3,3-difluoropiperidine carbamate heterocyclic compounds as nr2b nmda receptor antagonists

Abstract

Disclosed are chemical entities of Formula (I), wherein R1 and Z are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).

What is claimed is: 
     
         1 . A chemical entity, which is a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, (aryl)alkyl, heteroaryl or (heteroaryl)alkyl,
 wherein each of cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, (aryl)alkyl, heteroaryl and (heteroaryl)alkyl is independently optionally substituted with 1 to 3 groups independently selected from —F, —Cl, C 1 -C 4  alkyl, cyclopropyl, —C≡CH, —CFH 2 , —CF 2 H, —CF 3 , —CF 2 CH 3 , —CH 2 CF 3 , C 1 -C 4  alkoxy, —OCFH 2 , —OCF 2 H, —OCF 3 , —CN, —N(R 2 )(R 3 ), —NO 2 , C 1 -C 4  alkylthio, C 1 -C 4 alkylsulfonyl and —S(O) 2 CF 3 ;
 wherein each instance of R 2  and R 3  independently is —H or C 1 -C 4  alkyl, or —N(R 2 )(R 3 ) is 
 
 
 
       
         
           
           
               
               
           
         
         Z is 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl having ring carbon atoms, 1 nitrogen ring atom and 0-3 additional ring heteroatoms independently selected from N, O and S, which is optionally substituted with 1 or 2 R x  groups and optionally substituted with 1 R a  group, wherein each R x  is attached to a ring carbon atom and R a  is attached to a ring nitrogen atom;
 wherein:
 each instance of R x  independently is —F, —Cl, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OH, —OCH 3 , —OCF 3  or —CN; and 
 R a  is C 1-4  alkyl, C 3-4  cycloalkyl or —S(O) 2 —C 1-4  alkyl. 
 
 
       
     
     
         2 . The chemical entity of  claim 1 , wherein Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen heteroatoms. 
     
     
         3 . The chemical entity of  claim 1 , wherein Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 3 ring nitrogen heteroatoms. 
     
     
         4 . The chemical entity of  claim 1 , wherein Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 4 ring nitrogen heteroatoms. 
     
     
         5 . The chemical entity of  claim 1 , wherein Z is a 6-membered optionally substituted monocyclic heteraromatic ring system having ring carbon atoms, 1 ring nitrogen atom and 0 or 1 additional ring nitrogen atoms. 
     
     
         6 . The chemical entity of  claim 5 , wherein Z is a 6-membered optionally substituted monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms. 
     
     
         7 . The chemical entity of  claim 6 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms, wherein Z is optionally substituted with 1 or 2 R x  groups. 
     
     
         8 . The chemical entity of  claim 7 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms, wherein Z is substituted with 1 or 2 R x  groups. 
     
     
         9 . The chemical entity of  claim 8 , wherein Z is a 6-membered monocyclic heteraromatic ring system having ring carbon atoms and 2 ring nitrogen atoms, wherein Z is substituted with 1 R x  group. 
     
     
         10 . The chemical entity of any one of  claims 7 - 9 , wherein R x  is selected from —CH 3 , —CFH 2 , —CF 2 H, or —CF 3 . 
     
     
         11 . The chemical entity of  claims 1 - 10 , wherein R 1  is optionally substituted (aryl)alkyl. 
     
     
         12 . The chemical entity of  claim 11 , wherein R 1  is optionally substituted benzyl. 
     
     
         13 . The chemical entity of  claim 12  of formula (II): 
       
         
           
           
               
               
           
         
         wherein R 5 , R 6  and R 7  independently are —H, —F, —Cl, C 1 -C 4  alkyl, cyclopropyl, —C≡CH, —CFH 2 , —CF 2 H, —CF 3 , —CF 2 CH 3 , —CH 2 CF 3 , C 1 -C 4  alkoxy, —OCFH 2 , —OCF 2 H, —OCF 3 , —CN, —N(R 2 )(R 3 ), —NO 2 , C 1 -C 4  alkylthio, C 1 -C 4 alkylsulfonyl or —S(O) 2 CF 3 ;
 wherein each instance of R 2  and R 3  independently is —H or C 1 -C 4  alkyl, or —N(R 2 )(R 3 ) is 
 
       
       
         
           
           
               
               
           
         
       
     
     
         14 . The chemical entity of  claim 13 , wherein each of R 5 , R 6  and R 7  independently is —H, —F, —Cl, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —CH 2 CH 3 , —CF 2 CH 3 , —CH 2 CF 3 , isopropyl, tert-butyl, cyclopropyl, —OCF 3 , —OCF 2 H, —SCH 3 , —SCH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CF 3  or —C≡CH. 
     
     
         15 . The chemical entity of  claim 14 , wherein each of R 5 , R 6  and R 7  independently is —H, —F, —Cl, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —CH 2 CH 3 , —CF 2 CH 3 , —CH 2 CF 3 , cyclopropyl, —OCF 3 , —OCF 2 H, —SCH 3 , —S(O) 2 CH 3  or —C≡CH. 
     
     
         16 . The chemical entity of  claim 15 , wherein:
 R 5  is —H, —F, —Cl, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —CH 2 CH 3 , —CF 2 CH 3 , —CH 2 CF 3 , cyclopropyl, —OCF 3 , —OCF 2 H, —SCH 3 , —S(O) 2 CH 3  or —C≡CH;   R 6  is —H or —F; and   R 7 is —H, —F, —Cl or —CH 3 .   
     
     
         17 . The chemical entity of any of  claims 13 - 16 , wherein Z is Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, or Z20. 
     
     
         18 . The chemical entity of  claim 17 , wherein Z is Z1, Z2, Z5, Z6, Z8, Z17 or Z19. 
     
     
         19 . The chemical entity of any of  claims 13 - 16 , wherein Z is Z21, Z22, Z23, Z24, Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35 or Z36. 
     
     
         20 . The chemical entity of  claim 19 , wherein Z is Z21, Z22, Z24, Z29, Z30, Z35 or Z36. 
     
     
         21 . A pharmaceutical composition comprising the chemical entity of any one of  claims 1 - 20  and a pharmaceutically acceptable carrier. 
     
     
         22 . The pharmaceutical composition of  claim 21 , which is suitable for oral administration. 
     
     
         23 . A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment, comprising administering an effective amount of the chemical entity of any one of  claims 1 - 20 . 
     
     
         24 . The method of  claim 23 , wherein the disease or disorder is depression, pain, Parkinson's disease, Huntington's disease, Alzheimer's disease, cerebral ischaemia, traumatic brain injury, epilepsy or migraine. 
     
     
         25 . The method of  claim 24 , wherein the disease or disorder is depression.