IP Library › Patent Application 18825194

Patent Application

App. No. 18/825,194

PRODRUGS OF GANAXOLONE

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Patent No.: US None
App. No.: 18/825,194

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Abstract

This disclosure relates to ganaxolone derivatives, as well as methods of using the compounds (e.g., for treatment of a disease or disorder), methods of making the compounds, and pharmaceutical compositions and kits comprising the same.

Claims (203)

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein

Y is —C(O)— or —C(R A )(R B )— (e.g., —CH 2 —);

Z is absent, alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, —NR 1 —, —O—, or —S—, wherein the alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted;

X is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, cycloalkylene-alkyl, cycloalkylene-heteroalkyl, heterocyclylene-alkyl, heterocyclylene-heteroalkyl, —OC(O)-alkyl, —C(O)O-alkyl, —OC(O)-heteroalkyl, —C(O)O— heteroalkyl, —N 3 , —NR 1 R 2 , —OR 3 , or —SR 4 , wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted;

R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, cycloalkylene-alkyl, cycloalkylene-heteroalkyl, heterocyclylene-alkyl, or heterocyclylene-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted;

or R 1 and R 2 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R 3 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, cycloalkylene-alkyl, cycloalkylene-heteroalkyl, heterocyclylene-alkyl, or heterocyclylene-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted;

R 4 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted; and

R A and R B are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

2 . The compound of claim 1 , wherein Y is —C(O)—.

3 . The compound of claim 1 or 2 , wherein Z is methylene (e.g., unsubstituted methylene),

wherein

Z1 is absent, alkylene (e.g., methylene, e.g., unsubstituted methylene), alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein the alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted;

R 2 is hydrogen or alkyl;

R B and R C are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

each denotes the point of attachment of Z to X or Y.

4 . The compound of any one of the preceding claims , wherein X is a moiety selected from the group consisting of

wherein

R 2 is hydrogen or alkyl;

M is-C(H)(R D )— (e.g., —CH 2 —), —O—, or —N(R D )— (e.g., —N(Me)—);

P is an amino acid residue (e.g., glycine, alanine, valine, leucine, or proline), that may be a D-amino acid residue or L-amino acid residue, and is optionally substituted (e.g., at a terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group),

or P is a dipeptide moiety (e.g., a leucine-leucine moiety) that may comprise D-amino acids, L-amino acids, or a combination thereof, and is optionally substituted (e.g., at one or more nitrogen atoms, e.g., at a terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group);

Q is heteroalkyl or heterocyclyl, wherein the heteroalkyl or heterocyclyl is optionally substituted;

V is —O—, —N(H)—, or —N(Me)—;

X2 and X3 are each independently —CH 2 —, —O—, —S—, or —N(R G3 )— (e.g., —NH—);

R A , R B , R C , R D , R E , and R K are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R F and R H are each independently hydrogen or alkyl;

R G1 and R G2 are each independently hydrogen, alkyl, or an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), that may be a D-amino acid residue or L-amino acid residue, and is optionally substituted (e.g., at a terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group),

or R G1 and R G2 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

or R G3 and R G4 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R G5 is hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted;

R P is halo, —NH-alkyl, —NH-heteroalkyl, —N-(alkyl) 2 (e.g., —N(Me) 2 ), —N-(heteroalkyl) 2 (e.g., —N(CH 2 CH 2 OH) 2 ), or heterocyclyl (e.g., morpholinyl);

R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, —OR, —N(R G3 )(R G4 ); —NO 2 , —CN, or —NC;

R 11 , R 12 , R 13 , and R 14 are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, halo, or —N(R G3 )(R G4 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted,

or one of R 11 and R 12 , and one of R 13 and R 14 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R 15 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted; and

m is an integer of 1-5;

p is an integer between 0 and 4; and

denotes the point of attachment of X to Z, or X to Y when Z is absent.

5 . The compound of any one of the preceding claims , wherein X is a moiety selected from the group consisting of

wherein

R B , R C , and R K are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

R 2 is hydrogen or alkyl; and

R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, —OR, —N(R G3 )(R G4 ); —NO 2 , —CN, or —NC.

6 . The compound of any one of the preceding claims , wherein Y is —C(O)— and Z is alkylene (e.g., methylene).

7 . The compound of any one of the preceding claims , wherein R 1 and R 2 are not both hydrogen.

