IP Library › Patent Application 18003215

Patent Application

App. No. 18/003,215

NEUROACTIVE STEROIDS AND COMPOSITIONS THEREOF

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App. No.: 18/003,215

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Abstract

Provided herein is a compound of the Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 4a , R 4b , R 5 , R 6 , R 7 , R 11a , R 11b , R 15a , R 15b , R 16 , R 17 , R 19 , R X , R Y , and t are defined herein. 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.

Claims (268)

1 . A compound of Formula (I-1)

or a pharmaceutically acceptable salt thereof, wherein

Each of R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , R 11b , R 15a , and R 15b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , —NR D1 C(═O)R D1 , a substituted or unsubstituted 3-6 membered monocyclic heterocycle, or a substituted or unsubstituted 8-12 membered bicyclic heterocycle wherein the monocyclic or bicyclic heterocycle has 1-3 heteroatoms independently selected from N, O, and S;

Each R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted 3-6 membered monocyclic heterocycle or 8-12 membered bicyclic heterocycle wherein the monocyclic or bicyclic heterocycle has 1-3 heteroatoms independently selected from N, O, and S; or

any one of R 2a and R 2b , R 4a and R 4b , or R 11a and R 11b are joined together to form an oxo (═O) group;

Each of R 16 and R 17 is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —N(R A1 ), —CN(R A1 ) 2 , —C(O)R A1 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —NHC(═O)R A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , —S(═O) 2 OR A1 , or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S;

Each R A1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, —SO 2 R A2 , —C(O)R A2 , or two R A1 groups are joined together to form a substituted or unsubstituted 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, and S;

Each R A2 is independently substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S;

R 3a is unsubstituted C 1-6 alkyl, —CH 2 OCH 3 , or —CH 2 OCH 2 CH 3 ;

R 5 is hydrogen, unsubstituted methyl, or absent;

is a single bond or a double bond, provided that when is a single bond, R 5 is hydrogen or methyl, and when is a double bond, R 3 is absent;

R 19 is hydrogen or unsubstituted C 1-6 alkyl;

R X is hydrogen or substituted or unsubstituted C 1-6 alkyl; and

R Y is substituted or unsubstituted pyrazinyl, pyrimidine substituted with cyano, substituted or unsubstituted pyridine, or substituted phenyl, provided that

when R 3a is —CH 2 OCH 2 CH 3 and R Y is substituted or unsubstituted pyrazinyl, R 19 is unsubstituted methyl.

2 . The compound or pharmaceutically acceptable salt of claim 1 , wherein each of R 2a and R 2b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

3 . The compound or pharmaceutically acceptable salt of claim 1 or claim 2 , wherein each of R 2a and R 2b is independently hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen or —OH.

4 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 3 , wherein each of R 2a and R 2b is independently hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

5 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 4 , wherein one of R 2a and R 2b is hydrogen.

6 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 5 , wherein each of R 2a and R 2b is hydrogen.

7 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 6 , wherein each of R 4a and R 4b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

8 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 7 , wherein each of R 4a and R 4b is independently hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

9 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 8 , wherein each of R 4a and R 4b is independently hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

10 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 9 , wherein one of R 4a and R 4b is hydrogen.

11 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 10 , wherein each of R 4a and R 4b is hydrogen.

12 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 11 , wherein each of R 11a and R 11b is independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

13 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 12 , wherein each of R 11a and R 11b is independently hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen or C 1-6 alkoxy optionally substituted with 1-3 halogen.

14 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 13 , wherein each of R 11a and R 11b is independently hydrogen, —CH 3 , —CH 2 CH 3 , —OCH 3 , or —CH(CH 3 ) 2 .

15 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 14 , wherein one of R 11a and R 11b is hydrogen.

16 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 15 , wherein each of R 11a and R 11b is hydrogen.

17 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 16 , wherein R 7 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

18 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 17 , wherein R 7 is hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

19 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 18 , wherein R 7 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

20 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 19 , wherein R 7 is hydrogen.

21 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 20 , wherein R 6 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

22 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 21 , wherein R 6 is hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

23 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 22 , wherein R 6 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

24 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 23 , wherein R 6 is hydrogen.

25 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 24 , wherein R 16 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

26 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 25 , wherein R 16 is hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

27 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 26 , wherein R 16 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

28 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 27 , wherein R 16 is hydrogen.

