Prodrugs and conjugates of dimethyltryptamine
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , X, Y, Z, W, and m are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
1. A compound of Formula:
wherein R 1 and R 2 are independently hydrogen, alkyl, or cycloalkyl; or R 1 and R 2 , together with the atoms to which they are attached form a heterocyclic ring;
X, Y, and Z are independently hydrogen, halogen, —O—, —S—, —NR A —, or (P═O)—OR A (—OR′), wherein R′ and R A are independently hydrogen or alkyl;
R 3 , R 4 , and R 5 are independently absent, —(C═O)CHR 7 (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), or —(C═O)CH(NH 2 )(CH 2 ) n (NH)(C═NH)(NH 2 );
R 7 is hydrogen or alkyl;
R 9 is hydrogen, alkyl, or halogen;
R 11 is a pharmaceutically acceptable cation, hydrogen, deuterium, alkyl, or cycloalkyl; and
n is an integer from 2-7.
2. The compound of claim 1 , wherein R 1 and R 2 are alkyl.
3. The compound of claim 1 , wherein R 1 and R 2 are methyl.
4. The compound of claim 1 , wherein R 9 is hydrogen.
5. The compound of claim 1 , wherein R 11 is a pharmaceutically acceptable cation.
6. The compound of claim 1 , wherein R 11 is hydrogen.
7. A compound of Formula:
wherein R 1 and R 2 are independently hydrogen, alkyl, or cycloalkyl; or R 1 and R 2 , together with the atoms to which they are attached form a heterocyclic ring;
X, Y, and Z are independently hydrogen, halogen, —O—, —S—, —NR A —, or (P═O)—OR A (—OR′), wherein R′ and R A are independently hydrogen or alkyl;
R 3 , R 4 , and R 5 are independently absent, hydrogen, alkyl, —(C═O)-alkyl, —(C═O)(CH 2 ) n (NH 2 ), —(C═O)(CH 2 ) n (NH)(C═NH)(NH 2 ), or
L and M are independently alkyl or aryl;
R 9 is hydrogen, alkyl, or halogen;
R 11 is a pharmaceutically acceptable cation, hydrogen, deuterium, alkyl, or cycloalkyl; and
n is an integer from 2-7.
8. The compound of claim 7 , wherein R 1 and R 2 are alkyl.
9. The compound of claim 7 , wherein R 1 and R 2 are methyl.
10. The compound of claim 7 , wherein R 3 , R 4 , and R 5 are absent.
11. The compound of claim 7 , wherein R 9 is hydrogen.
12. The compound of claim 7 , wherein R 11 is a pharmaceutically acceptable cation.
13. The compound of claim 7 , wherein R 11 is hydrogen.
14. The compound of claim 7 , wherein X, Y, and Z are hydrogen.
15. A compound of Formula (VIII):
wherein:
R 1 and R 2 are independently hydrogen, alkyl, or cycloalkyl or R 1 and R 2 , together with the atoms to which they are attached, form a heterocyclic ring;
X, Y, and Z are independently hydrogen, halogen, —O—, —S—, —NR A —, or (P═O)—OR A (—OR′), wherein R′ and R A are independently hydrogen or alkyl;
R 3 , R 4 , and R 5 are independently absent, —(C═O)CHR 7 (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), or —(C═O)CH(NH 2 )(CH 2 ) n (NH)(C═NH)(NH 2 );
R 7 is hydrogen or alkyl;
R 9 is hydrogen, alkyl, or halogen;
R 11 and R 12 are independently a pharmaceutically acceptable cation, hydrogen, deuterium, alkyl, cycloalkyl or R 11 and R 12 , together with the atoms to which they are attached, form a heterocyclic ring; and
n is an integer from 2-7.
16. The compound of claim 15 , wherein R 1 and R 2 are alkyl.
17. The compound of claim 15 , wherein R 1 and R 2 are methyl.
18. The compound of claim 15 , wherein R 9 is hydrogen.
19. The compound of claim 15 , wherein R 11 is a pharmaceutically acceptable cation.
20. The compound of claim 15 , wherein R 11 is hydrogen.
21. The compound of claim 15 , wherein R 12 is a pharmaceutically acceptable cation.
22. The compound of claim 15 , wherein R 12 is hydrogen.
23. A compound of Formula (VIII):
wherein R 1 and R 2 are independently hydrogen, alkyl, or cycloalkyl; or R 1 and R 2 , together with the atoms to which they are attached form a heterocyclic ring;
X, Y, and Z are independently hydrogen, halogen, —O—, —S—, —NR A —, or (P═O)—OR A (—OR′), wherein R′ and R A are independently hydrogen or alkyl;
R 3 , R 4 , and R 5 are independently absent, hydrogen, alkyl, —(C═O)-alkyl, —(C═O)(CH 2 ) n (NH 2 ), —(C═O)(CH 2 ) n (NH)(C═NH)(NH 2 ), or
L and M are independently alkyl or aryl;
R 9 is hydrogen, alkyl, or halogen;
R 11 and R 12 are independently a pharmaceutically acceptable cation, hydrogen, deuterium, alkyl, cycloalkyl, or R 11 and R 12 together with the atoms to which they are attached form a heterocyclic ring; and
n is an integer from 2-7.
24. The compound of claim 23 , wherein R 1 and R 2 are alkyl.
25. The compound of claim 23 , wherein R 1 and R 2 are methyl.
26. The compound of claim 23 , wherein R 3 , R 4 , and R 5 are absent.
27. The compound of claim 23 , wherein R 9 is hydrogen.
28. The compound of claim 23 , wherein R 11 is a pharmaceutically acceptable cation.
29. The compound of claim 23 , wherein R 11 is hydrogen.
30. The compound of claim 23 , wherein X, Y, and Z are hydrogen.