Spiro-lactam NMDA receptor modulators and uses thereof

1. A compound having the formula:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:

R 1 is selected from the group consisting of —C 1 -C 4 alkyl, —C 1 -C 4 alkyl-phenyl, —C(O)—R 31 , —C(O)—O—R 32 , —O—C 1 -C 4 alkyl-phenyl, phenyl, and —CH(R 8 )—C(O)—R 9 ; wherein phenyl is optionally substituted by one, two or three substituents each independently selected from —C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, hydroxyl, and halogen;

R 2 is independently selected for each occurrence from the group consisting of H, —C 1 -C 4 alkyl, and —C 1 -C 4 haloalkyl;

R 3 , R 4 , R 6 , and R 7 are each independently selected for each occurrence from the group consisting of H, hydroxyl, halogen, cyano, —C 1 -C 4 alkyl, and —C 1 -C 4 haloalkyl; or R 3 and R 4 taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, —C 1 -C 3 alkyl, —C 1 -C 3 alkoxy, —C(O)NR a R b , and —NR a R b ;

R 5a is selected from the group consisting of —C 1 -C 4 alkyl and —C 1 -C 4 alkoxy; wherein C 1 -C 4 alkyl is substituted by one, two or three substituents each independently selected from —COOH, —C(O)NH 2 , —NR a R b , —SH, —C(O)—C 1 -C 4 alkyl, —C(O)—O—C 1 -C 4 alkyl, —O—C(O)—C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, phenyl, hydroxyl, and halogen; and phenyl, independently for each occurrence is optionally substituted by one, two or three substituents each independently selected from —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 alkoxy, —NR a R b , hydroxyl, cyano, and halogen;

R 5b is selected from the group consisting of H, halogen, cyano, —C 1 -C 4 alkyl, and —C 1 -C 4 haloalkyl;

R 8 and R 10 are independently selected from the group consisting of H and —C 1 -C 4 alkyl, wherein C 1 -C 4 alkyl is optionally substituted by one, two or three substituents each independently selected from —C(O)NR a R b , —NR a —C(O)—C 1 -C 4 alkyl, NR a R b , —SH, —C(O)—C 1 -C 4 alkyl, —C(O)—O—C 1 -C 4 alkyl, —O—C(O)—C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, —COOH, hydroxyl, and halogen;

R 9 and R 11 are independently selected from the group consisting of hydroxyl, —C 1 -C 4 alkoxy, and —NR a R b ;

R 31 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 3 -C 6 cycloalkyl, and phenyl;

R 32 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 3 -C 6 cycloalkyl, benzyl, and phenyl; and

R a and R b are each independently selected for each occurrence from the group consisting of H, —C 1 -C 4 alkyl, —C 1 -C 4 alkyl-phenyl, —C 1 -C 4 alkyl-C 3 -C 7 cycloalkyl, —C 1 -C 4 alkyl-heterocycloalkyl, and —C 1 -C 4 alkyl-heteroaryl, wherein heterocycloalkyl and heteroaryl include 1, 2, or 3 ring atoms independently selected from N, O and S, and phenyl is optionally substituted by one, two or three substituents selected from halogen, hydroxyl, —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —C 1 -C 3 alkyl and —C 1 -C 3 alkoxy; or

R a and R b taken together with the nitrogen to which they are attached form a 4-6-membered heterocycloalkyl or a 5-8-membered heteroaryl.

2. The compound of claim 1 , wherein each occurrence of R 3 , R 4 , R 6 , and R 7 is H.

3. The compound of claim 1 , wherein each occurrence of R 2 is H.

4. The compound of claim 1 , wherein R 1 is selected from the group consisting of:

wherein R a and R b are each independently selected for each occurrence from the group consisting of hydrogen and —C 1 -C 4 alkyl.

