Prodrugs of ganaolone

Abstract

The present disclosure relates to ganaolone 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 comprising the compounds.

Description

Background Art

[0001] Ganaxolone is a GABA receptor A Ganaxolone is a positive allosteric modulator of ganaxolone (GABA) and can increase GABA activity and inhibit neuronal excitability. Ganaxolone has very low water solubility, which greatly reduces its oral bioavailability and limits its potential clinical application.

[0002] Prodrug is itself usually has little or no pharmacologically active molecule, and it can be metabolized to release pharmacologically active drug (i.e. parent drug) after administration (e.g., in blood). Relative to parent drug, some prodrugs can be more easily absorbed and have excellent oral bioavailability. However, successfully producing a stable prodrug with excellent bioavailability relative to parent drug and suitable conversion to parent drug and safety (e.g., toxicity profile) 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 to ganaxolone (e.g., in vivo, e.g., by metabolic processes). 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 preparing the compounds, and pharmaceutical compositions and kits containing the same.

[0005] The compound of the present disclosure may be a compound of formula (I):

[0006]

[0007] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein Y is -C(O)- or -C(R A )(R B )– (e.g., –CH2–);

[0008] 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;

[0009] 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, heterocyclyl-alkyl, heterocyclyl-heteroalkyl, –OC(O)-alkyl, –C(O)O-alkyl, –OC(O)-heteroalkyl, –C(O)O-heteroalkyl, –N3, –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;

[0010] R 1 and R 2 each is 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0011] or R 1 and R 2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0012] 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0013] 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, heterocyclyl, aryl or heteroaryl is optionally substituted; and

[0014] R A and R B Each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0015] For example, the compound may be a compound of formula (I), wherein Y is -C(O)-.

[0016] The compound may be a compound of formula (I), wherein Z is a methylene group (eg, an unsubstituted methylene group), 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; and each Indicates the point where Z is attached to X or Y.

[0017] The compound of the present disclosure may be a compound of formula (II):

[0018]

[0019] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein:

[0020] X is as defined herein, for example, 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, heterocyclyl-alkyl, heterocyclyl-heteroalkyl, -OC(O)-alkyl, -C(O)O-alkyl, -OC(O)-heteroalkyl, -C(O)O-heteroalkyl, -N3, -NR1 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;

[0021] R 1 and R 2 each is 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0022] or R 1 and R 2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0023] 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0024] 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, heterocyclyl, aryl or heteroaryl is optionally substituted; and

[0025] R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

[0026] The compound may be a compound of formula (I) or (II), wherein X is a moiety selected from the group consisting of

[0027]

[0028] in

[0029] R 2 is hydrogen or alkyl;

[0030] M is –C(H)(R D )– (e.g., –CH2–), –O–, or –N(R D )–(e.g., –N(Me)–);

[0031] P is an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which may be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group),

[0032] or P is a dipeptide moiety (e.g., a leucine-leucine moiety) which may comprise D-amino acids, L-amino acids, or a combination thereof and is optionally substituted (e.g., at one or more nitrogen atoms, e.g., at a terminal nitrogen atom, e.g., with a carbonate group such as a carboxybenzyl (Cbz) group);

[0033] Q is heteroalkyl or heterocyclyl, wherein the heteroalkyl or heterocyclyl is optionally substituted;

[0034] V is –O–, –N(H)–, or –N(Me)–;

[0035] X2 and X3 are each independently -CH2-, -O-, -S- or -N(R G3 )–(e.g., –NH–);

[0036] 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;

[0037] R F and R H are each independently hydrogen or alkyl;

[0038] R G1 and R G2each independently hydrogen, alkyl or an amino acid residue (e.g. glycine, alanine, valine, leucine or proline), which may be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g. at the terminal nitrogen atom, for example by a carbonate group such as a carboxybenzyl (Cbz) group),

[0039] or R G1 and R G2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0040] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0041] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0042] R G5 is hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0043] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted;

[0044] R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, –OR J ,–N(R G3 )(R G4 ), –NO2, –CN or –NC;

[0045] 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,

[0046] or R 11 and R 12 One of them, and R 13 and R 14One of the following, taken together with the atoms to which they are attached, forms a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0047] R 15 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted;

[0048] m is an integer from 1 to 5;

[0049] p is an integer between 0 and 4; and

[0050] When Z is absent, represents the point of attachment of X to Z or X to Y, and in formula (II) Indicates X and –C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0051] For example, X can be where R 2 H, R B and R C are each independently an alkyl group (eg, a methyl group), and R K For hydrogen.

[0052] The compound may be a compound of formula (I), wherein Y is -C(O)- and Z is an alkylene group (e.g., a methylene group). The compound may be a compound of formula (I) or (II), wherein R 1 and R 2 Not all are hydrogen.

[0053] The compound may be a compound of formula (I) wherein Y is C(O)- and Z is an alkylene group (eg, a methylene group), and X is For example, the compound may be a compound of formula (I) wherein Y is C(O)- and Z is methylene, and X is And R 2 For hydrogen.

[0054] The compound may be a compound of formula (I) wherein Y is -C(O)- and Z is an alkylene group (eg, a methylene group), and X is For example, the compound may be a compound of formula (I) wherein Y is C(O)- and Z is methylene, and X is

[0055] Alternatively, the compound may be a compound of formula (I) wherein Y is -C(O)- and Z is an alkylene group (eg, a methylene group), and X is For example, the compound may be a compound of formula (I) wherein Y is -C(O)- and Z is an alkylene group (eg, a methylene group), and X is

[0056] The compound of the present disclosure may be a compound of formula (I-II):

[0057]

[0058] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein:

[0059] represents a single bond or a double bond;

[0060] Y 1 is alkylene (e.g., methylene), alkenylene, alkynylene, heteroalkylene, -C(O)-, -OC(O)-, -C(O)O-, -NR 1 -, -O-, or -S-, wherein the alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted;

[0061] 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 =0, wherein the heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0062] R 1 and R 2 each is 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0063] or R 1 and R 2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0064] 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0065] 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, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0066] R 7A and R 7B are each independently hydrogen or optionally substituted alkyl, or R 7A and R 7B One of them is bonded to Y through one or more carbon atoms or heteroatoms 1 to form a cyclic moiety (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl, e.g., pyrrole), and R 7A and R 7B The other of the groups is hydrogen or optionally substituted alkyl;

[0067] 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

[0068] R 7E and R 7F Each independently does not exist, is hydrogen, alkyl, heteroalkyl, -NR 1 R 2 、–OR 3 or –SR 4 , wherein the alkyl or heteroalkyl group is optionally substituted, or R 7E and R 7F each bonded to the same oxygen to form an oxo group, provided that when When it is a double bond, R 7E and R 7F One of them does not exist.

[0069] Y in formula (I-II) 1 Can be –O– or –N(R 1 )— (e.g., —N(H)—, —N(alkyl)—, or —N(heteroalkyl)—). For example, Y of formula (I-II) 1 Alternatively, Y in formula (I-II) 1 It can be –N(Me)–, –N(Et)–, –N(EtOH)– or –N( n PrOH)–.

[0070] The compound of formula (I-II) may be a compound of formula (I-IIa):

[0071] where Y 2 、R 1 、R 7C 、R 7D 、R 7E and R 7F As defined above; or the compound of formula (I-II) may be a compound of formula (I-IIb):

[0072] where Y 2 、R 7C 、R 7D 、R 7E and R 7F As defined above; or the compound of formula (I-II) may be a compound of formula (I-IIc):

[0073] where Y 2 、R 1 、R 7C 、R 7D and R 7E As defined above; or the compound of formula (I-II) may be a compound of formula (I-IId):

[0074] where Y 2 、R 7C 、R 7D and R 7E As defined above; or the compound of formula (I-II) may be a compound of formula (I-IIe):

[0075] where Y 2 As defined above.

[0076] Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId) or (I-IIe)2 , or when When it is a double bond, R 7E , which may be an optionally substituted heteroalkyl, -NR 1 R 2 (e.g., –NH2, –NHMe, or –NMe2), –OR 3 (e.g., –OH, –OMe, –OEt, or –O t Bu) or =O. For example, Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId) or (I-IIe) 2 , or when When it is a double bond, R 7E , may be -NH2, -NHMe or -OH. Alternatively, Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId) or (I-IIe) 2 , or when When it is a double bond, R 7E , may be an optionally substituted heteroalkyl, for example a substituted or unsubstituted heteroalkyl selected from the group consisting of:

[0077]

[0078]

[0079]

[0080] The compound may be a compound of formula (I-II), wherein R 7A and R 7B Each is hydrogen, R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group, and R 7E and R 7F Each is an alkyl group (eg, methyl).

[0081] The compound may be a compound of formula (I-II), wherein Y 1 for –NR 1 –, –O–, R 7A and R 7B Each is hydrogen, R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group, R 7E and R 7F Each is an alkyl group (eg, methyl group), and Y 2 is heteroalkyl or –OR 3 For example, the compound may be a compound of formula (I-II), wherein Y 1 For –O–, R7A and R 7B Each is hydrogen, R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group, R 7E and R 7F Each is an alkyl group (eg, methyl group), and Y 2 Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 For –O–, R 7A and R 7B Each is hydrogen, R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group, R 7E and R 7F Each is an alkyl group (eg, methyl group), and Y 2 for Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 For –O–, R 7A and R 7B Each is hydrogen, R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group, R 7E and R 7F Each is an alkyl group (eg, methyl group), and Y 2 for Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 For –O–, R 7A and R 7B Each is hydrogen, R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group, R 7E and R 7F Each is an alkyl group (eg, methyl group), and Y 2 for Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 For –O–, R 7A and R 7B Each is hydrogen, R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group, R 7E and R 7F Each is an alkyl group (eg, methyl group), and Y 2 for Alternatively, the compound may be a compound of formula (I-II), wherein Y 1 For –O–, R 7A and R 7BEach is hydrogen, R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group, R 7E and R 7F Each is an alkyl group (eg, methyl group), and Y 2 for

[0082] The compound of the present disclosure may be a compound of formula (IA)

[0083]

[0084] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0085] R 1 and R 2 each is 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0086] or R 1 and R 2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted; and

[0087] R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

[0088] The compound may be a compound of formula (I), (II) or (IA), wherein the X group of formula (I) or (II), or -N(R) of formula (IA) 1 )(R 2 ) group is a moiety selected from the group consisting of in

[0089] R 2 is hydrogen or alkyl;

[0090] M is –C(H)(R D )– (e.g., –CH2–), –O–, or –N(R D)–(e.g., –N(Me)–);

[0091] Q is heteroalkyl or heterocyclyl, wherein the heteroalkyl or heterocyclyl is optionally substituted;

[0092] V is –O–, –N(H)–, or –N(Me)–;

[0093] 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; and

[0094] represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or the nitrogen atom in formula (IA) and -C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0095] In some embodiments, the X group of formula (I) or formula (II), or -N(R) of formula (IA) 1 )(R 2 ) group is a moiety selected from the group consisting of:

[0096]

[0097]

[0098]

[0099]

[0100]

[0101] in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or the nitrogen atom in formula (IA) and -C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0102] The compound of the present disclosure may be a compound of formula (IA-a)

[0103]

[0104] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0105] G does not exist, is –C(O)– or –C(R 8A )(R 8B )– (e.g., –CH2–),

[0106] K is alkylene, heteroalkylene, -C(O)-, -OC(O)-, -C(O)O-, -O-, -O-(CH2)-, or -(CH2)-O-, wherein the alkylene or heteroalkylene is optionally substituted;

[0107] R 2 、R 7A 、R 7B 、R 8A and R 8B are each independently hydrogen or optionally substituted alkyl; and

[0108] R 9 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0109] In some embodiments, the compound of formula (I), (II) or (IA) is a compound of formula (IA-a), wherein G is -C(R 8A )(R 8B )–;K is –OC(O)–;R 2 、R 7A 、R 7B and R 9 are each hydrogen; and R 8A and R 8B G is independently hydrogen or an alkyl group (eg, methyl), wherein the carbon atom of the carbonyl group in —OC(O)— is bonded to G.

[0110] The compound of the present disclosure may be a compound of formula (IA-b)

[0111]

[0112] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0113] R 2 、R 8A and R 8Bare each independently hydrogen or optionally substituted alkyl; and

[0114] R 9 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0115] For example, the compound of formula (I), (II), (IA) or (IA-a) may be a compound of formula (IA-b) wherein R 2 is hydrogen; and R 8A and R 8B are each independently methyl.

[0116] The compound of the present disclosure may be a compound of formula (IB):

[0117]

[0118] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0119] 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

[0120] R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

[0121] X of formula (I) or (II), or -O-(R 3 ) group may be a moiety selected from the group consisting of:

[0122] in

[0123] P is an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which may be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group),

[0124] or P is a dipeptide moiety (e.g., a leucine-leucine moiety) which may comprise D-amino acids, L-amino acids, or a combination thereof and is optionally substituted (e.g., at one or more nitrogen atoms, e.g., at a terminal nitrogen atom, e.g., with a carbonate group such as a carboxybenzyl (Cbz) group);

[0125] 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;

[0126] R F and R H are each independently hydrogen or alkyl;

[0127] R G1 and R G2 each independently hydrogen, alkyl or an amino acid residue (e.g. glycine, alanine, valine, leucine or proline), which may be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g. at the terminal nitrogen atom, for example by a carbonate group such as a carboxybenzyl (Cbz) group),

[0128] or R G1 and R G2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0129] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0130] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0131] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted;

[0132] R K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0133] R Pis halo, –NH-alkyl, –NH-heteroalkyl, –N-(alkyl)2 (e.g., –N(Me)2), –N-(heteroalkyl)2 (e.g., –N(CH2CH2OH)2), or heterocyclyl (e.g., morpholinyl);

[0134] m is an integer from 1 to 5; and

[0135] represents the point of attachment of X and Z, or of X and Y when Z is absent, in formula (I); In formula (II), X and –C(R 7A )(R 7B ) group; and In formula (IB), the oxygen atom and –C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0136] In some aspects, the compound is a compound of formula (I), (II) or (IB), wherein the X group of formula (I) or (II), or -OR of formula (IB) 3 A group is a moiety selected from the group consisting of:

[0137]

[0138]

[0139]

[0140]

[0141] in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or the oxygen atom in formula (IB) and -C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0142] The compound of the present disclosure may be a compound of formula (IC)

[0143]

[0144] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0145] R4 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, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

[0146] R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

[0147] In some embodiments, the X group of formula (I) or (II), or the -S-(R 4 ) group is a moiety selected from the group consisting of: in

[0148] 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;

[0149] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0150] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0151] R G5 is hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0152] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl, or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl, or heterocyclyl is optionally substituted;

[0153] R K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0154] R Pis halo, –NH-alkyl, –NH-heteroalkyl, –N-(alkyl)2 (e.g., –N(Me)2), –N-(heteroalkyl)2 (e.g., –N(CH2CH2OH)2), or heterocyclyl (e.g., morpholinyl); and

[0155] represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or the sulfur atom and -C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0156] In some embodiments, the compound is a compound of formula (I), (II) or (IC), wherein the X group of formula (I) or (II), or -SR of formula (IC) 4 A group is a moiety selected from the group consisting of: in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or the sulfur atom and -C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0157] The compound of the present disclosure may be a compound of formula (ID)

[0158]

[0159] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof,

[0160] in

[0161] 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, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclylene, aryl or heteroaryl is optionally substituted.

[0162] In some embodiments, the X group of formula (I) or formula (II), or R in formula (ID) 5 A group is a moiety selected from the group consisting of: in

[0163] X2 and X3 are each independently -CH2-, -O-, -S- or -N(R G3 )–(e.g., –NH–);

[0164] R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, –OR J ,–N(R G3 )(R G4 ), –NO2, –CN or –NC;

[0165] 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,

[0166] or R 11 and R 12 One of them, and R 13 and R 14 One of the following, taken together with the atoms to which they are attached, forms a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0167] R 15 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted;

[0168] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0169] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0170] R Jis hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted;

[0171] and

[0172] p is an integer between 0 and 4; and

[0173] represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or R 5 The point of attachment of the group to the carbon atom of the –C(O)– group.

[0174] The compound may be a compound of formula (I), (II) or (ID), wherein the X group of formula (I) or (II), or R of formula (ID) 5 A group is a moiety selected from the group consisting of

[0175]

[0176]

[0177] in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or R 5 The point of attachment of the group to the carbon atom of the –C(O)– group.

[0178] The compound of the present disclosure may be a compound of formula (IE)

[0179]

[0180] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0181] R 6is 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, —SH, or —S-alkyl (e.g., —S-Me), wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

[0182] R A and R B Each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0183] In some embodiments, the X group of formula (I) or formula (II), or R of formula (IE) 6 The group is selected from The part of the group consisting of

[0184] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0185] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0186] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted;

[0187] and represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or R 6 Group and –C(R A )(R B ) – point of attachment to a carbon atom of a group.

[0188] The compound may be a compound of formula (I), (II) or (IE), wherein the X group of formula (I) or (II), or R of formula (IE) 6A group is a moiety selected from the group consisting of in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; represents the point of attachment of X and –C(R 7A )(R 7B ) group; or R 6 Group and –C(R A )(R B ) – point of attachment to a carbon atom of a group.

[0189] The compound of the present disclosure may be a compound provided in Table 1. For example, the compound may be or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain embodiments, the compound is or a pharmaceutically acceptable salt (e.g., hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof. In certain aspects, the present disclosure does not include compounds or a pharmaceutically acceptable salt (eg, hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof.

[0190] In some embodiments, the compounds of the present disclosure are

[0191]

[0192] or a pharmaceutically acceptable salt (eg, hydrochloride), solvate, hydrate, tautomer or stereoisomer thereof.

[0193] 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 have greater aqueous solubility and / or hydrophilicity relative to ganaxolone, e.g., as determined by a suitable measure of solubility and / or hydrophilicity such as log S, log P, log D, topological polar surface area (TPSA), acidic pKa, basic pKa, or a combination thereof.

[0194] In some aspects, the compounds disclosed herein can be prepared in the absence of solubilizing agents such as cyclodextrins (e.g., ) is administered to a subject. For example, the compounds disclosed herein may be administered to a subject in the absence of cyclodextrin (e.g., ) or can be administered to a subject with a relatively small amount of cyclodextrin (e.g., ), such as at 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 can include relatively small amounts of solubilizing agents (e.g., cyclodextrins, such as ), or does not include a solubilizing agent. For example, the pharmaceutical compositions disclosed herein may not include cyclodextrin (e.g., ), or containing relatively small amounts of cyclodextrin (e.g., ), such as less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% cyclodextrin by weight of the composition.

[0195] 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) may have higher water solubility and / or hydrophilicity relative to lipid-based derivatives of ganaxolone, e.g., as determined by suitable measures of solubility and / or hydrophilicity such as log S, log P, log D, topological polar surface area (TPSA), acidic pKa, basic pKa, or combinations thereof. The compounds disclosed herein may also have higher melting points relative to lipid-based derivatives of ganaxolone. For example, the compounds of the present disclosure can be solid (e.g., in powder or crystalline form) at ambient temperature (e.g., about 25° C.), or at a temperature between about 25° C. and about 100° C., or at a temperature between about 25° C. and about 80° C., or at a temperature between about 25° C. and about 60° C., or at a temperature between about 25° C. and about 40° C. Thus, the compounds of the present disclosure have certain advantages over lipid-based derivatives of ganaxolone, such as being more suitable for oral or intravenous administration, having greater bioavailability, and / or being easier to handle or formulate into pharmaceutical compositions for oral or intravenous administration.

[0196] 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 be converted (e.g., substantially converted) to ganaxolone by metabolic processes, for example, following administration of the compound to a subject. For example, after the compound is administered (e.g., orally or intravenously) to a subject, 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 can be, for example, removed within about 1 minute or more (e.g., about 2 minutes, about 4 minutes, about 6 minutes, about 8 minutes, or more). The ganaxolone is converted to ganaxolone within about 1 minute, 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 more.

[0197] 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 relative to the bioavailability of ganaxolone following administration of ganaxolone itself, e.g., by the same route of administration and at an equivalent dose. The bioavailability of ganaxolone can be determined by measuring serum concentrations of ganaxolone (e.g., to obtain C max or AUC).

[0198] 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 higher serum concentrations of ganaxolone relative to the serum concentrations achieved following administration of ganaxolone itself, e.g., by the same route of administration and at an equivalent dose (e.g., C maxor AUC). 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, for example, provide a longer serum half-life of ganaxolone following administration to a subject relative to the serum half-life achieved following administration of ganaxolone by, for example, the same route of administration and at an equivalent dose.

[0199] 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) can achieve a higher ganaxolone C relative to oral administration of an equivalent amount of ganaxolone. max 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) can achieve a higher AUC for ganaxolone relative 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) can achieve a higher AUC for ganaxolone relative to 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 AUC for ganaxolone relative to intravenous administration of an equivalent amount of ganaxolone.

[0200] 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 of Table 1) and a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable excipient disclosed herein).

[0201] 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 comprising administering to a subject in need thereof a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0202] For example, a method of treating a disease or disorder in a subject can comprise 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 comprise 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 pharmaceutically acceptable excipient. The compound or composition can be administered by any suitable route of administration, for example, the routes of administration disclosed herein, such as by oral administration or by intravenous administration.

[0203] Also disclosed herein are compositions for use in treating a disease or disorder in a subject, 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 of Table 1).

[0204] In other aspects, the present 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 preparation of a medicament effective for treating a disease or disorder in a subject.

[0205] The disease or disorder treated by the methods, compounds, compositions or drugs disclosed herein may be any suitable disease or disorder, such as a disease or disorder described herein. For example, the disease or disorder may be a neurological disorder. The disease or disorder may be an epileptic seizure disorder, an epileptic disorder, a genetic epilepsy disorder, an epilepsy-related disorder, a central nervous system disorder, a neurological disorder or a neurodegenerative disorder. The disease or disorder may be status epilepticus (SE). The disease or disorder may be a CDKL5 deficiency disorder. The disease or disorder may be combined tuberous sclerosis. The disease or disorder may be PCDH19-related epilepsy. The disease or disorder may be Lennox-Gastaut syndrome (LGS). BRIEF DESCRIPTION OF THE DRAWINGS

[0206] Figure 1A to Figure 1B The pharmacokinetics of exemplary ganaxolone prodrugs disclosed herein in a dog model are depicted. Figure 1A is a graph depicting mean plasma concentration (ng / mL) of Compound 111 as a function of time (h) following intravenous (5 mg / kg) or oral (25 mg / kg) administration of Compound 111 (along with vehicle) in a dog model. Figure 1B is a graph depicting mean plasma concentrations (ng / mL) of ganaxolone over time (h) following intravenous (5 mg / kg) or oral (25 mg / kg) administration of Compound 111 (along with vehicle) in a dog model.

[0207] Figures 2A to 2B The pharmacokinetics of intravenous (IV) doses of exemplary ganaxolone prodrugs disclosed herein in a dog model are depicted. Figure 2A is a graph depicting mean plasma concentrations (ng / mL) of ganaxolone (GNX) and Compound 224 over 8 hours following intravenous (2 mg / kg; bolus) administration of Compound 224 (along with vehicle) in a dog model. Figure 2B is a graph depicting the same pharmacokinetic study following IV administration of Compound 224 with the x-axis compressed (0-1 hour).

[0208] Figures 3A to 3BThe pharmacokinetics of oral (PO) doses of exemplary ganaxolone prodrugs disclosed herein in a dog model are depicted. Figure 3A is a graph depicting mean plasma concentrations (ng / mL) of ganaxolone (GNX) and Compound 224 over 36 hours following oral (10 mg / kg; bolus) administration of Compound 224 (along with vehicle) in a dog model. Figure 3B is a graph depicting the same pharmacokinetic study following PO administration of Compound 224 with the x-axis compressed (over 0-4 hours).