29 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 28 , wherein R 17 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C2.6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

30 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 29 , wherein R 17 is hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

31 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 30 , wherein R 17 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

32 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 31 , wherein R 17 is hydrogen.

33 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 32 , wherein R 19 is hydrogen or unsubstituted C 1-5 alkyl.

34 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 33 , wherein R 19 is hydrogen or unsubstituted C 1-4 alkyl.

35 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 34 , wherein R 19 is hydrogen, —CH 3 , or —CH 2 CH 3 .

36 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 35 , wherein R 19 is hydrogen.

37 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 35 , wherein R 19 is —CH 3 or —CH 2 CH 3 .

38 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 37 , wherein R 3 is unsubstituted C 1-6 alkyl.

39 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 38 , wherein R 3 is unsubstituted C 1-4 alkyl.

40 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I-1) is a compound of Formula (I-2)

or a pharmaceutically acceptable salt thereof, wherein

R 3a is —CH 2 OCH 3 or unsubstituted methyl;

R 5 is hydrogen, unsubstituted methyl, or absent;

is a single bond or a double bond, provided that when is a single bond, R 5 is hydrogen or methyl, and when is a double bond, R 5 is absent;

R 19 is hydrogen or substituted or unsubstituted C 1-6 alkyl;

R X is hydrogen or substituted or unsubstituted C 1-6 alkyl; and

R Y is pyridine substituted with cyano.

41 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I-1) is a compound of Formula (I-3)

or a pharmaceutically acceptable salt thereof, wherein

R 3 is —CH 2 OCH 3 or unsubstituted methyl;

R 5 is hydrogen, unsubstituted methyl, or absent;

is a single bond or a double bond, provided that when is a single bond, R 5 is hydrogen or methyl, and when is a double bond, R 3 is absent;

R 19 is hydrogen or substituted or unsubstituted C 1-6 alkyl;

R X is hydrogen or substituted or unsubstituted C 1-6 alkyl; and

R Y is pyridine substituted with fluoro.

42 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I-1) is a compound of Formula (I-a1):

or a pharmaceutically acceptable salt thereof.

43 . The compound or pharmaceutically acceptable salt of claim 40 , wherein the compound of Formula (I-2) is a compound of Formula (I-a2):

or a pharmaceutically acceptable salt thereof.

44 . The compound or pharmaceutically acceptable salt of claim 41 , wherein the compound of Formula (I-3) is a compound of Formula (I-a3):

or a pharmaceutically acceptable salt thereof.

45 . The compound or pharmaceutically acceptable salt of any one of claims 42 - 44 , wherein R 17 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

46 . The compound or pharmaceutically acceptable salt of any one of claims 42 - 45 , wherein R 17 is hydrogen.

47 . The compound or pharmaceutically acceptable salt of any one of claims 42 - 46 , wherein R 19 is hydrogen or unsubstituted C 1-4 alkyl.

48 . The compound or pharmaceutically acceptable salt of any one of claims 42 - 47 , wherein R 19 is hydrogen, —CH 3 , or —CH 2 CH 3 .

49 . The compound or pharmaceutically acceptable salt of any one of claims 42 - 48 , wherein R 3a is hydrogen, unsubstituted C14 alkyl, or —CH 2 OCH 2 CH 3 .

50 . The compound or pharmaceutically acceptable salt of any one of claims 42 - 49 , wherein R 5 is hydrogen.

51 . The compound or pharmaceutically acceptable salt of any one of claims 42 - 49 , wherein R 5 is unsubstituted methyl.

52 . The compound or pharmaceutically acceptable salt of claim 42 , wherein the compound of Formula (I-a1) is a compound of Formula (I-b1a) or Formula (I-b2a):

or a pharmaceutically acceptable salt thereof.

53 . The compound or pharmaceutically acceptable salt of claim 43 , wherein the compound of Formula (I-a2) is a compound of Formula (I-b1b) or Formula (I-b2b):

or a pharmaceutically acceptable salt thereof.

54 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (I-a3) is a compound of Formula (I-b1c) or Formula (I-b2c):

or a pharmaceutically acceptable salt thereof.

55 . The compound or pharmaceutically acceptable salt of claim 42 , wherein the compound of Formula (I-a1) is a compound of Formula (I-c1a) or Formula (I-c2a):

or a pharmaceutically acceptable salt thereof.

56 . The compound or pharmaceutically acceptable salt of claim 43 , wherein the compound of Formula (I-a2) is a compound of Formula (I-c1b) or Formula (I-c2b):

or a pharmaceutically acceptable salt thereof.

57 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (I-a3) is a compound of Formula (I-c1c) or Formula (I-c2c):

or a pharmaceutically acceptable salt thereof.

58 . The compound or pharmaceutically acceptable salt of claim 42 , wherein the comp und of Formula (I-a1) is a compound of Formula (I-d1a) or Formula (I-d2a):

or a pharmaceutically acceptable salt thereof.

59 . The compound or pharmaceutically acceptable salt of claim 43 , wherein the compound of Formula (I-a2) is a compound of Formula (I-d1b) or Formula (I-d2b):

or a pharmaceutically acceptable salt thereof.

60 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (I-a3) is a compound of Formula (I-d1c) or Formula (I-d2c):

or a pharmaceutically acceptable salt thereof.

61 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 60 , wherein R X is hydrogen or substituted or unsubstituted C 1-4 alkyl.

62 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 61 , wherein wherein R X is hydrogen, —CH 3 , or —CH 2 CH 3 .

63 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 62 , wherein R X is hydrogen.

64 . The compound or pharmaceutically acceptable salt of claim 42 , wherein the compound of Formula (I-a1) is a compound of Formula (I-e1):

or a pharmaceutically acceptable salt thereof.

65 . The compound or pharmaceutically acceptable salt of claim 43 , wherein the compound of Formula (I-a2) is a compound of Formula (I-e2):

or a pharmaceutically acceptable salt thereof.

66 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (I-a3) is a compound of Formula (I-e3):

or a pharmaceutically acceptable salt thereof.

67 . The compound or pharmaceutically acceptable salt of any one of claims 1 - 39 , 42 , 52 , 55 , 58 , or 64 , wherein R Y is selected from:

wherein

Each R D is independently hydrogen, halogen, —NO 2 , —CN, —OR GA , —N(R GA ) 2 , —C(═O)R GA , —C(═O)OR GA , —C(═O)N(R GA ) 2 , —OC(═O)R GA , —OC(═O)OR GA , —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 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3-10 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; or

two R D groups taken together with the atoms to which they are attached to form a substituted or unsubstituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having up to 3 heteroatoms independently selected from N, O, or S;

Each 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 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, 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 atoms to which they are attached to form a substituted or unsubstituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having up to 3 heteroatoms independently selected from N, O, or S; and

e is 0, 1, 2, 3, or 4.

68 . The compound or pharmaceutically acceptable salt of claim 67 , wherein R Y is selected from:

69 . A compound of Formula (I-4):

or a pharmaceutically acceptable salt thereof, wherein

any one of R 2a and R 2b , R 4a and R 4b , or R 11a and R 11b are joined together to form an oxo (═O) group;

R 3 is 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 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S;

R 5 is hydrogen, unsubstituted methyl, or absent;

is a single bond or a double bond, provided that when is a single bond, R 5 is hydrogen or methyl, and when is a double bond, R 5 is absent;

R 19 is hydrogen or substituted or unsubstituted C 1-6 alkyl;

R X is hydrogen or substituted or unsubstituted C 1-6 alkyl;

R Y is substituted or unsubstituted phenyl or a substituted or unsubstituted 3-6 membered monocyclic heteroaryl or 8-12 membered bicyclic heteroaryl wherein the monocyclic or bicyclic heteroaryl has 1-5 heteroatoms independently selected from N, O, and S; and

t is 2 or 3.

70 . The compound or pharmaceutically acceptable salt of claim 69 , wherein each of R 2a and R 2b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each R D1 is independently hydrogen, substituted or unsubstituted C1-alkyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

71 . The compound or pharmaceutically acceptable salt of claim 69 or claim 70 , wherein each of R 2a and R 2b is independently hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen or —OH.

72 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 71 , wherein each of R 2a and R 2b is independently hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

73 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 72 , wherein one of R 2a and R 2b is hydrogen.

74 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 73 , wherein each of R 2a and R 2b is hydrogen.

75 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 74 , wherein each of R 4a and R 4b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

76 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 75 , wherein each of R 4a and R 4b is independently hydrogen, Cia alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

77 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 76 , wherein each of R 4a and R 4b is independently hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

78 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 77 , wherein one of R 4a and R 4b is hydrogen.

