Selective octahydro-cyclopenta[c]pyrrole negative modulators of NR2B

1. A method of treating a disease mediated by the NR1/NR2B receptor comprising administering to a subject in need thereof an effective amount of a compound of Formula (II):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof

wherein:

L 1 is straight or branched C 1 -C 5 alkylenyl substituted with one or more substituents selected from the group consisting of OH and OR 10 provided that no more than one oxygen is attached to any carbon; or

L 1 is —C(O)—C 1 -C 3 alkylenyl- , wherein the —C(O)—group is connected with R 1 and the —C 1 -C 3 alkylenyl- group is connected with nitrogen;

R 1 is aryl or heteroaryl, both of which are optionally substituted with one or more substituents selected from the group consisting of OH, CN, halogen, O—R 10 , OPO 3 −2 M 2 , OP(O)(OH) 2 , SH, S—R 10 , C 1 -C 5 , straight or branched alkyl, NH 2 , NHR 10 , N(R 10 )(R 10 ′), and NHCOR 10 where M is a monovalent metal cation; or

R 1 is cycloalkyl;

each R 10 and R 10 ′ is independently selected from the group consisting of H; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, O—C 1 -C 5 alkyl, OPO 3 −2 M 2 , OP(O)(OH) 2 , OCOalkyl, and OC(O)Oalkyl where M is a monovalent metal cation; and cycloalkyl optionally substituted with one or more substituents selected from the group consisting of OH and O—C 1 -C 5 alkyl provided that no more than one oxygen is attached to any carbon; or R 10 and R 10 ′, together with the nitrogen to which R 10 and R 10 ′ are attached, optionally form a heterocycle;

Y and Y′ are independently H, F, or methyl;

L 2 is a bond, (CH 2 ) n , or (CHR 11 ) n ;

each R 11 is independently selected from the group consisting of H, —C 1 -C 5 alkylenyl—, —CO—C 1 -C 5 alkylenyl-, and -alkylenyl-CO-alkylenyl- ;

R 2 is phenyl, naphthyl, heteroaryl, or bicyclic heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, OR 10 , CN, NH 2 , NHR 10 , N(R 10 )(R 10 ′), SH, SR 10 ,—S(O) 2 R 10 , —S(O) 2 R 10 , —S(O) 2 NHR 10 , —S(O) 2 N(R 10 )(R 10 ′), —C(O)NH 2 , —C(O)NR 10 , and —C(O)N(R 10 )(R 10 ′); and

n is 1, 2, or 3.

2. The method of claim 1 , wherein the compound is of Formula (IIa):

or pharmaceutically acceptable salt, tautomer, or stereoisomer thereof

wherein:

A is independently N or CR x ;

U is O, S, NR y , C═O, or C(R x ) m ;

V is O, S, N, NR y , C═O, or C(R x ) m ;

each W is independently selected from O, S, C═O, N, NR y , or C(R x ) m ;

−−− is an optional double bond;

the E ring is partially or fully saturated;

X is CH or C;

Y is OH or O;

R 3 is H;

each m is independently 1 or 2;

R is H, OH, or CH 3 ;

R x is H, C 1-6 alkyl, halogen, —OH, or —OC 1-6 alkyl; and

R y is H, or C 1-6 alkyl.

3. The method of claim 1 , wherein the compound is of Formula (IIb):

or pharmaceutically acceptable salt, tautomer, or stereoisomer thereof

wherein:

A, B, C, and D are independently N or CR x ;

X is CH or C;

Y is OH or O;

R 3 is H; and

R x is H, C 1-6 alkyl, halogen, —OH, or —OC 1-6 alkyl; and

wherein two R x substituents are optionally combined to form a 5-6 membered heterocyclic or heteroaryl ring system.

4. The method of claim 1 , wherein L 1 is C 1 -C 2 alkylenyl or C 1 -C 2 branched alkylenyl substituted with OH.

5. The method of claim 1 , wherein L 1 is —C(O)—C 1 -C 3 alkylenyl- .

6. The method of claim 1 , wherein L 2 is a bond, (CH 2 ) n , or (CHR 11 ) n and n is 1.

7. The method of claim 1 , wherein Y and Y′ are methyl.

8. A method of treating a disease mediated by the NR1/NR2B receptor comprising administering to a subject in need thereof an effective amount of a compound, or pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, selected from the group consisting of

2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl)ethenone;

rac-4-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)phenol;

2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl)ethanone;

rac-6-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol;

2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(3-fluoro-4-hydroxyphenyl)ethanone; and

rac-4-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-hydroxyethyl)-2-fluorophenol.

