Aminotetraline activators of serotonin receptors
Provided herein are compounds of Formula (I), (I-A), (I-B), (II), (II-A), (II-B), (III), (M-A), (IV), and (IV-A), or pharmaceutically acceptable salt thereof described herein. Also provided herein are pharmaceutical compositions comprising a compound Formula (I), (I-A), (I-B), (II), (II-A), (II-B), (III), (III-A), (IV), and (IV-A), or pharmaceutically acceptable salt thereof, and methods of using a compound of Formula (I), (I-A), (I-B), (II), (II-A), (II-B), (III), (III-A), (IV), and (IV-A), or pharmaceutically acceptable salt thereof, e.g., in the treatment of a mental health disease or disorder.
1. A compound of Formula (III):
or a pharmaceutically acceptable salt thereof; wherein,
R 1 is independently methyl or C 2 -C 6 fluoroalkyl;
R 2 and R 3 are independently H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, halogen, CN, OR 7 , or —S(O)(Y)R 6 ;
Y is ═O or ═NH;
R 4 and R 5 are independently H or C 1 -C 6 fluoroalkyl;
R 6 and R 7 are independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl; and
X is CH or N;
wherein the compound is not 5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-2-amine; 5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine; 6-bromo-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine; 7-bromo-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine; 5,7,8-trimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine;
or 5,6,8-trimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine.
2. The compound of claim 1 , wherein R 1 is methyl.
3. The compound of claim 1 , wherein R 1 is C 2 -C 6 fluoroalkyl.
4. The compound of claim 1 , wherein R 2 is H.
5. The compound of claim 1 , wherein R 2 is a halogen.
6. The compound of claim 1 , wherein R 2 is F, Cl, or I.
7. The compound of claim 1 , wherein R 2 is CN.
8. The compound of claim 1 , wherein R 2 is —S(O) 2 R 6 .
9. The compound of claim 1 , wherein R 2 is —S(O)(NH)R 6 .
10. The compound of claim 1 , wherein R 3 is H.
11. The compound of claim 1 , wherein R 3 is a halogen.
12. The compound of claim 1 , wherein R 3 is F, Cl, or I.
13. The compound of claim 1 , wherein R 3 is CN.
14. The compound of claim 1 , wherein R 3 is —S(O) 2 R 6 .
15. The compound of claim 1 , wherein R 3 is —S(O)(NH)R 6 .
16. The compound of claim 1 , wherein R 2 and R 3 are H.
17. The compound of claim 1 , wherein X is CH.
18. The compound of claim 1 , wherein X is N.
19. The compound of claim 1 , wherein R 4 is H.
20. The compound of claim 1 , wherein R 5 is H.
21. The compound of claim 1 , wherein R 4 and R 5 are H.
22. The compound of claim 1 , having the following chemical formula:
23. A compound of Formula (IV):
or a pharmaceutically acceptable salt thereof; wherein,
R 1 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 3 is H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, halogen, CN, OR 7 , or SR 1 ;
R 4 and R 5 are independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 6 and R 7 are independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
X is CH or N;
Y is ═O or ═NH;
m is 0, 1, or 3; and
n is 0, 1, 2, or 3.
24. The compound of claim 23 , wherein Y is ═O.
25. The compound of claim 23 , wherein Y is ═NH.
26. The compound of claim 23 , wherein R 1 is C 1 -C 6 alkyl.
27. The compound of claim 26 , wherein R 1 is C 1 -C 3 alkyl.
28. The compound of claim 27 , wherein R 1 is methyl.
29. The compound of claim 23 , wherein R 1 is H.
30. The compound of claim 23 , wherein R 1 is C 1 -C 6 fluoroalkyl.
31. The compound of claim 23 , wherein R 3 is H.
32. The compound of claim 23 , wherein R 3 is halogen.
33. The compound of claim 23 , wherein R 4 is H.
34. The compound of claim 23 , wherein R 4 is C 1 -C 6 alkyl.
35. The compound of claim 23 , wherein R 5 is H.
36. The compound of claim 23 , wherein R 5 is C 1 -C 6 alkyl.
37. The compound of claim 23 , wherein R 4 and R 5 are H.
38. The compound of claim 23 , wherein X is CH.
39. The compound of claim 23 , wherein X is N.
40. The compound of claim 23 , wherein m is 0.
41. The compound of claim 23 , wherein m is 1.
42. The compound of claim 23 , wherein n is 1.
43. The compound of claim 23 , wherein n is 2.
44. The compound of claim 23 , wherein R 6 is H.
45. The compound of claim 23 , wherein R 6 is C 1 -C 6 alkyl.
46. The compound of claim 45 , wherein R 6 is C 1 -C 3 alkyl.
47. A compound selected from:
48. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
49. A method of treating a mental health disease or disorder, the method comprising administering a therapeutically effective amount of the composition of claim 48 .
50. The method of claim 49 , wherein the mental health disease or disorder is selected from the group consisting of major depressive disorder, treatment resistant depression, substance use disorders and eating disorders.
51. The method of claim 49 , wherein the mental health disease or disorder is selected from the group consisting of compulsive disorders, anxiety disorders, stress disorders, and rumination.
52. A pharmaceutical composition, comprising a compound of claim 23 and a pharmaceutically acceptable excipient.
53. A method of treating a mental health disease or disorder, the method comprising administering a therapeutically effective amount of the composition of claim 52 .
54. The method of claim 53 , wherein the mental health disease or disorder is selected from the group consisting of major depressive disorder, treatment resistant depression, substance use disorders and eating disorders.
55. The method of claim 53 , wherein the mental health disease or disorder is selected from the group consisting of compulsive disorders, anxiety disorders, stress disorders, and rumination.
56. A method of treating a mental health disease or disorder, the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a compound of Formula (II):
(I)
(II)
or a pharmaceutically acceptable salt thereof; wherein,
R 1 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 2 , and R 3 , are independently H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, halogen, CN, OR 1 S(O)NHR 1 R 2 , or SR 1 ;
R 4 and R 5 are independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
X is C or N;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3;
provided that when n is 0, than X is N.
57. The method of claim 56 , wherein the mental health disease or disorder is selected from the group consisting of major depressive disorder, treatment resistant depression, substance use disorders and eating disorders.
58. The method of claim 56 , wherein the mental health disease or disorder is selected from the group consisting of compulsive disorders, anxiety disorders, stress disorders, and rumination.