8 . A compound of Formula (I-II):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

denotes a single bond or a double bond;

Y 1 is alkylene (e.g., methylene), alkenylene, alkynylene, heteroalkylene, —C(O)—, —OC(O)—, —C(O)O—, —NR 1 —, —O—, or —S—, wherein the alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted;

Y 2 is heteroalkyl, heterocyclyl, heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, —NR 1 R 2 , —OR 3 , —SR 4 , ═NR 1 , or ═O, wherein the heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R 7A and R 7B are each independently hydrogen or optionally substituted alkyl, or one of R 7A and R 7B is bonded to Y 1 through one or more carbon atoms or heteroatoms to form a cyclic moiety (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl, e.g., pyrrole), and the other of the R 7A and R 7B groups is hydrogen or optionally substituted alkyl;

R 7C and R 7D are each independently hydrogen or optionally substituted alkyl, or R 7C and R 7D are each bonded to the same oxygen atom to form an oxo group; and

R 7E and R 7F are each independently absent, hydrogen, alkyl, heteroalkyl, —NR 1 R 2 , —OR 3 , or —SR 4 , wherein the alkyl or heteroalkyl is optionally substituted, or R 7E and R 7F are each bonded to the same oxygen to form an oxo group, with the proviso that when is a double bond, one of R 7E and R 7F is absent.

9 . The compound of claim 8 , wherein Y 1 is —O— or —N(R 1 )— (e.g., —N(H)—, —N(alkyl)-, or —N(heteroalkyl)-).

10 . The compound of claim 8 or 9 , selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomer thereof, wherein Y 2 , R 1 , R 7C , R 7D , R 7E , and R 7F are as defined in claim 8 .

11 . The compound of any one of claims 8-10 , wherein Y 2 , or R 7E when is a double bond, is optionally substituted heteroalkyl, —NR 1 R 2 (e.g., —NH 2 , —NHMe, or —NMe 2 ), —OR 3 (e.g., —OH, —OMe, —OEt, or —OtBu), or ═O, wherein R 1 , R 2 , and R 3 are as defined in claim 8 .

12 . The compound of any one of claims 8-11 , wherein Y 2 , or R 7E when is a double bond, is selected from the group consisting of:

13 . A compound of Formula (IA)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein

R 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

14 . The compound of claim 13 , wherein the —N(R 1 )(R 2 ) group is a moiety selected from the group consisting of

wherein R 2 , M, Q, V, R A , R B , R C , R D , R E and R K are as described in claim 1 , and denotes the point of attachment of the nitrogen atom to the carbon atom of the —C(R 7A )(R 7B ) group.

15 . The compound of claim 13 , wherein the —N(R 1 )(R 2 ) group is a moiety selected from the group consisting of

wherein R 2 , R 10 , R B , R C , R D , R E and R K are as described in claim 1 , and denotes the point of attachment of the nitrogen atom to the carbon atom of the —C(R 7A )(R 7B ) group.

16 . The compound of any one of claims 1-6 or 13-15 , wherein the X group of Formula (I), or the —N(R 1 )(R 2 ) group of Formula (IA), is a moiety selected from the group consisting of

wherein denotes the point of attachment of X to Z, or X to Y when Z is absent, in Formula (I); or the point of attachment of the nitrogen atom to the carbon atom of the —C(R 7A )(R 7B ) group in Formula (IA).

17 . The compound of any one of claims 1-6 or 13-15 , wherein the X group of Formula (I), or the —N(R 1 )(R 2 ) group of Formula (IA), is a moiety selected from the group consisting of

18 . A compound of any one of the preceding claims , wherein the compound is a compound of Formula (IA-a)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein

G is absent, —C(O)—, or —C(R 8A )(R 8B )— (e.g., —CH 2 —),

K is alkylene, heteroalkylene, —C(O)—, —OC(O)—, —C(O)O—, —O—, —O—(CH 2 )—, or —(CH 2 )—O—, wherein the alkylene or heteroalkylene is optionally substituted;

R 2 , R 7A , R 7B , R 8A , and R 8B are each independently hydrogen or optionally substituted alkyl; and

R 9 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

19 . The compound of claim 18 , wherein

G is —C(R 8A )(R 8B )—;

K is —OC(O)—;

R 2 , R 7A , R 7B , and R 9 are each hydrogen; and

R 8A and R 8B are each independently hydrogen or alkyl (e.g., methyl), wherein the carbon atom of the carbonyl group in —OC(O)— is bonded to G.