79 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 78 , wherein each of R 4a and R 4b is hydrogen.

80 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 79 , wherein each of R 11a and R 11b is independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

81 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 80 , wherein each of R 11a and R 11b is independently hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen or C 1-6 alkoxy optionally substituted with 1-3 halogen.

82 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 81 , wherein each of R 11a and R 11b is independently hydrogen, —CH 3 , —CH 2 CH 3 , —OCH 3 , or —CH(CH 3 ) 2 .

83 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 82 , wherein one of R 11a and R 11b is hydrogen.

84 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 83 , wherein each of R 11a and R 11b is hydrogen.

85 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 84 , wherein R 7 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

86 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 85 , wherein R 7 is hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

87 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 86 , wherein R 7 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

88 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 87 , wherein R 7 is hydrogen.

89 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 88 , wherein R 6 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O))R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

90 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 89 , wherein R 6 is hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

91 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 90 , wherein R 6 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

92 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 91 , wherein R 6 is hydrogen.

93 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 92 , wherein R 16 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

94 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 93 , wherein R 16 is hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

95 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 94 , wherein R 16 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

96 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 95 , wherein R 16 is hydrogen.

97 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 96 , wherein R 17 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C1b alkyl, substituted or unsubstituted C 2-6 alkenyl, —OR D1 , —OC(═O)R D1 , —NH 2 , or —N(R D1 ) 2 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

98 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 97 , wherein R 17 is hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 1-6 alkoxy optionally substituted with 1-3 halogen, or —OH.

99 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 98 , wherein R 17 is hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

100 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 99 , wherein R 17 is hydrogen.

101 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 100 , wherein R 19 is hydrogen or unsubstituted C 1-5 alkyl.

102 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 101 , wherein R 19 is hydrogen or unsubstituted C 1-4 alkyl.

103 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 102 , wherein R 19 is hydrogen, —CH 3 , or —CH 2 CH 3 .

104 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 103 , wherein R 19 is hydrogen.

105 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 104 , wherein R 19 is —CH 3 or —CH 2 CH 3 .

106 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 105 , wherein R 3 is unsubstituted C 1-6 alkyl.

107 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 106 , wherein R 3 is unsubstituted C 1-4 alkyl.

108 . The compound or pharmaceutically acceptable salt of claim 69 , wherein the compound of Formula (I-4) is a compound of Formula (I-a4)

or a pharmaceutically acceptable salt thereof.

109 . The compound or pharmaceutically acceptable salt of claim 69 , wherein the compound of Formula (I-4) is a compound of Formula (I-b4a) or (I-b5a)

or a pharmaceutically acceptable salt thereof.

110 . The compound or pharmaceutically acceptable salt of claim 69 , wherein the compound of Formula (I-4) is a compound of Formula (I-b4b) or (I-b5b)

or a pharmaceutically acceptable salt thereof.

111 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 110 , wherein R X is hydrogen or unsubstituted methyl.

112 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 111 , wherein R X is hydrogen.

113 . The compound or pharmaceutically acceptable salt of any one of claims 69 - 112 , wherein R Y is selected from:

wherein

Each R D is independently hydrogen, halogen, —NO 2 , —CN, —OR GA , —N(R GA ) 2 , —C(═O)R GA , —C(═O)OR GA , —C(═O)N(R GA ) 2 , —OC(═O)R GA , —OC(═O)OR GA , —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 C16 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3-10 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, or

two R GA are taken with the intervening atoms to form a substituted or unsubstituted 3-5-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S;

Each X is independently —N═ or —C(R D )═;

two R GA groups are taken with the intervening atoms to form a substituted or unsubstituted 5-6-membered heterocyclic ring having 2-3 heteroatoms independently selected from N, O, or S;

R X1 is hydrogen or substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; and

e is 0, 1, 2, or 3.

114 . The compound or pharmaceutically acceptable salt of claim 113 , wherein R Y is selected from:

wherein each instance of R D is, independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, —CN, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl; and

e is 0, 1, 2, or 3.

115 . The compound or pharmaceutically acceptable salt of claim 113 , wherein RP is selected from:

wherein each R is independently —CH 3 , —CH 2 CH 3 , -i-Pr, cyclopropyl, or —CN.

116 . The compound or pharmaceutically acceptable salt of claim 113 , wherein R Y is selected from:

117 . The compound or pharmaceutically acceptable salt of claim 116 , wherein R Y is:

118 . The compound or pharmaceutically acceptable salt of claim 116 , wherein R Y is:

119 . A compound selected from:

Compound No.

Structure

100

101

or a pharmaceutical acceptable salt thereof.

120 . A compound of Formula (X)

or a pharmaceutically acceptable salt thereof, wherein

R 2a is hydrogen or substituted or unsubstituted C 1-6 alkyl;

R 3a is substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkyl-O—C 1-6 alkyl;

R 19 is hydrogen or substituted or unsubstituted C 1-6 alkyl;

R Y is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-2 nitrogen atoms, wherein the 3-8 membered ring of R is optionally substituted with 1-3 groups independently selected from halogen, —CN, or C 1-6 alkyl; and

t is 1 or 2;

provided that when t is 1, R 3a is —CH 2 OCH 2 CH 3 , and R Y is substituted or unsubstituted pyrazinyl, then R 19 is —CH 3 .

121 . The compound or pharmaceutically acceptable salt of claim 120 , wherein Ra is hydrogen or unsubstituted C 1-3 alkyl.

122 . The compound or pharmaceutically acceptable salt of claim 121 , wherein Ra is hydrogen or —CH 3 .

123 . The compound or pharmaceutically acceptable salt of any one of claims 119 - 122 , wherein R 3 is unsubstituted C1.3 alkyl or unsubstituted C 1-3 alkyl-O—C 1-3 alkyl.

124 . The compound or pharmaceutically acceptable salt of any one of claims 119 - 123 , wherein R 3 is —CH 3 , —CH 2 CH 2 CH 3 , —CH 2 OCH 3 , or —CH 2 OCH 2 CH 3 .

125 . The compound or pharmaceutically acceptable salt of any one of claims 119 - 124 , wherein R 19 is hydrogen or unsubstituted C 1-3 alkyl.

126 . The compound or pharmaceutically acceptable salt of any one of claims 119 - 125 , wherein R 19 is hydrogen, —CH 3 , or —CH 2 CH 3 .

127 . The compound or pharmaceutically acceptable salt of any one of claims 119 - 126 , wherein R Y is substituted or unsubstituted pyrazinyl, pyrimidine substituted with cyano, substituted or unsubstituted phenyl, pyridine substituted with cyano or fluoro, or pyrazole substituted with two unsubstituted methyl groups.

128 . A compound of Formula (XI)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is unsubstituted C 1-3 alkyl;

R 19 is hydrogen or unsubstituted C 1-3 alkyl; and

Ring R Y is

wherein two of W 1 , W 2 , W 3 , W 4 , and W 5 are —N═, and the remainder are —C(R′)═; and

Each R′ is independently hydrogen or —CN, wherein at least one R′ is —CN.

129 . The compound or pharmaceutically acceptable salt of claim 128 , wherein R 1 is —CH 3 or —CH 2 CH 3 .

130 . The compound or pharmaceutically acceptable salt of claim 128 or 129 , wherein R 19 is hydrogen or —CH 3 .

131 . The compound or pharmaceutically acceptable salt of any one of claims 128 - 130 , wherein

W 1 and W 2 are —N═;

W 1 and W 3 are —N═;

W 1 and W 4 are —N═;

W 1 and W 5 are —N═; or

W 2 and W 4 are —N═.

132 . The compound or pharmaceutically acceptable salt of any one of claims 128 - 131 , wherein R Y is

133 . A pharmaceutical composition comprising a compound of any one of claims 1 - 132 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

134 . A method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 - 132 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 133 .

135 . The method of claim 134 , 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.

136 . The method of claim 135 , wherein the CNS-related disorder is depression.

137 . The method of claim 136 , wherein the depression is postpartum depression.

138 . The method of claim 136 , wherein the depression is a major depressive disorder.

139 . The method of claim 138 , wherein the major depressive disorder is moderate major depressive disorder.

140 . The method of claim 139 , wherein the major depressive disorder is severe major depressive disorder.

Assignments (2)

CHANGE OF NAME Recorded Apr 23, 2026

From: SAGE THERAPEUTICS, INC.

To: SAGE THERAPEUTICS, LLC

Reel/Frame 075472/0569 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2023

From: HAN, BINGSONG; BLANCO-PILLADO, MARIA JESUS

To: SAGE THERAPEUTICS, INC.

Reel/Frame 063680/0235 →