1-heterocyclyl isochromanyl compounds and analogs for treating cns disorders

Abstract

Disclosed are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, R a , R 1 , R 2 , R 3 , R 4 , R 6 , w and n1 are defined and described herein; compositions thereof; and methods of use thereof. These compounds are useful for treating a variety of neurological and psychiatric disorders, such as those described herein.

What is claimed is: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A is 
       
       
         
           
           
               
               
           
         
         m is 0, 1, or 2; 
         n1 is 1, 2, or 3; 
         R is —H or C 1 -C 3  alkyl; 
         R a  is —H or C 1 -C 3  alkyl; 
         R 1 , R 2 , R 3 , and R 4  are independently —H, halo, —OH, —NH 2 , C 1 -C 3  alkyl, —OR 7 , —NHR 7 , —N(R 7 )R 7 , —CN, phenyl, or 5- or 6-membered heteroaryl, wherein: 
         each instance of R 7  independently is unsubstituted C 1 -C 2  alkyl or C 1 -C 2  alkyl substituted with 1-3 halo, 
         each instance of C 1 -C 3  alkyl independently is unsubstituted or substituted with 1-3 halo, and 
         the phenyl or heteroaryl is unsubstituted or substituted with 1 or 2 groups independently selected from halo, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , ethyl, —CF 3 , and —CN, 
       
       optionally wherein
 two adjacent instances of R 1 , R 2 , R 3 , and R 4  together form —O—CH 2 —O—, —O—CH(CH 3 )—O—, —O—C(CH 3 ) 2 —O—, —O—CH 2 —CH 2 —O—, or —O—C(CH 3 ) 2 —C(CH 3 ) 2 —O—; 
 each instance of R 5  independently is halo, —CH 3 , or ethyl; 
 each instance of R 6  independently is halo, —CH 3 , ethyl or —OH; and 
 w is 0, 1, or 2. 
 
     
     
         2 . The compound of  claim 1  of formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 2  of formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 - 11 . (canceled) 
     
     
         12 . The compound of  claim 1  of formula (I-C): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n1 is 1. 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n1 is 2. 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n1 is 3. 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least three of R 1 , R 2 , R 3 , and R 4  are —H. 
     
     
         18 - 20 . (canceled) 
     
     
         21 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein two adjacent instances of R 1 , R 2 , R 3 , and R 4  together form —O—CH 2 —O—, —O—CH(CH 3 )—O—, or —O—C(CH 3 ) 2 —O—. 
     
     
         22 . (canceled) 
     
     
         23 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a  is —H and/or wherein R is —H. 
     
     
         24 - 27 . (canceled) 
     
     
         28 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0 and/or w is 0. 
     
     
         29 - 31 . (canceled) 
     
     
         32 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4  are independently —H, —F, —CH 3 , —OCH 3 , or —CN. 
     
     
         33 - 36 . (canceled) 
     
     
         37 . The compound of  claim 17 , or a pharmaceutically acceptable salt thereof, wherein:
 n1 is 2;   R a  is H;   m is 0;   w is 0;   R is H; and   R 1 , R 2 , R 3 , and R 4  are independently —H, —F, —CH 3 , —OCH 3 , or —CN.   
     
     
         38 . The compound of  claim 1 , selected from those depicted in Table 1: 
       
         
           
                 
                 
                 
               
                     
                   TABLE 1 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-79 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-80 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-81 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-82 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-83 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-84 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-85 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-86 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-87 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-88 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-89 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-90 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-91 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-92 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-93 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-94 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-95 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-96 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-114 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-115 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-116 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-117 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-126 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-127 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-128 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-133 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-135 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-136 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-143 
                 
                     
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I-144 
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The compound of  claim 39 , selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a mixture of two or more thereof. 
     
     
         41 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The compound of claim  45 , selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a mixture of two or more thereof. 
     
     
         43 . A composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         44 . A method for treating a neurological or psychiatric disorder in a patient, comprising administering to said patient an effective amount of the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof.