Ganaxolone prodrugs

Abstract

The present disclosure relates to ganaxolone derivatives, as well as methods of using the compounds (e.g., for treating a disease or disorder), methods of making the compounds, and pharmaceutical compositions and kits containing the same. The present disclosure relates to ganaxolone derivatives. The compounds disclosed herein can be metabolized (e.g., in vivo, e.g., by metabolic processes) to ganaxolone. The compounds disclosed herein are also more soluble than ganaxolone in aqueous solutions, such as plasma, gastric fluid, or intestinal fluid. Also disclosed herein are methods of using the compounds, methods of making the compounds, and pharmaceutical compositions and kits containing them.

Description

[Background technology]

[0001] Ganaxolone acts on the gamma-aminobutyric acid (GABA) receptor (GABA A Ganaxolone is a positive allosteric modulator of GABAergic receptor agonist (GABAergic receptor antagonist) and can increase GABAergic activity and inhibit neuronal excitability. Ganaxolone has very low aqueous solubility, which reduces its oral bioavailability and limits its clinical use.

[0002] A prodrug is typically a molecule that has little or no pharmacological activity of its own, and can be metabolized after administration to release (e.g., in the blood) the pharmacologically active drug (i.e., the parent drug). Some prodrugs can be absorbed more rapidly and have better oral bioavailability than the parent drug. However, success in creating a stable prodrug with better bioavailability than the parent drug and favorable conversion and safety (e.g., toxicity profile) to the parent drug is unpredictable.

[0003] Thus, there is an unmet need for ganaxolone prodrugs. Summary of the Invention

[0004] The present disclosure relates to ganaxolone derivatives. The compounds disclosed herein can be metabolized (e.g., in vivo, e.g., by metabolic processes) to ganaxolone. The compounds disclosed herein are also more soluble than ganaxolone in aqueous solutions, such as plasma, gastric fluid, or intestinal fluid. Also disclosed herein are methods of using the compounds, methods of making the compounds, and pharmaceutical compositions and kits containing them.

[0005] The compounds of the present disclosure have formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y is -C(O)- or -C(R A )(R B )-(e.g., -CH 2 -) and 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 2are 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 or R 1 and R 2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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 4is 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 is each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0006] For example, the compound can be a compound of formula (I) where Y is -C(O)-.

[0007] The compound can be of formula (I), where Z is methylene (e.g., unsubstituted methylene), [ka] wherein Z 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; [ka] indicates the point of attachment of Z to X or Y.

[0008] The compounds of the present disclosure have formula (II): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X is as defined herein, e.g., 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 2are 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 or R 1 and R 2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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 4is 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 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

[0009] The compound is of formula (I) or (II), wherein X is [ka] is a moiety selected from the group consisting of: 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) which may be a D- or L-amino acid residue, optionally substituted (e.g., at the 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) which may contain D-amino acids, L-amino acids, or combinations thereof, optionally substituted (e.g., at one or more nitrogen atoms, e.g., the 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 each independently represent -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 which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) and which are optionally substituted (e.g., at the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group), or R G1 and R G2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R G5 is hydrogen, alkyl, or heteroalkyl, where 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 10 is an alkyl, alkenyl, alkynyl, haloalkyl, halo, -OR J , -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 R 11 and R 12 On the other hand, R 13 and R 14 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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; m is an integer from 1 to 5; p is an integer between 0 and 4, and Of formula (I) [ka] indicates the point of attachment of X to Z, or, if Z is absent, to Y, and in formula (II), [ka] indicates the point of attachment of X to the carbon atom of the -C(R7A)(R7B) group.

[0010] For example, X is [ka] where R 2 is H and R B and R C are each independently alkyl (e.g., methyl), and R K is hydrogen.

[0011] The compound may be of formula (I), where Y is -C(O)- and Z is alkylene (e.g., methylene). The compound may be of formula (I) or (II), where R 1 and R 2 None of these are hydrogen.

[0012] The compound may be of formula (I), where Y is C(O)-, Z is alkylene (e.g., methylene), and X is [ka] For example, the compound can be a compound of formula (I) where Y is C(O)-, Z is methylene and X is [ka] and R 2 is hydrogen.

[0013] The compound may be of formula (I), where Y is -C(O)-, Z is alkylene (e.g., methylene), and X is [ka] For example, the compound can be a compound of formula (I) where Y is C(O)-, Z is methylene and X is [ka] It is.

[0014] Alternatively, the compound may be of formula (I), where Y is -C(O)-, Z is alkylene (e.g., methylene) and X is [ka] For example, the compound can be a compound of formula (I), where Y is -C(O)-, Z is alkylene (e.g., methylene), and X is [ka] It is.

[0015] The compounds of the present disclosure have formula (I-II): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein [ka] represents a single or double bond, Y 1 is an 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 2is 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 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 or R 1 and R 2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R 3is 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; R 7A and R 7B are each independently hydrogen or optionally substituted alkyl, or R 7A and R 7B is connected to Y via one or more carbon atoms or heteroatoms. 1 to form a cyclic moiety (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl, e.g., pyrrole), R 7A Groups and R 7B the other group is hydrogen or optionally substituted alkyl; R 7C and R 7D are each independently hydrogen or optionally substituted alkyl, or R7C and R 7D are each bonded to the same oxygen atom to form an oxo group, and R 7E and R 7F each independently represents absent, hydrogen, alkyl, heteroalkyl, -NR 1 R 2 , -OR 3 , or -SR 4 wherein 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 [ka] If is a double bond, R 7E and R 7F The condition is that one of the two is not present.

[0016] Y in formula (I-II) 1 is -O- or -N(R 1 )-(e.g., -N(H)-, -N(alkyl)-, or -N(heteroalkyl)-). For example, Y in formula (I-II) can be 1 Alternatively, Y in formula (I-II) can be -O- or -N(H)-. 1 is -N(Me)-, -N(Et)-, -N(EtOH)-, or -N( n PrOH)-.

[0017] The compound of formula (I-II) has the formula (I-IIa): [ka] wherein Y 2 , R 1 , R 7C , R 7D , R 7E , and R 7F is as defined above, or the compound of formula (I-II) has the formula (I-IIb): [ka] wherein Y 2 , R 7C , R 7D , R 7E , and R 7F is as defined above, or the compound of formula (I-II) has the formula (I-IIc): [ka] wherein Y 2 , R 1 , R 7C , R 7D , and R 7E is as defined above, or the compound of formula (I-II) has the formula (I-IId): [ka] wherein Y 2 , R 7C , R 7D , and R 7E is as defined above, or the compound of formula (I-II) has the formula (I-IIe): [ka] wherein Y 2 is as defined above.

[0018] Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) 2 ,or [ka] R when is a double bond 7E is optionally substituted heteroalkyl, -NR 1 R 2 (For example, -NH 2 , -NHMe, or -NMe 2 ), -OR 3 (For example, -OH, -OMe, -OEt, or -O tFor example, Y in formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) can be ═O. 2 ,or [ka] R when is a double bond 7E is -NH 2 Alternatively, Y in formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) can be -NHMe, -NHMe, or -OH. 2 ,or [ka] R when is a double bond 7E is an optionally substituted heteroalkyl, e.g., [ka] [ka] [ka] The heteroalkyl group may be a substituted or unsubstituted heteroalkyl selected from the group consisting of:

[0019] The compound is a compound of formula (I-II), wherein R 7A and R 7B are each hydrogen, and R 7C and R 7D are each bonded to the same oxygen atom to form an oxo group, and R 7E and R 7F may be a compound in which each is alkyl (e.g., methyl).

[0020] The compound is a compound of formula (I-II), wherein Y 1 Ha-NR 1 -, -O-, R 7A and R 7B are each hydrogen, and R 7C and R7D are each bonded to the same oxygen atom to form an oxo group, and R 7E and R 7F are each alkyl (e.g., methyl), and Y 2 is heteroalkyl or -OR 3 For example, the compound may be a compound of formula (I-II), wherein Y 1 is -O- and R 7A and R 7B are each hydrogen, and 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 alkyl (e.g., methyl), and Y 2 Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 is -O- and R 7A and R 7B are each hydrogen, and 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 alkyl (e.g., methyl), and Y 2 teeth [ka] Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 is -O- and R 7A and R 7B are each hydrogen, and 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 alkyl (e.g., methyl), and Y 2 teeth [ka] Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 is -O- and R7A and R 7B are each hydrogen, and 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 alkyl (e.g., methyl), and Y 2 teeth [ka] Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 is -O- and R 7A and R 7B are each hydrogen, and 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 alkyl (e.g., methyl), and Y 2 teeth [ka] Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 is -O- and R 7A and R 7B are each hydrogen, and 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 alkyl (e.g., methyl), and Y 2 teeth [ka] The compound may be a compound,

[0021] The compounds of the present disclosure have the formula (IA) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein 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 or R 1 and R 2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

[0022] The compound may be of formula (I), (II), or (IA), where the X group of formula (I) or (II), or the -N(R 1 )(R 2 ) group is [ka] is a moiety selected from the group consisting of: 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)-), Q is heteroalkyl or heterocyclyl, wherein the heteroalkyl or heterocyclyl is optionally substituted; V is -O-, -N(H)-, or -N(Me)-; 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; [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B ) group or the point of attachment of X to the carbon atom of the -C(R 7A )(R 7B ) group to a carbon atom.

[0023] In some embodiments, the X group of formula (I) or formula (II) or the —N(R 1 )(R 2 ) group is [ka] [ka] [ka] [ka] [ka] [ka] is a moiety selected from the group consisting of: [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B ) group or the point of attachment of X to the carbon atom of the -C(R 7A )(R 7B ) group to a carbon atom.

[0024] The compounds of the present disclosure have the formula (IA-a): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein G is absent, -C(O)-, or -C(R 8A )(R 8B )-(e.g., -CH 2 -) and 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, where the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0025] In some embodiments, the compound of Formula (I), (II), or (IA) is a compound of Formula (IA-a), where G is -C(R 8A )(R 8B )-, K is -OC(O)-, and R 2 , R 7A , R 7B , and R 9 are each hydrogen, and R 8A and R 8B are each independently hydrogen or alkyl (eg, methyl), and the carbon atom of the carbonyl group of -OC(O)- is bonded to G.

[0026] The compounds of the present disclosure have the formula (IA-b): [ka] or a pharma- ceutically 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 R 9 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0027] For example, a compound of formula (I), (II), (IA), or (IA-a) can be a compound of formula (IA-b), where R 2 is hydrogen, and R 8A and R 8B are each independently methyl.

[0028] The compounds of the present disclosure have formula (IB): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein 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 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

[0029] X of formula (I) or (II) or -O-(R 3 ) group is [ka] may be a moiety selected from the group consisting of During the ceremony, P is an amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) which may be a D- or L-amino acid residue, optionally substituted (e.g., at the 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) which may contain D-amino acids, L-amino acids, or combinations thereof, optionally substituted (e.g., at one or more nitrogen atoms, e.g., the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group); R Band 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; 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 which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) and which are optionally substituted (e.g., at the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group), or R G1 and R G2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; R Kis 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 (For example, -N(Me) 2 ), -N-(heteroalkyl) 2 (For example, -N(CH 2 CH 2 OH) 2 ), or heterocyclyl (e.g., morpholinyl); m is an integer from 1 to 5; and In formula (I), [ka] indicates the point of attachment of X to Z, or, if Z is absent, to Y, and in formula (II): [ka] indicates the point of attachment of X to the carbon atom of the -C(R7A)(R7B) group, and in formula (IB): [ka] indicates the point of attachment of the oxygen atom to the carbon atom of the -C(R7A)(R7B) group.

[0030] In some embodiments, the compound is a compound of formula (I), (II), or (IB), wherein the X group of formula (I) or (II), or the -OR group of formula (IB), 3 The base is [ka] [ka] [ka] [ka] [ka] [ka] is a moiety selected from the group consisting of: [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B ) group or the point of attachment of X to the carbon atom of the -C(R 7A )(R 7B ) group.

[0031] The compounds of the present disclosure have the formula (IC) [ka] or a pharma- ceutically 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.

[0032] In some embodiments, the X group of formula (I) or (II) or the -S-(R 4 ) group is [ka] is a moiety selected from the group consisting of During the ceremony, 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; R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R G5 is hydrogen, alkyl, or heteroalkyl, where 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 (For example, -N(Me)2 ), -N-(heteroalkyl) 2 (For example, -N(CH 2 CH 2 OH) 2 ), or heterocyclyl (e.g., morpholinyl), and [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B ) group or the point of attachment of X to the carbon atom of the -C(R 7A )(R 7B ) group to a carbon atom.

[0033] In some embodiments, the compound is of formula (I), (II), or (IC), wherein the X group of formula (I) or (II), or the -SR group of formula (IC), 4 The base is [ka] [ka] is a moiety selected from the group consisting of: [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B ) group or the point of attachment of X to the carbon atom of the -C(R 7A )(R 7B ) group to a carbon atom.

[0034] The compounds of the present disclosure have the formula (ID): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, During the ceremony, 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.

[0035] In some embodiments, the X group of formula (I) or formula (II) or R in formula (ID) 5 The base is [ka] is a moiety selected from the group consisting of: X2 and X3 each independently represent -CH 2 -, -O-, -S-, or -N(R G3 )-(e.g., -NH-), R 10 is an alkyl, alkenyl, alkynyl, haloalkyl, halo, -OR J , -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 G4wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted; or R 11 and R 12 On the other hand, R 13 and R 14 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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; R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl 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 [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B ) group or the point of attachment of R to the carbon atom of the -C(O)- group in formula (ID). 5The point of attachment of the group is indicated.

[0036] The compound may be of formula (I), (II), or (ID), wherein the X group of formula (I) or (II), or the R group of formula (ID), 5 The base is [ka] [ka] is a moiety selected from the group consisting of During the ceremony, [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B ) group or the point of attachment of R to the carbon atom of the -C(O)- group in formula (ID). 5 The point of attachment of the group is indicated.

[0037] The compounds of the present disclosure have the formula (IE) [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R 6 is an 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), where the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R A and R B is each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0038] In some embodiments, the X group of formula (I) or formula (II) or the R 6 The base is [ka] is a moiety selected from the group consisting of: R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; and, [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B) group or the point of attachment of X to the carbon atom of the -C(R A )(R B R for the carbon atom of the - group 6 The point of attachment of the group is indicated.

[0039] The compound may be of formula (I), (II), or (IE), where the X group of formula (I) or (II), or the R group of formula (IE), 6 The base is [ka] is a moiety selected from the group consisting of: [ka] represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I); 7A )(R 7B ) group or the point of attachment of X to the carbon atom of the -C(R A )(R B R for the carbon atom of the - group 6 The point of attachment of the group is indicated.

[0040] The compound of the present disclosure can be a compound listed in Table 1. For example, the compound is [ka] [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer, or stereoisomer thereof. In certain aspects, the present disclosure includes compounds [ka] nor its pharma- ceutically acceptable salts (e.g., hydrochloride salts), solvates, hydrates, tautomers, or stereoisomers.

[0041] In some embodiments, the compounds of the present disclosure are [ka] [ka] or a pharma- ceutically acceptable salt (eg, hydrochloride salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0042] The compounds disclosed herein (e.g., compounds of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or compounds in Table 1) have increased aqueous solubility and / or hydrophilicity compared to ganaxolone, as determined by a suitable measure of solubility and / or hydrophilicity, such as, for example, logS, logP, logD, topological polar surface area (TPSA), acid pKa, base pKa, or a combination thereof.

[0043] In some embodiments, the compounds disclosed herein may be administered to a subject without a solubility enhancer such as a cyclodextrin (e.g., CAPTISOL®). For example, the compounds disclosed herein may be administered to a subject without a cyclodextrin (e.g., CAPTISOL®) or with a relatively small amount of cyclodextrin (e.g., CAPTISOL®), e.g., a compound:cyclodextrin ratio of less than 1:1, e.g., less than 2:1, less than 3:1, less than 4:1, less than 5:1, less than 6:1, less than 7:1, less than 8:1, less than 9:1, less than 10:1, less than 15:1, less than 20:1, less than 25:1, less than 50:1, less than 99:1, or less. Similarly, the pharmaceutical compositions disclosed herein may include a relatively small amount of a solubility enhancer (e.g., a cyclodextrin such as CAPTISOL®) or may not include a solubility enhancer. For example, the pharmaceutical compositions disclosed herein may contain no cyclodextrin (e.g., CAPTISOL®) or may contain relatively small amounts of cyclodextrin (e.g., CAPTISOL®), e.g., less than 25% by weight, less than 20% by weight, less than 15% by weight, less than 10% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or less than 0.5% by weight of cyclodextrin in the composition.

[0044] The compounds disclosed herein (e.g., compounds of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or compounds of Table 1) have increased aqueous solubility and / or hydrophilicity relative to lipid-based derivatives of ganaxolone, as determined by a suitable measure of solubility and / or hydrophilicity, such as, for example, logS, logP, logD, topological polar surface area (TPSA), acid pKa, base pKa, or a combination thereof. The compounds of the present disclosure may also have a higher melting point relative to lipid-based derivatives of ganaxolone. For example, the compounds of the disclosure may be solid (e.g., in powder or crystalline form) at ambient temperature (e.g., about 25° C.), or at temperatures of about 25 to about 100° C., or at temperatures of about 25 to about 80° C., or at temperatures of about 25 to about 60° C., or at temperatures of about 25 to about 40° C. Thus, the compounds of the disclosure offer certain advantages over lipid-based derivatives of ganaxolone, such as being more suitable for oral or intravenous administration, being more bioavailable, and / or being easier to handle or formulate into pharmaceutical compositions for oral or intravenous administration.

[0045] A compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound in Table 1) may be converted (e.g., substantially converted) to ganaxolone by metabolic processes, for example, after administration of the compound to a subject. For example, after administration of a compound to a subject (e.g., orally or intravenously), about 1% or more (e.g., about 2%, about 4%, about 6%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, about 99.9%, or more) of the compound is present for, e.g., about 1 minute or longer (e.g., about 2 minutes, about 4 minutes, about 6 minutes, , about 8 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, or longer).

[0046] The compounds disclosed herein (e.g., compounds of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or compounds of Table 1) can provide increased bioavailability of ganaxolone, for example, compared to the bioavailability of ganaxolone following administration of ganaxolone itself at an equivalent dosage by the same route of administration. The bioavailability of ganaxolone can be increased (e.g., by the C max or to obtain the AUC) by measuring the serum concentration of ganaxolone.

[0047] The compounds disclosed herein (e.g., compounds of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or compounds of Table 1) can provide increased serum concentrations of ganaxolone (e.g., C ) relative to the serum concentrations achieved following administration of ganaxolone itself at an equivalent dosage by the same route of administration. max A compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound of Table 1) may, for example, provide a longer serum half-life of ganaxolone following administration to a subject, as compared to the serum half-life achieved following administration of ganaxolone itself at an equivalent dosage, for example, by the same route of administration.

[0048] For example, oral administration of a compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound of Table 1) may result in a higher ganaxolone C compared to oral administration of an equivalent amount of ganaxolone. maxOral administration of a compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound of Table 1) can achieve a higher ganaxolone AUC compared to oral administration of an equivalent amount of ganaxolone. Alternatively, intravenous administration of a compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound of Table 1) may result in a higher ganaxolone C than intravenous administration of an equivalent amount of ganaxolone. max Intravenous administration of a compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound of Table 1) can achieve a higher ganaxolone AUC compared to intravenous administration of an equivalent amount of ganaxolone.

[0049] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound in Table 1) and a pharma- ceutically acceptable excipient (e.g., a pharma- ceutically acceptable excipient disclosed herein).

[0050] Also disclosed herein are methods of using the compounds disclosed herein (e.g., compounds of Formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or compounds of Table 1). For example, disclosed herein are methods of treating a disease or disorder in a subject, including administering a compound disclosed herein or a pharmaceutical composition disclosed herein to a subject in need thereof.

[0051] For example, a method of treating a disease or disorder in a subject can include administering to a subject in need thereof a compound of Formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound of Table 1. A method of treating a disease or disorder in a subject can include administering to a subject in need thereof a composition comprising a compound of Formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound of Table 1, and a pharma- ceutically acceptable excipient. The compounds or compositions may be administered by any suitable route of administration, such as those routes of administration disclosed herein, for example, oral administration or by intravenous administration.

[0052] Also disclosed herein are compositions comprising a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound in Table 1), for use in treating a disease or disorder in a subject.

[0053] In other aspects, the disclosure relates to the use of a compound disclosed herein (e.g., a compound of Formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound of Table 1), or the use of a pharmaceutical composition disclosed herein, for the manufacture of a medicament effective to treat a disease or disorder in a subject.

[0054] The disease or disorder treated by the methods, compounds, compositions, or pharmaceuticals disclosed herein can be any suitable disease or disorder, such as the diseases or disorders described herein. For example, the disease or disorder can be a neurological disorder. The disease or disorder can be 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 disease. The disease or disorder can be status epilepticus (SE). The disease or disorder can be CDKL5 deficiency. The disease or disorder can be tuberous sclerosis. The disease or disorder can be PCDH19-associated epilepsy. The disease or disorder can be Lennox-Gastaut syndrome (LGS). [Brief description of the drawings]

[0055] [Figure 1] 1A and 1B show the pharmacokinetics of an exemplary ganaxolone prodrug disclosed herein in a dog model. A shows the mean plasma concentration (ng / mL) of compound 111 over time (hours) after intravenous (5 mg / kg) or oral (25 mg / kg) administration of compound 111 (with vehicle) in a dog model. B shows the mean plasma concentration (ng / mL) of ganaxolone over time (hours) after intravenous (5 mg / kg) or oral (25 mg / kg) administration of compound 111 (with vehicle) in a dog model. [Diagram 2]1A and 1B show the pharmacokinetics of intravenous (IV) administration of an exemplary ganaxolone prodrug disclosed herein in a dog model. A shows the mean plasma concentrations (ng / mL) of ganaxolone (GNX) and compound 224 over 8 hours following intravenous (2 mg / kg; bolus) administration of compound 224 (with vehicle) in a dog model. B shows the same pharmacokinetic study following IV administration of compound 224 with a compressed x-axis (0-1 hours). [Diagram 3] 1A and 1B show the pharmacokinetics of oral (PO) administration of an exemplary ganaxolone prodrug disclosed herein in a dog model. A shows the mean plasma concentrations (ng / mL) of ganaxolone (GNX) and compound 224 over 36 hours following oral (10 mg / kg; bolus) administration of compound 224 (with vehicle) in a dog model. B shows the same pharmacokinetic study following PO administration of compound 224 with a compressed x-axis (over 0-4 hours). [Figure 4] 1A and 1B show the pharmacokinetics of an exemplary ganaxolone prodrug disclosed herein in a dog model. A shows the mean plasma concentration (ng / mL) of compound 218 over time (hours) after intravenous (5 mg / kg) or oral (25 mg / kg) administration of compound 218 (with vehicle) in a dog model. B shows the mean plasma concentration (ng / mL) of ganaxolone over time (hours) after intravenous (5 mg / kg) or oral (25 mg / kg) administration of compound 218 (with vehicle) in a dog model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] The present disclosure relates to ganaxolone derivatives.The compounds disclosed herein can be metabolized (e.g., in vivo) to ganaxolone, and can be called ganaxolone prodrugs.Also disclosed herein are the methods of using the compounds, the methods of making the compounds, and pharmaceutical compositions and kits containing them.

[0057] Ganaxolone is a GABA receptor antagonist that provides the ability to treat neurological disorders such as seizures and epilepsy, among other disorders disclosed herein. A However, due to the poor water solubility and low oral bioavailability of ganaxolone, administration of a therapeutically effective amount of ganaxolone is best achieved by intravenous infusion or oral formulations of ganaxolone, such as aqueous suspensions, which require frequent administration and / or large amounts of the formulation. The compounds disclosed herein can address these shortcomings of ganaxolone because of their increased water solubility and bioavailability compared to ganaxolone, and can be metabolized to ganaxolone after administration (e.g., oral administration). Without wishing to be bound by theory, it is believed that the increased oral bioavailability of the compounds compared to ganaxolone allows the compounds to be rapidly absorbed from the intestine and enter the bloodstream, where the compounds are then converted (e.g., by metabolic processes) to ganaxolone to achieve therapeutic concentrations of ganaxolone in the bloodstream and / or central nervous system (CNS).

[0058] Thus, the present disclosure relates to compounds that include a ganaxolone moiety that is modified at a hydroxyl group by a cleavable moiety, e.g., an enzymatically cleavable moiety. For example, the cleavable moiety may be cleavable by an enzyme (e.g., an esterase) or through other mechanisms (e.g., direct chemical mechanisms). For example, after administration of a compound disclosed herein, the cleavable moiety may be cleaved (e.g., enzymatically) to provide ganaxolone. The compounds or compositions of the present disclosure may be administered, without limitation, orally, subcutaneously, intramuscularly, intravenously, intradermally, by inhalation, topically, rectally, intranasally, bucally, intravaginally, or via an implanted reservoir. In preferred embodiments, the compounds or compositions of the present disclosure are suitable for oral administration. In other preferred embodiments, the compounds or compositions of the present disclosure are suitable for intravenous administration. The present disclosure also relates to methods for treating neurological disorders, such as epilepsy or seizures. The methods disclosed herein may include orally administering to a subject in need of oral administration a therapeutically effective amount of a compound disclosed herein. Alternatively, the methods disclosed herein can include administering a therapeutically effective amount of a compound disclosed herein intravenously to a subject in need thereof.