[0209] Figures 4A to 4B The pharmacokinetics of exemplary ganaxolone prodrugs disclosed herein in a dog model are depicted. Figure 4A is a graph depicting mean plasma concentration (ng / mL) of Compound 218 as a function of time (h) following intravenous (5 mg / kg) or oral (25 mg / kg) administration of Compound 218 (along with vehicle) in a dog model. Figure 4B is a graph depicting mean plasma concentrations (ng / mL) of ganaxolone over time (h) following intravenous (5 mg / kg) or oral (25 mg / kg) administration of Compound 218 (with vehicle) in a dog model. DETAILED DESCRIPTION

[0210] The present disclosure relates to ganaxolone derivatives. The compounds disclosed herein can be metabolized to ganaxolone (e.g., in vivo) and can be referred to as ganaxolone prodrugs. Also disclosed herein are methods of using the compounds, methods of preparing the compounds, and pharmaceutical compositions and kits containing the same.

[0211] Ganaxolone can be used to modulate GABA A , which provides the ability to treat neurological disorders, including seizures and epilepsy, as well as other disorders disclosed herein. However, due to the poor water solubility and low oral bioavailability of ganaxolone, administration of therapeutically effective amounts of ganaxolone is best achieved through intravenous infusion or through oral formulations of ganaxolone, such as aqueous suspensions, which requires frequent administration and / or administration of large amounts of the formulation. The compounds disclosed herein may address this shortcoming of ganaxolone because they have greater water solubility and bioavailability than 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 greater oral bioavailability of the compounds relative to ganaxolone allows the compounds to be readily absorbed from the intestine into the bloodstream, and the compounds are subsequently converted to ganaxolone (e.g., through metabolic processes) to achieve therapeutic concentrations of ganaxolone in the bloodstream and / or central nervous system (CNS).

[0212] Thus, the present disclosure relates to compounds comprising a ganaxolone moiety modified at a hydroxyl group with a cleavable moiety (e.g., an enzymatic cleavable moiety). For example, the cleavable moiety can be cleaved by an enzyme (e.g., an esterase) or by other mechanisms (e.g., a direct chemical mechanism). For example, following administration of a compound disclosed herein, the cleavable moiety can be cleaved (e.g., enzymatically) to provide ganaxolone. The compounds or compositions disclosed herein may be administered orally, subcutaneously, intramuscularly, intravenously, intradermally, by inhalation, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In preferred embodiments, the compounds or compositions disclosed herein are suitable for oral administration. In other preferred embodiments, the compounds or compositions disclosed herein are suitable for intravenous administration. The present disclosure also relates to methods for treating neurological disorders such as epilepsy or epileptic seizures. The methods disclosed herein may comprise orally administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof. Alternatively, the methods disclosed herein may comprise intravenously administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof.

[0213] definition

[0214] All publications cited in this disclosure (e.g., scientific journal articles, patent publications, etc.) are incorporated by reference in their entirety. To the extent that the materials incorporated by reference herein contradict or are inconsistent with this specification, this specification replaces any such materials. The citation of any reference herein is not an admission that these references are prior art to the present disclosure. Various terms related to various aspects of this specification are used throughout the specification and claims. Unless otherwise indicated, these terms should have their ordinary meaning in the art. Other specifically defined terms will be interpreted in a manner consistent with the definitions provided herein.

[0215] As used herein, the term "alkyl" refers to a group having 1 to 18 carbon atoms (C 1-18 -alkyl) such as 1 to about 12 carbon atoms (C 1-12 -alkyl), or 1 to about 6 carbon atoms (C 1-6In some embodiments, the alkyl group may be a saturated hydrocarbon group of a hydrocarbon group having an isopropyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a norbornyl group, etc. Throughout this disclosure, abbreviations for describing various alkyl groups or their derivatives known in the art may be used, such as Me (methyl), Et (ethyl), Pr (propyl) (including iPr (isopropyl)), Bu (butyl) (including tBu (tert-butyl)), Bn (benzyl). Each example of an alkyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0216] As used herein, the term "alkenyl" refers to a group of straight or branched hydrocarbon groups having 2 to 18 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds. For example, an alkenyl group can have 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 In some embodiments, the present invention provides an alkylene radical. The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of alkylene radicals include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, and the like. Each example of an alkylene radical may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl").

[0217] As used herein, the term "alkynyl" refers to a group of straight or branched hydrocarbon groups having 2 to 18 carbon atoms and one or more carbon-carbon triple bonds. Alkynyl groups can have 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 (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. Each instance of an alkynyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkynyl").

[0218] As used herein, the term "heteroalkyl" refers to a non-cyclic stable linear or branched chain or combination thereof, comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S and Si may be located at any position of the heteroalkyl group. When "heteroalkyl" is listed, a specific heteroalkyl group is then listed such as -(CH2)-C(O)-OH, -N(R G1 )(R G2 ) etc., the terms heteroalkyl and –(CH2)-C(O)-OH, –N(R G1 )(R G2 ) are not redundant nor mutually exclusive. Rather, specific heteroalkyl groups are listed for clarity. Therefore, the term "heteroalkyl" should not be interpreted herein to exclude specific heteroalkyl groups such as -(CH2)-C(O)-OH, -N(R G1 )(R G2 ), etc. Each instance of a heteroalkyl group can independently be optionally substituted, i.e., unsubstituted (an “unsubstituted heteroalkyl”) or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a “substituted heteroalkyl”).

[0219] As used herein, the term "haloalkyl" refers to a non-cyclic linear or branched chain, or combinations thereof, comprising at least one carbon atom and at least one halogen (e.g., F, Cl, Br, and I). The halogen atom may be located at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CCl3, -CH2-CF3, -CH2-CCl3, -CH2-Cl, and -CH2-I. Each instance of a haloalkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted haloalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted haloalkyl").

[0220] As used herein, the term "alkoxy" refers to a group of the formula -O-alkyl. The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include haloalkoxy groups. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, 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.

[0221] As used herein, the term "aryl" refers to a stable aromatic ring system, which may be monocyclic or polycyclic, in which all ring atoms are carbon, and which may be substituted or unsubstituted. An aromatic ring system may have, for example, 3-7 ring atoms. Examples include phenyl (Ph), naphthyl, anthracenyl, and the like. Each instance of an aryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents.

[0222] As used herein, the term "heteroaryl" refers to an aryl group containing one or more ring heteroatoms. For example, a heteroaryl group may include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, or 9-membered bicyclic aromatic heterocycle consisting of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may 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.

[0223] As used herein, the term "cycloalkyl" refers to a group of non-aromatic cyclic hydrocarbon groups having three to ten carbon atoms in a ring structure and zero heteroatoms in a non-aromatic ring structure. Cycloalkyl can include cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, etc. Cycloalkyl groups can be monocyclic ("monocyclic cycloalkyl") or contain fused, bridged or spirocyclic ring systems, such as bicyclic systems ("bicyclic cycloalkyl"), and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes a ring system in which a cycloalkyl ring as defined above is fused to one or more aryl groups (wherein the attachment point is on the cycloalkyl ring), and in such examples, the carbon number continues to specify the carbon number in the cycloalkyl ring system. Each example of a cycloalkyl group can be optionally substituted independently, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") by one or more substituents.

[0224] As used herein, the term "heterocyclyl" refers to a group (i.e., a heterocyclic group) of a 3 to 10 yuan non-aromatic ring structure comprising atoms of at least two different elements in one or more rings. Heteroatoms can be selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In heterocyclyl groups containing one or more nitrogen atoms, when valence allows, the point of attachment can be a carbon or nitrogen atom. The heterocyclyl group can be monocyclic ("monocyclic heterocyclic radical") or fused, bridged or spirocyclic system, such as a bicyclic system ("bicyclic heterocyclic radical"), and can be saturated or can be partially unsaturated. The heterocyclyl bicyclic system can include one or more heteroatoms in one or two rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl or heterocyclyl ring, or a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Each instance of heterocyclyl can independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. Additional reference: Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997, as evidence that heterocyclyl is a well-recognized term in the field of organic chemistry.

[0225] Unless otherwise indicated, the terms "alkylene," "alkenylene," "alkynylene," or "heteroalkylene," by themselves or as part of another substituent, mean a divalent radical derived from an alkyl, alkenyl, alkynyl, or heteroalkyl group, respectively. For example, unless otherwise indicated, the term "alkenylene," by itself or as part of another substituent, means a divalent radical derived from an alkene. In the case of a heteroalkylene group, heteroatoms may also occupy one or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for 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, the formula -C(O)2R'- may represent both -C(O)2R'- and -R'C(O)2-. Each instance of an alkylene, alkenylene, alkynylene, or heteroalkylene group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkylene") or substituted ("substituted heteroalkylene") with one or more substituents.

[0226] As used herein, the terms "cycloalkylene," "heterocyclylene," "arylene," and "heteroarylene," by themselves or as part of another substituent, mean a divalent radical derived from cycloalkyl, heterocyclyl, aryl, and heteroarylene, respectively. Each instance of cycloalkylene, heterocyclylene, arylene, or heteroarylene can independently be optionally substituted, i.e., unsubstituted ("unsubstituted arylene") or substituted ("substituted heteroarylene") with one or more substituents.

[0227] As used herein, the term "dipeptide" refers to a portion consisting of two amino acid residues. For example, the dipeptides disclosed herein may be leucine-leucine (leu-leu), glycine-alanine (gly-ala), glycine-valine (gly-val). The dipeptide may be substituted or modified at any amino acid residue or both, for example to attach the dipeptide to another group or atom at the C-terminus or N-terminus or both. For example, the compounds disclosed herein may include a dipeptide having a free N-terminus (i.e., -NH2) and a C-terminus modified to form an ester group, or the compounds disclosed herein may include a dipeptide having an N-terminus modified to form a carbamate group and a C-terminus modified to form an ester group.

[0228] As used herein, the term "cyano" or "—CN" refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, eg, C≡N.

[0229] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0230] As used herein, the term "hydroxy" refers to a group of formula -OH.

[0231] As used herein, the term "nitro" refers to a substituent having two oxygen atoms bonded to a nitrogen atom, for example -NO2.

[0232] 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 =O in a carbonyl group (C=O). Oxo can be used to refer to compounds substituted with a double-bonded oxygen, for example, "oxo" can be used to refer to the oxygen substituent in -CH2-C(O)-CH3.

[0233] 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 alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, heteroalkenyl, heteroalkenylene, heteroalkynyl, heteroalkynylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl, heteroarylene moieties and the like, having substituents replacing one or more hydrogen atoms on one or more carbon or heteroatom(s) respectively of such moiety. Generally, the term "substituted" means that at least one hydrogen present on a group (eg, a hydrogen bonded to a carbon or nitrogen atom of the group) is replaced with a suitable substituent, such as described herein.Such substituents can be any suitable substituents, including, for example, alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –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), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0234] As used herein, the term "blocking group" refers to a group that is used to temporarily block a specific functional moiety (e.g., O, S, or N) so that a reaction can be selectively carried out at another reaction site in a multifunctional compound. It will be appreciated by those of ordinary skill in the art that synthetic methods and compounds as described herein can utilize a variety of blocking groups. Blocking groups can be introduced and removed at the appropriate stage during compound synthesis using methods known to those of ordinary skill in the art. Blocking groups are applied according to standard methods for organic synthesis as described in the literature (Theodora W. Greene and Peter G.M. Wuts (2007) Protecting Groups in Organic Synthesis, 4th edition, John Wiley and Sons, incorporated herein by reference in its entirety).

[0235] 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 (tert-butyldimethylsilyl ether), tribenzylsilyl ether, TBDPS (tert-butyldiphenylsilyl ether), esters (e.g., formates, acetates, benzoates (Bz), trifluoroacetates, dichloroacetates), carbonates, cyclopentane ... Acetals and ketals. In addition, nitrogen or amino protecting groups include, but are not limited to, carbamates (including methyl, ethyl, and substituted ethylcarbamates (e.g., Boc or Troc)), amides, cyclic imide derivatives, N-alkyl and N-arylamines, imine derivatives, and enamine derivatives. Amino protecting groups include, but are not limited to, fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), carboxylbenzyl (Cbz), acetamide, trifluoroacetamide, and the like. Certain other exemplary protecting groups are described in detail herein; however, it should be understood that the present disclosure is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups may be utilized according to methods known to those skilled in the art.

[0236] The compounds provided herein may exist in one or more specific 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; iso and trans forms; syncline and anticline forms; α and β forms; axial and equatorial forms; boat, chair, torsion, envelope and semi-chair forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0237] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In one embodiment, the stereochemistry depicted in the compound is relative rather than absolute. Isomers can be separated from the mixture by methods known to those skilled in the art, including 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 compounds described herein as individual isomers substantially free of other isomers and alternatively as mixtures of various isomers.

[0238] As used herein, a pure enantiomer compound is substantially free of the other enantiomer or stereoisomer of the compound (i.e., 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 over the "R" form. Alternatively, using another notation, the (+) form of the compound is substantially free of the (-) form of the compound, and is therefore in enantiomeric excess over the (-) form. The term "enantiomerically pure" or "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, greater than 99.9% or more of the enantiomer by weight. The weight can be based on the total weight of all enantiomers or stereoisomers of the compound.

[0239] The enantiomerically pure compounds disclosed herein may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. The diastereomerically pure compounds disclosed herein may also be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising a diastereomerically pure exo-compound may comprise, for example, about 90% excipient and about 10% diastereomerically pure exo-compound.

[0240] The active ingredients of the compositions disclosed herein may be formulated with little or no excipients or carriers.

[0241] The compounds disclosed herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H (D or deuterium), 3 H (T or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; N can be in any isotopic form, including 14 N and 15 N; F can be in any isotopic form, including 18 F. 19 F, etc.

[0242] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound prepared with a relatively nontoxic acid or base, depending on the specific substituent found on the corresponding compound. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (pure or in a suitable solvent (e.g., inert solvent)). 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 invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (pure or in a suitable solvent (e.g., inert solvent)). The example of pharmaceutically acceptable acid addition salt includes those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain compounds of the present disclosure may contain both basic and acidic functional groups, which allow the compound to be converted into base addition salts or acid addition salts. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the present invention.

[0243] As used herein, the term "solvate" refers to a form of a compound that is typically associated with a solvent by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), ether, and the like. The compounds of the present disclosure can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and also include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0244] As used herein, the term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a definite ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and where x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1), such as a hemihydrate (R·0.5H2O), and a polyhydrate (x is a number greater than 1, such as a dihydrate (R·2H2O) and a hexahydrate (R·6H2O).

[0245] As used herein, the term "tautomer" refers to interchangeable forms of a particular compound structure and compounds in which the displacement of hydrogen atoms and electrons is different. Thus, the two structures can be in equilibrium by the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert by treatment with an acid or base. Another example of tautomerism is the acid form and nitro form of phenylnitromethane, which are also formed by treatment with an acid or base. Tautomeric forms may be relevant to the optimal chemical reactivity and biological activity of the compound of interest.

[0246] Other definitions

[0247] The articles "a" and "an" are used herein to refer to one or to more than one (ie, 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.

[0248] The term "about" when referring to a measurable value such as an amount, duration, and the like is meant to encompass variations of ±20% or less, or in some cases ±15% or less, or in some cases ±10% or less, or in some cases ±5% or less, or in some cases ±1% or less, or in some cases ±0.1% or less relative to the specified value, as such variations are appropriate, e.g., to perform the disclosed methods.

[0249] As used herein, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., elements that are present in combination in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so combined. In addition to the elements specifically designated by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically designated. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising," a reference to "A and / or B" may, in one embodiment, refer to only A (optionally including elements other than B); in another embodiment, only B (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); and so on.

[0250] As used herein, the term "effective amount" refers to an amount of a compound, or composition or formulation of the compound (e.g., a ganaxolone derivative or prodrug, or a pharmaceutical composition thereof) as described herein that is sufficient to achieve the desired result under the conditions of administration. For example, an effective amount of a compound, or composition or formulation of the compound disclosed herein for treating an epileptic disorder is an amount that can control seizure activity, suppress seizures, allow the patient to recover from a state of hyperexcitement, prevent recurrence of seizures, or provide sustained suppression of seizures. A skilled clinician can determine the appropriate dosage based on a variety of considerations, including the severity of the disorder, the age, weight, general health of the subject, and other considerations. Typically, the compound is administered in an amount of about 0.01 mg to about 1800 mg.

