Spiro-lactam nmda receptor modulators and uses thereof

Abstract

Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.

1 .- 4 . (canceled) 
     
     
         5 . A compound represented by formula I: 
       
         
           
           
               
               
           
         
         or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein
 R b  is selected from the group consisting of H, halogen, hydroxyl, cyano and C 1 -C 6  alkyl; 
 R 1  is H or C 1 -C 6  alkyl; 
 R 2  is H or C 1 -C 6  alkyl; 
 R 3  is selected from the group consisting of H, C 1 -C 6  alkyl, and —C(O)OR 31 ; 
 R 31  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, —CH 2 —C 3 -C 10  cycloalkyl, —CH 2 -phenyl and —CH 2 -pyridyl; wherein C 3 -C 10  cycloalkyl is optionally substituted with from 1-3 independently selected C 1 -C 3  alkyl, and phenyl is optionally substituted with from 1-2 substituents independently selected from C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, nitro, halo, SO 2 Me, cyano and —OC(O)CH 3 ; 
 R 4  is H or C 1 -C 6  alkyl; 
 R 5  is —C 1 -C 6  alkylene-X, wherein X is selected from the group consisting of:
 (i) heteroaryl including from 5 to 6 ring atoms wherein 1 or 2 of the ring atoms are independently selected from the group consisting of N, O and S; and 
 (ii) heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, O and S; 
 wherein R 5  is optionally substituted with 
 
 
       
       
         
           
           
               
               
           
         
         
           
              and 
           
           R 6  is selected from the group consisting of H, halogen, hydroxyl, cyano, —O—C(O)—C 1 -C 6  alkyl, C 1 -C 6  alkyl and C 1 -C 6  alkoxy. 
         
       
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 5 , and a pharmaceutically acceptable excipient. 
     
     
         7 . A compound represented by formula I: 
       
         
           
           
               
               
           
         
         or a stereoisomer, and/or a pharmaceutically acceptable salt thereof, wherein
 R b  is selected from the group consisting of H, halogen, hydroxyl, cyano and C 1 -C 6  alkyl; 
 R 1  is H or C 1 -C 6  alkyl; 
 R 2  is H or C 1 -C 6  alkyl; 
 R 3  is selected from the group consisting of H, C 1 -C 6  alkyl, —C(O)OR 31  and —C(O)R 32 ; 
 R 31  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, —CH 2 —C 3 -C 10  cycloalkyl, —CH 2 -phenyl and —CH 2 — pyridyl; wherein C 3 -C 10  cycloalkyl is optionally substituted with from 1-3 independently selected C 1 -C 3  alkyl, and phenyl is optionally substituted with from 1-2 substituents independently selected from C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, nitro, halo, SO 2 Me, cyano and —OC(O)CH 3 ; 
 R 32  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl and pyridyl; wherein phenyl is optionally substituted with from 1-2 substituents independently selected from C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, nitro, halo, SO 2 Me, cyano and —OC(O)CH 3 ; 
 R 4  is H or C 1 -C 6  alkyl; 
 R 5  is X or —C 1 -C 6  alkylene-X, wherein X is heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, O and S; 
 wherein R 5  is optionally substituted with 
 
       
       
         
           
           
               
               
           
         
         
            and 
           R 6  is selected from the group consisting of H, halogen, hydroxyl, cyano, —O—C(O)—C 1 -C 6  alkyl, C 1 -C 6  alkyl and C 1 -C 6  alkoxy. 
         
       
     
     
         8 . A pharmaceutical composition comprising a compound of  claim 7 , and a pharmaceutically acceptable excipient. 
     
     
         9 . A compound represented b formula I: 
       
         
           
           
               
               
           
         
         or a stereoisomer, and/or a pharmaceutically acceptable salt thereof, wherein
 R b  is selected from the group consisting of H, halogen, hydroxyl, cyano and C 1 -C 6  alkyl; 
 R 1  is H or C 1 -C 6  alkyl; 
 R 2  is H or C 1 -C 6  alkyl; 
 R 3  is selected from the group consisting of H, C 1 -C 6  alkyl, and —C(O)R 32 ; 
 R 32  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl and pyridyl; wherein phenyl is optionally substituted with from 1-2 substituents independently selected from C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, nitro, halo, SO 2 Me, cyano and —OC(O)CH 3 ; 
 R 4  is H or C 1 -C 6  alkyl; 
 R 5  is —C 1 -C 6  alkylene-X, wherein X is heteroaryl including from 5 to 6 ring atoms wherein 1 or 2 of the ring atoms are independently selected from the group consisting of N, O and S; 
 wherein R 5  is optionally substituted with 
 
       
       
         
           
           
               
               
           
         
         
            and 
           R 6  is selected from the group consisting of H, halogen, hydroxyl, cyano, —O—C(O)—C 1 -C 6  alkyl, C 1 -C 6  alkyl and C 1 -C 6  alkoxy.