[0059] definition Any publications cited in this disclosure (e.g., scientific journal articles, patent publications, etc.) are incorporated by reference in their entirety. To the extent that any material incorporated by reference contradicts or is inconsistent with the present specification, the present specification takes precedence over any such material. The citation of any reference herein is not an admission that such reference is prior art to the present disclosure. Throughout the present specification and claims, various terms are used in connection with aspects of the specification. Such terms shall be given their ordinary meaning in the art unless otherwise indicated. Other terms that are specifically defined shall be interpreted in a manner consistent with the definitions set forth herein.

[0060] As used herein, the term "alkyl" refers to an alkyl group having 1 to 18 carbon atoms (C 1-18 -alkyl), for example, from 1 to about 12 carbon atoms (C 1-12 -alkyl), or 1 to about 6 carbon atoms (C 1-6 -alkyl) refers to the radical of a saturated hydrocarbon group having a substituted or unsubstituted aryl group. The alkyl group can be a straight or branched chain hydrocarbon group. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. Throughout this disclosure, abbreviations well known in the art may be used to represent various alkyl groups or their derivatives, such as Me (methyl), Et (ethyl), Pr (propyl) such as iPr (isopropyl), Bu (butyl) such as tBu (tert-butyl), Bn (benzyl), and the like. Each example of an alkyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, such as, for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkyl").

[0061] As used herein, the term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 18 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds. For example, an alkenyl group can be any group having 2 to 8 carbon atoms (C 2-8 -alkenyl), 2 to 6 carbon atoms (C 2-6 -alkenyl), 2 to 5 carbon atoms (C 2-5 -alkenyl), 2 to 4 carbon atoms (C 2-4 -alkenyl), or 2 to 3 carbon atoms (C 2-3-alkenyl). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, and the like. Each example of an alkenyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl").

[0062] As used herein, the term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having 2 to 18 carbon atoms and one or more carbon-carbon triple bonds. An alkynyl group is a group having 2 to 8 carbon atoms (C 2-8 -alkynyl), 2 to 6 carbon atoms (C 2-6 -alkynyl), 2 to 5 carbon atoms (C 2-5 -alkynyl), 2 to 4 carbon atoms (C 2-4 -alkynyl), or 2 to 3 carbon atoms (C 2-3 -alkynyl). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. Each example of an alkynyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, such as, for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkynyl").

[0063] As used herein, the term "heteroalkyl" refers to an acyclic, stable straight or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, where the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group. When "heteroalkyl" is described, followed by -(CH 2 )-C(O)-OH, -N(R G1 )(R G2 When specific heteroalkyl groups are mentioned, such as -(CH 2 )-C(O)-OH, -N(R G1 )(R G2 It will be understood that the terms -(CH) are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited for the sake of clarity. Thus, the term "heteroalkyl" is used herein to refer to specific heteroalkyl groups, such as -(CH 2 )-C(O)-OH, -N(R G1 )(R G2 ), etc. Each instance of a heteroalkyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents, e.g., with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted heteroalkyl").

[0064] As used herein, the term "haloalkyl" refers to an acyclic straight or branched chain, or combinations thereof, containing at least one carbon atom and at least one halogen (e.g., F, Cl, Br, and I). The halogen atom(s) may be placed at any position of the haloalkyl group. Exemplary haloalkyl groups include -CF 3 , -CCl 3 , -CH 2 -CF 3 , -CH 2 -CCl 3, -CH 2 -Cl, and -CH 2 Each example of a haloalkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted haloalkyl") or substituted with one or more substituents, such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted haloalkyl").

[0065] As used herein, the term "alkoxy" refers to a group of formula -O-alkyl. The term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0066] As used herein, the term "aryl" refers to a stable aromatic ring system, which may be monocyclic or polycyclic, whose ring atoms are all carbon and which may be substituted or unsubstituted. The aromatic ring system may have, for example, 3 to 7 ring atoms. Examples include phenyl (Ph), naphthyl, anthracyl, and the like. Each instance of an aryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").

[0067] As used herein, the term "heteroaryl" refers to an aryl group that includes one or more ring heteroatoms. For example, heteroaryl can include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, or 9-membered bicyclic aromatic heterocyclic ring that consists of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen atom can be substituted or unsubstituted (e.g., N or NR ’’ where R″ is H or another substituent as defined. Examples of heteroaryl groups include pyrrole, furan, indole, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0068] As used herein, the term "cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3-10 carbon atoms in the cyclic structure and zero heteroatoms in the non-aromatic cyclic structure. Cycloalkyl can include cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups can be monocyclic ("monocyclic cycloalkyl") or contain fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic cycloalkyl"), and can be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused with one or more aryl groups, and the point of attachment is on the cycloalkyl ring, in which case the carbon numbers continue to specify the carbon numbers in the cycloalkyl ring system. Each instance of a cycloalkyl group can be independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl").

[0069] As used herein, the term "heterocyclyl" refers to a radical of a 3-10 membered non-aromatic ring structure (i.e., a heterocyclic radical) that contains atoms of at least two different elements in the ring or rings. The heteroatoms may be selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), which may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, with the point of attachment being on the cycloalkyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the ring member numbers continue to designate the ring member numbers in the heterocyclyl ring system. Each instance of heterocyclyl can be independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). Additional reference is made to the Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997, as evidence that heterocycle is a well-established term in the field of organic chemistry.

[0070] The terms "alkylene," "alkenylene," "alkynylene," or "heteroalkylene," by themselves or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, or heteroalkyl, respectively. For example, the term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. In the case of heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, in the case of alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, a group of the formula -C(O) 2 R'- is -C(O) 2 R'- and -R'C(O) 2 Each instance of an alkylene, alkenylene, alkynylene, or heteroalkylene group can independently be optionally substituted, i.e., it can be unsubstituted (an "unsubstituted alkylene") or substituted with one or more substituents (a "substituted heteroalkylene").

[0071] As used herein, the terms "cycloalkylene," "heterocyclylene," "arylene," and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively. Each instance of cycloalkylene, heterocyclylene, arylene, or heteroarylene can independently be optionally substituted, i.e., it can be unsubstituted (an "unsubstituted arylene") or substituted with one or more substituents (a "substituted heteroarylene").

[0072] As used herein, the term "dipeptide" refers to a moiety composed of two amino acid residues. For example, the dipeptides disclosed herein can be leucine-leucine (Leu-Leu), glycine-alanine (Gly-Ala), glycine-valine (Gly-Val). The dipeptides can be substituted or modified at either amino acid residue or both residues, for example, to attach the dipeptide to another group or atom at the C-terminus or N-terminus, or at both ends. For example, the compounds disclosed herein can be modified with a free N-terminus (i.e., -NH 2 ) and a C-terminus modified to form an ester group, or in some cases the compounds disclosed herein include dipeptides having an N-terminus modified to form a carbamate group and a C-terminus modified to form an ester group.

[0073] As used herein, the term "cyano" or "-CN" refers to a substituent having a carbon atom connected to a nitrogen atom by a triple bond (eg, C≡N).

[0074] As used herein, the term “halo” or “halogen” refers to F, Cl, Br, or I.

[0075] As used herein, the term "hydroxy" refers to a group of formula --OH.

[0076] As used herein, the term "nitro" refers to a group consisting of two oxygen atoms attached to a nitrogen atom, e.g., -NO 2 It refers to a substituent having the following structure:

[0077] As used herein, the term "oxo" refers to an oxygen group that is double bonded to another atom, e.g., carbon. For example, "oxo" refers to the carbonyl group =O (C=O). Oxo can be used in reference to compounds that are substituted with a double bonded oxygen, e.g., "oxo" refers to -CH 2 -C(O)-CH 3 may be used to refer to the oxygen substituent of

[0078] As used herein, the term "substituted" with respect to substituted alkyl, substituted alkylene, substituted alkenyl, substituted alkenylene, substituted alkynyl, substituted alkynylene, substituted heteroalkyl, substituted heteroalkylene, substituted heteroalkenyl, substituted heteroalkenylene, substituted heteroalkynyl, substituted heteroalkynylene, substituted cycloalkyl, substituted cycloalkylene, substituted heterocyclyl, substituted heterocyclylene, substituted aryl, substituted arylene, substituted heteroaryl, substituted heteroarylene, and the like, refers to an alkyl moiety, an aryl group ... It refers to a moiety, such as an alkylene moiety, an alkenyl moiety, an alkenylene moiety, an alkynyl moiety, an alkynylene moiety, a heteroalkyl moiety, a heteroalkylene moiety, a heteroalkenyl moiety, a heteroalkenylene moiety, a heteroalkynyl moiety, a heteroalkynylene moiety, a cycloalkyl moiety, a cycloalkylene moiety, a heterocyclyl moiety, a heterocyclylene moiety, an aryl moiety, an arylene moiety, a heteroaryl moiety, a heteroarylene moiety, etc., having a substituent replacing one or more hydrogen atoms on one or more carbon or heteroatoms of the moiety. In general, the term "substituted" means that at least one hydrogen present in a group (e.g., a hydrogen bonded to a carbon or nitrogen atom of the group) is replaced with a suitable substituent, such as those described herein. Such substituents include, for example, alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8 Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2, -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2 , -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0079] As used herein, the term "protecting group" refers to a group that acts to temporarily block a particular functional moiety, e.g., O, S, or N, in a polyfunctional compound so that a reaction can be selectively carried out at another reactive site. Those skilled in the art will recognize that a variety of protecting groups may be utilized in the synthetic methods and compounds described herein. Protecting groups may be introduced and removed at appropriate stages in the synthesis of the compounds using methods known to those skilled in the art. Protecting groups may be selected from a wide variety of protecting groups, including those described in Theodora W. Greene and Peter G.M.Wuts (2007) Protecting Groups in Organic Synthesis, 4 th Standard methods of organic synthesis are applied as described in the 1990 edition of John Wiley and Sons, which is incorporated by reference in its entirety.

[0080] Exemplary protecting groups include, but are not limited to, oxygen, sulfur, nitrogen, and carbon protecting groups. For example, oxygen protecting groups include, but are not limited to, methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMB (p-methoxybenzyl ether), optionally substituted ethyl ethers, optionally substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilyl ether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzylsilyl ether, TBDPS (t-butyldiphenylsilyl ether), esters (e.g., formates, acetates, benzoates (Bz), trifluoroacetates, dichloroacetates), carbonates, cyclic acetals, and ketals. In addition, nitrogen or amino protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Boc or Troc)), amides, cyclic imide derivatives, N-alkyl and N-aryl amines, imine derivatives, and enamine derivatives. Amino protecting groups include, but are not limited to, fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), acetamide, trifluoroacetamide, and the like. While certain other exemplary protecting groups are detailed herein, it will be recognized that the disclosure is not intended to be limited to these protecting groups, but rather, a variety of additional equivalent protecting groups may be utilized according to methods known to those of skill in the art.

[0081] The compounds provided herein may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, cis and trans forms; E and Z forms; endo and exo forms; R, S, and meso forms; D and L forms; d and l forms; (+) and (-) forms; keto, enol, and enolate forms; syn and anti forms; synclinal and anticlinal forms; alpha and beta forms; axial and equatorial forms; boat, chair, twisted, envelope, and half-chair forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0082] The compounds described herein may contain one or more asymmetric centers and therefore can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In one embodiment, the stereochemistry shown in the compounds is relative rather than absolute. Isomers can be isolated by methods known to those skilled in the art, such as chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0083] As used herein, a pure enantiomer compound is substantially free of the other enantiomer or stereoisomer of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. Or, using another notation, the (+) form of the compound is substantially free of the (-) form of the compound and is therefore in enantiomeric excess of the (-) form. The terms "enantiomerically pure" or "enantiopure" or "pure enantiomer" indicate that a compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, more than 99.9% by weight, or more than 75% by weight of the enantiomer. The weight may be based on the total weight of all enantiomers or stereoisomers of the compound.

[0084] The enantiomerically pure compounds disclosed herein may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may, for example, comprise about 90% of excipients and about 10% of an enantiomerically pure R-compound. The diastereomerically pure compounds disclosed herein may also be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising a diastereomerically pure exo compound may, for example, comprise about 90% of excipients and about 10% of a diastereomerically pure exo compound.

[0085] The active ingredients of the compositions disclosed herein can be formulated with little or no excipients or carriers.

[0086] The compounds disclosed herein may also include one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), 3 It can be in any isotopic form, such as H (T or tritium) ; C is 12 C. 13 C, and14 C, etc.; O can be in any isotopic form, such as 16 O and 18 It can be in any isotopic form, such as O ; N is 14 N and 15 It can be in any isotopic form, such as N ; F is 18 F, 19 It can be in any isotopic form such as F.

[0087] The term "pharmaceutically acceptable salts" as used herein refers to salts of compounds prepared using relatively non-toxic acids or bases depending on the specific substituents found in each compound.When the compounds of the present disclosure contain relatively acidic functional groups, the neutral form of such compounds can be contacted with a sufficient amount of the desired base either directly or in a suitable solvent (e.g., inert solvent) to obtain base addition salts.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salts, or similar salts.When the compounds of the present disclosure contain relatively basic functional groups, the neutral form of such compounds can be contacted with a sufficient amount of the desired acid either directly or in a suitable solvent (e.g., inert solvent) to obtain acid addition salts. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, and organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as alginates, and salts of organic acids such as glucuronic or galacturonic acid. Certain compounds of the present disclosure can contain both basic and acidic functional groups, allowing the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those of ordinary skill in the art. Other pharma- ceutically acceptable carriers known to those of ordinary skill in the art are suitable for the present invention.

[0088] The term "solvate" as used herein refers to a compound that is associated with a solvent, usually through a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. The compounds of the present disclosure may be prepared, for example, in crystalline form and solvated. Suitable solvates include pharma- ceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, the solvate may be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0089] The term "hydrate" as used herein refers to a compound that is associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in stoichiometric ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be, for example, a compound having the general formula R xH 2 O, where R is a compound where x is a number greater than 0. A given compound may form multiple hydrates, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R 0.5H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R 2H 2 O) and hexahydrate (R 6H 2 O) is included.

[0090] The term "tautomers" as used herein refers to compounds that are interchangeable forms of a particular compound structure and differ in the replacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium with the movement of pi electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with acid or base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomers can be related to optimal chemical reactivity and biological activity of a compound of interest.

[0091] Other definitions The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0092] The term "about" when referring to a measurable value such as amount, duration, and the like, is intended to encompass variations from the particular value of up to ±20%, or in some cases up to ±15%, or in some cases up to ±10%, or in some cases up to ±5%, or in some cases up to ±1%, or in some cases up to ±0.1%, e.g., variations appropriate for practicing the disclosed methods.

[0093] The term "and / or" as used herein should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or not to the elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," may refer in one embodiment to only A (optionally including elements other than B), in another embodiment to only B (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0094] The term "effective amount" as used herein refers to an amount of a compound described herein or a composition or formulation of such a compound (e.g., a derivative or prodrug of ganaxolone, or a pharmaceutical composition thereof) sufficient to achieve a desired result under the conditions of administration. For example, an effective amount of a compound disclosed herein or a composition or formulation of such a compound for the treatment of an epilepsy disorder is an amount that manages seizure activity, suppresses seizures, recovers a patient from a hyperexcitable state, can prevent recurrence of seizures, or can provide continued suppression of seizures. A skilled clinician can determine the appropriate dose based on a variety of considerations, including the severity of the disorder, the subject's age, weight, overall health, and other considerations. Typically, the compound is administered in an amount of about 0.01 mg to about 1800 mg.

[0095] As used herein, the term "pharmaceutical composition" refers to a composition that includes at least one active agent (which may be any compound disclosed herein or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, e.g., any derivative or prodrug of ganaxolone disclosed herein) and at least one other agent, such as an excipient (e.g., a pharma- ceutically acceptable excipient). A pharmaceutical composition optionally contains one or more additional active agents. Where specified, the pharmaceutical composition meets the standards of US FDA good manufacturing practice (GMP) for human or non-human drugs. A "pharmaceutical combination" is a combination of at least two active agents, either combined in a single dosage form or together in separate dosage forms and provided with instructions for use of the active agents together to treat a disorder, e.g., a neurological disorder, e.g., 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 disease, e.g., status epilepticus, CDKL5 deficiency, tuberous sclerosis, PCDH19-associated epilepsy, or Lennox-Gastaut syndrome (LGS).

[0096] The term "pharmaceutical acceptable excipient" as used herein refers to a non-toxic material that can be formulated with the compounds disclosed herein to provide a pharmaceutical composition. Preferably, the pharmaceutical acceptable excipient is inert and does not interfere with the pharmacological activity of the compound with which it is formulated. The pharmaceutical acceptable excipients useful in the manufacture of the pharmaceutical compositions disclosed herein are any of those well known in the art, including, without limitation, diluents, dispersants, granulating agents, surfactants, emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, ion exchangers, salts, electrolytes, waxes, and / or oils. For example, the pharma- ceutically acceptable excipient can be alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), phosphates, glycine, sorbic acid, potassium sorbate, glyceride mixtures (e.g., saturated vegetable fatty acids), water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose or a derivative thereof, polyethylene glycol or a derivative thereof (e.g., PEG-300), sodium carboxymethylcellulose, polyacrylates, polyethylene-polyoxypropylene-block polymers, wool fat, cyclodextrins (e.g., CAPTISOL®), dimethylacetamide (DMA), polysorbates (e.g., TWEEN®, e.g., TWEEN-20®), or combinations thereof.

[0097] The term "subject" as used herein refers to any animal, such as any mammal, including, but not limited to, humans, non-human primates, rodents, etc. Non-human primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaque monkeys (e.g., rhesus monkeys). Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species (e.g., domestic cats), canine species (e.g., dogs, foxes, wolves), birds, and fish. In some embodiments, the subject is a mammal (e.g., a human, a rat, or a mouse). The subject can be male or female. The subject can be of any age, including elderly human subjects (e.g., 65 years or older), non-elderly human subjects (e.g., under 65 years), or human pediatric subjects (e.g., 18 years or younger). In some embodiments, the subject is a human.

[0098] As used herein, the terms "treat", "treatment", "treating" or grammatically related terms refer to a method of reducing the effects of a disease or disorder. As will be readily appreciated in the art, complete eradication of a disease, disorder, or its symptoms is preferred but not required for treatment. Desirable effects of treatment include, but are not limited to, prevention of the onset or recurrence of a disease or disorder, alleviation of symptoms, attenuation of any direct or indirect pathological consequences of a disease or disorder, or other improvement of any signs, symptoms, or consequences of a disease or disorder, such as prolonged survival, reduced morbidity, and / or reduced side effects.

[0099] Throughout this disclosure, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have all possible subranges and individual numerical values ​​within that range specifically disclosed. For example, the description of a range such as 1-6 should be considered to have subranges such as 1-5, 1-4, 1-3, 2-6, 2-4, 3-6, etc. specifically disclosed, as well as individual numerical values ​​within that range, e.g., 1, 2, 2.8, 3, 3.6, 4, 5, 5.4, and 6. As another example, a range such as 95-99% includes 95%, 96%, 97%, 98%, or 99% and all subranges such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98%, etc. This applies regardless of the breadth of the range.

[0100] Various embodiments of the compounds, compositions, kits, and methods herein are described in detail below, and additional definitions may be provided throughout the specification.

[0101] compound The compounds disclosed herein have formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: Y is -C(O)- or -C(R A )(R B )-(e.g., -CH 2 -) and 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 or R 1 and R 2together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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 is each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0102] Each optional substituent of the groups in formula (I) (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, an optional substituent can be an alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl, alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., methoxy (-OMe), ethoxy (-OEt), or benzyloxy (-OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2, -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0103] In some embodiments, Y is -C(O)- and X is -NR 1 R 2 , -OR 3 , or -SR 4 For example, Y can be -C(O)- and X is -NR 1 R 2 Y can be -C(O)- and X can be -OR 3 or Y can be -C(O)- and X is -SR 4 In some embodiments, Y is -C(O)- and Z is an optionally substituted alkylene. For example, Y can be -C(O)- and Z can be unsubstituted methylene; or Y can be -C(O)- and Z can be unsubstituted methylene. In some embodiments, Y is -C(O)- and X is -NR 1 R 2 , -OR 3 , or -SR 4 and Z is an optionally substituted alkylene. For example, Y can be -C(O)- and X is -NR 1 R 2 and Z can be unsubstituted methylene; Y can be -C(O)- and X can be -OR 3 and Z can be unsubstituted methylene; Y can be -C(O)- and X can be -SR4 and Z can be unsubstituted methylene; Y can be -C(O)- and X can be -NR 1 R 2 and Z can be a substituted methylene; Y can be -C(O)- and X can be -OR 3 and Z can be substituted methylene; Y can be -C(O)- and X can be -SR 4 and Z can be a substituted methylene.

[0104] In some embodiments, Z is methylene (e.g., unsubstituted methylene). In some embodiments, Z is [ka] wherein Z is absent, alkylene (e.g., methylene, e.g., unsubstituted methylene), alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene, where the alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted (e.g., with a substituent described herein), and R 2 is hydrogen or alkyl; R B and R C are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted (e.g., with substituents described herein), and each [ka] indicates the point of attachment of Z to X or Y. In some embodiments, Z1 is absent.

[0105] In some embodiments, Z is an optionally substituted alkylene (e.g., an optionally substituted methylene), where the optional substituents are those described herein. In some embodiments, Z is unsubstituted methylene. In some embodiments, Z is absent.

[0106] In some embodiments, Z is [ka] where R B , R C , and R 2 are each independently hydrogen, -N(R 2 The nitrogen atom of - is bonded to Y, the carbonyl group is bonded to X, and Z1 is as defined herein (e.g., unsubstituted methylene). In some embodiments, Z is [ka] where R B and R C are each independently hydrogen, -SC(R B )(R C The sulfur atom of - is bonded to Y, the carbonyl group is bonded to X, and Z1 is as defined herein (e.g., unsubstituted methylene). In some embodiments, Z is [ka] where R B and R C are each independently hydrogen, -OC(R B )(R C The oxygen atom of - is bonded to Y, the carbonyl group is bonded to X, and Z1 is as defined herein (e.g., unsubstituted methylene). In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is absent.

[0107] In some embodiments, R 1 is hydrogen, and R 2 is hydrogen. In some embodiments, R 1 and R 2 One of the groups is hydrogen, and the other is R 1 and R 2 and the other is optionally substituted alkyl. In some embodiments, R 1 and R 2 One of the groups is hydrogen, and the other is R 1 and R 2 The other is an optionally substituted heteroalkyl. The alkyl group or heteroalkyl group can be substituted with any suitable substituent, for example, the substituents described herein. For example, the alkyl group or heteroalkyl group can be substituted with one or more of an alkyl group, an oxo group, or a hydroxyl group.

[0108] Y can be -C(O)- and X is -NR 1 R 2 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 1 and R 2 each can be independently hydrogen; Y can be -C(O)- and X can be -NR 1 R 2 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 1 can be hydrogen, R 2can be a substituted alkyl (e.g., an alkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups); or Y can be -C(O)- and X is -NR 1 R 2 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 1 can be hydrogen, R 2 can be a substituted heteroalkyl (e.g., a heteroalkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups). For example, Y can be -C(O)- and X is -NR 1 R 2 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 1 can be hydrogen, R 2 can be a substituted tertiary butyl (e.g., a tertiary butyl substituted with an oxo group and a hydroxyl group). For example, Y can be -C(O)- and X can be -NR 1 R 2 Z can be unsubstituted methylene, R 1 can be hydrogen, R 2 can be a tertiary butyl substituted with an oxo group and a hydroxyl group; or Y can be -C(O)- and X is -NR 1 R 2 Z can be a substituted methylene; R 1 can be hydrogen, R 2 can be a tertiary butyl substituted with an oxo group and a hydroxyl group.

[0109] Y can be -C(O)- and X is -OR 3 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 3 can be hydrogen; Y can be -C(O)- and X can be -OR 3 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 3can be an optionally substituted alkyl (e.g., an alkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups); or Y can be -C(O)- and X is -OR 3 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 3 can be an optionally substituted heteroalkyl (e.g., a heteroalkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups). For example, Y can be -C(O)- and X is -OR 3 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 3 can be a substituted tertiary butyl (e.g., a tertiary butyl substituted with an oxo group, a thiol group, a hydroxyl group, and / or an amino group). For example, Y can be -C(O)- and X can be -OR 3 Z can be unsubstituted methylene, R 3 can be a tertiary butyl substituted with an oxo group, a thiol group, a hydroxyl group, and / or an amino group; or Y can be -C(O)- and X is -OR 3 Z can be a substituted methylene; R 3 can be a tertiary butyl substituted with oxo, hydroxyl, thiol, and / or amino groups.

[0110] Y can be -C(O)- and X is -SR 4 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 4 can be hydrogen; Y can be -C(O)- and X can be -SR 4 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 4can be an optionally substituted alkyl (e.g., an alkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups); or Y can be -C(O)- and X is -SR 4 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 4 can be an optionally substituted heteroalkyl (e.g., a heteroalkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups). For example, Y can be -C(O)- and X is -SR 4 Z can be an optionally substituted alkylene (e.g., an optionally substituted methylene), and R 4 can be a substituted tertiary butyl (e.g., a tertiary butyl substituted with an oxo group, a thiol group, a hydroxyl group, and / or an amino group). For example, Y can be -C(O)- and X can be -SR 4 Z can be unsubstituted methylene, R 4 can be tertiary butyl substituted with oxo, thiol, hydroxyl, and / or amino groups; or Y can be -C(O)- and X is -SR 4 Z can be a substituted methylene; R 4 can be a tertiary butyl substituted with oxo, hydroxyl, thiol, and / or amino groups.