[0251] As used herein, the term "pharmaceutical composition" is a composition comprising at least one active agent (which may be any compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, such as any ganaxolone derivative or prodrug disclosed herein) and at least one other substance, such as an excipient (e.g., a pharmaceutically acceptable excipient). Pharmaceutical compositions optionally contain one or more additional active agents. When specified, pharmaceutical compositions comply with the U.S. FDA's GMP (Good Manufacturing Practice) standards for human or non-human pharmaceuticals. A "pharmaceutical combination" is a combination of at least two active agents that can be combined in a single dosage form or provided together in separate dosage forms with instructions for using the active agents together to treat a disorder, such as 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 disorder, such as status epilepticus, CDKL5 deficiency disorder, combined tuberous sclerosis, PCDH19-related epilepsy, or Lennox-Gestapo syndrome (LGS).

[0252] As used herein, the term "pharmaceutically acceptable excipient" refers to a non-toxic material that can be formulated with the compounds disclosed herein to provide a pharmaceutical composition. Preferably, the pharmaceutically acceptable excipient is inert and does not interfere with the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable excipients that can be used to prepare the pharmaceutical compositions disclosed herein are any of those well known in the art and include, but are not limited to, diluents, dispersants, granulating agents, surfactants, emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, ion exchangers, salts, electrolytes, waxes, and / or oils. For example, pharmaceutically acceptable excipients can be alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), phosphate esters, 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose or its derivatives, polyethylene glycol or its derivatives (e.g., PEG-300), sodium carboxymethyl cellulose, polyacrylates, polyethylene-polyoxypropylene block polymers, lanolin, cyclodextrins (e.g., ), dimethylacetamide (DMA), polysorbates (e.g., For example ), or a combination thereof.

[0253] As used herein, the term "subject" refers to any animal, such as any mammal, including but not limited to humans, non-human primates, rodents, etc. Non-human primates include chimpanzees, crab-eating macaques, spider monkeys, and macaques (e.g., rhesus macaques). Rodents include mice, rats, marmots, ferrets, rabbits, and hamsters. Domestic and game animals include cattle, horses, pigs, deer, bison, buffaloes, felines (e.g., house cats), canines (e.g., dogs, foxes, wolves), birds, and fish. In some embodiments, the subject is a mammal (e.g., humans, rats, or mice). The subject may be male or female. The subject may be of any age, including elderly subjects (e.g., 65 years of age or older), non-elderly subjects (e.g., less than 65 years of age), or pediatric subjects (e.g., 18 years of age or younger). In some embodiments, the subject is human.

[0254] As used herein, the term "treat," "treatment," or grammatically related terms refers to a method for reducing the effects of a disease or disorder. As is readily understood in the art, complete eradication of a disease, disorder, or its symptoms is preferred, but not necessary for treatment. The desired therapeutic effect includes, but is not limited to, preventing the occurrence or recurrence of a disease or disorder, alleviating symptoms, reducing any direct or indirect pathological consequences of a disease or disorder, or other improvements in any signs, symptoms, or consequences of a disease or disorder, such as prolonging lifespan, reducing morbidity, and / or alleviating side effects.

[0255] Throughout this disclosure, various embodiments can be presented in range form. It should be understood that the description of range form is merely for convenience and brevity, and should not be construed as an inflexible limitation to the scope of the invention. Therefore, the description of a range should be considered to specifically disclose all possible subranges and individual numerical values ​​within the range. For example, a description such as a range of 1 to 6 should be considered to have specifically disclosed subranges, such as 1 to 5, 1 to 4, 1 to 3, 2 to 6, 2 to 4, 3 to 6, etc., as well as individual digits within the range, such as 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 width of the range.

[0256] Various embodiments of the compounds, compositions, kits, and methods herein are described in further detail below, and additional definitions may be provided throughout the specification.

[0257] Compound

[0258] The compounds disclosed herein may comprise the structure of Formula (I):

[0259]

[0260] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein:

[0261] Y is –C(O)– or –C(R A )(R B )– (e.g., –CH2–);

[0262] 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;

[0263] 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, heterocyclyl-alkyl, heterocyclyl-heteroalkyl, –OC(O)-alkyl, –C(O)O-alkyl, –OC(O)-heteroalkyl, –C(O)O-heteroalkyl, –N3, –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;

[0264] R 1 and R 2 each is 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0265] or R 1 and R 2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0266] 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0267] 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, heterocyclyl, aryl or heteroaryl is optionally substituted; and

[0268] R A and R B Each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0269] Each optional substituent of a group in Formula (I) (e.g., an optional substituent 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 the substituents described herein. For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-C8 heterocyclyl, e.g., morpholinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, or N-Boc-azacyclo alkyl), aryl (e.g., phenyl), heteroaryl (e.g., pyrrolyl, imidazolyl, or indolyl), halogen (e.g., –F, –Cl, –Br, or –I), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., methoxy (–OMe), ethoxy (–OEt), or benzyloxy (–OBn)), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, carboxylate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfinyl, sulfonyl, alkylsulfinyl, sulfonate, 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) may be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above. ,

[0270] In some aspects, Y is -C(O)-, and X is -NR 1 R 2 、–OR 3 or –SR 4 For example, Y may be -C(O)- and X may be -NR 1 R 2 ; Y may be –C(O)– and X may be –OR 3 ; or Y may be -C(O)- and X may be -SR 4 In some aspects, Y is -C(O)-, and Z is an optionally substituted alkylene. For example, Y can be -C(O)-, and Z can be an unsubstituted methylene; or Y can be -C(O)-, and Z can be an unsubstituted methylene. In some aspects, Y is -C(O)-; X is -NR 1 R 2 、–OR 3 or –SR 4 ; and Z is an optionally substituted alkylene. For example, Y may be -C(O)-, and X may be -NR 1 R 2 , and Z may be an unsubstituted methylene; Y may be -C(O)-, and X may be -OR 3 , and Z may be an unsubstituted methylene; Y may be –C(O)–, and X may be –SR 4 , and Z may be an unsubstituted methylene; Y may be -C(O)-, and X may be -NR 1 R 2 , and Z may be a substituted methylene; Y may be -C(O)-, and X may be -OR 3 , and Z may be a substituted methylene; Y may be -C(O)-, and X may be -SR 4 , and Z may be a substituted methylene group.

[0271] In some embodiments, Z is methylene (e.g., unsubstituted methylene). In some embodiments, Z is 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 (e.g., with a substituent described herein); R 2 is hydrogen or alkyl; and R B and R C is each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted (e.g., with substituents described herein); and each represents the point of attachment of Z to X or Y. In some embodiments, Z1 is absent.

[0272] In some embodiments, Z 1 is an optionally substituted alkylene (e.g., an optionally substituted methylene), wherein the optional substituent is a substituent as described herein. In some embodiments, Z is an unsubstituted methylene. In some embodiments, Z 1 is absent.

[0273] In some embodiments, Z is where R B 、R C and R 2 are each independently hydrogen, –N(R 2 )- is attached to Y, the carbonyl group is attached to X, and Z1 is as defined herein (e.g., unsubstituted methylene). In some embodiments, Z is where R B and R C are each independently hydrogen, –S–C(R B )(R C )- is attached to Y, the carbonyl group is attached to X, and Z1 is as defined herein (e.g., unsubstituted methylene). In some embodiments, Z is where R B and R C are each independently hydrogen, –O–C(R B )(R C )- is attached to Y, the carbonyl group is attached to X, and Z1 is as defined herein (e.g., unsubstituted methylene). In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is absent.

[0274] In some embodiments, R 1 is hydrogen, and R 2 In some embodiments, R 1 and R 2 One of them is hydrogen, and R 1 and R 2 The other of is optionally substituted alkyl. In some embodiments, R 1 and R 2 One of them is hydrogen, and R 1 and R 2 The other is an optionally substituted heteroalkyl. The alkyl or heteroalkyl group may be substituted with any suitable substituent, such as the substituents described herein. For example, the alkyl or heteroalkyl group may be substituted with one or more of an alkyl, oxo, or hydroxyl group.