5. The compound of claim 1 , wherein R 5b is selected from H and F.

6. A compound having the formula:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:

R 1 is selected from the group consisting of —C 1 -C 4 alkyl, —C 1 -C 4 alkyl-phenyl, and —CH(R 8 )—C(O)—R 9 ; wherein phenyl is optionally substituted by one, two or three substituents each independently selected from —C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, and halogen; and

R 5a is selected from the group consisting of —C 1 -C 4 alkyl and —C 1 -C 4 alkoxy; wherein C 1 -C 4 alkyl is optionally substituted by one, two or three substituents each independently selected from —COOH, —C(O)NH 2 , —NR a R b , —SH, —C(O)—C 1 -C 4 alkyl, —C(O)—O—C 1 -C 4 alkyl, —O—C(O)—C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, hydroxyl, and halogen; and phenyl is optionally substituted by one, two or three substituents each independently selected from —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 alkoxy, —NR a R b , hydroxyl, and halogen;

R 5b is selected from the group consisting of H, halogen, —C 1 -C 4 alkyl, and —C 1 -C 4 haloalkyl;

R 8 and R 10 are selected independently from the group consisting of H and —C 1 -C 4 alkyl, wherein C 1 -C 4 alkyl is optionally substituted by one, two or three substituents each independently selected from —C(O)NR a R b , —NR a —C(O)—C 1 -C 4 alkyl, —NR a R b , —SH, —C(O)—C 1 -C 4 alkyl, —C(O)—O—C 1 -C 4 alkyl, —O—C(O)—C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —COOH, hydroxyl, and halogen;

R 9 and R 11 are selected independently from the group consisting of hydroxyl, C 1 -C 4 alkoxy, and —NR a R b ; and

R a and R b are each independently selected for each occurrence from the group consisting of H, —C 1 -C 4 alkyl, —C 1 -C 4 alkyl-phenyl, —C 1 -C 4 alkyl-C 3 -C 7 cycloalkyl, —C 1 -C 4 alkyl-heterocycloalkyl, and —C 1 -C 4 alkyl-heteroaryl, wherein heterocycloalkyl and heteroaryl include 1, 2, or 3 ring atoms independently selected from N, O and S, and phenyl is optionally substituted by one, two or three substituents selected from halogen, hydroxyl, —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —C 1 -C 3 alkyl and —C 1 -C 3 alkoxy; or

R a and R b taken together with the nitrogen to which they are attached form a 4-6-membered heterocycloalkyl or a 5-8-membered heteroaryl.

7. The compound of claim 6 , wherein R is methyl; R 5b is H or halogen.

8. A compound having the formula:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:

R 5a is —CH 3 ;

R 5b is halogen;

R 8 is selected from the group consisting of H and C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl may be optionally substituted by one, two or three substituents each independently selected from —C(O)NR a R b , —NR a —C(O)—C 1 -C 4 alkyl, —NR a R b , —SH, —C(O)—C 1 -C 4 alkyl, —C(O)—O—C 1 -C 4 alkyl, —O—C(O)—C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —COOH, hydroxyl, and halogen; and

R 9 is selected from the group consisting of hydroxyl, C 1 -C 4 alkoxy, and —NR a R b ; and

R a and R b are each independently selected for each occurrence from the group consisting of H, —C 1 -C 4 alkyl, —C 1 -C 4 alkyl-phenyl, —C 1 -C 4 alkyl-C 3 -C 7 cycloalkyl, —C 1 -C 4 alkyl-heterocycloalkyl, and —C 1 -C 4 alkyl-heteroaryl, wherein heterocycloalkyl and heteroaryl include 1, 2, or 3 ring atoms independently selected from N, O and S, and phenyl is optionally substituted by one, two or three substituents selected from halogen, hydroxyl, —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —C 1 -C 3 alkyl and —C 1 -C 3 alkoxy; or

R a and R b taken together with the nitrogen to which they are attached form a 4-6-membered heterocycloalkyl or a 5-8-membered heteroaryl.

9. The compound of claim 8 , wherein R 8 is selected from the group consisting of H, methyl,

10. The compound of claim 8 , wherein R 9 is —NH 2 .

11. A compound represented by:

or a pharmaceutically acceptable salt and/or a stereoisomer thereof.

12. A pharmaceutical composition comprising a compound of claim 1 ; and a pharmaceutically acceptable excipient.

13. A method of treating of treating depression, attention deficit disorder, schizophrenia, anxiety, a migraine, or neuropathic pain in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of claim 1 .