[0111] The compound of formula (I) has the formula (II): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein 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 or R 1 and R 2together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

[0112] Each optional substituent of the groups in formula (II) (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, an optional substituent can be an alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1-C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8 Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2 , -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2, -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0113] In the compounds disclosed herein, e.g., compounds of formula (I) or formula (II), X is [ka] [ka] may be a moiety selected from the group consisting of: 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) which may be a D- or L-amino acid residue, optionally substituted (e.g., at the 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) which may contain D-amino acids, L-amino acids, or combinations thereof, optionally substituted (e.g., at one or more nitrogen atoms, e.g., the 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 each independently represent -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 which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) and which are optionally substituted (e.g., at the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group), or R G1 and R G2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R G5 is hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; R Jis hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; R P is halo (e.g., chloro), heterocyclyl (e.g., morpholinyl), -NH-alkyl, -NH-heteroalkyl, -N-(alkyl) 2 (For example, -N(Me) 2 ), or -N-(heteroalkyl) 2 (For example, -N(CH 2 CH 2 OH) 2 ) and R 10 is an alkyl, alkenyl, alkynyl, haloalkyl, halo, -OR J , -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 R 11 and R 12 On the other hand, R 13 and R 14 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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; m is an integer from 1 to 5; p is an integer between 0 and 4, and [ka] represents the bond of X in formula (I) to another group of the compound, for example, the bond of X to Z, or, if Z is not present, to Y; or, in formula (II), -C(R 7A )(R 7B ) group.

[0114] Each optional substituent of the above groups (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, optional substituents can be an alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2, -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0115] When P is an amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) or a dipeptide moiety (e.g., a leucine-leucine moiety), P can comprise one or more D-amino acids, L-amino acids, or combinations thereof. The amino acid residue or dipeptide moiety can be attached through its C-terminus and can further comprise a free N-terminus or an optionally substituted N-terminus, e.g., with a carboxybenzyl (Cbz) group. The amino acid residue or dipeptide moiety can alternatively be attached through its N-terminus and can further comprise a free C-terminus (e.g., -C(O)OH), an optionally substituted C-terminus.

[0116] In some embodiments, X is [ka] and R 2 is H and R B and R C are each independently alkyl (e.g., methyl), and R K is hydrogen.

[0117] In some embodiments, Y is -C(O)-, Z is alkylene (e.g., methylene), and X is [ka] It is.

[0118] In some embodiments, X is -NR 1 R 2 in the case of, R1 and R 2 In some embodiments, none of X is -NR 1 R 2 and R 1 If is water, R 2 is not an unsubstituted alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl). 1 R 2 and R 1 If is alkyl (e.g., methyl), then R 2 is not unsubstituted alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl).

[0119] In some embodiments, X is -OR 3 In the case of R 3 is not hydrogen. In some embodiments, X is -OR 3 In the case of R 3 is not unsubstituted alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl).

[0120] In some embodiments, X is -SR 4 In the case of R 4 is not hydrogen. In some embodiments, X is -SR 4 In the case of R 4 is not unsubstituted alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl).

[0121] In the compounds disclosed herein, e.g., compounds of formula (I) or formula (II), X is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] may be a moiety selected from the group consisting of: [ka] represents the bond of X in formula (I) to another group of the compound, for example, the bond of X to Z, or, if Z is not present, to Y; or, in formula (II), -C(R 7A )(R 7B ) group.

[0122] The compound of formula (I) or (II) has the formula (IA): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein 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 or R 1 and R 2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

[0123] In some embodiments, R1 and R 2 are each independently hydrogen. In some embodiments, R 1 is hydrogen, and R 2 is an optionally substituted alkyl (e.g., an alkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups). In some embodiments, R 1 is hydrogen, and R 2 is an optionally substituted heteroalkyl (e.g., heteroalkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups). In some embodiments, R 7A and R 7B are each independently hydrogen. For example, R 1 , R 7A and R 7B may each independently be hydrogen; R 2 can be a tertiary butyl substituted with an oxo group and a hydroxyl group.

[0124] -N(R 1 )(R 2 ) group is [ka] may be a moiety selected from the group consisting of During the ceremony, 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)-), Q is heteroalkyl or heterocyclyl, wherein the heteroalkyl or heterocyclyl is optionally substituted; V is -O-, -N(H)-, or -N(Me)-; R A , R B , R C , RD , 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; and, [ka] indicates the point of attachment of the nitrogen atom to the carbon atom of the -C(R7A)(R7B) group.

[0125] Each optional substituent of the groups in formula (IA) (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, an optional substituent can be an alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C8 Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2, -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0126] -N(R 1 )(R 2 ) group is [ka] [ka] [ka] [ka] [ka] [ka] may be a moiety selected from the group consisting of: [ka] indicates the point of attachment of the nitrogen atom to the carbon atom of the -C(R7A)(R7B) group.

[0127] The compound of formula (I), formula (II), or formula (IA) may be represented by formula (IA-a): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein G is absent, -C(O)-, or -C(R 8A )(R 8B )-(e.g., -CH 2 -) and K is alkylene, heteroalkylene, -C(O)-, -OC(O)-, -C(O)O-, -O-, -O-(CH 2 )- or -(CH 2 )-O-, wherein said 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, where the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0128] K is -OC(O)- or -(CH 2 )-O-, -OC(O)- or -(CH 2 )-O- group is G and R 9 The groups can be connected in either orientation (in other words, these groups can be connected to -C(O)O- and -O-(CH 2 For example, it will be understood that G can be considered equivalent to -C(R 8A )(R 8B )- and K is -OC(O)-, [ka] and [ka] It will be understood that both are described. In some embodiments, G is -C(R 8A )(R 8B )-, K is -OC(O)-, and the carbonyl group of -OC(O)- is bonded to G, i.e. [ka] It is.

[0129] Each optional substituent of the groups in formula (IA-a) (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, optional substituents can be an alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2, -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0130] In some embodiments, G is -C(R 8A )(R 8B )-, for example, -C(CH 3 ) 2 In some embodiments, K is -OC(O)-. In some embodiments, R 2 is hydrogen. In some embodiments, R 7A and R 7B are each independently hydrogen. In some embodiments, R 9 is hydrogen. In some embodiments, R 8A and R 8B are each independently alkyl (e.g., methyl). For example, G is -C(CH 3 ) 2 In some embodiments, G can be -C(CH 3 ) 2 -, K is -OC(O)-, and R 2 , R 7A and R 7B are each independently hydrogen.

[0131] The compound of formula (I), formula (II), formula (IA), or formula (IA-a) may be represented by formula (IA-b): [ka] or a pharma- ceutically 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 R 9 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0132] In some embodiments, R2 is hydrogen. 8A and R 8B is, each independently, alkyl (e.g., methyl). In some embodiments, R 8A and R 8B are each independently methyl. For example, R 2 can be hydrogen, R 8A and R 8B may each independently be methyl. In some embodiments, R 9 is hydrogen.

[0133] In some embodiments, R 2 is hydrogen, and R 8A and R 8B are each independently methyl; R 9 is hydrogen.

[0134] The compound of formula (I) or (II) has the formula (IB): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R 3is 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 7A and R 7B are each independently hydrogen or optionally substituted alkyl.

[0135] -O-(R 3 ) group is [ka] may be a moiety selected from the group consisting of During the ceremony, P is an amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) which may be a D- or L-amino acid residue, optionally substituted (e.g., at the 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) which may contain D-amino acids, L-amino acids, or combinations thereof, optionally substituted (e.g., at one or more nitrogen atoms, e.g., the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group); R B and R Care 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 which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) and which are optionally substituted (e.g., at the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group), or R G1 and R G2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; R Kis 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 (For example, -N(Me) 2 ), -N-(heteroalkyl) 2 (For example, -N(CH 2 CH 2 OH) 2 ), or heterocyclyl (e.g., morpholinyl); m is an integer from 1 to 5; and [ka] indicates the point of attachment of the oxygen atom to the carbon atom of the -C(R7A)(R7B) group.

[0136] Each optional substituent of the groups in formula (IB) (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, an optional substituent can be an alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8 Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2 , -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0137] -O-(R 3 ) group is [ka] [ka] [ka] [ka] [ka] [ka] may be a moiety selected from the group consisting of: [ka] indicates the point of attachment of the oxygen atom to the carbon atom of the -C(R7A)(R7B) group.

[0138] The compound of formula (I) or formula (II) may be represented by formula (IC): [ka] or a pharma- ceutically 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.

[0139] In formula (IC), -S-(R 4 ) group is [ka] may be a moiety selected from the group consisting of During the ceremony, 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; R G3and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R G5 is hydrogen, alkyl, or heteroalkyl, where 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 (For example, -N(Me) 2 ), -N-(heteroalkyl) 2 (For example, -N(CH 2 CH 2 OH) 2 ), or heterocyclyl (e.g., morpholinyl), and [ka] indicates the point of attachment of the sulfur atom to the carbon atom of the -C(R7A)(R7B) group.

[0140] Each optional substituent of the groups in formula (IC) (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, an optional substituent can be an alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8 Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2 , -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2, -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0141] In formula (IC), -S-(R 4 ) group is [ka] [ka] may be a moiety selected from the group consisting of: [ka] indicates the point of attachment of the sulfur atom to the carbon atom of the -C(R7A)(R7B) group.

[0142] The compound of formula (I) or (II) has the formula (ID): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, During the ceremony, R 5is 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.

[0143] -R in formula (ID) 5 The base is [ka] may be a moiety selected from the group consisting of: X2 and X3 each independently represent -CH 2 -, -O-, -S-, or -N(R G3 )-(e.g., -NH-), R 10 is an alkyl, alkenyl, alkynyl, haloalkyl, halo, -OR J , -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 R 11 and R 12 On the other hand, R 13 and R14 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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; R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl 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 [ka] is the R for the carbon atom of the -C(O)- group 5 The point of attachment of the group is indicated.

[0144] Each optional substituent of the groups in formula (ID) (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, an optional substituent can be an alkyl (e.g., C1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8 Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2 , -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2, -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0145] -R in formula (ID) 5 The base is [ka] [ka] may be a moiety selected from the group consisting of: [ka] is the R for the carbon atom of the -C(O)- group 5 The point of attachment of the group is indicated.

[0146] The compound of formula (I) or (II) has the formula (IE): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R 6 is an 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), where the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R A and R B is each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0147] R in formula (IE) 6 The base is [ka] may be a moiety selected from the group consisting of During the ceremony, R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, where alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; and, [ka] is -C(R A )(R B R for the carbon atom of the - group 6 The point of attachment of the group is indicated.

[0148] Each optional substituent of the groups in formula (IE) (e.g., optional substituents on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group) can be any suitable substituent, such as those described herein. For example, an optional substituent can be an alkyl (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8 Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2 , -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2, -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0149] R in formula (IE) 6 The base is [ka] may be a moiety selected from the group consisting of: [ka] is -C(R A )(R B R for the carbon atom of the - group 6 The point of attachment of the group is indicated.

[0150] The compounds of the present disclosure have formula (I-II): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein [ka] represents a single or double bond, Y 1 is an 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 R2 , -OR 3 , -SR 4 , =NR 1 or =O, wherein the heteroalkyl, cycloalkyl, heterocyclyl, 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 or R 1 and R 2 together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R 3is 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; R 7A and R 7B are each independently hydrogen or optionally substituted alkyl, or R 7A and R 7B is connected to Y via one or more carbon atoms or heteroatoms. 1 to form a cyclic moiety (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl, e.g., pyrrole), R 7A Groups and R 7B the other group is hydrogen or optionally substituted alkyl; R 7C and R 7D are each independently hydrogen or optionally substituted alkyl, or R7C and R 7D are each bonded to the same oxygen atom to form an oxo group, and R 7E and R 7F each independently represents absent, hydrogen, alkyl, heteroalkyl, -NR 1 R 2 , -OR 3 , or -SR 4 wherein the alkyl or heteroalkyl is optionally substituted, with the proviso that [ka] If is a double bond, R 7E and R 7F Either one of them is not present or R 7E and R 7F are each attached to the same oxygen to form an oxo group.

[0151] In some embodiments, Y in formula (I-II) 1 is -O- or -N(R 1 )-(e.g., -N(H)-, -N(alkyl)-, or -N(heteroalkyl)-). For example, Y in formula (I-II) 1 Alternatively, Y in formula (I-II) can be -O- or -N(H)-. 1 is -N(Me)-, -N(Et)-, -N(EtOH)-, or -N( n PrOH)-.

[0152] The compound of formula (I-II) has the formula (I-IIa): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y 2 , R 1 , R 7C , R 7D , R 7E , and R 7F is as defined above.

[0153] The compound of formula (I-II) has the formula (I-IIb): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y 2 , R 7C , R 7D , R 7E , and R 7F is as defined above.

[0154] The compound of formula (I-II) has the formula (I-IIc): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y 2 , R 1 , R 7C , R 7D , and R 7E is as defined above.

[0155] The compound of formula (I-II) has the formula (I-IId): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y 2 , R 7C , R 7D , and R 7E is as defined above.

[0156] The compound of formula (I-II) has the formula (I-IIe): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y 2is as defined above.

[0157] Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) 2 ,or [ka] R when is a double bond 7E is optionally substituted heteroalkyl, -NR 1 R 2 (For example, -NH 2 , -NHMe, or -NMe 2 ), -OR 3 (For example, -OH, -OMe, -OEt, or -O t For example, Y in formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) can be ═O. 2 ,or [ka] R when is a double bond 7E is -NH 2 , -NHMe, or -OH.

[0158] Alternatively, Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) 2 ,or [ka] R when is a double bond 7E is an optionally substituted heteroalkyl, e.g., [ka] [ka] [ka] The heteroalkyl group may be a substituted or unsubstituted heteroalkyl selected from the group consisting of:

[0159] For example, Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) 2 -OH, -NH 2 , -NHMe, -NMe 2 , [ka] may be selected from the group consisting of:

[0160] R in formula (I-II) 7A and R 7B may each independently be hydrogen.

[0161] R of formula (I-II), (I-IIa), (I-IIb), (I-IIc), or (I-IId) 7C and R 7D may each independently be hydrogen or methyl, or R 7C and R 7D may each be bonded to the same oxygen atom to form an oxo group.

[0162] R of formula (I-II), (I-IIa), (I-IIb), (I-IIc), or (I-IId) 7E and R 7F may each independently be hydrogen or methyl, or R 7C and R 7D may each be bonded to the same oxygen atom to form an oxo group.

[0163] R in formulae (I-II), (I-IIa), and (I-IIc) 1 can be hydrogen, alkyl, or heteroalkyl. For example, R in formulas (I-II), (I-IIa), and (I-IIc) can be 1is hydrogen, methyl, ethyl, -MeOH, -EtOH, or - n It may be PrOH.

[0164] Each optional substituent of a group in one of formulas (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe), e.g., optional substituents on an alkyl group, an alkylene group, an alkenyl group, an alkenylene group, an alkynyl group, an alkynylene group, a heteroalkyl group, a heteroalkylene group, a cycloalkyl group, a cycloalkylene group, a heterocyclyl group, a heterocyclylene group, an aryl group, or a heteroaryl group, can be any suitable substituent, e.g., the substituents described herein. For example, an optional substituent can be an alkyl group (e.g., C 1 -C 6 Alkyl), alkenyl (e.g., C 2 -C 6 alkenyl), alkynyl (e.g., C 2 -C 6 alkynyl), heteroalkyl (e.g., C 1 -C 6 heteroalkyl), haloalkyl (e.g., C 1 -C 6 Haloalkyl, for example, -CH 2 Cl, -CH 2 I, -(CH 2 ) 2 Cl, -(CH 2 ) 2 I, or -CF 3 ), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C 3 -C 8Heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azetidinyl), alkylaryl, e.g., benzyl, aryl, e.g., phenyl, heteroaryl, e.g., pyrrolyl, imidazolyl, or indolyl, halogen, e.g., -F, -Cl, -Br, or -I, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy, e.g., -OMe, -OEt, or -OBn, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino, e.g., -NH 2 , -NHMe, or -NMe 2 ), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfur -vinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl, -C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O-alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., -NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), -C(O)N(alkyl) 2, -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, -N(alkyl)C(O)N(alkyl) 2 , -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl) 2 , -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0165] Compounds disclosed herein, for example, compounds of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe), may have a structure as set forth in Table 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, a compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) is a hydrochloride (HCl) salt. In some embodiments, a compound disclosed herein is a hydrochloride (HCl) salt of a compound set forth in Table 1. In embodiments, a compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe) is a trifluoroacetic acid (TFA) salt. In some embodiments, a compound disclosed herein is a trifluoroacetic acid (TFA) salt of a compound set forth in Table 1.

[0166] It will be appreciated that certain compounds can form salts with multiple counterions, for example, two chloride ions, to form bis-HCl salts.Therefore, it will be appreciated that references herein to HCl salts can refer to monohydrochloride or bishydrochloride salts.Similarly, it will be appreciated that references herein to TFA salts can refer to monotrifluoroacetate or bis-trifluoroacetate salts.

[0167] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

[0168] In some embodiments, the compound of formula (I), (II), and (IA) is compound 100, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IA) is compound 101, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IA) is compound 102, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 103, or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 104, or a pharma-ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 105, or a pharma-ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 106, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 107, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 108, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 109, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 110, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IA), and (IA-a) are compound 111, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IA), (I-II), and (I-IIa) are compound 112, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IA), (I-II), and (I-IIa) are compound 113, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), and (IA) is compound 114, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 115, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compounds of formulas (I), (II), and (IA) are compound 116, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IA), (I-II), and (I-IIa) are compound 117, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IA), (I-II), and (I-IIa) are compound 118, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (IA) are compound 119, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IA), (IA-a), (IA-b), (I-II), (I-IIa), and (I-IIc) are compound 120, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (IA) are compound 121, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 122, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), and (IA) is compound 123, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 124, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 125, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 126, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 127, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 128, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 129, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (IA-a), (IA-b), (I-II), (I-IIa), and (I-IIc) is compound 130, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of Formula (I), (II), (IA), (IA-a), (IA-b), (I-II), (I-IIa), and (I-IIc) is compound 131, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 132, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 133, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 134, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 135, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 136, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 137, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 138, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 139, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 140, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) are compound 141, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formula (I), (II), (IA), (I-II), and (I-IIa) are compound 141, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 143, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 144, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (I-II), and (I-IIa) is compound 145, or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), and (I-IIa) is compound 146, or a pharma-ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), and (I-IIa) is compound 147, or a pharma-ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 148, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 149, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), (IA), (I-II), and (I-IIa) is compound 150, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), and (I-IIa) is compound 151, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IA), (I-II), and (I-IIa) is compound 152, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 153, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), and (I-IIa) is compound 154, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0169] In some embodiments, the compound of formula (I), (II), (IB), (I-II), and (I-IIb) is compound 200, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IB) is compound 201, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), and (I-IIb) is compound 202, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (IB) are compound 203, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IB), (I-II), and (I-IIb) are compound 204, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IB), (I-II), and (I-IIb) are compound 205, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IB), (I-II), and (I-IIb) is compound 206, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IB), (I-II), and (I-IIb) is compound 207, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), (IB), (I-II), and (I-IIb) is compound 208, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), and (I-IIb) is compound 209, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IB) is compound 210, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formula (I), (II), (IB), (I-II), and (I-IIb) are compound 211, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formula (I), (II), (IB), (I-II), and (I-IIb) are compound 212, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) are compound 213, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IB), (I-II), and (I-IIb) is compound 214, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IB), (I-II), and (I-IIb) is compound 215, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compounds of formulas (I), (II), (IB), (I-II), and (I-IIb) are compound 216, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (IB) are compound 217, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) are compound 218, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) are compound 219, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (IB) are compound 220, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (IB) are compound 221, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of Formulas (I), (II), and (IB) are compound 222, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of Formulas (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) are compound 223, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 224, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 225, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 226, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 227, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 228, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 229, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 230, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 231, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 232, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 233, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 234, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 235, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 236, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 237, or a pharma- ceutically acceptable salt (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 238, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 239, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 240, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) are compound 241, or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compounds of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) are compound 242, or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt). In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 243, or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), and (I-IIb) is compound 244, or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt or a TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), (I-IIe) is compound 245, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 246, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IB), (I-II), and (I-IIb) is compound 247, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0170] In some embodiments, the compounds of formulas (I), (II), (IC), and (I-II) are compound 300, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IC), and (I-II) are compound 301, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IC), and (I-II) are compound 302, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IC), and (I-II) are compound 303, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (IC) are compound 304, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IC), and (I-II) are compound 305, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IC), and (I-II) are compound 306, or a pharma- ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IC), and (I-II) are compound 307, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (IC), and (I-II) are compound 308, or a pharma-ceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compounds of Formulas (I), (II), (IC), and (I-II) are compound 309, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of Formulas (I), (II), (IC), and (I-II) are compound 310, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0171] In some embodiments, the compound of formula (I), (II), and (ID) is compound 400, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 401, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 402, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 403, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 404, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 405, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), and (ID) is compound 406, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), and (ID) is compound 407, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (II), and (ID) is compound 408, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II), and (ID) is compound 409, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 410, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 411, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 412, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 413, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (ID) is compound 414, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (ID) are compound 415, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), (ID), and (I-II) are compound 416, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (ID) are compound 417, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compounds of formulas (I), (II), (ID), and (I-II) are compound 418, or a pharma- ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (ID) are compound 419, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compounds of formulas (I), (II), and (ID) are compound 420, or a pharma-ceutically acceptable salt thereof (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0172] In some embodiments, the compound of formula (I), (II), and (IE) is compound 500, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IE) is compound 501, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IE) is compound 502, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IE) is compound 503, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IE) is compound 504, or a pharma- ceutically acceptable salt (e.g., an HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0173] Pharmaceutical Compositions and Kits The disclosure provides pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or a compound set forth in Table 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof), and optionally a pharma- ceutically acceptable excipient.

[0174] In some aspects, the pharmaceutical compositions described herein comprise a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient.

[0175] In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (II), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient.

[0176] In some embodiments, the pharmaceutical compositions described herein comprise a compound of formula (IA), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical compositions described herein comprise a compound of formula (IA-a), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical compositions described herein comprise a compound of formula (IA-b), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient.

[0177] In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (IB), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient.

[0178] In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (IC), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient.

[0179] In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (ID), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient.

[0180] In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (IE), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient.

[0181] In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (I-II), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (I-IIa), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (I-IIb), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (I-IIc), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (I-IId), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (I-IIe), or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharma- ceutically acceptable excipient.

[0182] In some embodiments, the pharmaceutical compositions described herein comprise a compound set forth in Table 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and, optionally, a pharma- ceutically acceptable excipient. The compound, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, is provided in an effective amount in the pharmaceutical composition.

[0183] The pharmaceutical compositions of the present disclosure may be prepared by any suitable method known in the art. Such methods may involve bringing into association a compound ("active ingredient", e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or Table 1) with one or more pharma- ceutically acceptable excipients (e.g., carriers or binders), and further forming and / or packaging the composition into a single- or multi-dose unit.

[0184] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as a single unit dose or a plurality of single unit doses. A single unit dose represents a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient (e.g., a compound disclosed herein, e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or Table 1). The amount of active ingredient is typically equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage.

[0185] The relative amounts of active ingredient and one or more pharma- ceutically acceptable excipients in a pharmaceutical composition of the present disclosure will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. For example, a pharmaceutical composition may contain from about 0.1% to about 100% by weight of an active ingredient (e.g., a compound of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), or Table 1).

[0186] Compositions of the present disclosure may be administered orally, parenterally (such as, without limitation, subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation (e.g., oral inhalation), topically, rectally, intranasally, buccally, intravaginally, or via an implanted reservoir. In some embodiments, compositions of the present disclosure are administered orally. In some embodiments, compositions of the present disclosure are administered intravenously.

[0187] The pharmaceutical compositions of the present disclosure may be orally administered in any acceptable dosage form, including, but not limited to, capsules, tablets, caplets, powders, lozenges, pastilles, suspensions (e.g., aqueous suspensions), or solutions. Oral dosage forms may include pharma- ceutically acceptable excipients (e.g., pharma-ceutically acceptable excipients disclosed herein), such as carriers, lubricants, diluents, emulsifiers, suspending agents, flavoring agents, coloring agents, disintegrating agents, and the like. For example, oral dosage forms disclosed herein may contain one or more of lactose, corn starch, magnesium stearate, sweeteners, dyes, polyethers (e.g., polyethylene glycol, e.g., PEG-300), cyclodextrins (e.g., CAPTISOL®), or polysorbates (e.g., TWEEN®, e.g., TWEEN-20®).

[0188] The pharmaceutical compositions of the present disclosure may be administered intravenously in any acceptable dosage form, including, but not limited to, an aqueous solution. The intravenous dosage form may include a pharma- ceutically acceptable excipient (e.g., a pharma- ceutically acceptable excipient disclosed herein), such as a carrier, a diluent, and the like. For example, the intravenous dosage form disclosed herein may include one or more of a polyether (e.g., polyethylene glycol, e.g., PEG-300), a cyclodextrin (e.g., CAPTISOL®), or a polysorbate (e.g., TWEEN®, e.g., TWEEN-20®).