[0275] Y may be –C(O)–, and X may be –NR 1 R 2 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 1 and R 2 Each of may independently be hydrogen; Y may be -C(O)-, X may be -NR 1 R 2 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), R 1 may be hydrogen, and R 2 can be substituted alkyl (e.g., alkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxy, heterocyclyl, aryl, or heteroaryl groups); or Y can be —C(O)—, and X can be —NR 1 R 2 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), R 1 may be hydrogen, and R 2 It can be a substituted heteroalkyl group (e.g., a heteroalkyl group substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups). For example, Y can be -C(O)-, and X can be -NR 1 R 2 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), R 1 may be hydrogen, and R 2 It may be a substituted tert-butyl group (for example, a tert-butyl group substituted with an oxo group and a hydroxyl group). For example, Y may be -C(O)-, and X may be -NR 1 R 2 , Z can be an unsubstituted methylene, R 1 may be hydrogen, and R 2It may be a tert-butyl group substituted with an oxo and hydroxyl group; or Y may be -C(O)-, and X may be -NR 1 R 2 , Z can be a substituted methylene, R 1 may be hydrogen, and R 2 It may be tert-butyl substituted with oxo and hydroxy groups.

[0276] Y may be –C(O)–, and X may be –OR 3 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 3 can be hydrogen; Y can be –C(O)–, and X can be –OR 3 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 3 can be optionally substituted alkyl (e.g., alkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxy, heterocyclyl, aryl, or heteroaryl groups); or Y can be —C(O)—, and X can be —OR 3 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 3 can be an optionally substituted heteroalkyl group (e.g., a heteroalkyl group substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups). For example, Y can be —C(O)—, and X can be —OR 3 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 3 It may be a substituted tert-butyl group (eg, a tert-butyl group substituted with an oxo, thiol, hydroxyl, and / or amino group). For example, Y may be -C(O)-, and X may be -OR 3 , Z may be an unsubstituted methylene, and R 3 It may be a tert-butyl group substituted with an oxo, thiol, hydroxyl and / or amino group; or Y may be -C(O)-, and X may be -OR 3 , Z may be a substituted methylene group, and R 3 The tert-butyl group may be substituted with oxo, hydroxyl, thiol and / or amino groups.

[0277] Y may be –C(O)–, and X may be –SR 4 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 4 can be hydrogen; Y can be –C(O)–, and X can be –SR 4 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 4 can be optionally substituted alkyl (e.g., alkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxy, heterocyclyl, aryl, or heteroaryl groups); or Y can be —C(O)—, and X can be —SR4 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 4 can be an optionally substituted heteroalkyl group (e.g., a heteroalkyl group substituted with one or more alkyl, oxo, thiol, amino, hydroxyl, heterocyclyl, aryl, or heteroaryl groups). For example, Y can be -C(O)-, and X can be -SR 4 , Z may be an optionally substituted alkylene group (eg, an optionally substituted methylene group), and R 4 It may be a substituted tert-butyl group (e.g., a tert-butyl group substituted with an oxo, thiol, hydroxyl, and / or amino group). For example, Y may be -C(O)-, and X may be -SR 4 , Z may be an unsubstituted methylene group, and R 4 It may be a tert-butyl group substituted with oxo, thiol, hydroxyl and / or amino groups; or Y may be -C(O)-, and X may be -SR 4 , Z may be a substituted methylene group, and R 4 The tert-butyl group may be substituted with oxo, hydroxyl, thiol and / or amino groups.

[0278] The compound of formula (I) may be a compound of formula (II):

[0279]

[0280] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein:

[0281] 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, heterocyclyl-alkyl, heterocyclyl-heteroalkyl, –OC(O)-alkyl, –C(O)O-alkyl, –OC(O)-heteroalkyl, –C(O)O-heteroalkyl, –N3, –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;

[0282] R 1 and R 2each is 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0283] or R 1 and R 2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0284] 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

[0285] R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

[0286] Each optional substituent of a group in Formula (II) (e.g., an optional substituent 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 the substituents described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0287] In the compounds disclosed herein, such as compounds of formula (I) or formula (II), X may be a moiety selected from the group consisting of

[0288]

[0289]

[0290] in

[0291] R 2 is hydrogen or alkyl;

[0292] M is –C(H)(R D )– (e.g., –CH2–), –O–, or –N(R D )–(e.g., –N(Me)–);

[0293] P is an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which may be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group),

[0294] or P is a dipeptide moiety (e.g., a leucine-leucine moiety) which may comprise D-amino acids, L-amino acids, or a combination thereof and is optionally substituted (e.g., at one or more nitrogen atoms, e.g., at a terminal nitrogen atom, e.g., with a carbonate group such as a carboxybenzyl (Cbz) group);

[0295] Q is heteroalkyl or heterocyclyl, wherein the heteroalkyl or heterocyclyl is optionally substituted;

[0296] V is –O–, –N(H)–, or –N(Me)–;

[0297] X2 and X3 are each independently -CH2-, -O-, -S- or -N(R G3 )–(e.g., –NH–);

[0298] 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;

[0299] R F and R H are each independently hydrogen or alkyl;

[0300] R G1 and R G2 each independently hydrogen, alkyl or an amino acid residue (e.g. glycine, alanine, valine, leucine or proline), which may be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g. at the terminal nitrogen atom, for example by a carbonate group such as a carboxybenzyl (Cbz) group),

[0301] or R G1 and R G2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0302] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0303] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0304] R G5 is hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0305] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted;

[0306] R P is halo (e.g., chloro), heterocyclyl (e.g., morpholinyl), –NH-alkyl, –NH-heteroalkyl, –N-(alkyl)2 (e.g., –N(Me)2), or –N-(heteroalkyl)2 (e.g., –N(CH2CH2OH)2);

[0307] R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, –OR J ,–N(R G3 )(R G4 ), –NO2, –CN or –NC;

[0308] R 11 、R 12 、R 13 and R14 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,

[0309] or R 11 and R 12 One of them, and R 13 and R 14 One of the following, taken together with the atoms to which they are attached, forms a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0310] R 15 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted;

[0311] m is an integer from 1 to 5;

[0312] p is an integer between 0 and 4; and

[0313] represents the point of attachment of X to another group of the compound, for example, the point of attachment of X to Z or, when Z is absent, to Y in formula (I), or the point of attachment of X to -C(R) in formula (II). 7A )(R 7B ) group is attached to a carbon atom of the

[0314] Each optional substituent of the groups described above (e.g., an optional substituent 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 the substituents described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0315] 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), it may comprise one or more D-amino acids, L-amino acids, or a combination thereof. The amino acid residue or dipeptide moiety may be attached via its C-terminus and may also comprise a free N-terminus or an N-terminus that is optionally substituted with, for example, a carboxybenzyl (Cbz) group. The amino acid residue or dipeptide moiety may alternatively be attached via its N-terminus and may also comprise a free C-terminus (e.g., —C(O)OH), an optionally substituted C-terminus.

[0316] In some embodiments, X is R 2 H, R B and R C are each independently an alkyl group (eg, a methyl group), and R K For hydrogen.

[0317] In some embodiments, Y is -C(O)- and Z is alkylene (eg, methylene), and X is

[0318] In some embodiments, when X is -NR 1 R 2 When R 1 and R 2 In some embodiments, when X is -NR 1 R 2 , and R 1 When it is hydrogen, R 2 is not an unsubstituted alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecyl, or dodecyl). In some embodiments, when X is —NR 1 R 2 , and R 1 When R is an alkyl group (e.g., a methyl group), 2 It is not an unsubstituted alkyl group (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecyl, or dodecyl).

[0319] In some embodiments, when X is -OR 3 When R 3 In some embodiments, when X is -OR 3 When R 3It is not an unsubstituted alkyl group (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecyl, or dodecyl).

[0320] In some embodiments, when X is -SR 4 When R 4 In some embodiments, when X is -SR 4 When R 4 It is not an unsubstituted alkyl group (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecyl, or dodecyl).

