Spiro-lactam NMDA receptor modulators and uses thereof
Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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: H; —C 1 -C 4 alkyl; —C 1 -C 4 alkyl-phenyl, wherein phenyl is substituted by one, two or three substituents each independently selected from —C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, hydroxyl, and halogen; —C(O)—R 31 ; —C(O)—O—R 32 ; —O—C 1 -C 4 alkyl-phenyl, 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; phenyl, 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 —CH(R 8 )—C(O)—R 9 ;
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 hydroxyl, halogen, cyano, —O—C 1 -C 4 alkyl-phenyl, —C(O)—C 1 -C 4 alkyl, —NR a —C(O)—C 1 -C 4 alkyl, —NR a —C(O)—O—C 1 -C 4 alkyl, —NR a R b , and —NR a CH(R 10 )—C(O)—R 11 ; 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, 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; or
R 5a and R 5b taken together form an oxo group;
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, —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. The compound of claim 1 , wherein R 5a is selected from the group consisting of hydroxyl, halogen, —O—CH 2 -Ph, —NH 2 , —NH—C 1 -C 4 alkyl, —NH—C(O)—C 1 -C 4 alkyl, —NH—C(O)—O—C 1 -C 4 alkyl, and —NR a CH(R 10 )—C(O)—R 11 , wherein C 1 -C 4 alkyl is optionally substituted by one or two substituents each independently selected from —C(O)NH 2 , —NH 2 , —SH, —OC(O)CH 3 , hydroxyl, and halogen;
R 10 is selected from the group consisting of H and C 1 -C 4 alkyl, wherein C 1 -C 4 alkyl is optionally substituted by one or two 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 11 is selected from the group consisting of hydroxyl, —C 1 -C 4 alkoxy, and —NR a R b .
7. The compound of claim 1 , wherein R 5b is H; and
R 5a is selected from the group consisting of hydroxyl, halogen, —O—CH 2 -Ph, —NH 2 ,
8. 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 H, —C 1 -C 4 alkyl, —C 1 -C 4 alkyl-phenyl, and —CH(R 8 )—C(O)—R 9 ; wherein phenyl is 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 hydroxyl, halogen, cyano, —O—C 1 -C 4 alkyl-phenyl, —C(O)—C 1 -C 4 alkyl, —NR a —C(O)—C 1 -C 4 alkyl, —NR a —C(O)—O—C 1 -C 4 alkyl, —NR a R b , and —NR a CH(R 10 )—C(O)—R 11 ; 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; or
R 5a and R 5b taken together form an oxo group;
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 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 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)NH2, —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 1 is H or —CH(R 8 )—C(O)—R 9 ;
R 8 is selected from the group consisting of H and C 1 -C 4 alkyl, wherein —C 1 -C 4 alkyl is optionally substituted by one or two substituents each independently selected from —C(O)NH 2 , —NH 2 , —SH, —O—C(O)—C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, —COOH, and hydroxyl; and
R 9 is selected independently from the group consisting of hydroxyl, —C 1 -C 4 alkoxy, and —NR a R b .
10. The compound of claim 9 , wherein R 8 is selected from the group consisting of H, methyl,
11. The compound of claim 8 , wherein R 5a is selected from the group consisting of hydroxyl, halogen, —O—CH 2 -Ph, —NH 2 , —NH—C 1 -C 4 alkyl, —NH—C(O)—C 1 -C 4 alkyl, —NH—C(O)—O—C 1 -C 4 alkyl, and —NR a CH(R 10 )—C(O)—R 11 ; wherein C 1 -C 4 alkyl is optionally substituted by one or two substituents each independently selected from —C(O)NH 2 , —NH 2 , —SH, —OC(O)CH 3 , hydroxyl, and halogen; and
R 5b is H or halogen.
12. A compound having the formula:
or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:
R 5a is selected from the group consisting of H, hydroxyl, halogen, —CH 3 , —C(O)—C 1 -C 4 alkyl, —O—CH 2 -Ph, —NH 2 , —NH—C 1 -C 4 alkyl, —NH—C(O)—C 1 -C 4 alkyl, —NH—C(O)—O—C 1 -C 4 alkyl, and —NR a CH(R 10 )—C(O)—R 11 ; wherein C 1 -C 4 alkyl is optionally substituted by one or two substituents each independently selected from —C(O)NH 2 , —NH 2 , —SH, —OC(O)CH 3 , hydroxyl, and halogen;
R 5b is H or halogen;
R 8 and R 10 are selected independently 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 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)NH2, —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.
13. The compound of claim 12 , wherein R 5a is selected from the group consisting of H, hydroxyl, halogen, methyl, —O—CH 2 -Ph, —NH 2 , —NH—C 1 -C 4 alkyl, —NH—C(O)—C 1 -C 4 alkyl, and —NH—C(O)—O—C 1 -C 4 alkyl, wherein C 1 -C 4 alkyl is optionally substituted by one or two substituents each independently selected from —C(O)NH 2 , —NH 2 , —SH, —OC(O)CH 3 , hydroxyl, and halogen.
14. The compound of claim 12 , wherein R 5a is selected from the group consisting of H, hydroxyl, halogen, methyl, —O—CH 2 -Ph, —NH 2 ,
15. The compound of claim 12 , wherein R 5b is H or halogen; and
R 5a is selected from the group consisting of H, hydroxyl, halogen, methyl, —O—CH 2 -Ph, —NH 2 ,
16. The compound of claim 12 , wherein R 8 is selected from the group consisting of H, methyl,
17. The compound of claim 12 , wherein R 9 is —NH 2 ).
18. A pharmaceutical composition comprising a compound of claim 1 ; and a pharmaceutically acceptable excipient.
19. A method of treating depression, attention deficit disorder, schizophrenia, anxiety, or a migraine, in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of claim 1 .
20. A method of treating neuropathic pain, in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of claim 1 .
21. A pharmaceutical composition comprising a compound of claim 12 ; and a pharmaceutically acceptable excipient.
22. A method of treating depression, attention deficit disorder, schizophrenia, anxiety, or a migraine, in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of claim 12 .
23. A method of treating neuropathic pain, in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of claim 12 .
24. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and a pharmaceutically acceptable salt and/or a stereoisomer thereof.
25. The compound of claim 12 , wherein the compound is selected from:
and a pharmaceutically acceptable salt and/or a stereoisomer thereof.