[0189] A pharmaceutical composition or dosage form (e.g., an intravenous dosage form) disclosed herein can be a composition or dosage form that does not contain a solubility enhancing agent such as a cyclodextrin (e.g., CAPTISOL®). For example, a pharmaceutical composition or dosage form (e.g., an intravenous dosage form) disclosed herein can include a compound disclosed herein without a cyclodextrin (e.g., CAPTISOL®), or with a relatively small amount of cyclodextrin such that the ratio of compound:cyclodextrin is less than 1:1, e.g., less than 2:1, less than 3:1, less than 4:1, less than 5:1, less than 6:1, less than 7:1, less than 8:1, less than 9:1, less than 10:1, less than 15:1, less than 20:1, less than 25:1, less than 50:1, less than 99:1, or less.

[0190] Pharmaceutical compositions or dosage forms (e.g., intravenous dosage forms) disclosed herein may contain a relatively small amount of a solubility enhancer (e.g., a cyclodextrin such as CAPTISOL®) or may not contain a solubility enhancer. For example, pharmaceutical compositions or dosage forms (e.g., intravenous dosage forms) disclosed herein may contain no cyclodextrin (e.g., CAPTISOL®) or may contain a relatively small amount of cyclodextrin (e.g., CAPTISOL®), e.g., less than 25% by weight, less than 20% by weight, less than 15% by weight, less than 10% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or less than 0.5% by weight of cyclodextrin in the composition.

[0191] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood that such compositions are generally suitable for administration to other animals. It will also be appreciated that pharmaceutical compositions can be modified to make such compositions suitable for administration to a variety of animals, and that one of skill in the art can use routine experimentation to design and / or perform such modifications.

[0192] The compounds disclosed herein are typically formulated into dosage unit forms, for example, single unit dosage forms, for ease of administration and uniformity of dosage.However, it will be understood that the total daily usage of the compounds or compositions disclosed herein will be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any particular subject or organism will vary depending on a variety of factors, including, but not limited to, the disease or disorder being treated and the severity of the disease or disorder being treated; the activity of the specific compound or composition being administered; the specific compound or composition being administered; the age, weight, general health, sex, and / or diet of the subject; the time of administration, route of administration, and excretion or metabolic rate of the specific compound or composition being administered; the duration of treatment, the drugs used in combination or simultaneously with the specific compound or composition being administered; and similar factors known in the art.

[0193] The amount of compound or composition required to achieve an effective dose varies from subject to subject depending on various factors, such as the species, age, and general condition of the subject; the severity of the side effects or disorder; the identity of the particular compound or composition; the method of administration, etc. The desired dosage may be delivered once or more per day, such as once per day, twice per day, three times per day, etc., or may be delivered less frequently, such as every other day, every third day, every week, every two weeks, every three weeks, once a month, etc. The desired dosage may be delivered as needed. The desired dosage may also be delivered using multiple administrations, such as two, three, four, five, or more administrations.

[0194] The effective amount of the compound for administration varies depending on the subject's body weight. For example, the effective amount of the compound for administration once or more per day to a human adult weighing 70 kg may contain about 0.0001 mg to about 3 g, for example, about 0.0001 mg to about 2 g, about 0.0001 mg to about 1 g, about 0.001 mg to about 1 g, about 0.01 mg to about 1 g, about 0.1 mg to about 1 g, about 1 mg to about 1 g, about 1 mg to about 750 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, about 5 mg to about 100 mg, or about 10 mg to about 100 mg of the compound per unit dosage form.

[0195] It will be understood that the dosage ranges set forth herein provide guidance for administration to adults, and that the amounts administered (e.g., to a pediatric subject) can be determined by a medical professional or one of ordinary skill in the art and will be lower or the same as the amounts administered to an adult.

[0196] The compounds and compositions described herein can be administered in combination with one or more additional pharmaceutical agents.The compounds and compositions disclosed herein can be administered in combination with additional pharmaceutical agents that improve their bioavailability, improve the effectiveness of treatment, reduce or modify the metabolism of the compound, or inhibit the excretion and / or modify the distribution of the compound in the body.It will be understood that the additional pharmaceutical agents used may achieve the desired effect on the same disorder as the compound or composition, and / or may achieve a different effect.

[0197] The compound or composition can be administered simultaneously with, prior to, or after one or more additional pharmaceutical agents, which may be useful, for example, as a combination therapy. Pharmaceutical agents include substances with therapeutic effects. Pharmaceutical agents also include substances with prophylactic effects. Each additional pharmaceutical agent can be administered at the dose and / or time determined for that pharmaceutical agent. The additional pharmaceutical agents can be administered in a single dose or separately in different doses, together with each other and / or with the compounds or compositions described herein. The particular combination to be used in the regimen takes into account the compatibility of the compounds of the present invention with the additional pharmaceutical agents and / or with the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination are lower than the levels utilized individually.

[0198] Kits (e.g., pharmaceutical packs) are also encompassed by the present disclosure. The kits may be useful for the prevention and / or treatment of diseases or disorders disclosed herein, such as neurological disorders (e.g., epilepsy). The kits may include a compound or composition disclosed herein and a container (e.g., a blister pack, a vial, a bottle, an ampoule, a dispenser package, a syringe, or other suitable container). In some embodiments, the kits may further include a second container that includes a pharmaceutical excipient, for example, for diluting or suspending the compound or composition. In some embodiments, the compound or composition provided in the container and the second container are combined to form one unit dosage form, or a plurality of unit dosage forms.

[0199] Pharmacokinetics The compounds and pharmaceutical compositions disclosed herein can provide enhanced pharmacokinetic and pharmacodynamic profiles, for example, as compared to ganaxolone. In particular, the compounds and pharmaceutical compositions disclosed herein have superior oral bioavailability as compared to ganaxolone. After administration (e.g., oral or intravenous), the compounds disclosed herein can be converted to ganaxolone in vivo (e.g., by metabolic processes). The compounds disclosed herein can be referred to as ganaxolone prodrugs. Thus, administration of the compounds disclosed herein can provide enhanced pharmacokinetic and pharmacodynamic profiles as compared to administration of ganaxolone (e.g., C max or AUC). Without wishing to be bound by theory, it is believed that the increased bioavailability of the compounds disclosed herein compared to the amount achieved by administration of ganaxolone itself ultimately increases the exposure of ganaxolone and / or improves the maintenance of steady-state ganaxolone following administration (e.g., oral administration). This effect may be due, in part, to the increased solubility, hydrophilicity, and / or absorption rate of the compounds disclosed herein compared to ganaxolone, as well as their ability to be converted to ganaxolone by metabolic processes.

[0200] Similarly, the compounds and pharmaceutical compositions disclosed herein can provide higher concentrations of ganaxolone in the CNS following administration to a subject (e.g., intravenously or orally) compared to the concentrations achieved when ganaxolone is administered to a subject in an equivalent amount and by the same route of administration.

[0201] The compounds and pharmaceutical compositions disclosed herein may be used to improve the bioavailability of administration of ganaxolone itself (e.g., the C maxor AUC), as compared to at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, about 320%, or The composition may have a bioavailability, e.g., oral bioavailability, that is 5%, about 350%, about 375%, about 400%, about 425%, about 450%, about 475%, about 500%, about 525%, about 550%, about 575%, about 600%, about 625%, about 650%, about 675%, about 700%, about 725%, about 750%, about 775%, about 800%, about 825%, about 850%, about 875%, about 900%, about 925%, about 950%, about 975%, about 1000% or more.

[0202] Because the compounds disclosed herein can be converted in situ (e.g., by metabolic processes) to ganaxolone, the enhanced bioavailability achieved by the compounds disclosed herein is due to the C max In addition to measuring plasma ganaxolone levels and area under the curve (AUC) levels, max In some embodiments, the compounds and pharmaceutical compositions disclosed herein can be measured by the C levels achieved following oral administration of a composition comprising ganaxolone and / or the AUC levels of ganaxolone. max and / or AUC of ganaxolone max and / or increase the AUC.

[0203] The compounds and pharmaceutical compositions described herein provide maximum ganaxolone plasma concentrations (C) of about 100 ng / mL to about 1200 ng / mL. maxFor example, the compounds may provide a concentration of about 100 ng / mL, about 110 ng / mL, about 120 ng / mL, about 130 ng / mL, about 140 ng / mL, about 150 ng / mL, about 160 ng / mL, about 170 ng / mL, about 180 ng / mL, about 190 ng / mL, about 200 ng / mL, about 210 ng / mL, about 220 ng / mL, about 230 ng / mL, about 240 ng / mL, about 250 ng / mL, about 260 ng / mL, about 270 ng / mL, about 280 ng / mL, about 290 ng / mL, about 300 ng / mL, about 310 ng / mL, about 320 ng / mL, about 330 ng / mL, about 340 ng / mL, about 350 ng / mL, about 360 ng / mL, about 370 ng / mL, about 380 ng / mL, about 390 ng / mL, about 400 ng / mL, about 410 ng / mL, about 420 ng / mL, about 430 ng / mL, about 440 ng / mL, about 450 ng / mL, about 460 ng / mL, about 470 ng / mL, about 480 ng / mL, about 490 ng / mL, about 500 ng / mL, about 510 ng / mL, about 520 ng / mL, about 530 ng / mL, about 540 ng / mL, about 550 ng / mL, about 560 ng / mL, about 570 ng / mL, about 580 ng / mL, about 590 ng / mL, about L, approximately 330ng / mL, approximately 340ng / mL, approximately 350ng / mL, approximately 360ng / mL, approximately 370ng / mL, approximately 380ng / mL, approximately 390ng / mL, approximately 400ng / mL, approximately 410ng / mL, approximately 420ng / mL, approximately 430ng / mL, approximately 440ng / mL, approximately 450ng / mL, approximately 460ng / mL, approximately 470ng / mL, approximately 480ng / mL, approximately 490ng / mL, approximately 500ng / mL, approximately 510ng / mL, approximately 520ng / mL, approximately 530ng / mL, approximately 540ng / mL, approximately 550ng / mL, approximately 560ng / mL, 570ng / mL, approximately 580ng / mL, approximately 590ng / mL, approximately 600ng / mL, approximately 610ng / mL, approximately 620ng / mL, approximately 630ng / mL, approximately 640ng / mL, approximately 650ng / mL, approximately 660ng / mL, approximately 670ng / mL, approximately 680ng / mL, approximately 690ng / mL, approximately 700ng / mL, approximately 710ng / mL, approximately 720ng / mL, approximately 730ng / mL, approximately 740ng / mL, approximately 750ng / mL, approximately 760ng / mL, approximately 770ng / mL, approximately 780ng / mL, approximately 790ng / mL, 800ng / mL, about 810ng / mL, about 820ng / mL, about 830ng / mL, about 840ng / mL, about 850ng / mL, about 860ng / mL, about 870ng / mL, about 880ng / mL, about 890ng / mL, about 900ng / mL, about 910ng / mL, about 920ng / mL, about 930ng / mL, 940ng / mL, about 950ng / mL, about 960ng / mL, about 970ng / mL, about 980ng / mL, about 990ng / mL, about 1000ng / mL, about 1100ng / mL, or about 1200ng / mL or more max can be achieved.

[0204] The compounds and pharmaceutical compositions described herein provide improved efficacy and efficacy in the treatment of ganaxolone C compared to other oral compositions containing ganaxolone. max can be increased by at least about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, or more.

[0205] The compounds and pharmaceutical compositions disclosed herein can increase the ganaxolone AUC compared to the AUC achieved following oral administration of another composition containing ganaxolone. For example, oral administration of a compound or pharmaceutical composition disclosed herein can result in a ganaxolone AUC of about 100 ng / mL / hr to about 1,200 ng / mL / hr, e.g., about 200 ng / mL / hr to about 1,200 ng / mL / hr, about 300 ng / mL / hr to about 1,200 ng / mL / hr, about 400 ng / mL / hr to about 1,200 ng / mL / hr, about 500 ng / mL / hr to about 1,200 ng / mL / hr, about 600 ng / mL / hr to about 1,200 ng / mL / hr, about 700 ng / mL / hr to about 1,200 ng / mL / hr, about 800 ng / mL / hr to about 1,200 ng / mL / hr, or about 900 ng / mL / hr to about 1,200 ng / mL / hr. AUC is calculated AUC to final measured concentration (AUC 0.t ), e.g., over a 24-hour period (AUC 0-24 )

[0206] The compounds and pharmaceutical compositions disclosed herein provide mean ganaxolone plasma concentrations (C) of about 100 ng / mL to about 1,200 ng / mL, about 200 ng / mL to about 1,200 ng / mL, about 300 ng / mL to about 1,200 ng / mL, about 400 ng / mL to about 1,200 ng / mL, about 500 ng / mL to about 1,200 ng / mL, about 600 ng / mL to about 1,200 ng / mL, about 700 ng / mL to about 1,200 ng / mL, about 800 ng / mL to about 1,200 ng / mL, or about 900 ng / mL to about 1,200 ng / mL. ave) can be administered at a dose that results in

[0207] The compounds and pharmaceutical compositions disclosed herein can be administered at a dose that results in a plasma ganaxolone concentration of about 100 ng / mL to about 1,200 ng / mL, about 200 ng / mL to about 1,200 ng / mL, about 300 ng / mL to about 1,200 ng / mL, about 400 ng / mL to about 1,200 ng / mL, about 500 ng / mL to about 1,200 ng / mL, about 600 ng / mL to about 1,200 ng / mL, about 700 ng / mL to about 1,200 ng / mL, about 800 ng / mL to about 1,200 ng / mL, or about 900 ng / mL to about 1,200 ng / mL.

[0208] How to use The present disclosure also relates to methods of treating a disease or disorder. The methods disclosed herein can include administering (e.g., orally or intravenously) a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof.

[0209] The methods may be suitable for treating any type of seizure disorder, epilepsy disorder, genetic epilepsy disorder, epilepsy-related disorder, central nervous system disorder, neurological disorder, neurodegenerative disease, and the like.

[0210] Disorders that the methods disclosed herein may be suitable for treating, including epilepsy disorders and / or epilepsy-related disorders, include focal seizures, essential tremor, generalized seizures, acute repetitive seizures, pediatric epilepsy, reflex epilepsy, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus, SCN8 A epilepsy, catamenial epilepsy, Angelman syndrome, benign epilepsy with centrotemporal spikes (BECTS), CDKL5 deficiency (CDKL5 disorder), autosomal dominant nocturnal frontal lobe epilepsy (ADFE), absence epilepsy, childhood absence epilepsy (CAE), Doose syndrome, Dravet syndrome, early myoclonic epilepsy (EME), epilepsy with generalized tonic-clonic seizures, myoclonic absence epilepsy, infantile spasms, and the like. West syndrome, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), myoclonic absence epilepsy, frontal lobe epilepsy, juvenile myoclonic epilepsy (JME), Lyfora progressive myoclonic epilepsy, Ohtahara syndrome, Rett syndrome, refractory childhood epilepsy (ICE), Panaetopoulos syndrome, Rasmussen syndrome, progressive myoclonic epilepsy, ring chromosome 20 syndrome, temporal lobe epilepsy , infantile epilepsy with migratory focal seizures, fragile X syndrome epilepsy, Sturge-Weber syndrome, PCDH19-related epilepsy including PCDH19 childhood epilepsy, tuberous sclerosis, Dup15q syndrome, Jeavons syndrome, febrile illness-associated epilepsy syndrome (FIRES), autoimmune encephalitis / encephalopathy due to anti-LGI1, anti-NMDAR, anti-GABA-B receptor, or anti-GAD65 antibodies, FOXG1-related epilepsy, Syngap1-related These include, but are not limited to, epilepsy, Aicardi syndrome, sleep-related hyperkinetic epilepsy, continuous spike-and-wave epileptic encephalopathy of sleep (CSWS), infantile myoclonic epilepsy, Rasmussen syndrome, developmental and epileptic encephalopathies (unclassified), focal epilepsy, juvenile absence epilepsy, post-traumatic epilepsy, epilepsy due to cortical dysplasia, and catamenial epilepsy, increased seizure activity, seizure recurrence, and infantile spasms.

[0211] Epilepsy and / or epilepsy-related disorders suitable for treatment with the methods disclosed herein include CDKL5 deficiency, tuberous sclerosis, and PCDH19-associated epilepsy. Another disorder suitable for treatment with the methods disclosed herein is Lennox-Gastaut syndrome (LGS).

[0212] The methods disclosed herein can also be used to treat other neurological disorders, such as anxiety, agitation, or depression (eg, postpartum depression).

[0213] Additional medical conditions in which seizures are manifestations that can be treated using the methods disclosed herein include, but are not limited to, preeclampsia / eclampsia, drug-related seizures (prescription drugs including, for example, antihistamines, antibiotics, antidepressants, schizophrenia medications, as well as illicit drugs such as PCP, cocaine, and amphetamines), drug withdrawal (such as withdrawal from THC, opioids, alcohol, or barbiturates), or antiepileptic drug (AED) non-compliance.

[0214] Other disorders that may be treated by the methods, compounds, or compositions disclosed herein are described in International Application Nos. PCT / US2006 / 045626, PCT / US2007 / 024606, PCT / US2010 / 045176, PCT / US2016 / 016977, PCT / US2016 / 057120, PCT / US2017 / 056565, PCT / US2018 / 028151, PCT / US2019 / 026224, and PCT / US2020 / 027014. Nos. 018 / 060037, PCT / US2019 / 064850, PCT / US2020 / 044843, PCT / US2020 / 063648, PCT / US2021 / 060459, and PCT / US2021 / 061937; U.S. Pat. No. 10,391,105; and U.S. Patent Publication No. 2019 / 0111059, each of which is incorporated by reference in its entirety herein.

[0215] The methods disclosed herein are suitable for treating seizures. For example, the methods disclosed herein are suitable for treating status epilepticus (SE). The methods disclosed herein are suitable for any form of SE, such as early status epilepticus, confirmed status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus (e.g., focal non-convulsive status epilepticus, complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, fine non-convulsive status epilepticus), generalized convulsive status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges, and periodic unilateral epileptiform discharges. The methods can also be used to treat subjects who have failed first-line (e.g., benzodiazepines), second-line (e.g., fosphenytoin disodium, valproic acid, or levetiracetam), and / or third-line (thiopental, midazolam, pentobarbital, or propofol) treatments.

[0216] Other seizures that the methods disclosed herein may be suitable for treating include epileptic seizures, acute repetitive seizures, cluster seizures, continuous ...

[0217] The compounds and pharmaceutical compositions disclosed herein can also be administered as prophylactics to treat central nervous system and / or neurological disorders. Exemplary central nervous system and / or neurological disorders that may be suitable for treatment using the formulations disclosed herein include autism spectrum disorder, Rett syndrome, Tourette syndrome, obsessive-compulsive disorder, insomnia, parasomnia, oppositional defiant disorder, conduct disorder, severe mood dysregulation disorder, agitation, anxiety, generalized anxiety disorder, social anxiety disorder, panic disorder, anxiety or agitation due to Alzheimer's dementia, schizophrenia, drug withdrawal syndrome (alcohol, benzodiazepines, barbirates, and cocaine), post-traumatic stress disorder (PTSD), tremor, essential tremor, spasticity due to cerebral palsy, depression (major depression, major depressive disorder, The present invention relates to a neurocognitive disorder, including depression, major depression, unipolar depression, unipolar disorder, recurrent depression, postpartum or postpartum depression, atypical depression, melancholic depression, psychotic major depression (PMD), catatonic depression, seasonal affective disorder (SAD), dysthymia, overlapping depression, depressive personality disorder (DPD), recurrent brief depression (RBD), minor depressive disorder, bipolar disorder or manic depression, post-traumatic stress disorder, postmenopausal depression, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, mood disorders or suicidal behavior, attention deficit hyperactivity disorder, or delirium. The compound or composition may also be used as a sedative or analgesic.

[0218] The present disclosure further includes a method of treating seizures resulting from a neurodegenerative disease, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. The present disclosure includes a method of treating seizures resulting from an inflammatory disease, such as multiple sclerosis. The present disclosure includes a method of treating seizure disorders resulting from lysosomal storage diseases, including Niemann-Pick disease type C (NPS), Tay-Sachs, Batten disease, Sandhoff disease, and Gaucher disease.

[0219] Preferred subjects are humans, although typically any mammal may be treated according to the methods disclosed herein, including domestic animals such as dogs, cats and horses.

[0220] The modified forms of ganaxolone intended as prodrugs are not converted to ganaxolone as expected. For example, conventional methods of forming ganaxolone prodrugs have resulted in compounds that have improved aqueous solubility or oral absorption compared to ganaxolone, but are not sufficiently converted to ganaxolone in vivo to provide therapeutically effective serum concentrations of ganaxolone. Thus, there is a significant level of unpredictability in designing compounds suitable as ganaxolone prodrugs that are sufficiently stable (e.g., relatively stable at bench, relatively stable in plasma, and relatively stable in gastric and / or intestinal fluids), have sufficient oral bioavailability, and can be converted to ganaxolone after administration to provide therapeutic serum concentrations of ganaxolone. Thus, it is surprising and unexpected that certain compounds disclosed herein are sufficiently stable, have improved solubility and other physicochemical properties related to bioavailability, and are efficiently converted to ganaxolone by metabolic processes (see, for example, Example 121). Even minor modifications to the compound structure have been found to significantly reduce or eliminate the ability of the compound to be converted to ganaxolone or adversely affect its stability, demonstrating the high degree of unpredictability and difficulty in designing useful ganaxolone prodrugs.

[0221] Synthesis method The compounds disclosed herein can be prepared according to known processes. Schemes 1-3 below represent general synthetic schemes for preparing the compounds of the present disclosure (e.g., compounds of formula (I), (II), (IA), (IA-a), (IA-b), (IB), (IC), (ID), (IE), (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), (I-IIe), and compounds of Table 1). These schemes are illustrative and are not intended to limit the possible procedures that one skilled in the art may use to prepare the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Various modifications to these methods can be envisioned by those skilled in the art to achieve results similar to those described below. Optional protecting groups can be added as described, for example, in Greene et al. Protective Groups in Organic Synthesis (4 th ed. 2006). It will be appreciated that syntheses not explicitly shown in the general schemes may involve, for example, one or more additional steps of protection and / or deprotection of nitrogen or oxygen atoms, saponification, and / or salt formation (e.g., by treatment with an acid).

[0222] Compounds of formula (I) may generally be prepared, for example, according to Scheme 1: [ka] Scheme 1. Exemplary synthesis of compounds of formula (I). It can be prepared according to where X, Z, and Y are as defined herein, and LG is a suitable leaving group (e.g., halogen, OSO 2 Me, OMs, OTs, OTf, or OH. The reaction can be catalyzed by heat and / or a reagent (e.g., an acid or base) or catalyst and can be carried out in any suitable solvent, such as an inert organic solvent.

[0223] Compounds of formula (II) can generally be prepared, for example, according to Scheme 2: [ka] Scheme 2. Exemplary synthesis of compounds of formula (II). It can be prepared according to In the formula, X, R 7A and R 7B is as defined herein, and LG is a suitable leaving group (e.g., halogen, OSO 2 Me, OMs, OTs, OTf, or OH. The reaction can be catalyzed by heat and / or a reagent (e.g., an acid or base) or catalyst and can be carried out in any suitable solvent, such as an inert organic solvent.

[0224] Alternatively, compounds of formula (II) may generally be prepared, for example, as shown in Scheme 3: [ka] Scheme 3. Exemplary synthesis of compounds of formula (II). It can be prepared according to In the formula, X, R 7A and R 7B is as defined herein, and LG is a suitable leaving group (e.g., halogen, OSO 2 Me, OMs, OTs, OTf, or OH. The reaction can be catalyzed by heat and / or a reagent (e.g., an acid or base) or catalyst and can be carried out in any suitable solvent, such as an inert organic solvent.

[0225] For example, the base used in the synthesis of the compounds disclosed herein according to one of Schemes 1-3 can include an inorganic base, such as potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, and the like, or an organic base, such as an amine base (e.g., triethylamine (TEA), diisopropylamine, diisopropylethylamine (DIPEA), pyrrolidine, or pyridine).

[0226] For example, acids used in the synthesis of compounds disclosed herein according to one of Schemes 1-3 can include hydrochloric acid, sulfuric acid, nitric acid, tosylic acid, trifluoroacetic acid, acetic acid, and the like.

[0227] For example, solvents used in the synthesis of compounds disclosed herein according to one of Schemes 1-3 can include dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), dichloromethane (DCM), 1,4-dioxane, acetonitrile, methanol, ethanol, toluene, diethyl ether, methyl tert-butyl ether (MTBE), etc. Water can also be used as a solvent, either alone or in a mixture with one or more other solvents, such as those described herein.

[0228] For example, the reaction for preparing a compound disclosed herein according to one of schemes 1-3 can be carried out at any suitable temperature. For example, the reaction for preparing a compound disclosed herein can be carried out at room temperature, below room temperature, or above room temperature. The reaction for preparing a compound disclosed herein can be carried out at 0°C or below, for example, at -5°C, -10°C, -25°C, -50°C, -78°C, -80°C, -100°C, or below. The reaction for preparing a compound disclosed herein can be carried out at 25°C or above, for example, at 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, or above.

[0229] For example, reactions described herein according to one of Schemes 1-3 may be followed by further separation and purification steps, such as chromatography (e.g., flash column chromatography, high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC), etc.), crystallization, trituration, filtration, lyophilization, etc.

[0230] Equivalent It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the disclosed compounds, compositions, kits, and methods will be apparent and may be made using suitable equivalents without departing from the scope of the disclosure or embodiments. Certain compounds, compositions, kits, and methods have been described in detail herein and will be more clearly understood by reference to the following examples, which are presented for illustrative purposes only and are not intended to be limiting. EXAMPLES

[0231] Materials and Methods Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without purification.