20 . The compound of any one of the preceding claims , wherein the compound is a compound of Formula (IA-b)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein

R 2 , R 8A , and R 8B are each independently hydrogen or optionally substituted alkyl; and

21 . The compound of any one of claims 18-20 , wherein

R 2 is hydrogen; and

R 8A and R 8B are each independently methyl.

22 . A compound of Formula (IB):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein

R 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

23 . The compound of claim 22 , wherein the —O—(R 3 ) group is a moiety selected from the group consisting of

wherein

R F and R H are each independently hydrogen or alkyl;

R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted;

R K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R P is halo, —NH-alkyl, —NH-heteroalkyl, —N-(alkyl) 2 (e.g., —N(Me) 2 ), —N-(heteroalkyl) 2 (e.g., —N(CH 2 CH 2 OH) 2 ), or heterocyclyl (e.g., morpholinyl);

m is an integer of 1-5; and

denotes the point of attachment of the oxygen atom to the carbon atom of the —C(R 7A )(R 7B ) group.

24 . The compound of claim 22 , wherein the —O—(R 3 ) group is a moiety selected from the group consisting of

wherein

R K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

25 . The compound of any one of claims claim 1, 2, or 22-24 , wherein the X group of Formula (I), or the —O—R 3 group of Formula (IB), is a moiety selected from the group consisting of

wherein denotes the point of attachment of X to Z, or X to Y when Z is absent, in Formula (I); or the point of attachment of the oxygen atom to the carbon atom of the —C(R 7A )(R 7B ) group in Formula (IB).

26 . The compound of any one of claims claim 1, 2, or 22-24 , wherein the X group of Formula (I), or the —O—R 3 group of Formula (IB), is a moiety selected from the group consisting of

27 . A compound of Formula (IC)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein

R 4 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, or heteroalkylene-heteroaryl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted; and

R 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

28 . The compound of claim 27 , wherein the-S—(R 4 ) group is a moiety selected from the group consisting of

wherein

R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

R G5 is hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

R is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted;

R K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

R P is halo, —NH-alkyl, —NH-heteroalkyl, —N-(alkyl) 2 (e.g., —N(Me) 2 ), —N-(heteroalkyl) 2 (e.g., —N(CH 2 CH 2 OH) 2 ), or heterocyclyl (e.g., morpholinyl); and

denotes the point of attachment of the sulfur atom to the carbon atom of the —C(R 7A )(R 7B ) group.

29 . The compound of any one of claims 1, 2, 27 or 28 , wherein the X group of Formula (I), or the —S—R 4 group of Formula IC, is a moiety selected from the group consisting of

wherein denotes the point of attachment of X to Z, or X to Y when Z is absent, in Formula (I); or the point of attachment of the sulfur atom to the carbon atom of the —C(R 7A )(R 7B ) group in Formula (IC).

30 . A compound of Formula (ID)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein

R 5 is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, cycloalkylene-alkyl, cycloalkylene-heteroalkyl, heterocyclylene-alkyl, or heterocyclylene-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted.

31 . The compound of claim 30 , wherein R 5 comprises a moiety selected from group consisting of

wherein

X2 and X3 are each independently —CH 2 —, —O—, —S—, or —N(R G3 )— (e.g., —NH—);

R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, —OR, —N(R G3 )(R G4 ); —NO 2 , —CN, or —NC;

R 15 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted;

R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted;

and

p is an integer between 0 and 4; and

denotes the point of attachment of the R 5 group to the carbon atom of the —C(O)— group.

32 . The compound of any one of claims 1, 2, 30, or 31 , wherein the X group of Formula (I), or the R 5 group of Formula (ID), is a moiety selected from the group consisting of

wherein denotes the point of attachment of X to Z, or X to Y when Z is absent, in Formula (I); or the point of attachment of the R 5 group to the carbon atom of the —C(O)— group in Formula (ID).

33 . A compound of Formula (IE)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein

R 6 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, —OC(O)-alkyl, —C(O)O-alkyl, —OC(O)-heteroalkyl, —C(O)O-heteroalkyl, —N 3 , —SH, or —S-alkyl (e.g., —S-Me), wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

34 . The compound of claim 33 , wherein R 6 is a moiety selected from the group consisting of

wherein

R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted;

and denotes the point of attachment of the R 6 group to the carbon atom of the —C(R A )(R B )— group.

