N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[C]pyrrole negative allosteric modulators of NR2B

1. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, and panic disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein:

L 1 is straight or branched C 1 -C 5 alkylene substituted with OH;

R 1 is cycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more substituents selected from the group consisting of OH, CN, halogen, —C 1 -C 6 alkylaryl, —O—C 1 -C 6 alkylaryl, 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 , NHS(O) 2 R 10 , N(R 10 )(R 10 ′), and NHCOR 10 , where M is a monovalent metal cation;

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 , OC(O)-alkyl, and OC(O)O-alkyl 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, form a heterocycle selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;

X is selected from O, S, —S(O)—, and —S(O) 2 —;

Y and Y′ are independently H, halogen, or C 1 -C 5 alkyl;

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

each R n 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, C 1 -C 6 alkyl, OR 10 , CN, NH 2 , NHR 10 , N(R 10 )(R 10 ′), -nitro, SH, SR 10 , SOR 10 , SO 2 R 10 , SO 2 NHR 10 , SO 2 N(R 10 )(R 10 ′), CONH 2 , CONR 10 , and CON(R 10 )(R 10 ′); and

n is 1, 2, or 3;

wherein cycloalkyl is a monocyclic saturated carbon ring containing 3-18 carbon atoms; and

wherein heteroaryl is a monocyclic, bicyclic, or polycyclic aromatic radical of 5 to 10 ring atoms and containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and when containing two fused rings, the aryl groups optionally have an unsaturated or partially saturated ring fused with a fully saturated ring.

2. The method of claim 1 , wherein L 2 is a bond and R 2 is phenyl 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 , SOR 10 , SO 2 R 10 , SO 2 NHR 10 , SO 2 N(R 10 )(R 10 ′), CONH 2 , CONR 10 , and CON(R 10 )(R 10 ′).

3. The method of claim 2 , wherein X is O.

4. The method of claim 2 , wherein R 1 is aryl or heteroaryl, each of which is substituted with one or more substituents selected from the group consisting of OH, halogen, OR 10 , SH, SR 10 , NH 2 , NHR 10 , and NHCOR 10 .

5. The method of claim 2 , wherein Y and Y′ are hydrogen.

6. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, is selected from the group consisting of:

7. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, panic disorder, and major depressive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ia):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein:

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

is an optional double bond;

X is CH or C;

U is OH or O;

Y and Y′ are independently H, halogen, or C 1 -C 6 alkyl;

R 3 is H;

each R x is independently H, C 1 -C 6 alkyl, halogen, —OH, —NHS(O) 2 R 10 , or —OC 1 -C 6 alkyl;

R 10 is 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 , OC(O)alkyl, and OC(O)O-alkyl where M is a monovalent metal cation; and cycloalkyl optionally substituted with one or more substituents selected from the group consisting of OH, O—C 1 -C 5 alkyl provided that no more than one oxygen is attached to any carbon; and

L 2 is a bond or (CH 2 ) n , wherein n is 1 or 2.

14. The method of claim 13 , wherein the compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer, is selected from the group consisting of:

15. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, panic disorder, and major depressive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, the compound selected from the group consisting of:

16. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, panic disorder, and major depressive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound that is

or a pharmaceutically acceptable salt thereof.

17. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, panic disorder, and major depressive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound that is

or a pharmaceutically acceptable salt thereof.

18. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, panic disorder, and major depressive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound that is

or a pharmaceutically acceptable salt thereof.

19. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, panic disorder, and major depressive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound that is

or a pharmaceutically acceptable salt thereof.

20. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, panic disorder, and major depressive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound that is

or a pharmaceutically acceptable salt thereof.

21. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, panic disorder, and major depressive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound that is

or a pharmaceutically acceptable salt thereof.