[0232] Preparation and analysis methods LC / MS data (ESI+) were determined on a Waters Alliance 2695 HPLC / MS (Waters Symmetry C18, 4.6 × 75 mm, 3.5 μm) or (Phenomenex C18, 4.6 × 75 mm, 3.0 μm) equipped with a 2996 diode array detector (210-400 nm); the solvent system was 5-95% acetonitrile (MeCN) in water (with 0.1% trifluoroacetic acid (TFA)) over 9 min using a linear gradient, with retention times in minutes. Mass spectrometry was performed on a Waters ZQ using electrospray in positive mode.

[0233] LC / MS data (ESI-) were determined on a Shimadzu Prominence HPLC / MS (Phenomenex Luna C18, 3.0 × 50 mm, 3 μm) equipped with a 2996 diode array detector (210-400 nm); the solvent system was 5-95% MeCN in water (with 0.1% formic acid) over 5 min using a linear gradient, and retention times are in minutes. Mass spectrometry was performed on an Applied Biosystems MDS Sciex API 2000 using electrospray in negative mode. Alternatively, LC / MS data (ESI-) were determined on a Waters Alliance 2695 HPLC / MS (Phenomenex C18, 4.6 × 75 mm, 3.0 μm) equipped with a 2996 diode array detector (210-400 nm); the solvent system was 5-95% MeCN in water (with 0.1% formic acid) over 9 min using a linear gradient, and retention times are in minutes. Mass spectrometry was performed on a Waters ZQ using electrospray in positive mode.

[0234] HRMS data were determined on a Bruker micrOTOF II by The University of Notre Dame Mass Spectrometry & Proteomics Facility.

[0235] Preparative reversed-phase HPLC was performed on a Waters Sunfire column (19 x 50 mm, C18, 5 μm) using a 10 min mobile phase gradient of 10% acetonitrile / water to 90% acetonitrile / water, 0.1% TFA as buffer, and detection wavelengths of 214 nm and 254 nm. Injection and fraction collection were performed on a Gilson 215 liquid handling system using Trilution LC software.

[0236] NMR spectra were recorded on a Varian Oxford 300 MHz in CDCl3 unless otherwise stated. Chemical shifts (δ) are expressed in ppm downfield from tetramethylsilane (TMS).

[0237] Purity is generally 95% or greater by NMR or LCMS unless otherwise noted.

[0238] Example 1. Synthesis of compound 404. [ka] A 250 mL three-neck flask equipped with an overhead stirrer, drying tube, and addition funnel was charged with ganaxolone (1.01 g, 3.04 mmol) and 30 mL of 1,2-dichloroethane to produce a thick slurry. To this was charged DMAP (0.74 g, 6.04 mmol), which caused the reaction mixture to clear. To this was added Et 3 N (2.55 mL, 13.28 mmol) was charged to produce a clear solution which was stirred at ambient temperature for 15 minutes. A solution of chloroacetic anhydride (5.18 g, 30.3 mmol) dissolved in 35 mL of 1,2-DCE was added via addition funnel over 15 minutes. Upon addition, the reaction immediately turned to a neon yellow solution, then a slurry, and finally a dark brown solution. The reaction was allowed to stir for 1 hour and then quenched with 100 mL of 1 M HCl. The mixture was allowed to stir for 5 minutes. The phases were separated and the lower organic layer was washed with Na 2 SO 4 The mixture was dried at rt for approximately 30 min, concentrated, and dried on a high vacuum pump to a dark semi-solid material. The solid was dissolved in 10 mL of DCM and then concentrated onto silica gel. The resulting brown solid was dried under high vacuum for 30 min. A 20 gram silica cartridge was then prepared for use and a gradient of 0-5% EtOAc / Hexanes was run for 10 volumes, followed by a hold at 5% for 15 volumes. After the hold, the EtOAc gradient was increased to 100% followed by a hold of 5 volumes. Concentration of the product containing fractions afforded compound 404 as a solid (1.1439 g). HRMS (ESI+): C 24 H 38 ClO 3 Calculated m / z [M+H] + : 409.2504, measured value 409.2517; 1H NMR 300MHz DMSO, d6 δ: 3.98-4.05 (s, 2H), 2.47-2.58 (m, 1H), 2.09-2.30 (m, 4H), 1.89-2.06 (m, 2H), 1.47-1.77 (m, 10H), 1.90-1.46 (m, 10H), 0.69-1.03 (m, 5H), 0.57-0.67 (m, 3H).

[0239] Example 2. Synthesis of Compound 100 [ka] 1-(2-Methoxyphenyl)-piperazine (12.9 mg, 0.07 mmol) and K 2 CO 3 To a solution of 404 (10 mg, 0.07 mmol) in MeCN (0.55 mL) was added compound 404 (25 mg, 0.06 mmol) and the contents were stirred overnight and heated to 50° C. After the reaction was deemed complete by TLC, 0.5 M HCl (15 mL) was added followed by ethyl acetate (15 mL). The organic layer was separated and washed with water (15 mL) and brine (15 mL) and diluted with Na 2 SO 4 The organic layer was decanted and the solvent removed in vacuo. The crude product was purified by column chromatography using an ISCO™ chromatography system. The resulting free base was treated with 2.0 M HCl / diethyl ether (2 mL) and the solvent removed in vacuo to give compound 100 as a solid (44.7 mg). LCMS (ESI+): RT = 5.55 min, (M+H)+ = 565.55;HRMS (ESI+): C 35 H 53 N 2 O 4 Calculated m / z [M+H] + : 565.4000, measured value 565.4003; 1 H NMR 300MHz CD 3OD δ: 6.87 - 7.13 (m, 4 H), 4.21 (s, 2 H), 3.85 (s, 3 H), 3.44-3.67 (m, 4 H), 3.14-3.39 (m, 4 H, consistent with solvent), 2.54-2.63 (br. s, 1 H), 2.10 - 2.30 (m, 2 H), 2.09 (s, 3 H), 1.84 - 2.07 (m, 2 H), 1.57 - 1.77 (m, 5 H), 1.55 (s, 3 H), 1.09 - 1.52 (m, 11 H), 0.85 - 1.06 (m, 1 H), 0.83 (s, 3 H), 0.74 (m, 1 H), 0.59 (s, 3 H).

[0240] Example 3. Synthesis of Compound 101 [ka] Following a similar procedure as outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine for morpholine, compound 101 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 460.36;HRMS (ESI+) C 28 H 46 NO 4 Calculated m / z [M+H] + : 460.3421, measured value 460.3416; 1 H NMR δ: 4.03-4.22 (br. s, 4 H), 3.77 (s, 2 H), 3.38 - 3.52 (br. s, 4 H), 2.48-2.57 (br. s, 1 H), 2.15 - 2.29 (m, 2 H), 2.11 (s, 3 H), 1.80 - 2.06 (m, 2 H), 1.54 - 1.75 (m, 5 H), 1.53 (s, 3 H), 1.12 - 1.49 (m, 11 H), 0.82 - 1.11 (m, 1 H), 0.77 (s, 3 H), 0.69-0.75 (m, 1 H), 0.60 (s, 3 H).

[0241] Example 4. Synthesis of Compound 102 [ka] Following a similar procedure as outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine for methylpiperazine, compound 102 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 473.39; HRMS (ESI+) C 29 H 49 N 2 O 3 Calculated m / z [M+H]+: 473.3738, found 473.3732; 1 H NMR (CD 3 OD) δ: 3.83 (s, 2 H), 3.12-3.62 (m, 8 H, consistent with solvent), 2.94 (s, 3 H), 2.54-2.62 (br. s, 1 H), 2.10-2.28 (m, 2 H), 2.08 (s, 3 H), 1.82 - 2.05 (m, 2 H), 1.52 - 1.75 (m, 5 H), 1.50 (s, 3 H), 1.08 - 1.48 (m, 11 H), 0.83 - 1.06 (m, 1 H), 0.81 (s, 3 H), 0.68-0.79 (m, 1 H), 0.58 (s, 3 H).

[0242] Example 5. Synthesis of Compound 103 [ka] Following a similar procedure as outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine for glycine ethyl ester, compound 103 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 476.45; HRMS (ESI+) C 28 H 46 NO 5 Calculated m / z [M+H] + : 476.3370, measured value 476.3362; 1 H NMR CD 3OD δ: 4.30 (q, J=7.4 Hz, 2 H), 4.00 (s, 2 H), 3.98 (s, 2 H), 2.59 (t, J=8.4 Hz, 1 H), 2.10 - 2.25 (m, 2 H), 2.09 (s, 3 H), 1.85 - 2.06 (m, 2 H), 1.54 - 1.76 (m, 5 H), 1.52 (s, 3 H), 1.08 - 1.50 (m, 14 H), 0.84 - 1.02 (m, 1 H), 0.82 (s, 3 H), 0.64-0.80 (m, 1 H), 0.59 (s, 3 H).

[0243] Example 6. Synthesis of Compound 104 [ka] Following a similar procedure as outlined in Example 2, substituting N-(2-methoxyethyl)methylamine for 1-(2-methoxyphenyl)-piperazine, compound 104 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 462.36;HRMS (ESI+) C 28 H 48 NO 4 Calculated m / z [M+H] + : 462.3578, measured value 462.3566; 1 H NMR CD 3 OD δ: 4.09-4.23 (br. s., 2 H), 3.75 (t, J=5.0 Hz, 2 H), 3.43 - 3.54 (br. s, 2 H), 3.41 (s, 3 H), 2.99 (s, 3 H), 2.60 (t, J=9.08 Hz, 1 H), 2.12 - 2.29 (m, 2 H), 2.10 (s, 3 H), 1.85 - 2.08 (m, 2 H), 1.55 - 1.79 (m, 5 H), 1.54 (s, 3 H), 1.11 - 1.53 (m, 11 H), 0.86 - 1.05 (m, 1 H), 0.84 (s, 3 H), 0.65 - 0.82 (m, 1 H), 0.61 (s, 3 H).

[0244] Example 7. Synthesis of Compound 105 [ka] Following a similar procedure as outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine for sarcosine ethyl ester, compound 105 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 490.41; 1 H NMR CD 3 OD δ: 4.33 (q, J=7.0 Hz, 2 H), 4.20 (s, 4 H), 3.05 (s, 3 H), 2.60 (t, J=8.6 Hz, 1 H), 2.12 - 2.29 (m, 2 H), 2.10 (s, 3 H), 1.87 - 2.08 (m, 2 H), 1.56 - 1.82 (m, 5 H), 1.55 (s, 3 H), 1.13 - 1.54 (m, 14 H), 0.86 - 1.07 (m, 1 H), 0.84 (s, 3 H), 0.69 - 0.83 (m, 1 H), 0.60 (s, 3 H).

[0245] Example 8. Synthesis of Compound 106 [ka] Following a similar procedure as outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine for D-alanine methyl ester hydrochloride, compound 106 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 476.31; HRMS (ESI+) C 28 H 46 NO 5 Calculated m / z [M+H] + : 476.3370, measured value 476.3376; 1 H NMR CD 3OD δ: 4.15 (q, J=7.0 Hz, 1 H), 3.98 (d, J=2.3 Hz, 2 H), 3.86 (s, 3 H), 2.60 (t, J=8.8 Hz, 1 H), 2.12 - 2.28 (m, 2 H), 2.10 (s, 3 H), 1.87 - 2.08 (m, 2 H), 1.55 - 1.78 (m, 8 H), 1.54 (s, 3 H), 1.12 - 1.53 (m, 11 H), 0.87 - 1.06 (m, 1 H), 0.84 (s, 3 H), 0.74 - 0.82 (m, 1 H), 0.60 (s, 3 H).

[0246] Example 9. Synthesis of Compound 107 [ka] Following a similar procedure as outlined in Example 2, substituting aminoethanol for 1-(2-methoxyphenyl)-piperazine, compound 107 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 434.16;HRMS (ESI+) C 26 H 44 NO 4 Calculated m / z [M+H] + : 434.3265, measured value 434.3258; 1 H NMR CD 3 OD δ: 3.95 (s, 2 H), 3.81 (t, J=5.2 Hz, 2 H), 3.18 (t, J=5.0 Hz, 2 H), 2.60 (t, J=8.8 Hz, 1 H), 2.12 - 2.28 (m, 2 H), 2.10 (s, 3 H), 1.88 - 2.08 (m, 2 H), 1.55 - 1.77 (m, 5 H), 1.53 (s, 3 H), 1.11 - 1.52 (m, 11 H), 0.88 - 1.06 (m, 1 H), 0.84 (s, 3 H), 0.74 - 0.82 (m, 1 H), 0.60 (s, 3 H).

[0247] Example 10. Synthesis of Compound 108 [ka] Following a similar procedure as outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine for L-valine methyl ester, compound 108 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 504.30;HRMS (ESI+) C 30 H 50 NO 5 Calculated m / z [M+H] + : 504.3684, measured value 504.3695; 1 H NMR CD 3 OD δ: 4.03 (d, J=3.5 Hz, 1 H), 3.98 (s, 2 H), 3.88 (s, 3 H), 2.61 (t, J=8.8 Hz, 1 H), 2.31 - 2.46 (m, 1 H), 2.13 - 2.30 (m, 2 H), 2.11 (s, 3 H), 1.86 - 2.09 (m, 2 H), 1.55 - 1.79 (m, 5 H), 1.54 (s, 3 H), 1.17 - 1.53 (m, 11 H), 1.14 (d, J=7.0 Hz, 3 H), 1.07 (d, J=7.0 Hz, 3 H), 0.87 - 1.02 (m, 1 H), 0.84 (s, 3 H), 0.65 - 0.83 (m, 1 H), 0.60 (s, 3 H).

[0248] Example 11. Synthesis of Compound 109 [ka] Following a similar procedure as outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine for glycine tert-butyl ester, compound 109 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 504.23;HRMS (ESI+) C 30 H 50 NO 5Calculated m / z [M+H] + : 504.3684, measured value 504.3673; 1 H NMR δ: 3.39 - 3.50 (m, 4 H), 2.75-2.90 (br. s, 1 H), 2.51 (t, J=9.1 Hz, 1 H), 2.11 - 2.26 (m, 2 H), 2.10 (s, 3 H), 1.82 - 2.09 (m, 2 H), 1.51 - 1.73 (m, 5 H), 1.49 (s, 3 H), 1.48 (s, 9 H), 1.04 - 1.46 (m, 11 H), 0.82 - 1.02 (m, 1 H), 0.76 (s, 3 H), 0.64 - 0.75 (m, 1 H), 0.59 (s, 3 H).

[0249] Example 12. Synthesis of Compound 110 [ka] Following a similar procedure as outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine for glycine methyl ester, compound 110 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 462.29; HRMS (ESI+) C 27 H 44 NO 5 Calculated m / z [M+H] + : 462.3214, measured value 462.3207; 1 H NMR δ: 4.03 (s, 2 H), 4.00 (s, 2 H), 3.86 (s, 3 H), 2.61 (t, J=8.8 Hz, 1 H), 2.13 - 2.28 (m, 2 H), 2.11 (s, 3 H), 1.88 - 2.08 (m, 2 H), 1.56 - 1.80 (m, 5 H), 1.54 (s, 3 H), 1.14 - 1.54 (m, 11 H), 0.87 - 1.07 (m, 1 H), 0.84 (m, 3 H), 0.72 - 0.82 (m, 1 H), 0.60 (s, 3 H).

[0250] Example 13. Synthesis of Compound 300 [ka] To a solution of BOC-cysteamine (23.8 mg, 0.13 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (20.5 mg, 0.13 mmol), and NaI (9.2 mg, 0.06 mmol) in MeCN (2 mL) was added compound 404 (50 mg, 0.12 mmol). The contents were stirred overnight at ambient temperature. After the reaction was deemed complete by TLC, the mixture was diluted with saturated NH 4 A 1:1 mixture of aqueous Cl and water (7 mL) was added, followed by dichloromethane (DCM) (9 mL). The organic layer was separated and washed with 1:1 NH 4 Cl: Wash with water (9 mL) and add Na 2 SO 4 The aqueous phase from the extraction was washed with DCM (9 mL) and then separated and diluted with Na 2 SO 4 The extract was dried at 40° C. and filtered through a phase separator column as described above. The organic layers were combined and the solvent removed in vacuo. The crude product was purified by column chromatography using an ISCO™ chromatography system to give compound 300 as an oil (61.6 mg). LCMS (ESI+): RT = 7.91 min, (M+H)+ = 550.45;HRMS (ESI+): C 31 H 51 NNaO 5 Calculated m / z for S [M+H] + : 572.3380, measured value 572.3371; 1H NMR 300 MHz δ: 4.92-5.05 (br. s, 1 H), 3.28 - 3.50 (m, 2 H), 3.18 (s, 2 H), 2.77 (t, J=6.1, 2 H), 2.53 (t, J=8.8, 1 H), 2.13 - 2.25 (m, 2 H), 2.11 (s, 3 H), 1.88 - 2.03 (m, 2 H), 1.49 - 1.74 (m, 5 H), 1.48 (s, 3 H), 1.45 (s, 9 H), 1.08 - 1.43 (m, 11 H), 0.83 - 1.01 (m, 1 H), 0.77 (s, 3 H), 0.68 - 0.75 (m, 1 H), 0.60 (s, 3 H).

[0251] Example 14. Synthesis of Compound 301 [ka] 2-Mercaptoethanol (57.3 mg, 0.73 mmol) and K 2 CO 3 To a solution of (101 mg, 0.73 mmol) in MeCN (2 mL) was added compound 404 (200 mg, 0.49 mmol). The contents were stirred overnight and heated to 50 °C. After the reaction was deemed complete by TLC, saturated NH 4 A 1:1 mixture of aqueous Cl and water (7 mL) was added, followed by DCM (9 mL). The organic layer was separated and washed with 1:1 NH 4 Cl: Wash with water (9 mL) and add Na 2 SO 4 The aqueous phase from the extraction was washed with DCM (9 mL) and then separated and diluted with Na 2 SO 4The extract was dried at 40° C. and filtered through a phase separator column as described above. The organic layers were combined and the solvent removed in vacuo. The crude product was purified by column chromatography using an ISCO™ chromatography system to give compound 301 as a solid (177 mg). LCMS (ESI+): RT = 6.86 min, (M+H)+ = 451.25;HRMS (ESI+): m / z calculated for C26H42NaO4S [M+H] + : 473.2696, measured value 473.2692; 1 H NMR 300 MHz δ: 3.78 (t, J=5.5 Hz, 2 H), 3.22 (s, 2 H), 2.84 (t, J=5.5 Hz, 2 H), 2.52 (t, J=8.8 Hz, 1 H), 2.13-2.24 (m, 2 H), 2.11 (s, 3 H), 1.90-2.07 (m, 2 H), 1.51 - 1.73 (m, 6 H), 1.48 (s, 3 H), 1.09 - 1.47 (m, 11 H), 0.83 - 1.00 (m, 1 H), 0.77 (s, 3 H), 0.66 - 0.76 (m, 1 H), 0.60 (s, 3 H).

[0252] Example 15. Synthesis of Compound 302 [ka] A solution of compound 300 (43.2 mg, 0.08 mmol) in 4N HCl / dioxane (1 mL) was vigorously stirred at ambient temperature for 10 min. The mixture was diluted with DCM (9 mL) and then with water (8 mL). The organic layer was separated, washed with brine (9 mL) and concentrated to 10 mL. 2 SO 4 The aqueous layer was washed with DCM (9 mL) and then separated and diluted with Na 2 SO 4The organic layers were combined and the solvent removed in vacuo, then lyophilized to remove residual dioxane. Compound 302 was isolated as a solid (HCl salt; 30.7 mg). LCMS (ESI+): RT = 5.64 min, (M+H)+ = 450.25;HRMS (ESI+): C 26 H 44 NO 3 Calculated m / z for S [M+H] + : 450.3036, measured value 450.3042; 1 H NMR 300 MHz CD3OD δ: 3.33 (s, 2 H), 3.15 (t, J=6.7 Hz, 2 H), 2.91 (t, J=6.7 Hz, 2 H), 2.61 (t, J=9.1 Hz, 1 H), 2.13 - 2.24 (m, 2 H), 2.11 (s, 3 H), 1.87 - 2.08 (m, 2 H), 1.49 - 1.83 (m, 5 H), 1.48 (s, 3 H), 1.13 - 1.48 (m, 11 H), 0.86 - 1.06 (m, 1 H), 0.83 (s, 3 H), 0.63-0.82 (m, 1 H), 0.60 (s, 3 H).

[0253] Example 16. Preparation of Compound 303 [ka] To a solution of morpholin-4-yl-acetic acid (184 mg, 1.3 mmol), N,N'-diisopropylcarbodiimide (479 mg, 3.8 mmol), and 4-(dimethylamino)pyridine (464 mg, 3.8 mmol) in DCM (4 mL) was added compound 301 (190 mg, 0.42 mmol). The contents were stirred overnight at ambient temperature. After the reaction was deemed complete by TLC, the mixture was diluted with saturated NH 4 A 1:1 mixture of aqueous Cl and water (18 mL) was added, followed by DCM (14 mL). The organic layer was separated and washed with 1:1 NH 4 Cl: Wash with water (18 mL) and add Na 2 SO 4The aqueous phase from the extraction was washed with DCM (18 mL) and then separated and diluted with Na 2 SO 4 The extract was dried at 40° C. and filtered through a phase separator column as described above. The organic layers were combined and the solvent removed in vacuo. The crude product was purified by column chromatography using an ISCO™ chromatography system, followed by further purification using a Gilson™ Semi Prep HPLC system to give compound 303 as a solid (TFA salt; 166 mg). LCMS (ESI+): RT = 5.51 min, (M+H)+ = 578.34;HRMS (ESI+): C 32 H 52 NO 6 Calculated m / z for S [M+H] + : 578.3510, measured value 578.3504; 1 H NMR 300 MHz CD3OD δ: 4.48 (t, J=6.5 Hz, 2 H), 4.24 (s, 2 H), 3.88-4.00 (br. s, 4 H), 3.35-3.50 (br. s, 4 H), 3.27 (s, 2 H), 2.96 (t, J=4.7, 2 H), 2.61 (t, J=9.1 Hz, 1 H), 2.12 - 2.22 (m, 2 H), 2.11 (s, 3 H), 1.88 - 2.07 (m, 2 H), 1.48 - 1.77 (m, 5 H), 1.47 (s, 3 H), 1.15 - 1.45 (m, 11H), 0.86 - 1.05 (m, 1 H), 0.83 (s, 3 H), 0.72 - 0.81 (m, 1 H), 0.60 (s, 3 H).

[0254] Example 17: Synthesis of Compound 200 [ka] Compound 404 (75.6 mg, 0.18 mmol), 4-morpholineacetic acid (125 mg, 0.95 mmol) and sodium iodide (46.7 mg, 0.31 mmol) were added to anhydrous DMF (3 mL) to give a clear orange solution. The solution was stirred at ambient temperature for 15 min. After 15 min, Cs 2 CO 3 (292 mg, 0.90 mmol) was added and the resulting mixture was heated to 70° C. and allowed to stir overnight. The reaction mixture was cooled and diluted with 25 mL of EtOAc and then quenched with 15 mL of water. The layers were separated and the EtOAc layer was diluted with 15 mL of saturated NaHCO 3 Wash twice with Na 2 SO 4 The mixture was dried at rt for 30 min, filtered and concentrated to give a clear orange oil. The crude mixture was purified by column chromatography. The oil was dissolved in DCM and stripped onto silica gel. The silica gel was dried under high vacuum for 15 min, then loaded onto a 4 gram cartridge and eluted using EtOAc in hexanes isocratically run at 25% EtOAc, then a gradient increasing to 50%, then a gradient increasing to 100% EtOAc. Compound 200 (free base; 81.1 mg) was obtained as an oil. HRMS (ESI+): m / z calculated for C30H48NO6 [M+H] + : 518.3476, measured value 518.3484; 1 H NMR 300MHz δ: 4.50-4.68 (m, 2H), 3.71-3.83 (m, 4H), 3.29-3.38 (m, 2H), 2.58-2.73 (m, 4H), 2.45-2.57 (m, 1H), 2.06-2.30 (m, 6H), 1.94-2.05 (m, 1H), 1.86 (dd, J=11.14 Hz, 2.34 Hz, 1H),1.05-1.76 (m, 19H), 0.71-1.03 (m, 4H), 0.57-0.65 (m, 3H).

[0255] Compound 200 (free base; 42.4 mg, 0.08 mmol) was dissolved in 2 mL of Et 2 2M HCl in Et 2O to give a clear solution and stirred for 5 min.2 HO (50 μL, 0.1 mmol) was added and a white precipitate formed. The reaction was allowed to stir for 10 min. The precipitate was isolated by filtration and washed with 5 mL of Et 2 O. The solid was then placed under high vacuum and dried overnight to give compound 200 HCl salt. HRMS (ESI+): 30 H 48 NO 6 Calculated m / z [M+H] + : 518.3476, measured value 518.3484; 1 H NMR 300MHz δ: 4.58-4.81 (m, 2H), 4.02-4.36 (m, 3H), 3.94 (br. s., 2H), 3.40-3.61 (m, 4H), 2.53 (t, J = 8.76 Hz, 1H), 2.08-2.28 (m, 5H), 1.95-2.07 (m, 1H), 1.86 (d, J = 8.79 Hz, 1H), 1.08-1.78 (m, 19 H), 0.74-1.04 (m, 4H), 0.59-0.73 (m, 4H).

