19-nor neuroactive steroids and methods of use thereof

1. A compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

represents a single or double bond;

R 1 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl;

R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, or —OR A2 , wherein R A2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl;

R 3a is hydrogen or —OR A3 , wherein R A3 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b are joined to form an oxo (═O) group;

each instance of R 4a and R 4b is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, alkoxy, halogen, or —OR A4 , wherein R A4 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 is in the alpha or beta configuration; and provided if the between C5 and C6 is a double bond, R 4b is absent;

each instance of R 5 is independently halogen, —NO 2 , —CN, —N(R GA ) 2 , —C(═O)R GA , —C(═O)OR GA , —OC(═O)R GA , —OC(═O)OR GA , —C(═O)N(R GA ) 2 , —N(R GA )C(═O)R GA , —OC(═O)N(R GA ) 2 , —N(R GA )C(═O)OR GA , —S(═O) 2 R GA , —S(═O) 2 OR GA , —OS(═O) 2 R GA , —S(═O) 2 N(R GA ) 2 , or —N(R GA )S(═O) 2 R GA ; substituted or unsubstituted C 3-4 carbocyclyl, substituted or unsubstituted 3- to 4-membered heterocyclyl, or optionally two R GA are taken with the intervening atoms to form a substituted or unsubstituted 3- to 4-membered carbocyclic or heterocyclic ring;

each instance of R GA is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and

e is 1, 2, 3, 4, or 5.

2. The compound or pharmaceutically acceptable salt of claim 1 , wherein e is 1.

3. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 5 is —OR GA wherein R GA is hydrogen or substituted or unsubstituted C 1-6 alkyl.

4. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 5 is —OH.

5. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 5 is —S(═O) 2 R GA wherein R GA is substituted or unsubstituted C 1-6 alkyl.

6. The compound or pharmaceutically acceptable salt of claim 5 , wherein R 5 is —S(═O) 2 CH 3 .

7. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 5 is —C(═O)R GA wherein R GA is substituted or unsubstituted C 1-6 alkyl.

8. The compound or pharmaceutically acceptable salt of claim 7 , wherein R 5 is —C(═O)CH 3 .

9. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 5 is —C(═O)N(R GA ) 2 wherein R GA is hydrogen or substituted or unsubstituted C 1-6 alkyl.

10. The compound or pharmaceutically acceptable salt of claim 9 , wherein R 5 is —C(═O)NHCH 3 .

11. The compound or pharmaceutically acceptable salt of claim 1 , wherein between C5 and C6 is a single bond.

12. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (III) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. A method for positively modulating a GABA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the subject has a CNS-related disorder.

16. The method of claim 15 , wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus.

17. The method of claim 14 , wherein the compound is administered orally, subcutaneously, intravenously, or intramuscularly.

18. The method of claim 14 , wherein the compound is administered chronically.

19. The method of claim 16 , wherein the CNS-related disorder is a mood disorder, and the mood disorder is depression.

20. A method for treating a CNS-related disorder related to GABA-modulation in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of

(a) a compound of Formula (III)

or a pharmaceutically acceptable salt thereof, wherein:

represents a single or double bond;

R 1 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl;

R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, or —OR A2 , wherein R A2 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl;

R 3a is hydrogen or —OR A3 , wherein R A3 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b are joined to form an oxo (═O) group;

each instance of R 4a and R 4b is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, alkoxy, halogen, or —OR A4 , wherein R A4 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocyclyl, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 is in the alpha or beta configuration; and provided if the between C5 and C6 is a double bond, R 4b is absent;

each instance of R 5 is independently halogen, —NO 2 , —CN, —OR GA , —N(R GA ) 2 , —C(═O)R GA , —C(═O)OR GA , —OC(═O)R GA , —OC(═O)OR GA , —C(═O)N(R GA ) 2 , —N(R GA )C(═O)R GA , —OC(═O)N(R GA ) 2 , —N(R GA )C(═O)OR GA , —S(═O) 2 R GA , —S(═O) 2 OR GA , —OS(═O) 2 R GA , —S(═O) 2 N(R GA ) 2 , or —N(R GA )S(═O) 2 R GA ; substituted or unsubstituted C 3-4 carbocyclyl, substituted or unsubstituted 3- to 4-membered heterocyclyl, or optionally two R GA are taken with the intervening atoms to form a substituted or unsubstituted 3- to 4-membered carbocyclic or heterocyclic ring;

each instance of R GA is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and

e is 1, 2, 3, 4, or 5; or

(b) a pharmaceutical composition comprising a compound of Formula (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

21. The method of claim 20 , wherein e is 1.

22. The method of claim 21 , wherein R 5 is —OR GA wherein R GA is hydrogen or substituted or unsubstituted C 1-6 alkyl.

23. The method of claim 22 , wherein R 5 is —OH.

24. The method of claim 21 , wherein R 5 is —S(═O) 2 R GA wherein R GA is substituted or unsubstituted C 1-6 alkyl.

25. The method of claim 21 , wherein R 5 is —C(═O)R GA wherein R GA is substituted or unsubstituted C 1-6 alkyl.

26. The method of claim 21 , wherein R 5 is —C(═O)N(R GA ) 2 wherein R GA is hydrogen or substituted or unsubstituted C 1-6 alkyl.

27. The method of claim 20 , wherein between C5 and C6 is a single bond.

28. The method of claim 20 , wherein the compound of Formula (III) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

29. The method of claim 20 , wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus.

30. The method of claim 20 , wherein compound of Formula (III) or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered orally, subcutaneously, intravenously, or intramuscularly.

31. The method of claim 20 , wherein the compound is administered chronically.

32. The method of claim 20 , wherein the CNS-related disorder is a mood disorder, and the mood disorder is depression.

33. The method of claim 32 , wherein the depression is postnatal depression.