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.

What is claimed is: 
     
         1 - 4 . (canceled) 
     
     
         5 . A compound represented by formula I: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, an N-oxide 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 , wherein 
 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 selected from the group consisting of: 
 (i) phenyl; 
 (ii) 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 
 (iii) 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 . The compound of  claim 5 , wherein R 1  is H. 
     
     
         7 . The compound of  claim 5 , wherein R 2  is H. 
     
     
         8 . The compound of  claim 5 , wherein R 3  is H. 
     
     
         9 . The compound of  claim 5 , wherein R 3  has formula —C(O)OR 31 , wherein 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  alkenyl, 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 . 
     
     
         10 . The compound of  claim 9 , wherein R 31  is C 1 -C 6  alkyl. 
     
     
         11 . The compound of  claim 10 , wherein R 31  is tert-butyl. 
     
     
         12 . The compound of  claim 5 , wherein R 3  has formula —C(O)R 32 , wherein 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 . 
     
     
         13 . The compound of  claim 12 , wherein R 32  is C 1 -C 6  alkyl. 
     
     
         14 . The compound of  claim 13 , wherein R 32  is —CH 3  or iso-propyl. 
     
     
         15 . The compound of  claim 5 , wherein R 5  is X. 
     
     
         16 . The compound of  claim 5 , wherein R 5  is —C 1 -C 6  alkylene-X. 
     
     
         17 . The compound of  claim 16 , wherein R 5  is substituted with —CH(R 4 )(R 6 ). 
     
     
         18 . The compound of  claim 17 , wherein R 5  is substituted on the alkylene portion with —CH(R 4 )(R 6 ). 
     
     
         19 . The compound of  claim 18 , wherein R 5  has the formula —CH(CHR 4 R 6 )—X. 
     
     
         20 . The compound of  claim 17 , wherein R 4  is C 1 -C 6  alkyl. 
     
     
         21 . The compound of  claim 17 , wherein R 4  is methyl. 
     
     
         22 . The compound of  claim 17 , wherein R 6  is hydroxyl. 
     
     
         23 . The compound of  claim 16 , 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. 
     
     
         24 . The compound  claim 5 , wherein R b  is H. 
     
     
         25 . The compound of  claim 5 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, an N-oxide and/or a pharmaceutically acceptable salt thereof. 
     
     
         26 . A pharmaceutical composition comprising a compound of  claim 5 , and a pharmaceutically acceptable excipient. 
     
     
         27 . The pharmaceutical composition of  claim 26 , suitable for oral administration. 
     
     
         28 . The pharmaceutical composition of  claim 26 , suitable or intravenous administration. 
     
     
         29 . A method of treating of treating depression, Alzheimer's disease, attention deficit disorder, schizophrenia or anxiety, in a patient in need thereof, the method comprising:
 administering to said patient therapeutically effective amount of a compound of  claim 5 .