[0256] Example 18: Synthesis of Compound 202 [ka] Following a similar procedure as outlined in Example 17, substituting dimethylglycine for 4-morpholineacetic acid, compound 202 was obtained as the HCl salt. HRMS (ESI+) C 28 H 46 NO 5 Calculated m / z [M+H] + : 476.3370, measured value 476.3372; 1 H NMR δ:Free base) δ: 4.45-4.75 (m, 2H), 3.29 (s, 2H), 2.28-2.72 (m, 4H), 1.76-2.28 (m, 5H), 1.02-1.75 (m, 23H), 0.67-1.02 (M, 6H), 0.58 (s, 3H).

[0257] Example 19: Synthesis of Compound 203 [ka] Following the procedure outlined in Example 17 (without the step to form the HCl salt), 4-morpholineacetic acid was replaced with 3-ethoxypropionic acid to give compound 203. HRMS (ESI+) C 29 H 46 NaNO 6 Calculated m / z [M+H] + : 513.3187, measured value 513.3198; 1 H NMR δ: 4.46-4.64 (m, 2H), 3.66-3.81 (m, 2H), 3.43-3.59 (m, 2H), 2.63-2.77 (m, 2H), 2.45-2.57 (m, 1H), 2.05-2.29 (m, 5H), 1.93-2.04 (m, 1H), 1.81-1.92 (m, 1H), 1.05-1.73 (m, 22H), 0.71-1.00 (m, 5H), 0.51-0.66 (s, 3H).

[0258] Example 20: Synthesis of Compound 204 [ka] Following the procedure outlined in Example 17 (without the step to form the HCl salt), compound 204 was obtained by replacing 4-morpholineacetic acid with 2-(2-methoxyethoxy)acetic acid. HRMS (ESI+) C 29 H 46 NaNO 7 Calculated m / z [M+H] + : 529.3136, measured value 529.3137; 1H NMR δ: 4.54-4.72 (m, 2H), 4.27 (s, 2H), 3.71-3.83 (m, 2H), 3.56-3.69 (m, 2H), 3.33-3.47 (m, 3H), 2.44-2.59 (m, 1H), 2.07-2.28 (m, 5H), 1.82-2.05 (m, 2H), 1.07-1.76 (m, 19H), 0.70-1.01 (m, 5H), 0.58 (s, 3H).

[0259] Example 21: Synthesis of Compound 205 [ka] Following the procedure outlined in Example 17 (without the step to form the HCl salt), compound 205 was obtained by substituting 2-[2-(2-methoxyethoxy)ethoxy]acetic acid for 4-morpholineacetic acid. HRMS (ESI+) C 31 H 50 NaO 8 Calculated m / z [M+H] + : 573.3398, measured value 573.3399; 1 H NMR δ: 4.51-4.69 (m, 2H), 4.25 (s, 2H), 3.50-3.86 (m, 8H), 3.36 (s, 3H), 2.46-2.55 (m, 1H), 2.06-2.27 (m, 6H), 1.97 (d, J =11.72 Hz, 1H), 1.86 (d, J = 11.14 Hz, 2H), 1.09-1.73 (m, 18H), 0.71-1.01 (m, 4H), 0.57 (s, 3H).

[0260] Example 22: Synthesis of Compound 206 [ka] Following the procedure outlined in Example 17 (without the step to form the HCl salt), compound 206 was obtained by replacing 4-morpholineacetic acid with N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucine. HRMS (ESI+) C 44 H 67 N 2 O 8 Calculated m / z [M+H] + : 751.489194, measured value 751.489134; 1 H NMR δ: 7.22-7.42 (m, 5H), 6.52 (d, J = 7.62 Hz, 1H), 5.35 (d, J = 8.21 Hz, 1H), 5.08 (s, 2H), 4.55-4.73 (m, 2H), 4.20-4.24 (m, 1H), 2.41-2.56 (m, 1H), 1.83-2.27 (m, 8H), 1.08-1.78 (m, 24H), 0.83-1.00 (m, 13H), 0.67-0.80 (m, 4H), 0.57 (s, 3H).

[0261] Example 23: Synthesis of Compound 207 [ka] Following the procedure outlined in Example 17 (without the step to form the HCl salt), 4-morpholineacetic acid was replaced with CBz-L-Ala-Gly-OH to give compound 207. HRMS (ESI+) C 37 H 53 N 2 O 8 Calculated m / z [M+H] + : 653.379643, measured value 653.378352; 1H NMR δ: 7.28-7.45 (m, 5H), 6.74 (br. s. 1H), 5.44 (d, J = 6.45 Hz, 1H), 5.03-5.23 (m, 2H), 4.51-4.68 (m, 2H), 4.24-4.41 (m, 1H), 4.10-4.24 (m, 2H), 2.46-2.59 (m, 1H), 2.07-2.30 (m, 5H), 1.85-2.04 (m, 2H), 1.07-1.77 (m, 20H), 0.83-1.02 (m, 1H), 0.68-1.04 (m, 7H), 0.59 (s, 3H).

[0262] Example 24: Synthesis of Compound 208 [ka] Following a similar procedure as outlined in Example 17, substituting 4-methyl-1-piperazineacetic acid for 4-morpholineacetic acid, compound 208 was obtained as the bis-HCl salt. HRMS (ESI+) C 31 H 51 N 2 O 5 Calculated m / z [M+H] + : 531.379249, measured value 531.378222; 1 H NMR (MeOD) δ: 4.88-5.00 (m, 4H), 4.73-4.85 (m, 2H), 4.29-4.43 (m, 2H), 3.02 (s, 3H), 2.63 (t, J = 8.79 Hz, 1H), 1.98-2.27 (m, 7H), 1.86-1.95 (m, 1H), 1.13-1.78 (m, 23H), 0.92-1.08 (m, 2H), 0.73-0.86 (m, 4H), 0.60 (s, 3H).

[0263] Example 25: Synthesis of Compound 201 [ka] To a suspension of compound 404 (72.1 mg, 0.18 mmol), trifluoroacetic acid (100 mg, 0.88 mmol) and sodium iodide (30 mg, 0.20 mmol) was added 3 mL of anhydrous DMF to give a clear orange solution. The solution was allowed to stir at ambient temperature for 15 min. After 15 min, Cs 2 CO 3 (278 mg, 0.85 mmol) was added and the resulting mixture was heated to 70° C. After stirring for 18 h, the reaction was cooled and diluted with 25 mL of EtOAc and then quenched with 15 mL of water. After separation of the layers, the EtOAc layer was diluted with 15 ml of saturated NaHCO 3 Wash twice with Na 2 SO 4 The crude mixture was purified by column chromatography. The oil was dissolved in DCM and stripped onto silica gel. The silica gel was dried under high vacuum for 30 min, then loaded onto a 4 gram cartridge and eluted with EtOAc in hexanes, running 0-10% EtOAc for 10 volumes, holding at 10% for 10 volumes, then increasing the gradient to 50%, then a final gradient to 100% EtOAc. Compound 201 (73.3 mg) was obtained as a crystalline solid. HRMS (ESI+): C 24 H 38 NaNO 4 Calculated m / z [M+H] + : 413.2662,Measured value 413.2662; 1 H NMR 300MHz CDCl3 δ: 4.04-4.11 (m, 2H), 2.52 (t, J=9.08 Hz, 1H), 2.38-2.45 (m, 1H), 2.08-2.27 (m, 5H), 1.89-2.05 (m, 2H), 1.05-1.73 (m, 20H), 0.87-1.01 (m, 1H), 0.67-0.80 (m, 4H), 0.59 (s, 3H).

[0264] Example 26: Synthesis of Compound 500 [ka] Ganaxolone (2.53 g, 7.61 mmol) was added to a solution of 75 mL of DMSO and acetic anhydride (26 mL, 275.05 mmol) to give a thin slurry. To this slurry was added acetic acid (0.5 mL, 8.73 mmol) and the reaction was stirred at room temperature overnight to give a clear solution. The reaction was diluted with 300 mL of EtOAc and then washed with 75 mL of H 2 O. The mixture was stirred and allowed to settle. The lower aqueous layer was allowed to drip and the process was repeated a total of four times. The washed organics were dried over sodium sulfate, filtered and concentrated to give a clear light yellow oil that was dried under vacuum. The crude reaction mixture was purified by column chromatography. The oil was loaded onto an 80 gram cartridge eluting with 0.5%-3% EtOAc / Hexanes. The desired fractions were combined and concentrated. After drying under vacuum, compound 500 was obtained as a solid (2.31 g). HRMS (ESI+): m / z calculated for C24H41O2S [M+H] + : 393.2822, measured value 393.2830; 1 H NMR 300MHz CDCl3 δ: 4.36-4.50 (m, 2H), 2.46-2.57 (m, 1H), 2.06-2.23 (m, 7H), 1.94-2.06 (m, 2H), 1.10-1.79 (m, 22H), 0.83-1.01 (m, 1H), 0.70-0.81 (m,4H), 0.59 (s,3H).

[0265] Example 27: Synthesis of Compound 503 [ka] To a solution of compound 500 (107 mg, 0.27 mmol), 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (60.4 mg, 0.34 mmol) and 3 mL of dichloromethane was added 4A molecular sieves (0.25 g) to give a thick white slurry. The reaction was cooled to 0° C. in an ice bath and the Bu 4 NBr (0.1 mg, 0.31 mmol) was added, followed by CuBr 2 (68.5 mg, 0.31 mmol) was added. 2Upon addition of the hexanes, the reaction turned deep purple. The reaction was allowed to warm to ambient temperature. After stirring for 18 h, the reaction was diluted with 25 mL of EtOAc and then filtered to remove the molecular sieves. The sieves were washed with 15 mL of EtOAc. The combined organic phase was then washed with 15 mL of saturated NaHCO 3 The organic phase was washed twice with 15 mL of saturated NaCl solution. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give a clear orange oil. The crude mixture was purified by column chromatography. The oil was purified by CH 2 Cl 2 The eluate was dissolved in hexane and stripped onto silica gel. The silica gel was dried under high vacuum for 30 minutes, then loaded onto a 4 gram cartridge and eluted with EtOAc in hexane, 15% EtOAc, hold for 10 volumes, then ramped to 100 for 5 volumes, hold for 10 volumes. Compound 503 (57.3 mg) was obtained as an oil. HRMS (ESI+): C 30 H 50 NaO 7 Calculated m / z [M+H] + : 545.3449, measured value 545.3448; 1 H NMR 300MHz CDCl3 δ: 5.33-5.44 (m, 2H), 4.10 (s, 2H), 3.59-3.77 (m, 6H), 3.49-3.57 (m, 2H), 3.34 (s, 3H), 2.44-2.55 (m, 1H), 2.05-2.18 (m, 4H), 1.91-2.01 (m, 1H), 1.09-1.77 (m, 21H), 0.97-1.08 (m, 1H), 0.70-0.96 (m, 4H), 0.55 (s, 3H).

[0266] Example 28: Synthesis of Compound 502 [ka] Following the procedure outlined in Example 27, substituting 2-[2-(2-methoxyethoxy)ethoxy]acetic acid for N-Cbz-glycine, compound 502 was obtained. HRMS (ESI+) C 33 H 47 NNaO 6 Calculated m / z [M+H] + : 576.3296, measured value 576.3287; 1 H NMR δ: 7.27-7.45 (m, 5H), 5.37-5.50 (M, 2H), 5.24-5.32 (m, 1H), 5.10-5.18 (m, 2H), 3.95-4.02 (m, 2H), 2.46-2.57 (m, 1H), 2.07-2.20 (m, 4H), 1.92-2.05 (m, 1H), 1.10-1.82 (m, 21H), 0.74-1.04 (m, 5H), 0.55-0.69 (m, 3H).

[0267] Example 29: Synthesis of Compound 209 [ka] Following the procedure outlined in Example 17 (without the step to form the HCl salt), 4-morpholineacetic acid was replaced with Cbz-L-valyl-glycine to give compound 209. HRMS (ESI+) C 39 H 57 N 2 O 8 Calculated m / z [M+H] + : 681.410943, measured value 681.411352; 1H NMR δ: 7.30-7.41 (m, 5H), 6.81 (d, J = 4.69 Hz, 1H), 5.53 (d, J = 9.38 Hz, 1H), 5.06-5.14 (m, 2H), 4.55-4.63 (m, 2H), 4.05-4.20 (m, 3H), 2.46-2.58 (m, 1H), 2.07-2.27 (m, 5H), 1.93-2.04 (m, 2H), 1.82-1.92 (m, 1H), 1.43-1.75 (m, 10H),1.08-1.43(m, 1)H), 0.89-1.07 (m, 6H), 0.71-0.84 (m, 3H), 0.57 (s, 3H).

[0268] Example 30: Synthesis of Compound 210 [ka] Following the procedure outlined in Example 17 (without the step to form the HCl salt), 4-morpholineacetic acid was replaced with Cbz-D-proline to give compound 210. HRMS (ESI+) C 37 H 52 NO 7 Calculated m / z [M+H] + : 644.355774,actual value 644.355320; 1 H NMR δ: 7.26-7.44 (m, 5H), 5.06-5.22 (m, 2H), 4.33-4.55 (m, 2H), 3.59-3.71 (m, 1H), 3.43-3.58 (m, 1H), 2.53 (t, J = 8.79 Hz, 1H), 2.16-2.30 (m, 3H), 2.11 (s, 3H), 1.80-2.04 (m, 4H), 1.10-1.74 (m, 21H), 0.83-1.02 (m, 2H), 0.76 (s 3H), 0.60 (s, 3H).

[0269] Example 31: Synthesis of Compound 211 [ka] Following the procedure outlined in Example 17, but substituting (S)-2-morpholin-4-yl-propionic acid hydrochloride for 4-morpholine acetic acid, compound 211 was obtained as the hydrochloride salt. HRMS (ESI+) C 31 H 50 NO 6 Calculated m / z [M+H] + : 532.363265, measured value 532.362510; 1 H NMR δ: 4.08-4.30 (m, 2H), 3.74-4.07 (m, 2H), 3.39-3.74 (m, 4H), 2.80-3.28 (m, 5H), 1.95-2.13 (m, 1H), 1.47-1.83 (m, 7H), 0.59-1.47 (m, 21H), 0.43 (br s, 1H), 0.19-0.36 (m, 4H), 0.04-0.19 (m, 3H).

[0270] Example 32: Synthesis of Compound 212 [ka] Following the procedure outlined in Example 17, but substituting (R)-2-morpholin-4-yl-propionic acid hydrochloride for 4-morpholine acetic acid, compound 212 was obtained as the hydrochloride salt. HRMS (ESI+) C 31 H 50 NO 6 Calculated m / z [M+H] + : 532.363265, measured value 532.363688; 1H NMR δ: 4.57-4.76 (m, 2H), 4.24-4.52 (m, 2H), 3.92-4.17 (M, 3H), 3.29-3.70 (m, 4H), 2.52 (t, J = 8.79 Hz, 1H), 2.08-2.29 (m, 5H), 2.01 (d, J = 11.14 Hz, 1H), 1.85 (d, J = 4.69 Hz, 3H), 1.53-1.76 (m, 9H), 1.49 (s, 3H), 1.04-1.47 (m, 11H), 0.87-1.03 (m, 1H), 0.69-0.82 (m, 3H), 0.60 (s, 3H).

[0271] Example 33: Synthesis of Compound 213 [ka] Following a similar procedure as outlined in Example 17, substituting α,α-dimethyl-4-morpholineacetic acid hydrochloride for 4-morpholineacetic acid, compound 213 was obtained as the hydrochloride salt. HRMS (ESI+) C 32 H 52 NO 6 Calculated m / z [M+H] + : 546.378915, measured value 546.378119; 1 H NMR δ: 4.59-4.75 (m, 2H), 4.42-4.58 (m, 2H), 3.98 (d, J = 12.31 Hz, 2H), 3.54 (br. s 4H), 2.51 (t, J = 9.08 Hz, 1H), 2.07-2.28 (m, 6H), 1.80-2.06 (m, 9H), 1.04-1.75 (m, 24H), 0.85-1.01 (m, 1H), 0.68-0.81 (m, 4H), 0.60 (s, 3H).

[0272] Example 34: Synthesis of Compound 111 [ka] Compound 404 (114 mg, 0.28 mmol) was dissolved in 5 mL of DMSO, giving a clear, nearly colorless solution after 10 min. To this solution was added ammonium hydroxide 28-30 wt % (0.25 mL, 2.07 mmol), which immediately caused a color change to red-orange. The reaction was allowed to stir at ambient temperature. After stirring for 18 h, the reaction was worked up as follows: diluted with 25 mL of EtOAc, then quenched with 15 mL of water. Transfer to a separatory funnel and dropwise add the lower aqueous portion. Add 15 mL of H 2 Extract twice with 2024, dropping the lower aqueous portion each time. The washed organic layer is then diluted with Na 2 SO 4 The mixture was dried at 4° C. for 30 min, filtered and concentrated to give a clear orange oil upon drying. The sample was dissolved in 2 mL of absolute EtOH to give a clear light brown solution. This was diluted with 2N HCl in Et 2 2H2O (0.2 mL, 0.4 mmol) was charged, causing the solution to darken, but no solids were observed. After stirring for 30 min, the reaction was placed on a rotary evaporator and the solvent removed. This formed a foam which was dried under high vacuum to give compound 111 (91.2 mg) as the hydrochloride salt. HRMS (ESI+): 24 H 41 ClNO 3 Calculated m / z [M+H] + : 390.300271, measured value 390.300526; 1 H NMR (MeOD) δ: 3.98 (d, J = 2.34 Hz, 1H), 3.25-3.42 (m, 2H overlaps with solvent), 2.61 (t, J = 8.50 Hz, 1H), 1.89-2.28 (m, 6H), 1.15-1.79 (m, 24H), 0.75-1.06 (m, 4H), 0.60 (s, 3H).

[0273] Example 35: Synthesis of Compound 112 [ka] Compound 111 (from Example 34, 31.6 mg, 0.07 mmol) and 4-morpholinylacetic acid (13.2 mg, 0.09 mmol) were added to DCM (4 mL). The mixture was cooled to 0° C. in an ice-water bath and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.10 mmol), and hydroxybenzotriazole (14.5 mg, 0.11 mmol) were added to produce a slurry that became clear upon addition of diisopropylethylamine (40 μL, 0.23 mmol). The resulting orange solution was allowed to warm to ambient temperature overnight. The reaction was diluted with 10 mL of DCM and diluted with 10 mL of H 2 The mixture was transferred to a separatory funnel and the phases were separated. The organics were then washed with 10 mL of saturated NaHCO 3 The washed organics were washed with 10 mL of NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product. The crude product was purified by column chromatography using an ISCO™ chromatography system to give compound 112 (free base) as a solid (17.1 mg). HRMS (ESI+): 30 H 49 N 2 O 5 Calculated m / z [M+H] + : 517.3636, measured value 517.3635; 1 H NMR δ: 7.57 (br. s., 1H), 3.93-4.16 (m, 3H), 3.66-3.83 (m, 5H), 3.06 (s, 2H), 2.45-2.65 (m, 6H), 1.93-2.30 (m, 9H), 1.85 (d, J = 12.89 Hz, 1H), 1.04-1.75 (m, 27H), 0.84-1.02 (m, 2H), 0.68-0.81 (m, 5H), 0.59 (s, 3H).

[0274] The resulting free base was treated with 2.0 M HCl / diethyl ether (2 mL) and the solvent removed in vacuo to give compound 112 as a solid hydrochloride salt (19.8 mg). HRMS (ESI+):30 H 49 N 2 O 5 Calculated m / z [M+H] + : 517.3636, measured value 517.3635; 1 H NMR δ: 9.07 (br. s., 1H), 4.11 (br. s., 4H), 3.96 (br. s., 4H), 3.74 (br. s., 2H), 3.28 (br. s., 2H), 2.60-2.49 (m, 1H), 2.30-2.07 (m, 6H), 2.06-1.95 (mm 2H), 1.83(d, J = 13.5 hz, 2H), 1.76-7.56 (m, 5H), 1.54-1.08 (m, 21H), 1.00 (br. s., 1H), 0.85-0.71 (m, 5H), 0.60 (s, 3H).

[0275] Example 36: Synthesis of Compound 114 [ka] Compound 404 (125 mg, 0.31 mmol) and sodium iodide (46.7 mg, 0.31 mmol) were dissolved in 3 mL of anhydrous DMF to give a clear orange solution. This solution was allowed to stir at ambient temperature for 15 min, after which a 2 M solution of methylamine in tetrahydrofuran (THF) (150 μL, 0.30 mmol) was added, followed by Cs 2 CO 3 (127.4 mg, 0.39 mmol) was added and the resulting mixture was heated to 70° C. After stirring for 2 h, the reaction was cooled and diluted with 25 mL of EtOAc and then quenched with 15 mL of water. After separation of the layers, the EtOAc layer was diluted with 15 ml of saturated NaHCO 3 The washed organic phase was washed twice with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give a clear orange oil. The crude product was purified by column chromatography using an ISCO™ chromatography system to give compound 114 (free base; 36.1 mg) as a solid. HRMS (ESI+):25 H 42 NO 3 Calculated m / z [M+H] + : 404.3159,Measured value 404.3159; 1 H NMR δ: 3.36-3.54 (m, 2H), 2.42-2.59 (m, 4H), 1.81-2.30 (m, 8H), 10.03-1.73 (m, 23H), 0.82-1.02 (m, 2H), 0.65-0.82 (m, 5H), 0.49-0.63 (m, 3H).

[0276] The free base 114 (33.6 mg, 0.08 mmol) was dissolved in diethyl ether (Et 2 2 mL) was added to give a clear solution. The solution was allowed to stir for 5 minutes. The reaction flask was filled with 2M HCl in Et 2 2H2O (50 ul, 0.100 mmol) was added, resulting in the formation of a precipitate. The reaction was stirred for an additional 10 min. The precipitate was isolated by filtration and washed with 5 mL of Et 2 O and dried under vacuum to give compound 114 as the hydrochloride salt (31.4 mg). HRMS (ESI+): m / z calculated for C25H42NO3 [M+H] + : 404.3159,Measured value 404.3159; 1 H NMR δ: 3.78 (br. s., 2H), 2.84 (br. s., 3H), 2.53 (t, J = 8.50 Hz, 1H), 2.08-2.35 (m, 5H), 2.00 (d, J = 11.14 Hz, 1H), 1.89 (d, J = 8.21 Hz, 1H), 1.07-1.78 (m, 23H), 0.97 (d, J = 8.21 Hz, 1H), 0.72-0.85 (m, 4H), 0.60 (s, 3H).

[0277] Example 37: Synthesis of Compound 115 [ka] Following a similar procedure as outlined in Example 35, compound 404 was substituted for compound 114 to give compound 115 as the hydrochloride salt (18.7 mg). HRMS (ESI+): C 31 H 51 N 2 O 5 Calculated m / z [M+H] + : 531.3792, measured value 531.3782; 1 H NMR δ: 4.25 (s, 1H), 4.17-3.95 (m, 2H), 3.66-3.86 (m, 7H), 3.25 (s, 2H), 3.22-3.12 (m, 4H), 2.98 (s, 2H), 2.58-2.52 (m, 8H), 2.40-2.09 (m, 11H), 2.07-1.80 (m, 4H), 1.79-1.08 (m, 33H), 1.03-0.75 (m, 7H), 0.74-0.57 (m, 4H).

[0278] Example 38: Synthesis of Compound 218 [ka] Following a similar procedure as outlined in Example 17, substituting 2-aminoisobutyric acid for 4-morpholineacetic acid, compound 218 (101.6 mg) was obtained as a solid. HRMS (ESI+): Calculated m / z for C28H46NO5 [M+H] + : 476.3370,Measured value 476.3370; 1 H NMR δ: 4.63-4.45 (m, 2H), 2.56-2.43 (m, 1H), 2.30-2.03 (m, 6H), 2.01-1.92 (m, 1H), 1.89-1.73 (m,4H), 1.72-1.05 (m, 29H), 1.00-0.82 (m, 1H), 0.81-0.66 (m, 4H), 0.62-0.51 (m, 3H).

[0279] Example 39: Preparation of Compound 125 [ka] Compound 404 (150 mg, 0.37 mmol) and sodium iodide (96 mg, 0.64 mmol) were added to anhydrous DMF (3 mL) to give a clear orange solution. The solution was allowed to stir at ambient temperature for 15 min, methyl 2-aminoisobutyrate·HCl (302 mg, 1.96 mmol) was added, followed by diisopropylethylamine (850 μL, 0.49 mmol) and the resulting mixture was heated to 50° C. After 22 h, the reaction was cooled. The reaction was diluted with 25 mL of EtOAc and then quenched with 15 mL of water. After separation of the layers, the EtOAc layer was washed twice with 15 mL of 1N HCl and then with 15 mL of brine. The washed organics were washed with Na 2 SO 4 The mixture was dried at rt for 30 min, filtered and concentrated to give a clear light brown oil. The crude product was purified by column chromatography using an ISCO™ chromatography system to give compound 125 (85.1 mg) as an oil. HRMS (ESI+): 29 H 48 NO 5 Calculated m / z [M+H] + : 490.3527,Measured value 490.3527; 1 H NMR δ: 3.71 (s, 3H), 3.30 (s, 2H), 2.52 (t, J = 8.8 Hz, 1H), 2.30-2.08 (m, 6H), 2.05-1.87 (m, 2H), 1.74-1.38 (m, 20H), 1.38-1.33 (m, 8H), 0.92 (dq, J = 5.3, 11.9 Hz, 1H), 0.81-0.68 (m, 4H), 0.60 (s, 3H).

