Multicyclic compounds and methods of use thereof
Provided herein are multicyclic compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. For example, disclosed herein are compounds having formula (IIa) shown below, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the variables are defined herein. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.
1. A compound of formula (IIa):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
(i) R 1 and R 3 together with the atoms to which they are attached form 5-membered heterocyclyl, and R 4 is hydrogen or C 1 -C 6 alkyl; or (ii) R 3 and R 4 together form a double bond and together with R 1 and the atoms to which they are attached form a 5-membered heteroaryl;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 5 is hydrogen or C 1 -C 6 alkyl;
R 6 and R 7 are each independently (i) hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl C 1 -C 6 alkyl, 6- to 10-membered aryl, or 6- to 10-membered C 1 -C 6 aralkyl; or (ii) —(CH 2 ) p —R 11 , wherein R 11 is CF 3 , CN, nitro, amino, hydroxyl, C 3 -C 7 cycloalkoxyl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl;
m is 0, 1, or 2;
n is 0, 1, or 2; and
each occurrence of p is independently 0, 1, or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0.
3. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.
4. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, CF 3 , ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.
5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen.
6. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R 3 together with the atoms to which they are attached form a pyrrolidinyl; and R 4 is hydrogen or C 1 -C 6 alkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 4 together form a double bond and together with R 1 and the atoms to which they are attached form an imidazoyl, pyrazolyl, or thiazolyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R 3 together with the atoms to which they are attached form a 5-membered heterocyclyl; and R 4 is hydrogen or C 1 -C 6 alkyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is hydrogen.
10. The compound of claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen.
11. The compound of claim 10 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is hydrogen or methyl.
12. The compound of claim 11 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is hydrogen.
13. The compound of claim 11 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, CF 3 , ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.
14. The compound of claim 13 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, or CF 3 .
15. The compound of claim 14 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0.
16. The compound of claim 15 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.
17. The compound of claim 16 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 1 together with the atoms to which they are attached form a pyrrolidinyl.
18. The compound of claim 8 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 8 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 8 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 8 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 4 together form a double bond and together with R 1 and the atoms to which they are attached form a 5-membered heteroaryl.
23. The compound of claim 22 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen.
24. The compound of claim 23 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is hydrogen or methyl.
25. The compound of claim 24 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, CF 3 , ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.
26. The compound of claim 25 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 and R 7 are each independently hydrogen, fluoro, chloro, methyl, or CF 3 .
27. The compound of claim 26 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0.
28. The compound of claim 27 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.
29. The compound of claim 28 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 4 together form a double bond and together with R 1 and the atoms to which they are attached form an imidazoyl, pyrazolyl, or thiazolyl.
30. The compound of claim 22 , wherein the compound is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
31. The compound of claim 22 , wherein the compound is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
32. The compound of claim 22 , wherein the compound is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
33. The compound of claim 22 , wherein the compound is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
34. The compound of claim 22 , wherein the compound is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
35. The compound of claim 22 , wherein the compound is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
36. The compound of claim 22 , wherein the compound is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
37. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.