9. A compound of Formula (III):

or pharmaceutically acceptable salt, prodrug, solvate, hydrates, tautomer, or stereoisomer thereof

wherein:

L 1 is straight or branched C 1 -C 5 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, OR 10 , NH 2 , NHR 10 , and N(R 10 )(R 10 ′) provided that no more than one oxygen or nitrogen is attached to any carbon; or

L 1 is selected from the group consisting of —C(O)—, —C(O)O—, —C(O)—C 1 -C 3 alkylenyl- ,—S(O) 2 —, —S(O) 2 NH—, —C(O)NH—, —C(O)NR 10 —, and a bond;

each R 10 and R 10 ′ is independently selected from the group consisting H; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, O—C 1 -C 5 alkyl, OPO 3 −2 M 2 , OP(O)(OH) 2 , OC(O)alkyl, and OC(O)Oalkyl where M is a monovalent metal cation; and cycloalkyl optionally substituted with one or more substituents selected from the group consisting of OH and O—C 1 -C 5 alkyl provided that no more than one oxygen is attached to any carbon; or R 10 and R 10 ′, together with the nitrogen to which R 10 and R 10 ′ are attached, optionally form a heterocycle;

R 1 is aryl or heteroaryl, both of which are optionally substituted with one or more substituents selected from the group consisting of OH, CN, halogen, O—R 10 ,OPO 3 −2 M 2 , OP(O)(OH) 2 , SH, S—R 10 , C 1 -C 5 alkyl, branched alkyl, NH 2 , NHR 10 , N(R 10 )(R 10 ′), and NHCOR 10 where M is a monovalent metal cation; or

R 1 is straight or branched C 1 -C 6 alkyl or cycloalkyl;

X is selected from the group consisting of H, halogen, OH, O—C 1 -C 6 straight or branched alkyl, O branched alkyl, C 1 -C 5 straight alkyl, and C 1 -C 5 branched alkyl;

L 2 is —(CH 2 ) n —or —(CHR 11 ) n —, or a bond;

each R 11 is independently selected from the group consisting of H, —C 1 -C 5 alkylenyl- , —CO—C 1 -C 5 alkylenyl- , and -alkylenyl —CO—alkylenyl- ;

R 2 is phenyl, naphthyl, heteroaryl, or bicyclic heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, OR 10 , CN, NH 2 , NHR 10 , N(R 10 )(R 10 ′), SH, SR 10 ,—S(O) 2 R 10 , —S(O) 2 R 10 , —S(O) 2 NHR 10 , —S(O) 2 N(R 10 )(R 10 ′), —C(O)NH 2 , —C(O)NR 10 , and —C(O)N(R 10 )(R 10 ′); and

n is 1, 2, or 3.

10. The compound of claim 9 , which is of Formula (IIIa):

or pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof wherein:

X is CH or C; and

Y is OH or O.

11. The compound of claim 9 wherein Li is straight or branched C 1 -C 5 alkyl substituted with OH.

12. The compound of claim 9 wherein Li is —C(O)—C 1 -C 3 alkylenyl- or —C(O)O—.

13. The compound of claim 9 wherein L 2 is a bond.

14. The compound of claim 9 wherein L 2 is (CH 2 ) n or (CHR 11 ) n and n is 1 or 2.

15. The compound of claim 9 wherein R 2 is phenyl, unsubstituted or unsubstituted with OH, OR 10 , or CN.

16. The compound of claim 9 wherein R 1 is C 1 -C 6 alkyl or cycloalkyl.

17. The compound of claim 9 wherein R 1 is aryl or heteroaryl substituted with OH.

18. The compound of claim 9 wherein R 1 is phenyl substituted with OH.

19. The compound of claim 9 selected from the group consisting of:

2-(6-benzyl-6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-1-(4-hydroxyphenyl)ethanone; and

rac-6-benzyl-2-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-2-azaspiro[3.3]heptan-6-ol.

20. A pharmaceutical composition comprising the compound of claim 9 .