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(0)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-l):
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 , and R 12 is hydrogen;
R 3a is methyl;
R 18 is methyl or ethyl;
R 19 is hydrogen, methyl, or ethyl;
R Y is methyl or cyano;
each R D is hydrogen;
q is 0, 1, 2, 3, 4, or 5; and
R 55a and R 55b join together with their intervening atoms to form
wherein
p is 1, and
R a is —CN.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 19 is methyl or hydrogen.
3. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 19 is methyl.
4. The compound or pharmaceutically acceptable salt of claim 1 , wherein R Y is methyl.
5. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 55a and R 55b join together with their intervening atoms to form
6. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I-l) is a compound of Formula (I-m) or a compound of Formula (I-n):
or a pharmaceutically acceptable salt thereof.
7. The compound or pharmaceutically acceptable salt of claim 6 , wherein the compound of Formula (I-l) is a compound of Formula (I-m)
or a pharmaceutically acceptable salt thereof.
8. The compound or pharmaceutically acceptable salt of claim 7 , wherein R 19 is methyl or hydrogen.
9. The compound or pharmaceutically acceptable salt of claim 8 , wherein R 19 is methyl.
10. The compound or pharmaceutically acceptable salt of claim 7 , wherein R Y is methyl.
11. The compound or pharmaceutically acceptable salt of claim 7 , wherein R 55a and R 55b join together with their intervening atoms to form
12. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I-l) is a compound of Formula (I-Il):
or a pharmaceutically acceptable salt thereof, wherein each of R 15a , R 15b , R 16a , and R 16b is hydrogen.
13. The compound or pharmaceutically acceptable salt of claim 12 , wherein the compound of Formula (I-Il) is a compound of Formula (I-Im) or a compound of Formula (I-In)
or a pharmaceutically acceptable salt thereof.
14. The compound or pharmaceutically acceptable salt of claim 13 , wherein the compound of Formula (I-Il) is a compound of Formula (I-Im)
or a pharmaceutically acceptable salt thereof.
15. The compound or pharmaceutically acceptable salt of claim 14 , wherein R 55a and R 55b join together with their intervening atoms to form
16. A compound selected from
Example
Structure
Example
Structure
305
306
317
318
325
326
51
52
355
356
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable excipient.