Deuterated tryptamine derivatives and methods of use
View Patent ↗The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with a serotonin 5-HT 2 receptor.
1. A compound according to Formula (III)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
X 1 and X 2 are deuterium,
Y 1 and Y 2 are hydrogen or deuterium,
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 4 is hydroxyl,
R 5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen or deuterium.
2. A compound according to Formula (III-a)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 4 is hydroxyl,
R 5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen or deuterium.
3. A compound according to Formula (III-c)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
4. The compound of claim 3 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
5. The compound of claim 3 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
6. A compound according to Formula (III-d)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl,
under the proviso that when R 2 , R 6 , and R 7 are all hydrogen, R 8 and R 9 are not both —CD 3 .
7. The compound of claim 6 , wherein R 9 is hydrogen.
8. The compound of claim 6 , wherein R 9 is deuterium.
9. The compound of claim 6 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
10. The compound of claim 6 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
11. A compound according to Formula (III-g)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
12. The compound of claim 11 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
13. The compound of claim 11 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
14. A compound according to Formula (III-h)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
15. The compound of claim 14 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
16. The compound of claim 14 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
17. A compound according to Formula (III j)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
18. The compound of claim 17 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
19. The compound of claim 17 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
20. A compound according to Formula (III-k)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 4 is hydroxyl,
R 5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen or deuterium.
21. A compound according to Formula (III-n)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl,
under the proviso that when R 2 , R 6 , and R 7 are all hydrogen, R 8 and R 9 are not both —CD 3 .
22. The compound of claim 21 , wherein R 9 is hydrogen.
23. The compound of claim 21 , wherein R 9 is deuterium.
24. The compound of claim 21 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
25. The compound of claim 21 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
26. A compound according to Formula (III-o)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
27. The compound of claim 26 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
28. The compound of claim 26 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
29. A compound according to Formula (III-p)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
30. The compound of claim 29 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
31. The compound of claim 29 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
32. A compound according to Formula (III-q)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
33. The compound of claim 32 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
34. The compound of claim 32 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
35. A compound according to Formula (III-r)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
36. The compound of claim 35 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
37. The compound of claim 35 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
38. A compound according to Formula (III-s)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
39. The compound of claim 38 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
40. The compound of claim 38 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
41. A compound according to Formula (III-t)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
42. The compound of claim 41 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
43. The compound of claim 41 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
44. A compound according to Formula (III-u)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
45. The compound of claim 44 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
46. The compound of claim 44 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
47. A compound according to Formula (III-v)
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R 2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
R 6 and R 7 are selected from hydrogen, deuterium, and halogen,
R 8 is an unsubstituted or partially or fully deuterated methyl or ethyl, and
R 9 is hydrogen, deuterium, or an unsubstituted or partially or fully deuterated methyl or ethyl.
48. The compound of claim 47 , wherein R 2 is independently selected from hydrogen, deuterium, halogen, and an unsubstituted or partially or fully deuterated methyl or ethyl.
49. The compound of claim 47 , wherein R 8 and R 9 are not both unsubstituted or partially or fully deuterated ethyl.
50. A compound, wherein the compound is:
51. A compound of the following structure:
52. A method of treating a subject with a disease or disorder comprising administering to the subject a therapeutically effective amount of the compound of claim 50 , wherein the disease or disorder is a cardiovascular disorder including atherosclerosis.
53. A method of treating a subject with a disease or disorder comprising administering to the subject a therapeutically effective amount of the compound of claim 50 , wherein the disease or disorder is alcohol use disorder.