PRODRUGS OF DIMETHYLTRYPTAMINE AND DERIVATIVES THEREOF
Provided herein are compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B), pharmaceutically acceptable salts thereof, and compositions thereof, wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , A, B, E, W, X, and n are defined herein. The disclosed compounds are useful for treating various diseases, including depression and associated conditions.
1 . A compound of Formula (I-A):
or a pharmaceutically acceptable salt thereof,
wherein:
A is N or C—VR 16 ;
B is N or C—YR 4 ;
E is N or C—ZR 5 , wherein no more than two of A, B, and E are N;
W is O, S, or NR 6 ;
V, X, Y, and Z are each independently absent, O, S, or NH;
R 1 and R 2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl;
R 3 , R 4 , R 5 , and R 16 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or —P(O)(OH) 2 ;
R 6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene- optionally substituted cycloalkyl, or optionally substituted heteroalkyl;
R 7 and R 8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R 7 and R 8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring;
R 9 and R 10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R 9 and R 10 taken together with the atom to which they are attached form an oxo;
R 11 and R 12 are each independently alkyl, deuterated alkyl, —O − , —OH, —OD, —O-alkyl, —O— cycloalkyl, —O-alkylene-cycloalkyl, —O-aryl, or —OM, wherein M is a pharmaceutically acceptable cation, or R 11 and R 12 together with the atoms to which they are attached form a heterocyclyl, and the alkyl, cycloalkyl, aryl and heterocyclyl are each optionally substituted;
R 13 is H, D, halogen, deuterated alkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, —C(O)-(alkylene- optionally substituted aryl), or —O—C(O)—NHR 15 , or R 11 and R 13 taken together with the atoms to which they are attached form an optionally substituted heterocyclic ring comprising 4-7 carbon atoms;
R 14 is H, D, halogen, haloalkyl, —OH, an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and
R 5 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
2 . The compound of claim 1 , wherein A is C—VR 16 .
3 . The compound of claim 1 , wherein V is absent.
4 . The compound of claim 2 , wherein R 16 is H.
5 . The compound of claim 1 , wherein B in C—YR 4 .
6 . The compound of claim 5 , wherein Y is absent.
7 . The compound of claim 5 , wherein Y is G.
8 . The compound of claim 5 , wherein R 4 is H, optionally substituted C 1-5 alkyl, or —P(O)(OH) 2 .
9 . The compound of claim 5 , wherein R 4 is methyl.
10 . The compound of claim 1 , wherein E is C—ZR 5 .
11 . The compound of claim 10 , wherein Z is absent.
12 . The compound of claim 10 , wherein R 5 is H.
13 . The compound of claim 1 , wherein X is absent.
14 . The compound of claim 1 , wherein X is O.
15 . The compound of claim 1 , wherein R 3 is H, optionally substituted C 1-5 alkyl, or —P(O)(OH) 2 .
16 . The compound of claim 1 , wherein W is NR 6 .
17 . The compound of claim 16 , wherein R 6 is H or optionally substituted C 1-5 alkyl.
18 . The compound of claim 16 , wherein R 6 is H.
19 . The compound of claim 1 , wherein R 1 and R 2 are each independently H or optionally substituted C 1-5 alkyl.
20 . The compound of claim 1 , wherein R 1 and R 2 are each optionally substituted C 1-5 alkyl.
21 . The compound of claim 20 , wherein R 1 and R 2 are methyl.
22 . The compound of claim 1 , wherein R 7 and R 8 are each independently H, F, or optionally substituted C 1-5 alkyl.
23 . The compound of claim 1 , wherein R 7 and R 8 are each H.
24 . The compound of claim 1 , wherein R 9 and R 10 are each independently H, F, or optionally substituted C 1-5 alkyl.
25 . The compound of claim 1 , wherein R 9 and R 10 are each H.
26 . The compound of claim 1 , wherein R 9 and R 10 taken together with the atom to which they are attached form an oxo.
27 . The compound of claim 1 , wherein R 11 and R 12 are each independently —O—, —OH, —O—C 1-5 alkyl, or -OM.
28 . The compound of claim 1 , wherein R 11 is O − and R 12 is —OH, —O—C 1-5 alkyl, or -OM.
29 . The compound of claim 1 , wherein R 11 and R 12 are each —O—C 1-5 alkyl.
30 . The compound of claim 27 , wherein R 11 and R 12 are each independently —OMe, —OEt, —OiPr, or -OtBu.
31 . The compound of claim 27 , wherein R 11 and R 12 are each independently —O—C 1-5 haloalkyl.
32 . The compound of claim 27 , wherein R 11 and R 12 are —OCH 2 CF 3 .
33 . The compound of claim 1 , wherein M is Na + , K + , or NH 4 + .
34 . The compound of claim 1 , wherein R 11 and R 12 are each —OH.
35 . The compound of claim 1 , wherein R 11 and R 12 taken together with the atoms to which they are attached form an optionally substituted heterocyclyl.
36 . The compound of claim 1 , wherein R 11 and R 12 taken together with the atoms to which they are attached form an optionally substituted 5- to 12-membered heterocyclyl.
37 . The compound of claim 35 , wherein the optionally substituted heterocyclyl is:
38 . The compound of claim 1 , wherein R 11 and R 12 are each deuterated alkyl.
39 . The compound of claim 1 , wherein R 11 and R 12 are each deuterated methyl.
40 . The compound of claim 1 , wherein R 13 is H or optionally substituted C 1-5 alkyl.
41 . The compound of 40 , wherein R 13 is methyl, ethyl, or isopropyl.
42 . The compound of claim 1 , wherein R 14 is H, F, Cl, Br, or C 1-5 alkyl.
43 . The compound of claim 1 , wherein R 14 is H.
44 . The compound of claim 1 , wherein R 14 is haloalkyl.
45 . The compound of claim 1 , wherein R 14 is —CF 3 .
46 . The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
47 . The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
48 . The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
49 . The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
50 - 77 . (canceled)
78 . The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
79 . The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
80 . A composition comprising (i) a compound of claim 1 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient.
81 . An oral dosage form comprising the pharmaceutical composition of claim 80 .
82 . A method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering a pharmaceutical composition of 80 to the subject.
83 . A method of treating depression in a subject in need thereof, comprising administering a pharmaceutical composition of claim 80 to the subject.
84 . The method of claim 83 , wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).
85 . A method of treating an anxiety disorder in a subject in need thereof, comprising a pharmaceutical composition of claim 80 to the subject.