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

1. A method of treating an emotional disorder selected from bipolar disorder, obsessive-compulsive disorder, and depression, 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 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 alkyl, 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 they are attached, may 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 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, 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 may have an unsaturated or partially saturated ring fused with a fully saturated ring.

2. The method of claim 1 , wherein the emotional disorder is selected from bipolar disorder, and obsessive-compulsive disorder.

3. The method of claim 2 , wherein the bipolar disorder is bipolar depression.

4. The method of claim 1 , wherein the emotional disorder is major depressive disorder or depression.

5. The method of claim 1 , wherein the emotional disorder is refractory or treatment resistant depression.

6. The method of claim 1 , wherein L 2 is a bond and R 2 is phenyl optionally substituted with one or more 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 , CON(R 10 )(R 10 ′).

7. The method of claim 6 , wherein X is O.

8. The method of claim 6 , 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 .

9. The method of claim 6 , wherein Y and Y′ are hydrogen.

10. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer 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. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

17. A method of treating an emotional disorder selected from bipolar disorder, obsessive-compulsive disorder, and depression, 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 C1-C6 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 and 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.

18. The method of claim 17 , wherein the compound is selected from the group consisting of:

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

19. A method of treating an emotional disorder selected from bipolar disorder, obsessive-compulsive disorder, and depression, the method comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of:

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

20. A method of treating depression, the method comprising administering to a subject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.

21. The method of claim 20 , wherein the depression is refractory or treatment resistant depression.

22. A method of treating depression, the method comprising administering to a subject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.

23. The method of claim 22 , wherein the depression is refractory or treatment resistant depression.

24. A method of treating depression, the method comprising administering to a subject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.

25. The method of claim 24 , wherein the depression is refractory or treatment resistant depression.

26. A method of treating depression, the method comprising administering to a subject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.

27. The method of claim 26 , wherein the depression is refractory or treatment resistant depression.

28. A method of treating depression, the method comprising administering to a subject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.

29. The method of claim 28 , wherein the depression is refractory or treatment resistant depression.

30. A method of treating depression, the method comprising administering to a subject in need thereof an effective amount of the compound

or a pharmaceutically acceptable salt thereof.

31. The method of claim 30 , wherein the depression is refractory or treatment resistant depression.