Benzoxazine derivatives and uses thereof

Abstract

The present invention provides a compound of the formula: a pharmaceutically acceptable salt or a prodrug thereof, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Y, Z 1 , m, n, and p are as defined herein. The present invention also provides compositions comprising, methods for using, and methods for preparing Compound of Formula I.

1 - 69 . (canceled) 
     
     
         70 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt or a prodrug thereof, 
       wherein
 m is an integer from 0 to 2; 
 each of n and p is independently an integer from 2 to 3; 
 Y is —S(O 2 )— or —S(O 2 )—N(R 10 )—, where R 10  is hydrogen or lower alkyl; 
 Z 1  is CH or N; 
 each of R 1  and R 2  is independently hydrogen or alkyl; 
 R 3  is alkyl, aryl, haloalkyl, heterocyclyl, or heteroaryl; 
 each R 4  is independently halo, alkyl, haloalkyl, alkoxy, cyano, —SO 2 R a , —C(═O)—NR b R c , —SO 2 —NR b R c , —SR b , —N(R b )—C(═O)—R c , —C(═O)—R b , or —N(R b )—SO 2 —R a ,
 where
 each R a  is independently alkyl or haloalkyl, and 
 each of R b  and R c  is independently hydrogen, alkyl, or haloalkyl; 
 
 
 each of R 5 , R 6 , R 7 , and R 8  is independently hydrogen or alkyl; and 
 R 9  is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or benzyl; or R 9  and one of R 5 , R 6 , R 7 , or R 8  together with the atoms to which they are attached form a heterocycloamino ring with 5 to 7 ring atoms. 
 
     
     
         71 . The compound according to  claim 70 , wherein Z 1  is N. 
     
     
         72 . The compound according to  claim 71  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , m, n, p, and Y are as defined in  claim 71 . 
 
     
     
         73 . The compound according to  claim 71  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , m, n, p, and Y are as defined in  claim 71 . 
 
     
     
         74 . The compound according to  claim 73 , wherein n and p are 2. 
     
     
         75 . The compound according to  claim 74 , wherein Y is —SO 2 —. 
     
     
         76 . The compound according to  claim 75 , wherein R 1  and R 2  are hydrogen. 
     
     
         77 . The compound according to  claim 76 , wherein each R 4  is independently halo or alkyl. 
     
     
         78 . The compound according to  claim 77 , wherein each R 4  is independently chloro or methyl. 
     
     
         79 . The compound according to  claim 78 , wherein m is 1. 
     
     
         80 . The compound according to  claim 79 , wherein R 3  is aryl. 
     
     
         81 . The compound according to  claim 80 , wherein R 3  is optionally substituted phenyl or optionally substituted naphthyl. 
     
     
         82 . The compound according to  claim 81 , wherein R 3  is phenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-methanesulfonylaminophenyl, 2-methanesulfonylphenyl, 2-carbamoylphenyl, 3-methanesulfonylphenyl, 4-methanesulfonylphenyl, 3-fluorophenyl, naphthyl, 2,4-difluorophenyl, 2-cyanophenyl, 2-chloro-4-fluorophenyl, 2-methyl-5-fluorophenyl, or 5-chloronaphthyl. 
     
     
         83 . The compound according to  claim 81 , wherein R 3  is phenyl or halide substituted phenyl. 
     
     
         84 . The compound according to  claim 83 , wherein R 3  is phenyl, 2-chlorophenyl or 2-fluorophenyl. 
     
     
         85 . A method for producing a compound of  claim 71 , said method comprising:
 (a) contacting an aryl halide of the formula:   
       
         
           
           
               
               
           
         
       
       with a heterocyclyl of the formula: 
       
         
           
           
               
               
           
         
       
       in the presence of a coupling catalyst to produce a heterocyclyl-substituted phenyl of the formula: 
       
         
           
           
               
               
           
         
         (b) deprotecting the heterocyclyl-substituted phenyl to produce a deprotected heterocyclyl-substituted phenyl of the formula: 
       
       
         
           
           
               
               
           
         
       
       and
 (c) contacting the deprotected heterocyclyl-substituted phenyl with a compound of the formula:
   R 3 —Y—W
 
 
 
       to produce the compound of  claim 71 , 
       wherein
 R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , m, n, and p are as defined in  claim 71 ; 
 W is an activating group; 
 R 11  is a nitrogen protecting group; and 
 X 1  is a halide. 
 
     
     
         86 . A method for producing a compound of  claim 71 , said method comprising:
 (a) contacting a halogenated aryl of the formula:   
       
         
           
           
               
               
           
         
       
       with a compound of the formula:
   R 3 —Y—W
 
 
       to produce a halogenated phenyl compound of the formula: 
       
         
           
           
               
               
           
         
       
       and
 (b) coupling the halogenated phenyl compound with a heterocyclyl compound of the formula: 
 
       
         
           
           
               
               
           
         
       
       in the presence of a coupling catalyst to produce the compound of  claim 71 , 
       wherein
 Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , m, n, and p are as defined in  claim 71 ; 
 W is an activating group; and 
 X 1  is a halide.
 A composition comprising: 
 
 (a) a therapeutically effective amount of a compound of  claim 70 ; and 
 (b) a pharmaceutically acceptable carrier. 
 
     
     
         87 . A method for treating a CNS disease state in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of  claim 70 .