Piperazine substituted azapine derivatives and uses thereof
The present disclosure relates to compounds of Formula (I) and (II): and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating H1 and 5-HT 2A receptors and are to be used in the treatment of sleep disorders, such as sleep fragmentation, disturbed sleep/arousals, and arousal threshold.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, or C 3 -C 6 cycloalkyl;
R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, or C 3 -C 6 cycloalkyl; or
R 1 and R 2 together with the atoms to which they are attached form a C 3 -C 6 saturated or partially unsaturated cycloalkyl or a 3- to 14-membered saturated or partially unsaturated heterocycle comprising 1-5 heteroatoms selected from N, O, and S;
R 3 is H, halogen, —S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, or C 3 -C 6 cycloalkyl;
R 4 is H, halogen, —S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, or C 3 -C 6 cycloalkyl;
R 5 is H, halogen, —S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, or C 3 -C 6 cycloalkyl;
R 6 is H, halogen, —S(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, or C 3 -C 6 cycloalkyl;
R 7 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 8 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl,
provided that at least one of R 3 , R 4 , R 5 , and R 6 is H.
2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.
3. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkyl.
4. The compound of claim 1 , wherein R 3 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl.
5. The compound of claim 1 , wherein R 4 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
6. The compound of claim 1 , wherein R 5 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, S(C 1 -C 6 alkyl), or C 1 -C 6 haloalkyl.
7. The compound of claim 1 , wherein R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl.
8. The compound of claim 1 , wherein R 7 , R 8 , and R 9 are H.
9. The compound of claim 1 , wherein the compound is of Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein,
R 3 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl;
R 4 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 5 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, S(C 1 -C 6 alkyl), or C 1 -C 6 haloalkyl; and
R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl.
10. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
22. A method of treating increased sleep fragmentation in a subject in need thereof by administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof.