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 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 - 35 . (canceled)  
     
     
         36 . 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 the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein 
 m is an integer from 0 to 3;  
 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, or R 1  and R 2  together with the carbon to which they are attached may form a carbocyclic group with 3 to 6 ring atoms;  
 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)—, 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.  
 
 
     
     
         37 . The method of  claim 36 , wherein the disease state comprises psychoses, schizophrenia, manic depressions, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease.  
     
     
         38 . A method for treating memory disorders or Alzheimer's disease in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein 
 m is an integer from 0 to 3;  
 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, or R 1  and R 2  together with the carbon to which they are attached may form a carbocyclic group with 3 to 6 ring atoms;  
 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.  
 
 
     
     
         39 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein: 
 R 3  is alkyl, aryl, haloalkyl, heterocyclyl, or heteroaryl; and  
 R 9  is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or benzyl.  
 
 
     
     
         40 . The compound of  claim 39 , wherein R 3  is aryl or heteroaryl.  
     
     
         41 . The compound of  claim 40 , wherein R 9  is hydrogen or alkyl.  
     
     
         42 . The compound of  claim 41 , wherein R 3  is optionally substituted phenyl.  
     
     
         43 . The compound of  claim 42 , wherein R 9  is hydrogen or methyl.  
     
     
         44 . The compound of  claim 43 , wherein R 3  is phenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-methanesulfonylaminophenyl, 2-methanesulfonylphenyl, 2-carbamoylphenyl, 3-methanesulfonylphenyl, 4-methanesulfonylphenyl, 3-fluorophenyl, naphthylene-1-yl, 2,4-difluorophenyl, 2-cyanophenyl, 2-chloro-4-fluorophenyl, 5-fluoro-2-methylphenyl, 5-chloronaphthyl, naphthylene-2-yl, 4-fluoro-2-methylphenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 4-(piperazin-1-yl)-phenyl, or 2,3-dihydrobenzo[1,4]dioxinyl  
     
     
         45 . The compound of  claim 41 , wherein R 3  is optionally substituted heteroaryl.  
     
     
         46 . The compound of  claim 45 , wherein R 3  is quinolin-8-yl, thiophen-2-yl, 5-chlorothiophen-2-yl, isoquinolin-5-yl, 4-(Benzo[1,2,5]thiadiazole-4-yl, 1-methyl-1H-imidazole-4-yl, or 4-(Benzo[1,2,5]oxadiazole-4-yl.  
     
     
         47 . The compound of  claim 43 , wherein R 3  is 2-halophenyl.  
     
     
         48 . The compound of  claim 43 , wherein R 3  is 2-fluorophenyl.  
     
     
         49 . The compound of  claim 48 , wherein R 9  is hydrogen.  
     
     
         50 . A composition comprising: 
 (a) a therapeutically effective amount of a compound of  claim 39;  and    (b) a pharmaceutically acceptable carrier.