35 . The compound of any one of claims 1, 2, 33, or 34 , wherein the X group of Formula (I), or the R 6 group of Formula (IE), is a moiety selected from the group consisting of

wherein denotes the point of attachment of X to Z, or X to Y when Z is absent, in Formula (I); or the point of attachment of the R 6 group to the carbon atom of the —C(R A )(R B )— group.

36 . The compound of any one of the preceding claims , wherein the compound is a compound selected from Table 1.

37 . The compound of any one of claims 1-26 or 36 , wherein the compound is selected from the group consisting of

and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof.

38 . The compound of any one of claims 1-26 or 36 , wherein the compound is selected from the group consisting of

and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof.

39 . The compound of any one of claims 1-4, 6, 13, 14, 16, 36, or 37 , wherein the compound is

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

40 . The compound of any one of claims 1-38 , wherein the compound is not

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

41 . The compound of any one of the preceding claims , wherein the compound has a higher aqueous solubility and or hydrophilicity relative to ganaxolone, e.g., as determined by logS, logP, logD, topological polar surface area (TPSA), acid pKa, base pKa, or a combination thereof.

42 . The compound of any one of the preceding claims , wherein the compound is substantially converted to ganaxolone by a metabolic process, e.g., following administration to a subject.

43 . The compound of any one of the preceding claims , wherein the compound has a higher bioavailability of ganaxolone, relative to ganaxolone delivered by the same route of administration at an equivalent amount, e.g., as determined by serum concentration of ganaxolone (e.g., C max or AUC).

44 . The compound of any one of the preceding claims , wherein the compound provides higher serum concentrations of ganaxolone (e.g., C max or AUC) and/or a longer half-life of ganaxolone, e.g., following administration to a subject, relative to ganaxolone delivered by the same route of administration at an equivalent amount.

45 . A pharmaceutical composition, comprising a compound of any one of the preceding claims , and a pharmaceutically acceptable excipient.

46 . A method of treating a disease or disorder in a subject, comprising administering to a subject in need thereof a compound of any one of claims 1-44 , or a pharmaceutical composition of claim 45 .

47 . The method of claim 46 , wherein the administering comprises oral administration or intravenous administration.

48 . A composition for use in treating a disease or disorder in a subject, comprising a therapeutically effective amount of a compound of any one of claims 1-44 , or a pharmaceutical composition of claim 45 .

49 . Use of a compound of any one of claims 1-44 , or a pharmaceutical composition of claim 45 , for the production of a medicament effective for treating a disease or disorder in a subject.

50 . The method of claim 46 or 47 , the composition for use of claim 48 , or the use of claim 49 , wherein the disease or disorder is a neurological disorder.

51 . The method of claim 46 or 47 , the composition for use of claim 48 , or the use of claim 49 , wherein the disease or disorder is a seizure disorder, an epilepsy disorder, a genetic epilepsy disorder, an epilepsy-related disorder, a central nervous system disorder, a neurological disorder, or a neurodegenerative disorder.

52 . The method of claim 46 or 47 , the composition for use of claim 48 , or the use of claim 49 , wherein the disease or disorder is status epilepticus (SE).

53 . The method of claim 46 or 47 , the composition for use of claim 48 , or the use of claim 49 , wherein the disease or disorder is CDKL5 Deficiency Disorder.

54 . The method of claim 46 or 47 , the composition for use of claim 48 , or the use of claim 49 , wherein the disease or disorder is Tuberous Sclerosis Complex.

55 . The method of claim 46 or 47 , the composition for use of claim 48 , or the use of claim 49 , wherein the disease or disorder is PCDH19-related epilepsy.

56 . The method of claim 46 or 47 , the composition for use of claim 48 , or the use of claim 49 , wherein the disease or disorder is Lennox-Gastaut syndrome.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2025

From: MARINUS PHARMACEUTICALS, INC.

To: IMMEDICA PHARMA US INC.

Reel/Frame 071115/0717 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 6, 2024

From: WROBEL, JAY E.; SAUSKER, JUSTIN BARRETT; REITZ, ALLEN B.; TICE, COLIN M.; BINDER, RANDALL JEFFREY

To: FOX CHASE CHEMICAL DIVERSITY CENTER, INC.

Reel/Frame 068504/0756 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 6, 2024

From: FOX CHASE CHEMICAL DIVERSITY CENTER, INC.

To: MARINUS PHARMACEUTICALS, INC.

Reel/Frame 068504/0776 →