Spiro-lactam NMDA receptor modulators and uses thereof
Disclosed are compounds having enhanced potency in the modulation of NMD A receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein
R b is selected from the group consisting of H, halogen, hydroxyl, cyano and C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl and a nitrogen protecting group;
R 4 is H or C 1 -C 6 alkyl;
R 5 is X or —C 1 -C 6 alkylene-X, wherein X is selected from the group consisting of:
(i) heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, O, and S; and
(ii) heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, O, and S;
wherein R 5 is optionally substituted with
and
R 6 is selected from the group consisting of H, halogen, hydroxyl, cyano, —O—C(O)—C 1 -C 6 alkyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
2. The compound of claim 1 , wherein R 1 is H.
3. The compound of claim 1 , wherein R 2 is H.
4. The compound of claim 1 , wherein R 3 is H.
5. The compound of claim 1 , wherein R 3 is a nitrogen protecting group.
6. The compound of claim 5 , wherein R 3 has formula —C(O)OR 31 , wherein R 31 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, —CH 2 —C 3 -C 10 cycloalkyl, —CH 2 -phenyl, and CH 2 -pyridyl, wherein C 3 -C 10 cycloalkyl is optionally substituted with from 1-3 independently selected C 1 -C 3 alkyl, and wherein phenyl is optionally substituted with from 1-2 substituents independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, nitro, halo, SO 2 Me, cyano and —OC(O)CH 3 .
7. The compound of claim 6 , wherein R 31 is C 1 -C 6 alkyl.
8. The compound of claim 7 , wherein R 31 is tert-butyl.
9. The compound of claim 5 , wherein R 3 has formula —C(O)R 32 , wherein R 32 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, and pyridyl, wherein phenyl is optionally substituted with from 1-2 substituents independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, nitro, halo, SO 2 Me, cyano and —OC(O)CH 3 .
10. The compound of claim 9 , wherein R 32 is C 1 -C 6 alkyl.
11. The compound of claim 10 , wherein R 32 is —CH 3 or iso-propyl.
12. The compound of claim 1 , wherein R 5 is X.
13. The compound of claim 10 , wherein X is heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, O, and S.
14. The compound of claim 13 , wherein X is selected from the group consisting of 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, and pyrimidinyl.
15. The compound of claim 12 , wherein R 5 is substituted with —CH(R 4 )(R 6 ).
16. The compound of claim 15 , wherein R 4 is C 1 -C 6 alkyl.
17. The compound of claim 15 , wherein R 4 is methyl.
18. The compound of claim 15 , wherein R 6 is selected from the group consisting of hydroxyl, —O—C(O)—C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
19. The compound of claim 18 , wherein R 6 is hydroxyl.
20. The compound of claim 1 , wherein R 5 is —C 1 -C 6 alkylene-X.
21. The compound of claim 1 , wherein R 5 is —C 1 -C 2 alkylene-X.
22. The compound of claim 21 , wherein R 5 is substituted with —CH(R 4 )(R 6 ).
23. The compound of claim 22 , wherein R 5 is substituted on the alkylene portion with —CH(R 4 )(R 6 ).
24. The compound of claim 23 , wherein R 5 has the formula —CH(CHR 4 R 6 )—X.
25. The compound of claim 22 , wherein R 4 is C 1 -C 6 alkyl.
26. The compound of claim 22 , wherein R 4 is methyl.
27. The compound of claim 22 , wherein R 6 is selected from the group consisting of hydroxyl, —O—C(O)—C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
28. The compound of claim 27 , wherein R 6 is hydroxyl.
29. The compound of claim 20 , wherein X is heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, O, and S.
30. The compound of claim 20 , wherein X is selected from the group consisting of 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, and pyrimidinyl.
31. The compound of claim 1 , wherein R b is H.
32. The compound of claim 1 , wherein the compound is selected from
the group consisting of
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.
33. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
34. The pharmaceutical composition of claim 33 , suitable for oral administration.
35. The pharmaceutical composition of claim 33 , suitable for intravenous administration.
36. A method of treating of treating depression, Alzheimer's disease, attention deficit disorder, schizophrenia, or anxiety, in a patient in need thereof, the method comprising:
administering to said patient a pharmaceutically effective amount of a compound of claim 1 .
37. A compound represented by formula I:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein
R b is selected from the group consisting of H, halogen, hydroxyl, cyano or C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl and a nitrogen protecting group;
R 4 is H or C 1 -C 6 alkyl;
R 5 is X or —C 1 -C 6 alkylene-X, wherein X is selected from the group consisting of a 4- to 6-membered heteroaryl ring having 1, 2, or 3 heteroatoms selected from O, S, and N, and a 4- to 6-membered heterocyclyl ring having 1, 2, or 3 heteroatoms selected from O, S, and N, and wherein R 5 is optionally substituted with
and
R 6 is selected from the group consisting of H, halogen, hydroxyl, cyano, —O—C(O)—C 1 -C 6 alkyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
38. The compound of claim 37 , wherein R 1 is H.
39. The compound of claim 37 , wherein R 2 is H.
40. The compound of claim 37 , wherein R 3 is H.
41. The compound of claim 37 , wherein R 4 is C 1 -C 6 alkyl.
42. The compound of claim 37 , wherein R 4 is methyl.
43. The compound of claim 37 , wherein R 5 is X, and wherein X is a 5- to 6-membered heteroaryl ring selected from the group consisting of azetidine, pyrrolidine, pyrazolidine, pyridine, pyrimidine, isooxazolidine, imidazolidine, oxazolidine, thiazolidine, and isothiazolidine.
44. The compound of claim 37 , wherein R 5 is
45. The compound of claim 37 , wherein R 5 is X, and wherein X is optionally substituted with
46. The compound of claim 37 , wherein R 6 is hydroxyl.
47. The compound of claim 37 , wherein the compound is
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.
48. A compound represented by formula II:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl and a nitrogen protecting group; and
R 7 is a 4- to 6-membered heteroaryl ring having 1, 2, or 3 heteroatoms selected from O, S, and N, optionally substituted on a free carbon by a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, hydroxyl, cyano, and phenyl.
49. A compound represented by formula III:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein
R b is selected from the group consisting of H, halogen, hydroxyl, cyano and C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl and a nitrogen protecting group;
R 4 is H or C 1 -C 6 alkyl;
X is selected from the group consisting of a 4- to 6-membered heteroaryl ring having 1, 2, or 3 heteroatoms selected from O, S, and N, and a 4- to 6-membered heterocyclyl ring having 1, 2, or 3 heteroatoms selected from O, S, and N, wherein
is present on a free carbon of X; and
R 6 is selected from the group consisting of H, halogen, hydroxyl, cyano, —O—C(O)—C 1 -C 6 alkyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
50. The compound of claim 49 , wherein R 1 is H.
51. The compound of claim 49 , wherein R 2 is H.
52. The compound of claim 49 , wherein R 3 is H.
53. The compound of claim 49 , wherein R 4 is C 1 -C 6 alkyl.
54. The compound of claim 49 , wherein R 4 is methyl.
55. The compound of claim 49 , wherein R b is H.
56. The compound of claim 49 , wherein X is
57. The compound of claim 49 , wherein R 6 is hydroxyl.
58. The compound of claim 49 , wherein the compound is
59. A pharmaceutical composition comprising a compound of claim 37 , and a pharmaceutically acceptable excipient.
60. The pharmaceutical composition of claim 59 , suitable for oral administration.
61. The pharmaceutical composition of claim 59 , suitable for intravenous administration.
62. A method of treating of treating depression, Alzheimer's disease, attention deficit disorder, schizophrenia, or anxiety, in a patient in need thereof, the method comprising:
administering to said patient a pharmaceutically effective amount of a compound of claim 37 .
63. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.