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

1. 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 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 )(NR 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 they are attached, may 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)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. A compound of claim 1 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 which allows the E ring to be 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. A compound of claim 1 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, wherein two R x substituents can combine to form a 5-6 membered heterocyclic or heteroaryl ring system.

4. A compound of claim 1 , or pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein L 1 is C 1 -C 2 alkylenyl or C 1 -C 2 branched alkylenyl substituted with OH.

5. A compound of claim 1 , or pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein L 1 is —C(O)—C 1 -C 3 alkylenyl-.

6. A compound of claim 1 , or pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein L 2 is a bond, (CH 2 ) n , or (CHR 11 ) n and n is 1.

7. A compound of claim 1 , or pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Y and Y′ are methyl.

8. 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)ethanone;

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 pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof.