1-heterocyclyl isochromanyl compounds and analogs for treating CNS disorders
Disclosed are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, R a , R 1 , R 2 , R 3 , R 4 , R 6 , w and n1 are defined and described herein; compositions thereof; and methods of use thereof. These compounds are useful for treating a variety of neurological and psychiatric disorders, such as those described herein.
1. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
m is 0, 1, or 2;
R is —H or C 1 -C 3 alkyl;
R a is —H or C 1 -C 3 alkyl;
R 1 , R 2 , R 3 , and R 4 are independently —H, halo, —OH, —NH 2 , C 1 -C 3 alkyl, —OR 7 , —NHR 7 , —N(R 7 )R 7 , —CN, phenyl, or 5- or 6-membered heteroaryl, wherein:
each instance of R 7 independently is unsubstituted C 1 -C 2 alkyl or C 1 -C 2 alkyl substituted with 1-3 halo,
each instance of C 1 -C 3 alkyl independently is unsubstituted or substituted with 1-3 halo, and
the phenyl or heteroaryl is unsubstituted or substituted with 1 or 2 groups independently selected from halo, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , ethyl, —CF 3 , and —CN,
optionally wherein
two adjacent instances of R 1 , R 2 , R 3 , and R 4 together form —O—CH 2 —O—, —O—CH(CH 3 )—O—, —O—C(CH 3 ) 2 —O—, —O—CH 2 —CH 2 —O—, or —O—C(CH 3 ) 2 —C(CH 3 ) 2 —O—;
each instance of R 5 independently is halo, —CH 3 , or ethyl;
each instance of R 6 independently is halo, —CH 3 , ethyl or —OH;
w is 0, 1, or 2; and
provided that the compound is not:
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least two of R 1 , R 2 , R 3 , and R 4 are —H.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least three of R 1 , R 2 , R 3 , and R 4 are —H.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the 5- or 6-membered heteroaryl has at least 1 nitrogen ring atom and is unsubstituted or substituted with 1 group selected from halo,
—OH, —OCH 3 , —OCF 3 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , ethyl, —CF 3 , and —CN.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is unsubstituted pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl, or oxazolyl.
6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is unsubstituted pyridyl or isoxazolyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein two adjacent instances of R 1 , R 2 , R 3 , and R 4 together form —O—CH 2 —O—, —O—CH(CH 3 )—O—, or —O—C(CH 3 ) 2 —O—.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein two adjacent instances of R 1 , R 2 , R 3 , and R 4 together form —O—CH 2 —O—.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a is —H.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is —H.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each instance of R 5 is —F or —CH 3 .
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each instance of R 6 is —F or —CH 3 .
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each instance of R 6 is —CH 3 .
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein w is 0.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0 and w is 0.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are independently —H, halo, C 1 -C 3 alkyl, —OR 7 or —CN.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are independently —H, —F, —CH 3 , —OCH 3 , or —CN.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —F or —CH 3 .
20. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
21. The composition according to claim 20 , wherein said composition is a pharmaceutically acceptable composition.
22. A compound selected from:
or a pharmaceutically acceptable salt thereof.
23. A composition comprising a compound according to claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
24. The composition according to claim 23 , wherein said composition is a pharmaceutically acceptable composition.
25. A compound of formula:
or a pharmaceutically acceptable salt thereof.
26. A compound of claim 25 , or a pharmaceutically acceptable salt thereof, selected from:
or a mixture of two or more thereof.
27. A composition comprising a compound according to claim 25 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
28. The composition according to claim 27 , wherein said composition is a pharmaceutically acceptable composition.
29. A composition comprising a compound according to claim 26 , or a pharmaceutically acceptable salt thereof, or a mixture of two or more thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
30. The composition according to claim 29 , wherein said composition is a pharmaceutically acceptable composition.
31. A compound of formula:
or a pharmaceutically acceptable salt thereof.
32. A composition comprising a compound according to claim 31 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
33. The composition according to claim 32 , wherein said composition is a pharmaceutically acceptable composition.