; 
         R 34  is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents q is 0, 1, 2 3 or 4; 
         t is 0, 1, 2, 3 or 4; and 
         b is 1 or 2; and 
       
       (iv) any combination of (i)-(iii). 
     
     
         6 . (canceled) 
     
     
         7 . (canceled)