[0280] Example 40: Synthesis of Compound 126 [ka] Following a similar procedure as outlined in Example 39, but substituting tert-butyl 2-amino-2-methylpropanoate·HCl (302 mg, 1.96 mmol) for methyl 2-aminoisobutyrate·HCl, compound 126 (188 mg) was obtained as a solid. HRMS (ESI+): C 32 H 54 NO 5 Calculated m / z [M+H] + : 532.3997, measured value 532.3999; 1 H NMR δ: 8.03 (s, 1H), 3.79-3.56 (m, 2H), 2.96 (s, 3H), 2.89 (s, 3H), 2.52 (t, J = 8.8 Hz, 1H), 2.31-2.08 (m, 6H), 2.04-1.88 (m, 2H), 1.78-1.11 (m, 27H), 1.06-0.89 (m, 1H), 0.85-0.73 (m, 4H), 0.60 (s, 3H).

[0281] Example 41: Synthesis of Compound 305 [ka] Following a similar procedure as outlined in Example 39, but substituting 2-mercapto-2-methylpropanoic acid methyl ester for methyl 2-aminoisobutyrate·HCl, the methyl ester compound (39.1 mg) was obtained as an oil, which was used directly in the next step without further purification. HRMS (ESI+): C 29 H 47 O 5 Calculated m / z for S [M+H] + : 507.313872, measured value 507.313659; 1H NMR δ: 3.77-3.69 (m, 3H), 3.37 (s, 2H), 2.58-2.47 (m, 1H), 2.23-2.08 (m, 6H), 2.04-1.88 (m, 2H), 1.74-1.43 (m, 21H), 1.42-1.32 (m, 4H), 1.31-1.11 (m, 8H), 0.92 (dq, J = 5.3, 11.9 Hz, 1H), 0.82-0.71 (m, 4H), 0.59 (s, 3H).

[0282] To a solution of the ester (62 mg, 0.13 mmol) in methanol (5 mL) at room temperature was added aqueous NaOH (1.0 M, 1 mL). After 18 h, the reaction was diluted with 25 mL of EtOAc and then washed with 15 mL of H 2 The mixture was quenched with O. The layers were separated and the aqueous layer was acidified to pH 1 with 2.0 mL of 2N HCl. The aqueous layer was extracted twice with 15 mL of DCM. 2 SO 4 The DCM phase was dried using, filtered and concentrated to give compound 305 as an oil (10 mg). 1 H NMR δ: 3.42 (s, 2H), 2.51 (t, J = 9.08 Hz, 1H), 2.26-2.06 (m, 6H), 2.06-1.85 (m, 3H), 1.72-1.58 (m, 4H), 1.54 (s, 6H), 1.51-1.45 (m, 5H), 1.42-1.31 (m, 5H), 1.30-1.08 (m, 10H), 1.00-0.81 (m, 2H), 0.80-0.70 (m, 4H), 0.58 (s, 3H).

[0283] Example 42: Synthesis of Compound 307 [ka] N,N-Dimethyl-1,2-ethylenediamine (38.9 mg, 0.44 mmol) and compound 305 (45 mg, 0.091 mmol) were dissolved in 4 mL of DCM. The mixture was cooled to approximately 0 °C in an ice bath and EDCI·HCl (22 mg, 0.11 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (40 μl, 0.23 mmol) were added. The resulting pale yellow solution was allowed to warm slowly to ambient temperature overnight. After 21 h, the reaction was diluted with 25 mL of EtOAc and then washed with 15 mL of H 2 The mixture was transferred to a separatory funnel and the lower aqueous portion was discarded. The organics were washed with 15 mL of saturated NaHCO 3 The organic layer was then washed with 15 ml of saturated brine. 2 SO 4 The crude product was purified by column chromatography using an ISCO™ chromatography system to give compound 307 as an oil (free base; 34.3 mg). The free base was treated with 2.0 M HCl / diethyl ether (2 mL) and the solvent was removed in vacuo to give compound 307 as a solid hydrochloride salt (38.3 mg). HRMS (ESI+): 32 H 55 N 2 O 4 Calculated m / z for S [M+H] + : 563.3863, measured value 563.3877; 1 H NMR δ: 8.10 (br. s., 1H), 3.76-3.53 (m, 3H), 3.38 (s, 2H), 3.21 (t, J = 5.0 Hz, 2H), 2.88 (s, 6H), 2.53 (t J = 9.1 Hz, 1H), 2.25-2.06 (m, 6H), 1.99 (d, J = 12.3 Hz, 1H), 1.87 (d, J = 14.1 Hz, 1H), 1.73-1.09 (m, 24H), 1.02-0.70 (m, 5H), 0.59 (s, 3H).

[0284] Example 43: Synthesis of Compound 124 [ka] Compound 110 (from Example 12; 62 mg, 0.13 mmol) was dissolved in 5 mL of MeOH. 1 mL of 1 M aqueous NaOH was added and the resulting solution was allowed to stir at ambient temperature. After 21 h, the reaction was diluted with 25 mL of EtOAc and then diluted with 15 mL of H 2 The mixture was transferred to a separatory funnel and the upper organics were discarded. The aqueous layer was then dried and acidified to pH 1 with 2.0 mL of 2N HCl. The aqueous layer was extracted twice with 15 mL of DCM. 2 SO 4 The organics were dried using HCl, filtered and concentrated to give compound 124 as an oil (58.9 mg). HRMS (ESI+): C 26 H 42 NO 5 Calculated m / z [M+H] + : 448.3027, measured value 448.3051; 1 H NMR δ: 4.01-3.88 (m, 2H), 3.68 (s, 2H), 2.62 (t, J = 8.8 Hz, 1H), 2.30-1.86 (m, 7H), 1.78-1.10 (m, 19H), 1.07-0.69 (m, 7H), 0.60 (s, 3H).

[0285] Example 44: Synthesis of Compound 304 [ka] Compound 404 (74 mg, 0.18 mmol) and sodium iodide (49 mg, 0.33 mmol) were suspended in 5 mL of 1,4 dioxane, thiourea (14.5 mg, 0.19 mmol) was added, and the mixture was then heated to 85° C. After stirring for 18 h, the reaction was cooled and diluted with 25 mL of EtOAc and then quenched with 15 mL of water. The EtOAc layer was washed with 15 mL of H 2 Wash once with 15 mL of O, then with 15 mL of brine, and 2 SO 4The solid was dried at rt and then dried in vacuum to give a yellow solid. The solid was then taken up in 10 mL of 1,4 dioxane to give a clear yellow solution. To this was added 4N HCl in 1,4 dioxane (50 ul, 0.200 mmol). The solution was allowed to stir for 15 minutes and then frozen in dry ice. The yellow solid was placed in a freeze dryer and lyophilized to give compound 304 as a solid hydrochloride salt (77.8 mg). HRMS (ESI+): Calcd for C25H41ClN2O3S m / z [M+H] + : 449.2832, measured value 449.2827; 1 H NMR δ: 9.63-8.79 (bs. s., 3H), 4.03-3.84 (s, 1H), 3.77-3.58 (m, 3H), 2.51 (q, J = 8.8 Hz, 1H), 2.26-2.02 (m, 6H), 1.51-1.06 (m, 17H), 1.51-1.06 (m, 17H), 1.04-0.78 (m, 2H), 0.76-0.69 (m, 3H), 0.56 (s, 3H).

[0286] Example 45: Synthesis of Compound 214 [ka] Compound 209 (from Example 29; 97 mg, 0.14 mmol) was dissolved in 10 mL of absolute EtOH. The solution was degassed under vacuum and then backfilled with nitrogen. This was completed three times. The solution was charged with 5% aqueous Pd / C (98.1 mg, 0.05 mmol). The dark suspension was degassed under vacuum and then backfilled with hydrogen. This was completed three times and the reaction was cooled to 10° C. 2 The reaction was allowed to stir overnight under a balloon. After stirring for 18 h, the reaction was diluted with 25 mL of EtOAc and filtered through a plug of Celite. The plug was rinsed with additional EtOAc and then concentrated to give a cloudy residue. The flask containing the residue was filled with 2 mL of Et 2 The reaction flask was filled with 2M HCl in Et 2 HO (100 μL, 0.2 mmol) was added. Upon addition of HCl, the resulting precipitate was isolated by filtration and washed with 5 mL of Et2 O. The solid was then placed under high vacuum to dry overnight to give compound 214 (57.3 mg) as the hydrochloride salt. HRMS (ESI+): 31 H 51 ClN 2 O 6 Calculated m / z [M+H] + : 547.3742, measured value 547.3731; 1 H NMR δ: 4.71-4.53 (m, 2H), 4.31-3.92 (m, 3H), 3.25 (br. s., 1H), 2.59-2.48 (m, 1H), 2.28-2.08 (m, 5H), 2.07-1.77 (m, 5H), 1.75-1.35 (m, 14H), 1.33-1.03 (m, 16H), 1.03-0.87 (m, 3H), 0.82-0.69 (m, 4H), 0.61 (s, 3H).

[0287] Example 46: Synthesis of Compound 215 [ka] Compound 209 was replaced with compound 206 (from example 22) in a similar manner to the procedure outlined in example 45 to give compound 215. HRMS (ESI+) C 36 H 61 ClN 2 O 6 Calculated m / z [M+H] + : 617.4524, measured value 617.4526; 1 H NMR δ: 4.85-4.73 (m, 1H), 4.73-4.59 (m, 2H), 4.58-4.39 (m, 1H), 2.84-2.60 (m, 1H), 2.50 (t, J = 8.5 Hz, 1H), 2.30-2.06 (m, 5H), 2.04-1.78 (m, 4H), 1.75-1.53 ​​(m, 7H), 1.52-1.06 (m, 19H), 1.03-0.83 (m, 13H), 0.74 (s, 4H), 0.58 (s, 3H).

[0288] Example 47: Synthesis of Compound 216 [ka] Compound 209 was replaced with compound 207 (from example 23) in a similar manner to the procedure outlined in example 45 to give compound 216. HRMS (ESI+) C 29 H 47 CN 2 O 6 Calculated m / z [M+H] + : 519.3429, measured value 519.3418; 1 H NMR (MeOD) δ: 4.59-4.69 (m, 2H), 4.10-4.69 (m,2H), 4.02 (s, 1H), 3.90-3.95 (m, 1H), 3.05 (q, J = 7.03 Hz, 1H), 2.57-2.68 (m, 1H), 1.85-2.27 (m, 7H), 1.12-1.76 (m, 29H). 0.73-1.06 (m, 6H), 0.60 (s, 3H δ).

[0289] Example 48: Synthesis of Compound 128 [ka] Following the procedure outlined in Example 2, but substituting L-proline benzyl ester hydrochloride (297 mg, 1.23 mmol) for 1-(2-methoxyphenyl)-piperazine, compound 128 (79.6 mg) was obtained as a solid. HRMS (ESI+): C 36 H 52 NO 5 Calculated m / z [M+H] + : 578.3840, measured value 578.3844; 1H NMR δ: 7.45-7.19 (m, 5H), 5.28-5.07 (m, 2H), 3.77 (dd, J = 4.4, 9.1 Hz, 1H), 3.59-3.44 (m, 2H), 3.23-3.08 (m, 1H), 2.92 (q, J = 7.6 Hz, 1H), 2.51 (t, J = 8.5 Hz, 1H), 2.31-1.81 (m, 13H), 1.76-1.06 (m, 16H), 1.03-0.67 (m, 6H), 0.60 (s, 3H).

[0290] Example 49: Synthesis of Compound 224 [ka] Following the procedure outlined in Example 17 (without the step to form the HCl salt), but substituting 2-hydroxyisobutyric acid (166 mg, 1.60 mmol) for 4-morpholineacetic acid, compound 224 (91.3 mg) was obtained as a foam. HRMS (ESI+): C 28 H 44 NaO 6 Calculated m / z [M+H] + : 499.3030, measured value 499.3027; 1 H NMR δ: 4.63 (s, 2H), 3.00 (s, 1H), 2.60-2.46 (m, 1H), 2.35-1.97 (m, 8H), 1.85 (d, J = 11.7 Hz, 1H), 1.75-1.07 (m, 21H), 1.04-0.86 (m, 2H), 0.83-0.68 (m, 5H), 0.61 (s, 3H).

[0291] Example 50: Synthesis of Compound 504 [ka] A solution of compound 500 (from Example 26; 122 mg, 0.31 mmol), cyclohexene (0.5 mL, 4.94 mmol) in DCM was cooled to -78 °C in a dry ice-acetone bath. After stirring for 5 min, thionyl chloride (22 μL, 0.30 mmol) was added in one portion and the contents were allowed to warm slowly to ambient temperature overnight. After stirring for 18 h, the reaction mixture was concentrated to a residue. The residue was then dissolved in 5 mL of DMF and NaI (62.1 mg, 0.41 mmol) and 4-morpholinylacetic acid (182 mg, 1.25 mmol) were added. The resulting mixture was stirred for 5 min, after which cesium carbonate (430 mg, 1.32 mmol) was added, resulting in a bright yellow slurry. The slurry was heated to 70 °C. After stirring for 18 h, the reaction was diluted with 25 mL of EtOAc and 15 mL of H 2 O to give a clear biphasic solution. After separation, the EtOAc layer was washed with 15 mL of saturated NaHCO 3 The solution was washed twice with 15 mL of saturated NaCl solution. 2 SO 4 The organic phase was dried using hexanes, filtered and concentrated to give an orange residue, which was then dried under high vacuum. The crude product was purified by column chromatography using an ISCO™ chromatography system to give compound 504 as a solid (47.1 mg). HRMS (ESI+): C 29 H 48 NO 5 Calculated m / z [M+H] + : 490.3527,Measured value 490.3527; 1 H NMR δ: 5.44-5.30 (m, 2H), 3.80-3.65 (m, 4H), 3.16-3.12 (s, 2H), 2.59-2.52 (m, 5H), 2.15-1.91 (m, 9H), 1.73-1.49 (m, 8H), 1.46-1.02 (m, 22H), 0.95-0.78 (m, 1H), 0.58-0.53 (m, 4H), 0.54 (s, 3H).

[0292] Example 51: Synthesis of Compound 217 [ka] Compound 201 (from Example 25; 75.7 mg, 0.19 mmol) and CuBr (40 mg, 0.18 mmol) were dissolved in 5 mL of DCM to give a dark green solution. To this solution was added N-(2-isocyanatoethyl)-N,N-dimethylamine (23.4 mg, 0.21 mmol). The reaction was stirred at ambient temperature for 20 h, then diluted with 25 mL of EtOAc and diluted with H 2 The solution was then washed three times with 15 mL of O (15 mL) and then with 15 mL of brine. 2 SO 4 The crude product was purified by column chromatography using an ISCO™ chromatography system to give compound 217 (free base; 18.7 mg). 1 H NMR δ: 5.71 (br. s., 1H), 4.65-4.41 m, 2H), 3.46-3.30 (m, 3H), 2.67-2.48 (m, 4H), 2.46-2.31 (m, 7H), 2.31-2.07 (m, 6H), 2.05-1.83 (m, 2H), 1.78-1.07 (m, 23H), 1.04-.075 (m, 5H), 0.59 (s, 3H).

[0293] The free base was treated with 2.0M HCl / diethyl ether (200 uL) and the solvent removed in vacuo to give compound 217 as a solid hydrochloride salt (21.9 mg). HRMS (ESI+): 29 H 49 N 2 O 5 Calculated m / z [M+H] + : 505.3636, measured value 505.3624; 1H NMR δ: 7.01-6.84 (m, 1H), 4.65-4.39 (m, 2H), 3.69 (br. s., 2H), 3.25 (br. s., 2H), 2.90 (br. s, 6H), 2.52 (t, J = 8.5 Hz, 1H), 2.79-1.78 (m, 8H), 1.75-1.54 (m, 5H), 1.53-1.07 (m, 22H), 1.03-0.67 (m, 7H), 0.59 (s, 3H).

[0294] Example 52. Synthesis of compound 407 [ka] To a solution of ganaxolone (665 mg, 2.0 mmol) in pyridine (4.65 mL) was added succinic anhydride (1.2 g, 12 mmol) and DMAP (244 mg, 2.0 mmol). The reaction vessel was sealed and heated to reflux, which allowed the reagents to dissolve. After 42 h, the reaction mixture was cooled to ambient temperature and poured into cold water (95 mL). The pH was adjusted to 3 with 1N HCl, and the organic layer was extracted with ethyl acetate (75 mL, 2 times). The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the organic extract was concentrated and purified by silica gel chromatography using 0-100% ethyl acetate / hexane to give compound 404 as a solid (225 mg). HRMS (ESI+): C 26 H 40 NaO 5 Calculated m / z [M+Na] + : 455.2768, measured value 455.2762; 1H NMR δ = 2.96 - 2.78 (m, 2H), 2.70 - 2.53 (m, 10H), 2.44 - 2.40 (m, 1H), 2.40 - 2.36 (m, 1H), 2.25 - 2.15 (m, 2H), 2.11 (s, 4H), 1.99 (br d, J=11.7 Hz, 1H), 1.94 - 1.84 (m, 2H), 1.72 - 1.60 (m, 4H), 1.59 - 1.49 (m, 2H), 1.48 - 1.42 (m, 5H), 1.41 - 1.33 (m, 4H), 1.26 (t, J=7.0 Hz, 5H), 1.22 - 1.09 (m, 6H), 0.89 (s, 1H), 0.80 - 0.72 (m, 4H), 0.59 (s, 3H).

[0295] Example 53: Synthesis of Compound 408 [ka] Following a similar procedure as outlined in Example 52, substituting 3-oxabicyclo[3.1.0]hexane-2,4-dione for succinic anhydride, compound 408 was obtained. LCMS (ESI) m / z 467.41 (M+ Na). + ;HRMS (ESI+) C 27 H 41 O 5 Calculated m / z [M+H] + : 445.2949, measured value 445.2950; 1 H NMR CDCl 3δ: 2.79 (dd, J=2.6, 8.5 Hz, 1H), 2.59 - 2.45 (m, 1H), 2.22 (br d, J=2.9 Hz, 1H), 2.17 (br s, 1H), 2.30 - 2.15 (m, 1H), 2.11 (s, 5H), 2.09 (s, 1H), 2.08 (s, 1H), 2.04 - 1.95 (m, 2H), 1.89 (ddd, J=2.6, 6.6, 11.9 Hz, 2H), 1.74 - 1.52 (m, 8H), 1.47 (s, 4H), 1.43 - 1.29 (m, 7H), 1.26 (t, J=7.0 Hz, 6H), 0.90 (s, 1H), 0.83 - 0.72 (m, 5H), 0.60 (s, 3H).

[0296] Example 54: Synthesis of Compound 420 [ka] Following a similar procedure as outlined in Example 52, substituting 2,2-dimethylsuccinic anhydride for succinic anhydride, compound 420 was obtained. LCMS (ESI) m / z 483.24 (M+ Na). + ; 1 H NMR δ: 2.62 (s, 1H), 2.60 (d, J=2.9 Hz, 2H), 2.52 (br t, J=8.8 Hz, 2H), 2.27 - 2.13 (m, 3H), 2.11 (s, 6H), 2.05 - 1.96 (m, 3H), 1.90 (br d, J=12.9 Hz, 2H), 1.77 - 1.54 (m, 8H), 1.45 (d, J=1.2 Hz, 7H), 1.39 (br d, J=2.9 Hz, 4H), 1.31 (s, 14H), 1.28 - 1.16 (m, 13H), 1.02 - 0.80 (m, 4H), 0.77 (s, 2H), 0.76 (s, 4H), 0.74 - 0.65 (m, 3H), 0.60 (s, 5H).

[0297] Example 55. Synthesis of compound 410 [ka] To a solution of compound 404 (from Example 52; 96 mg, 0.22 mmol) in dichloromethane (1.1 mL) were added EDCI·HCl (85 mg, 0.44 mmol), 2-dimethylaminoethylamine (0.048 mL, 0.44 mmol), and DMAP (27 mg, 0.22 mmol) sequentially. The reaction mixture was stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate and 1N HCl (aq) was added. Brine was added to break up the resulting emulsion and the phases were separated. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were dried over sodium sulfate and filtered. The combined extracts were concentrated and purified by silica gel chromatography using 0-10% methanol / dichloromethane (buffered with ammonium hydroxide) to give an impure material that was purified by reverse phase preparative HPLC with 5-95% acetonitrile / water (buffered with trifluoroacetic acid). Lyophilization of the product-containing fractions afforded compound 410 as the trifluoroacetate salt (53 mg). HRMS (ESI+): C 30 H 51 N 2 O 4 Calculated m / z [M+H] + : 503.3843, measured value 503.3856; 1 H NMR (DMSO-d 6 ) δ = 3.42 - 3.29 (m, 3H), 3.10 (q, J=5.9 Hz, 3H), 2.78 (d, J=4.1 Hz, 7H), 2.53 (s, 1H), 2.45 (d, J=5.9 Hz, 2H), 2.39 - 2.28 (m, 2H), 2.16 - 1.89 (m, 7H), 1.79 - 1.67 (m, 1H), 1.66 - 1.46 (m, 5H), 1.43 - 1.19 (m, 11H), 1.12 (br s, 5H), 0.73 (s, 4H), 0.49 (s, 3H).

[0298] Example 56: Synthesis of Compound 409 [ka] Similar to the procedure outlined in Example 55, substituting 2-dimethylaminoethanol for dimethylaminoethylamine, compound 409 was obtained as the hydrochloride salt. LCMS (ESI) m / z 504.31 (M+ H)+; HRMS (ESI+) C 30 H 50 NO 5 Calculated m / z [M+H] + : 504.3684, measured value 504.3690; 1 H NMR DMSO-d 6 ) δ = 4.38 - 4.27 (m, 3H), 3.36 (br d, J=4.7 Hz, 2H), 2.81 (d, J=4.7 Hz, 5H), 2.54 (td, J=2.6, 4.8 Hz, 4H), 2.09 (br s, 1H), 1.95 (br d. 0.99 - 0.78 (m, 1H), 0.74 (s, 2H), 0.71 - 0.62 (m, 1H), 0.50 (s, 2H). Example 57: Synthesis of Compound 411 [ka] Compound 404 was replaced with compound 408 (from example 53) in a similar manner to the procedure outlined in example 55 to give compound 411 as the trifluoroacetate salt. LCMS (ESI) m / z 515.75 (M+ H)+; HRMS (ESI+) C 31 H 51 N 2 O 4 Calculated m / z [M+H] + : 515.3843, measured value 515.3857; 1 H NMR (DMSO-d 6) δ = 8.23 ​​- 8.13 (m, 2H), 6.87 (d, J=7.0 Hz, 2H), 3.11 (s, 6H), 2.80 - 2.66 (m, 2H), 2.31 - 2.22 (m, 1H), 2.09 - 2.02 (m, 4H), 2.01 - 1.87 (m, 4H), 1.82 - 1.68 (m, 1H), 1.64 - 1.47 (m, 4H), 1.34 - 1.30 (m, 5H), 1.21 (s, 2H), 1.17 - 1.06 (m, 5H), 0.75 - 0.68 (m, 4H), 0.49 (s, 3H). Example 58: Synthesis of Compound 412 [ka] Compound 404 was replaced with compound 420 (from example 54) in a similar manner to the procedure outlined in example 55 to give compound 412 as the trifluoroacetate salt. LCMS (ESI) m / z 531.41 (M+ H)+; HRMS (ESI+) C 32 H 55 N 2 O 4 Calculated m / z [M+H] + : 531.4156, measured value 531.4150; 1 H NMR (DMSO-d 6 ) δ = 7.79 (t, J=5.6 Hz, 1H), 3.36 (q, J=5.9 Hz, 3H), 3.10 (q, J=5.9 Hz, 2H), 2.80 (d, J=4.7 Hz, 6H), 2.59 - 2.50 (m, 1H), 2.02 (br s, 2H), 1.73 (br d, J=11.7 Hz, 1H), 1.67 - 1.47 (m, 4H), 1.36 (s, 7H), 1.29 - 1.20 (m, 3H), 1.14 (s, 7H), 0.97 - 0.80 (m, 1H), 0.73 (s, 3H), 0.70 - 0.63 (m, 1H), 0.49 (s, 3H). Example 59: Synthesis of Compound 413 [ka] Similar to the procedure outlined in Example 55, compound 404 was replaced with compound 420 (from Example 54) and dimethylaminoethylamine was replaced with 2-dimethylaminoethanol to give compound 413 as the trifluoroacetic acid salt. LCMS (ESI) m / z 532.39 (M+ H)+; HRMS (ESI+) C 32 H 54 NO 5 Calculated m / z [M+H] + : 532.3997, measured value 532.3986; 1 H NMR (DMSO-d6) δ = 4.36 - 4.22 (m, 3H), 3.37 (br s, 3H), 3.15 - 2.86 (m, 6H), 2.81 (br d, J=4.7 Hz, 7H), 2.76 - 2.69 (m, 1H), 2.65 - 2.56 (m, 4H), 2.04 (s, 6H), 1.99 - 1.91 (m, 2H), 1.77 - 1.68 (m, 1H), 1.55 (br d, J=10.5 Hz, 6H), 1.37 (s, 8H), 1.31 - 1.23 (m, 4H), 1.18 (br s, 8H), 1.12 (br s, 4H), 0.73 (s, 3H), 0.49 (s, 3H).

