Neuroactive steroids and their methods of use
Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 19 , R 5 , R 3a , R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 6a , R 6b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 18 , R D , and q are defined herein. L is selected from the group consisting of: wherein A indicates the point of attachment at C17 and wherein X is selected from the group consisting of —C(O)N(R 55a )(R 55b ), —N(R 55a )(R 55b ), —N(R 55b )C(O)(R 55a ), and R 55C wherein R 55c is carbon-bound substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.
1. A compound of Formula (I-v):
or a pharmaceutically acceptable salt thereof, wherein
each of R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 6a , R 6b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , and R 19 is hydrogen;
each of R 3a , R 18 , and R Y is methyl;
each R D is hydrogen;
q is 0, 1, 2, 3, 4, or 5; and
R 55c is
wherein
each R a is independently hydrogen, halogen, —CN, —OR D4 , —N(R D4 ) 2 , or substituted or unsubstituted C 1-6 alkyl, each R D4 is independently hydrogen or substituted or unsubstituted C 1-6 alkyl, and
p is 0, 1, or 2.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 55c is
each R a is independently hydrogen, halogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
3. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 55c is
each R a is independently hydrogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
4. The compound or pharmaceutically acceptable salt of claim 3 , wherein p is 1 and R a is hydrogen, —CN, or unsubstituted C 1-6 alkyl.
5. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 55c is
each R a is independently hydrogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
6. The compound or pharmaceutically acceptable salt of claim 5 , wherein p is 1, and R a is hydrogen, —CN, or unsubstituted C 1-6 alkyl.
7. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I-v) is a compound of Formula (I-Iw1) or a compound of Formula (I-Ix1):
or a pharmaceutically acceptable salt thereof.
8. The compound or pharmaceutically acceptable salt of claim 7 , wherein the compound of Formula (I-v) is a compound of Formula (I-Iw1)
or a pharmaceutically acceptable salt thereof.
9. The compound or pharmaceutically acceptable salt of claim 8 , wherein R 55c is
each R a is independently hydrogen, halogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
10. The compound or pharmaceutically acceptable salt of claim 9 , wherein R 55c is
each R a is independently hydrogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
11. The compound or pharmaceutically acceptable salt of claim 10 , wherein p is 1, and R a is hydrogen, —CN, or unsubstituted C 1-6 alkyl.
12. The compound or pharmaceutically acceptable salt of claim 9 , wherein R 55c is
each R a is independently hydrogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
13. The compound or pharmaceutically acceptable salt of claim 12 , wherein p is 1, and R a is hydrogen, —CN, or unsubstituted C 1-6 alkyl.
14. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I-v) is a compound of Formula (I-Ix1)
or a pharmaceutically acceptable salt thereof.
15. The compound or pharmaceutically acceptable salt of claim 14 , wherein R 55c is
each R a is independently hydrogen, halogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
16. The compound or pharmaceutically acceptable salt of claim 15 , wherein R 55c is
each R a is independently hydrogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
17. The compound or pharmaceutically acceptable salt of claim 16 , wherein p is 1, and R a is hydrogen, —CN, or unsubstituted C 1-6 alkyl.
18. The compound or pharmaceutically acceptable salt of claim 15 , wherein R 55c is
each R a is independently hydrogen, —CN, or substituted or unsubstituted C 1-6 alkyl, and p is 0, 1, or 2.
19. The compound or pharmaceutically acceptable salt of claim 18 , wherein p is 1, and R a is hydrogen, —CN, or unsubstituted C 1-6 alkyl.
20. A compound selected from
Example
Structure
435
436
437
438
439
440
441
442
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.