PRODRUGS OF DIMETHOXYPHENYLALKYLAMINE ACTIVATORS OF SEROTONIN RECEPTORS
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and X are defined herein. Also provided are pharmaceutical compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof, and methods of using a compound of Formula (I) or pharmaceutically acceptable salt thereof, e.g., in the treatment of a mental health disease or disorder.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydrogen, deuterium, alkyl, or haloalkyl;
R 2 , R 3 , R 4 , and R 5 , independently are hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, —OH, —OD; or
R 2 and R 3 or R 4 and R 5 together are carbonyl;
R 6 is hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, —OH, or —OD;
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, halogen, —OH, or —OD;
R 11 is hydrogen, deuterium, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, halogen, —OH, —OMe, or —CN;
R 12 is COR 13 , CONHR 13 , COOR 13 ,
wherein R 13 , R 14 , R 16 , R 17 , R 18 , R 19 , and R 20 independently are hydrogen, deuterium, alkyl, or heteroalkyl; and
wherein R 15 is hydrogen, deuterium, alkyl, heteroalkyl, or carbonyl;
each X is independently —CR 21 or N;
wherein R 21 is hydrogen, halogen, or alkyl.
2 . The compound of claim 1 , wherein
R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
R 2 , R 3 , R 4 , and R 5 , independently are C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 heterocyclyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 heterocyclyl;
R 7 , R 8 , R 9 , and R 10 independently are C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 heterocyclyl;
R 11 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 heterocyclyl;
R 12 is COR 13 , CONHR 13 , COOR 13 ,
wherein R 13 , R 14 , R 16 , R 17 , R 18 , R 19 , and R 20 independently are C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl; and
wherein R 15 is C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl; and
each X independently is —CR 21 or N;
wherein R 21 is C 1 -C 6 alkyl.
3 . The compound of any of claims 1-2 , wherein R 9 is halogen.
4 . The compound of claim 3 , wherein R 9 is Cl.
5 . The compound of any of claims 1-4 , wherein R 7 is C 1 -C 6 alkyl.
6 . The compound of claim 5 , wherein R 7 is methyl.
7 . The compound of any of claims 1-6 , wherein each X is —CH.
8 . The compound of any of claims 1-6 , wherein at least one X is N.
9 . The compound of any of claims 1-7 , wherein at least two X are N.
10 . The compound of any of claims 1-9 , wherein R 1 is C 1 -C 6 alkyl.
11 . The compound of claim 10 , wherein R 1 is methyl.
12 . The compound of any of claims 1-11 , wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 10 , and R 11 are hydrogen.
13 . The compound of any of claims 1-12 , wherein R 11 is C 1 -C 6 haloalkyl.
14 . The compound of claim 13 , wherein R 1 is —CF 3 .
15 . The compound of any of claims 1-12 , wherein R 11 is halogen.
16 . The compound of claim 15 , wherein R 1 is Cl.
17 . The compound of claim 15 , wherein R 11 is Br.
18 . The compound of claim 15 , wherein R 11 is F.
19 . The compound of any of claims 1-18 , wherein R 12 is
20 . The compound of any of claims 1-18 , wherein R 12 is
21 . The compound of claim 20 , wherein R 19 is hydrogen.
22 . The compound of any of claims 20-21 , wherein R 20 is C 1 -C 6 alkyl.
23 . The compound of claim 22 , wherein R 20 is methyl.
24 . The compound of any of claims 1-18 , wherein R 12 is
25 . The compound of claim 24 , wherein R 17 is hydrogen.
26 . The compound of any of claims 24-25 , wherein R 18 is C 1 -C 6 alkyl.
27 . The compound of claim 26 , wherein R 18 is methyl.
28 . The compound of any of claims 1-18 , wherein R 12 is
29 . The compound of claim 28 , wherein R 14 is C 1 -C 6 alkyl.
30 . The compound of claim 29 , wherein R 14 is methyl.
31 . The compound of any of claims 28-30 , wherein R 15 is carbonyl.
32 . The compound of any of claims 28-31 , wherein R 16 is C 1 -C 6 alkyl.
33 . The compound of claim 32 , wherein R 16 is —C(CH 3 ) 3 .
34 . The compound of any of claims 1-18 , wherein R 12 is —COR 13 .
35 . The compound of claim 34 , wherein R 13 is C 1 -C 6 heteroalkyl.
36 . The compound of claim 35 , wherein R 13 is —CH 2 NH 2 .
37 . The compound of any of claims 1-18 , wherein R 12 is —COOR 13 .
38 . The compound of claim 37 , wherein R 13 is C 1 -C 6 alkyl.
39 . The compound of claim 38 , wherein R 13 is ethyl.
40 . A compound selected from:
41 . A composition comprising the compound of any of claims 1-40 and a pharmaceutically acceptable carrier.
42 . A method for treating one or more conditions that are responsive to serotonin receptor activation, comprising administering to a subject in need thereof an effective amount of the compound of any of claims 1-40 or the composition of claim 41 .
43 . A method of treating a neurological disorder, comprising administering to a subject in need thereof an effective amount of the compound of any of claims 1-40 or the composition of claim 41 .
44 . The method of claim 43 , wherein the neurological disorder is major depressive disorder (MDD), treatment resistant depression (TRD), substance use disorder (SUD), an anxiety disorder including acute stress disorder agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, or specific phobia; an eating disorder including anorexia nervosa or bulimia nervosa; or rumination.
45 . A method of activating a 5-HT receptor comprising administering to a patient the compound of claim 1 .
46 . The method of claim 45 , wherein said 5-HT receptor is a 5-HT2A, 5-HT2B, or 5-HT2C receptor.
47 . The method of claim 46 , wherein said compound is one of the compounds of claim 40 .