[0299] Example 60. Synthesis of compound 419 [ka] Under nitrogen at 0° C., N,N-diisopropylethylamine (0.174 mL, 1 mmol) was added to a solution of ganaxolone (83 mg, 0.25 mmol) and DMAP (37 mg, 0.3 mmol) in dichloromethane (2 mL), followed by dropwise addition of triphosgene (49 mg, 0.165 mmol) in dichloromethane (1.1 mL). The reaction was stirred at this temperature for 3.5 hours, then cooled to 0° C. and 2-dimethylaminoethylamine (0.13 mL, 1.25 mmol) was added. The reaction was allowed to warm to ambient temperature with stirring overnight. The reaction was then diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine and dried over sodium sulfate. The extract was filtered, concentrated, and purified by silica gel chromatography using 0-10% methanol / dichloromethane to give compound 419, which was converted to the hydrochloride salt with HCl (15 mg). HRMS (ESI+): C 27 H 46 NO 4 Calculated m / z [M+H] + : 448.3421,Measured value 448.3421; 1 H NMR δ = 4.17 (t, J=5.9 Hz, 2H), 2.62 (t, J=5.9 Hz, 2H), 2.56 - 2.45 (m, 1H), 2.31 (s, 5H), 2.10 (s, 3H), 2.03 - 1.94 (m, 1H), 1.88 (td, J=2.6, 14.1 Hz, 1H), 1.73 - 1.53 (m, 4H), 1.46 (s, 3H), 1.44 - 1.33 (m, 3H), 1.27 - 1.11 (m, 7H), 1.08 (s, 1H), 1.01 - 0.80 (m, 2H), 0.76 (s, 4H), 0.59 (s, 3H).

[0300] Example 61. Synthesis of compound 220 [ka] To a solution of di(N-succinimidyl)carbonate (384 mg, 1.5 mmol) in dichloromethane (14 mL) was added 2-dimethylaminoethanol (0.17 mL, 1.65 mmol) dropwise under nitrogen. The reaction was stirred overnight at ambient temperature to give a 0.11 M solution of N',N'-dimethylaminoethyl O-succinimidyl carbonate, which was used directly in the next step without purification. LCMS: m / z = 252.54 (M+Na). + .

[0301] To a mixture of compound 201 (from Example 25; 76 mg, 0.2 mmol) and DMAP (48 mg, 0.39 mmol) under nitrogen was added a 0.11 M solution of N',N'-dimethylaminoethyl O-succinimidyl carbonate in dichloromethane (5.6 mL) followed by N,N-diisopropylethylamine (0.07 mL, 0.39 mmol). The reaction was stirred overnight under nitrogen at ambient temperature. The mixture was diluted with water and the organic phase was extracted with ethyl acetate (2x). The combined organic layers were washed with brine and dried over sodium sulfate. The extracts were filtered, concentrated, and purified by silica gel chromatography with 0-10% methanol / dichloromethane to give compound 220, which was converted to the hydrochloride salt using HCl (36 mg). HRMS (ESI+): C 29 H 48 NO 6 Calculated m / z [M+H] + : 506.3476, measured value 506.3486; 1H NMR δ = 4.55 (d, J=3.5 Hz, 2H), 4.29 (t, J=5.9 Hz, 2H), 2.63 (t, J=5.9 Hz, 2H), 2.56 - 2.47 (m, 1H), 2.33 - 2.28 (m, 6H), 2.27 - 2.15 (m, 1H), 2.11 (s, 3H), 2.03 - 1.95 (m, 1H), 1.91 (dd, J=2.6, 11.4 Hz, 1H), 1.51 - 1.46 (m, 4H), 1.45 - 1.11 (m, 13H), 0.97 (t, J=7.3 Hz, 1H), 0.94 - 0.85 (m, 1H), 0.82 - 0.73 (m, 4H), 0.59 (s, 3H).

[0302] Example 62. Synthesis of compound 222 [ka] To a solution of compound 201 (from Example 25, 78 mg, 0.2 mmol) in pyridine cooled to 20° C. under nitrogen was added a solution of tert-butyl 3-[(chlorocarbonyl)oxy]azetidine-1-carboxylate (235 mg, 1.0 mmol) in dichloromethane (1 mL) dropwise. The reaction was allowed to warm slowly to ambient temperature with stirring over 4 hours. The reaction was cooled to 0° C. and quenched with 1N HCl (aq) and extracted with ethyl acetate (2×). The combined organic layers were washed with brine and dried over sodium sulfate. The extracts were filtered, concentrated, and purified by silica gel chromatography using 0-25% ethyl acetate / hexanes to give the compound containing intermediate Cbz, which was used immediately in the next step (109 mg). LCMS: m / z 612.37 (M+Na) + .

[0303] To a solution of the Cbz-containing compound (25 mg, 0.045 mmol) in dichloromethane (0.95 mL) was added trifluoroacetic acid (0.047 mL). The reaction was stirred (2 h) and then concentrated and purified by reverse-phase preparative HPLC. Lyophilization of the product-containing fractions afforded compound 111 as the trifluoroacetate salt (14 mg). HRMS (ESI+): 28 H 44 NO 6 Calculated m / z [M+H] + : 490.3163, measured value 490.3165; 1 H NMR (DMSO-d 6 ) δ = 5.36 - 5.09 (m, 1H), 4.68 (s, 2H), 4.31 (br dd, J=5.9, 12.3 Hz, 2H), 4.12 - 3.93 (m, 2H), 2.71 (quintet J=1.8 Hz, 1H), 2.57 - 2.53 (m, 2H), 2.42 (t, J=1.8 Hz, 1H), 2.25 (quintet J=1.9 Hz, 1H), 2.13 - 2.06 (m, 1H), 2.05 - 2.01 (m, 4H), 2.00 - 1.91 (m, 2H), 1.87 - 1.71 (m, 1H), 1.56 (br d, J=5.9 Hz, 4H), 1.53 (s, 2H), 1.41 (s, 3H), 1.31 (br d, J=8.2 Hz, 4H), 1.22 (s, 1H), 1.11 (br d, J=2.9 Hz, 5H), 0.76 (s, 1H), 0.74 (s, 2H), 0.49 (s, 3H).

[0304] Example 63. Synthesis of compound 414 [ka] To a solution of N-(tert-butoxycarbonyl)aspartic acid 1-benzyl ester (1.94 g, 6 mmol) in dichloromethane (6 mL) was added a 1 M solution of N,N'-dicyclohexylcarbodiimide (3 mL, 3 mmol). The reaction was stirred overnight at ambient temperature, then filtered and concentrated. The resulting oily residue, N-(tert-butoxycarbonyl) 1-benzyl ester 4-aspartic acid anhydride, was used in the next step without further purification.

[0305] To a solution of ganaxolone (100 mg, 0.3 mmol) and DMAP (73 mg, 0.6 mmol) in dichloromethane (3 mL) under nitrogen was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) followed by a solution of N-(tert-butoxycarbonyl) 1-benzyl ester 4-aspartic anhydride (3 mmol) in dichloromethane (3.5 mL). The reaction was stirred overnight at ambient temperature under nitrogen. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate, diluted with dichloromethane, and the layers separated. The organic layer was washed with 1N HCl (aq) and dried over sodium sulfate. The extract was filtered, concentrated, and purified by silica gel chromatography using 0-25% ethyl acetate to give the intermediate containing Boc and benzyl ester protecting groups (194 mg) as a solid that was used directly in the next step without further purification. LCMS: m / z = 660.48 (M+Na) + .

[0306] To a solution of the protected intermediate (190 mg, 0.3 mmol) in methanol (6.0 mL) was added palladium on carbon (35 mg, 10 wt%). The reaction mixture was purged and refilled with hydrogen (three times) and stirred vigorously overnight. Consumption of starting material was evident by LC / MS, the reaction mixture was filtered, and the filtrate was concentrated to give the Boc-protected intermediate, which was used directly in the next step.

[0307] The Boc-protected intermediate (64 mg, 0.117 mmol) was dissolved in 2N HCl / diethyl ether (0.58 mL, 1.17 mmol) at ambient temperature. Complete consumption of starting material was evident by LC / MS after approximately 1 h, and the reaction mixture was concentrated. Purification by reverse-phase preparative HPLC using 5-95% acetonitrile (buffered with trifluoroacetic acid) and lyophilization afforded compound 414 as the trifluoroacetate salt (20 mg). HRMS (ESI+): C 26 H 42 NO 5 Calculated m / z [M+H] + : 448.3057, measured value 448.3050; 1 H NMR (DMSO-d 6 ) δ = 2.99 - 2.65 (m, 2H), 2.59 - 2.51 (m, 1H), 2.16 - 2.06 (m, 1H), 2.03 (s, 3H), 1.97 (t, J=11.7 Hz, 2H), 1.76 (br d, J=11.1 Hz, 1H), 1.67 - 1.47 (m, 5H), 1.40 (s, 4H), 1.37 - 1.24 (m, 5H), 1.12 (br s, 6H), 0.98 - 0.82 (m, 1H), 0.73 (s, 3H), 0.71 - 0.63 (m, 1H), 0.49 (s, 3H);MS: m / z = 448.23 (M+H+).

[0308] Example 64: Synthesis of Compound 416 [ka] Following a similar procedure as outlined in Example 63, substituting N-(tert-butoxycarbonyl)aspartic acid 1-benzyl ester for N-(tert-butoxycarbonyl)-L-glutamic acid 1-benzyl ester, compound 416 was obtained as the trifluoroacetate salt. LCMS (ESI) m / z 484.21 (M+Na). + ;HRMS (ESI+) C 27 H 44 NO 5Calculated m / z [M+H] + : 448.3057, measured value 448.3050; 1 H NMR (DMSO-d 6 ) δ = 3.80 - 3.65 (m, 2H), 3.58 (d, J=11.1 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.75 - 2.68 (m, 1H), 2.58 - 2.52 (m, 2H), 2.46 - 2.33 (m, 1H), 2.33 - 2.23...

Claims

1. Formula (I): 【Chemistry 301】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Y is -C(O)- or -C(R Ａ ) (R Ｂ ) - (e.g., -CH ２ -) and 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 said 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 said 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 atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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 said 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 said 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 said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

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

3. Z is methylene (e.g., unsubstituted methylene); 【Chemistry 302】 and During the ceremony, Z1 is absent, alkylene (e.g., methylene, e.g., unsubstituted methylene), alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein said 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 said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and each 【Chemistry 303】 3. The compound of claim 1 or 2, wherein indicates the point of attachment of Z to X or Y.

4. X, 【Chemistry 304】 is a moiety selected from the group consisting of During the ceremony, 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, which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline), optionally substituted (e.g., at the 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) which may contain D-amino acids, L-amino acids, or combinations thereof, optionally substituted (e.g., at one or more nitrogen atoms, e.g., the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group); Q is heteroalkyl or heterocyclyl, said heteroalkyl or heterocyclyl being optionally substituted; V is -O-, -N(H)-, or -N(Me)-; X2 and X3 each independently represent -CH ２ -, -O-, -S-, or -N(R Ｇ３ )-(for example, -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 said 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 which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) and which are optionally substituted (e.g., at the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group); Or R Ｇ１ and R Ｇ２ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｇ３ and R Ｇ４ are each independently hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; Or R Ｇ３ and R Ｇ４ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｇ５ is hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; R Ｊ is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein said alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; R Ｐ is halo, -NH-alkyl, -NH-heteroalkyl, -N-(alkyl) ２ (For example, -N(Me) ２ ), —N-(heteroalkyl) ２ (For example, -N(CH ２ CH ２ O.H. ２ ), or heterocyclyl (e.g., morpholinyl); R １０ is an alkyl, alkenyl, alkynyl, haloalkyl, halo, -OR Ｊ , -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 said alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted; Or R １１ and R １２ One of the two, and R １３ and R １４ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R １５ is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted; and m is an integer from 1 to 5, p is an integer between 0 and 4; and 【Chemistry 305】 4. A compound according to any one of the preceding claims, wherein indicates the point of attachment of X to Z, or, if Z is not present, of X to Y.

5. X, 【Chemistry 306】 is a moiety selected from the group consisting of: R Ｂ , R Ｃ , and R Ｋ are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｇ１ and R Ｇ２ are each independently hydrogen, alkyl, or an amino acid residue which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) and which are optionally substituted (e.g., at the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group); Or R Ｇ１ and R Ｇ２ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｇ３ and R Ｇ４ are each independently hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; Or R Ｇ３ and R Ｇ４ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R ２ is hydrogen or alkyl, R １０ is an alkyl, alkenyl, alkynyl, haloalkyl, halo, -OR Ｊ , -N(R Ｇ３ ) (R Ｇ４ );-NO ２ , -CN, or -NC.

6. 2. A compound according to any one of the preceding claims, wherein Y is -C(O)- and Z is alkylene (eg methylene).

7. R １ and R ２ 5. A compound according to any one of the preceding claims, wherein none of: is hydrogen.

8. Formula (I-II): 【Chemistry 307】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein 【Chemistry 308】 represents a single or double bond, Y １ is an alkylene (e.g., methylene), alkenylene, alkynylene, heteroalkylene, —C(O)—, —OC(O)—, —C(O)O—, —NR １ -, -O-, or -S-, wherein said 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 said heteroalkyl, cycloalkyl, heterocyclyl, 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 said 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 atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which 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 said 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 said alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted; R ７Ａ and R ７Ｂ are each independently hydrogen or optionally substituted alkyl, or R ７Ａ and R ７Ｂ is connected to Y via one or more carbon atoms or heteroatoms １ to form a cyclic moiety (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl, e.g., pyrrole), R ７Ａ Groups and R ７Ｂ the other group 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 【Chemistry 309】 When is a double bond, R ７Ｅ and R ７Ｆ or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, provided that one of: is not present.

9. Y １ is -O- or -N(R １ 9. The compound of claim 8, wherein the alkyl group is -N(H)-, -N(alkyl)-, or -N(heteroalkyl)-. 【Request 10】 【Chemical 310】 and pharma- ceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, wherein Y ２ , R １ , R ７Ｃ , R ７Ｄ , R ７Ｅ , and R ７Ｆ 10. The compound according to claim 8 or 9, wherein is as defined in claim 8.

11. Y ２ ,or 【Chemistry 311】 When R is a double bond ７Ｅ is optionally substituted heteroalkyl, —NR １ R ２ (For example, -NH ２ , -NHMe, or -NMe ２ ), -OR ３ (For example, -OH, -OMe, -OEt, or -O ｔ Bu), or =O, where R １ , R ２ , and R ３ The compound according to any one of claims 8 to 10, wherein is as defined in claim 8.

12. Y ２ ,or 【Chemistry 312】 When R is a double bond ７Ｅ but, 【Chemistry 313-1】 【Hua 313-2】 【Chemistry 313-3】 The compound according to any one of claims 8 to 11, selected from the group consisting of:

13. Formula (IA) 【Chemistry 314】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein 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 said 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 atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R7 Ａ and R7 Ｂ are each independently hydrogen or optionally substituted alkyl, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

14. -N(R １ ) (R ２ ) group, 【Chemistry 315】 is a moiety selected from the group consisting of In the formula, R ２ ,M.,Q.,V.,R. Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ and R Ｋ is as claimed in claim 1, 【Chemistry 316】 14. The compound of claim 13, wherein indicates the point of attachment of the nitrogen atom to the carbon atom of the -C(R7A)(R7B) group.

15. -N(R １ ) (R ２ ) group, 【Chemistry 317】 is a moiety selected from the group consisting of In the formula, R ２ , R １０ , R Ｂ , R Ｃ , R Ｄ , R Ｅ and R Ｋ is as claimed in claim 1, 【Chemistry 318】 14. The compound of claim 13, wherein indicates the point of attachment of the nitrogen atom to the carbon atom of the -C(R7A)(R7B) group.

16. The X group of formula (I) or the —N(R １ ) (R ２ ) group, 【Hua 319-1】 【Hua 319-2】 【Hua 319-3】 【Hua 319-4】 is a moiety selected from the group consisting of: 【Chemistry 320】 represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I), or -C(R ７Ａ ) (R ７Ｂ 16. The compound of any one of claims 1 to 6 or 13 to 15, wherein the nitrogen atom indicates the point of attachment to the carbon atom of the aryl group.

17. The X group of formula (I) or the —N(R １ ) (R ２ ) group, 【Chemistry 321】 is a moiety selected from the group consisting of During the ceremony, 【Chemistry 322】 represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I), or -C(R ７Ａ ) (R ７Ｂ 16. The compound of any one of claims 1 to 6 or 13 to 15, wherein the nitrogen atom indicates the point of attachment to the carbon atom of the aryl group.

18. The compound has the formula (IA-a) 【Chemical 323】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein G is absent, -C(O)-, or -C(R ８Ａ ) (R ８Ｂ ) - (e.g., -CH ２ -) and K is an alkylene, a heteroalkylene, —C(O)—, —OC(O)—, —C(O)O—, —O—, or —O—(CH ２ ) - or -(CH ２ ) —O—, wherein said 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 4. The compound of any one of the preceding claims, wherein is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

19. G is -C(R ８Ａ ) (R ８Ｂ ) - and 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); 19. The compound of claim 18, wherein the carbon atom of the carbonyl group of -OC(O)- is bonded to G.

20. The compound has the formula (IA-b): 【Chemical 324】 or a pharma- ceutically 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 R ９ 4. The compound of any one of the preceding claims, wherein is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

21. R ２ is hydrogen, and R ８Ａ and R ８Ｂ The compound according to any one of claims 18 to 20, wherein each is independently methyl.

22. Formula (IB): 【Chemistry 325】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein 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 said alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted; R7 Ａ and R7 Ｂ are each independently hydrogen or optionally substituted alkyl, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

23. -O-(R ３ ) group, 【Chemical 326】 is a moiety selected from the group consisting of During the ceremony, P is an amino acid residue, which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline), optionally substituted (e.g., at the 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) which may contain D-amino acids, L-amino acids, or combinations thereof, optionally substituted (e.g., at one or more nitrogen atoms, e.g., the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group); R Ｂ and R Ｃ are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said 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 which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) and which are optionally substituted (e.g., at the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group); Or R Ｇ１ and R Ｇ２ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｇ３ and R Ｇ４ are each independently hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; Or R Ｇ３ and R Ｇ４ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｊ is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein said alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; R Ｋ is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｐ is halo, -NH-alkyl, -NH-heteroalkyl, -N-(alkyl) ２ (For example, -N(Me) ２ ), -N-(heteroalkyl) ２ (For example, -N(CH ２ CH ２ O.H. ２ ), or heterocyclyl (e.g., morpholinyl); m is an integer from 1 to 5; and 【Chemical 327】 23. The compound of claim 22, wherein indicates the point of attachment of the oxygen atom to the carbon atom of the -C(R7A)(R7B) group.

24. -O-(R ３ ) group, 【Chemical 328】 is a moiety selected from the group consisting of: R Ｂ and R Ｃ are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｋ is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｇ１ and R Ｇ２ are each independently hydrogen, alkyl, or an amino acid residue which may be a D- or L-amino acid residue (e.g., glycine, alanine, valine, leucine, or proline) and which are optionally substituted (e.g., at the terminal nitrogen atom, e.g., by a carbonate group, e.g., a carboxybenzyl (Cbz) group); Or R Ｇ１ and R Ｇ２ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R Ｇ３ and R Ｇ４ are each independently hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; Or R Ｇ３ and R Ｇ４ 23. The compound of claim 22, wherein: together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

25. X group of formula (I) or -O-R group of formula (IB) ３ The base is 【Hua 329-1】 【Hua 329-2】 【Hua 329-3】 is a moiety selected from the group consisting of: 【Chemistry 330】 represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I), or -C(R ７Ａ ) (R ７Ｂ 25. The compound of any one of claims 1, 2, or 22-24, wherein the oxygen atom is attached to a carbon atom of the aryloxy group.

26. X group of formula (I) or -O-R group of formula (IB) ３ The base is 【Hua 331-1】 【Hua 331-2】 【Chemistry 331-3】 is a moiety selected from the group consisting of: 【Chemical 332】 represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I), or -C(R ７Ａ ) (R ７Ｂ 25. The compound of any one of claims 1, 2, or 22-24, wherein the oxygen atom is attached to a carbon atom of the aryloxy group.

27. Formula (IC) 【Chemical 333】 or a pharma- ceutically 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 said alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted; and R7 Ａ and R7 Ｂ are each independently hydrogen or optionally substituted alkyl, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

28. -S-(R ４ ) group, 【Chemical 334】 is a moiety selected from the group consisting of During the ceremony, R and R are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｇ３ and R Ｇ４ are each independently hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; Or R Ｇ３ and R Ｇ４ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｇ５ is hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; R Ｊ is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein said alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; R Ｋ is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｐ is halo, -NH-alkyl, -NH-heteroalkyl, -N-(alkyl) ２ (For example, -N(Me) ２ ), -N-(heteroalkyl) ２ (For example, -N(CH ２ CH ２ O.H. ２ ), or heterocyclyl (e.g., morpholinyl), and 【Chemical 335】 28. The compound of claim 27, wherein indicates the point of attachment of the sulfur atom to the carbon atom of the -C(R7A)(R7B) group.

29. The X group of formula (I) or -S-R ４ The base is 【Hua 336-1】 【Hua 336-2】 is a moiety selected from the group consisting of During the ceremony, 【Chemical 337】 represents the attachment point of X to Z, or, if Z is absent, to Y, in formula (I), or -C(R ７Ａ ) (R ７Ｂ 30. A compound according to any one of claims 1, 2, 27 or 28, wherein the sulfur atom is attached to a carbon atom of the aryl group.

30. Formula (ID) 【Chemical 338】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, During the ceremony, 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 said alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl is optionally substituted, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

31. R ５ but, 【Chemical 339】 and During the ceremony, X2 and X3 each independently represent -CH ２ -, -O-, -S-, or -N(R Ｇ３ )-(for example, -NH-), R １０ is an alkyl, alkenyl, alkynyl, haloalkyl, halo, -OR Ｊ , -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 said alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted; Or R １１ and R １２ One of the two, and R １３ and R １４ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R １５ is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted; R Ｇ３ and R Ｇ４ are each independently hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; Or R Ｇ３ and R Ｇ４ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｊ is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein said alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; and p is an integer between 0 and 4; and 【Chemistry 340】 is R relative to the carbon atom of the -C(O)- group. ５ 31. The compound of claim 30, showing the point of attachment of the group.

32. X group of formula (I) or R ５ The base is 【Hua 341-1】 【Hua 341-2】 is a moiety selected from the group consisting of During the ceremony, 【Chemical 342】 represents the point of attachment of X to Z, or, if Z is not present, to Y, in formula (I), or R to a carbon atom of the -C(O)- group in formula (ID). ５ 32. The compound of any one of claims 1, 2, 30, or 31, indicating the point of attachment of the group.

33. Formula (IE) 【Chemical 343】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R ６ is an 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 said alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R Ａ and R Ｂ are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

34. R ６ but, 【Chemical 344】 is a moiety selected from the group consisting of During the ceremony, R Ｇ３ and R Ｇ４ are each independently hydrogen, alkyl, or heteroalkyl, wherein said alkyl or heteroalkyl is optionally substituted; Or R Ｇ３ and R Ｇ４ together with the atom to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R Ｊ is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein said alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted; and, 【Chemical 345】 is -C(R Ａ ) (R Ｂ R to the carbon atom of the - group ６ 34. The compound of claim 33, showing the point of attachment of the group.

35. Group X of formula (I) or R of formula (IE) ６ The base is 【Chemical 346】 is a moiety selected from the group consisting of: 【Chemical 347】 represents the point of attachment of X to Z, or, if Z is absent, to Y, in formula (I), or -C(R Ａ ) (R Ｂ )-group carbon atom ６ 35. The compound of any one of claims 1, 2, 33, or 34, indicating the point of attachment of the group.

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

37. The compound is 【Chemical 348】 37. The compound of any one of claims 1 to 26 or 36, selected from the group consisting of: and pharma- ceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof.

38. The compound is 【Chemical 349】 37. The compound of any one of claims 1 to 26 or 36, selected from the group consisting of: and pharma- ceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof.

39. The compound is 【Chemistry 350】 40. The compound of any one of claims 1 to 4, 6, 13, 14, 16, 36, or 37, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

40. The compound is 【Chemistry 351】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

41. The compound of any one of the preceding claims, wherein the compound has greater aqueous solubility and / or hydrophilicity than ganaxolone, e.g., as determined by log S, log P, log D, topological polar surface area (TPSA), acid pKa, base pKa, or a combination thereof.

42. 2. A compound according to any one of the preceding claims, wherein the compound is substantially converted to ganaxolone by metabolic processes, e.g., after administration to a subject.

43. The compound may, for example, reduce the serum concentration of ganaxolone (e.g., C ｍａｘ 4. A compound according to any one of the preceding claims, having a higher bioavailability of ganaxolone as determined by AUC or AUC) relative to an equivalent amount of ganaxolone delivered by the same route of administration.

44. For example, the compound may provide a higher serum concentration of ganaxolone (e.g., C) after administration to a subject compared to an equivalent amount of ganaxolone delivered by the same route of administration. ｍａｘ 4. A compound according to any one of the preceding claims, which provides a gonaxolone half-life and / or a reduced agonist concentration (AUC) and / or a reduced agonist concentration (AUC).

45. 10. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharma- ceutically acceptable excipient.

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

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

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

49. Use of a compound according to any one of claims 1 to 44 or a pharmaceutical composition according to claim 45 for the manufacture of a medicament effective to treat a disease or disorder in a subject.

50. 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. 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 seizure disorder, an epilepsy disorder, a genetic epilepsy disorder, an epilepsy-related disorder, a central nervous system disorder, a neurological disorder, or a neurodegenerative disease.

52. 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 status epilepticus (SE).

53. 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 CDKL5 deficiency.

54. 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 tuberous sclerosis.

55. 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 PCDH19-associated epilepsy.

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

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