[0321] In the compounds disclosed herein, such as compounds of formula (I) or formula (II), X may be a moiety selected from the group consisting of

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] in represents the point of attachment of X to another group of the compound, for example, the point of attachment of X to Z or, when Z is absent, to Y in formula (I), or the point of attachment of X to -C(R) in formula (II). 7A )(R 7B ) group is attached to a carbon atom of the

[0336] The compound of formula (I) or formula (II) may be a compound of formula (IA):

[0337]

[0338] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0339] R 1 and R 2 each is 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0340] or R 1 and R 2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted; and

[0341] R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

[0342] In some embodiments, R 1 and R 2 are each independently hydrogen. In some embodiments, R 1 is hydrogen, and R 2 is optionally substituted alkyl (e.g., alkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxy, heterocyclyl, aryl, or heteroaryl groups). 1 is hydrogen, and R 2 is optionally substituted heteroalkyl (e.g., heteroalkyl substituted with one or more alkyl, oxo, thiol, amino, hydroxy, heterocyclyl, aryl, or heteroaryl groups). 7A and R 7B Each independently is hydrogen. For example, R 1 、R 7A and R 7B are each independently hydrogen, and R 2 It may be tert-butyl substituted with oxo and hydroxy groups.

[0343] -N(R1 )(R 2 ) group may be a moiety selected from the group consisting of

[0344]

[0345] in

[0346] R 2 is hydrogen or alkyl;

[0347] M is –C(H)(R D )– (e.g., –CH2–), –O–, or –N(R D )–(e.g., –N(Me)–);

[0348] Q is heteroalkyl or heterocyclyl, wherein the heteroalkyl or heterocyclyl is optionally substituted;

[0349] V is –O–, –N(H)–, or –N(Me)–;

[0350] 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;

[0351] and Indicates the nitrogen atom and –C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0352] Each optional substituent of a group in Formula (IA) (e.g., an optional substituent 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 the substituents described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0353] -N(R 1 )(R 2 ) group may be a moiety selected from the group consisting of

[0354]

[0355]

[0356]

[0357]

[0358]

[0359] in Indicates the nitrogen atom and –C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0360] The compound of formula (I), formula (II) or formula (IA) may be a compound of formula (IA-a):

[0361]

[0362] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0363] G does not exist, is –C(O)– or –C(R 8A )(R 8B )– (e.g., –CH2–),

[0364] K is alkylene, heteroalkylene, -C(O)-, -OC(O)-, -C(O)O-, -O-, -O-(CH2)-, or -(CH2)-O-, wherein the alkylene or heteroalkylene is optionally substituted;

[0365] R 2 、R 7A 、R 7B 、R 8A and R 8B are each independently hydrogen or optionally substituted alkyl; and

[0366] R 9is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0367] It should be understood that when K is -OC(O)- or -(CH2)-O-, the -OC(O)- or -(CH2)-O- group can be attached to G and R in either orientation. 9 groups (in other words, these groups can be considered equivalent to –C(O)O– and –O–(CH2)–, respectively). For example, when G is –C(R 8A )(R 8B )- and K is OC(O)-, it should be understood that the description In some embodiments, G is -C(R 8A )(R 8B )– and K is –OC(O)–, and the carbonyl group in –OC(O)– is bonded to G, i.e.

[0368] Each optional substituent of a group in Formula (IA-a) (e.g., an optional substituent 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 the substituents described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0369] In some embodiments, G is -C(R 8A )(R 8B )-, for example, -C(CH3)2-. In some embodiments, K is -OC(O)-. In some embodiments, R 2 In some embodiments, R 7A and R 7B are each independently hydrogen. In some embodiments, R 9 In some embodiments, R 8A and R 8B Each is independently an alkyl group (e.g., methyl). For example, G can be -C(CH3)2-. In some embodiments, G is -C(CH3)2-, K is -OC(O)-, and R 2 、R 7A and R 7B are each independently hydrogen.

[0370] The compound of formula (I), formula (II), formula (IA) or formula (IA-a) may be a compound of formula (IA-b):

[0371]

[0372] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0373] R 2 、R 8A and R 8B are each independently hydrogen or optionally substituted alkyl; and

[0374] R 9 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0375] In some embodiments, R 2 In some embodiments, R 8A and R 8B Each is independently alkyl (eg, methyl). In some embodiments, R 8A and R 8B Each independently represents a methyl group. For example, R 2 may be hydrogen and R 8A and R 8BIn some embodiments, R 9 For hydrogen.

[0376] In some embodiments, R 2 is hydrogen, R 8A and R 8B are each independently methyl, and R 9 For hydrogen.

[0377] The compound of formula (I) or formula (II) may be a compound of formula (IB):

[0378]

[0379] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0380] 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

[0381] R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

[0382] -O-(R 3 ) group may be a moiety selected from the group consisting of

[0383]

[0384] in

[0385] P is an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which may be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group),

[0386] or P is a dipeptide moiety (e.g., a leucine-leucine moiety) which may comprise D-amino acids, L-amino acids, or a combination thereof and is optionally substituted (e.g., at one or more nitrogen atoms, e.g., at a terminal nitrogen atom, e.g., with a carbonate group such as a carboxybenzyl (Cbz) group);

[0387] 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;

[0388] R F and R H are each independently hydrogen or alkyl;

[0389] R G1 and R G2 each independently hydrogen, alkyl or an amino acid residue (e.g. glycine, alanine, valine, leucine or proline), which may be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g. at the terminal nitrogen atom, for example by a carbonate group such as a carboxybenzyl (Cbz) group),

[0390] or R G1 and R G2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0391] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0392] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0393] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted;

[0394] R K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0395] R P is halo, –NH-alkyl, –NH-heteroalkyl, –N-(alkyl)2 (e.g., –N(Me)2), –N-(heteroalkyl)2 (e.g., –N(CH2CH2OH)2), or heterocyclyl (e.g., morpholinyl);

[0396] m is an integer from 1 to 5; and

[0397] Indicates the oxygen atom and –C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0398] Each optional substituent of a group in Formula (IB) (e.g., an optional substituent 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 the substituents described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0399] -O-(R 3 ) group may be a moiety selected from the group consisting of

[0400]

[0401]

[0402]

[0403]

[0404]

[0405] in Indicates the oxygen atom and –C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0406] The compound of formula (I) or formula (II) may be a compound of formula (IC):

[0407]

[0408] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0409] 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, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

[0410] R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

[0411] In formula (IC), –S-(R 4 ) group may be a moiety selected from the group consisting of

[0412]

[0413] in

[0414] 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;

[0415] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0416] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0417] R G5 is hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0418] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted;

[0419] R K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0420] R P is halo, –NH-alkyl, –NH-heteroalkyl, –N-(alkyl)2 (e.g., –N(Me)2), –N-(heteroalkyl)2 (e.g., –N(CH2CH2OH)2), or heterocyclyl (e.g., morpholinyl); and

[0421] represents the sulfur atom and –C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0422] Each optional substituent of a group in Formula (IC) (e.g., an optional substituent 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 the substituents described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0423] In formula (IC), –S-(R 4 ) group may be a moiety selected from the group consisting of

[0424] in represents the sulfur atom and –C(R 7A )(R 7B ) group is attached to a carbon atom of the

[0425] The compound of formula (I) or formula (II) may be a compound of formula (ID):

[0426]

[0427] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof,

[0428] in

[0429] 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, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclylene, aryl or heteroaryl is optionally substituted.

[0430] –R in formula (ID) 5 The group may be a moiety selected from the group consisting of

[0431]

[0432] in

[0433] X2 and X3 are each independently -CH2-, -O-, -S- or -N(R G3 )–(e.g., –NH–);

[0434] R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, –OR J ,–N(R G3 )(RG4 ), –NO2, –CN or –NC;

[0435] 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,

[0436] or R 11 and R 12 One of them, and R 13 and R 14 One of the following, taken together with the atoms to which they are attached, forms a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0437] R 15 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted;

[0438] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0439] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0440] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted;

[0441] and

[0442] p is an integer between 0 and 4; and

[0443] Represents R 5 The point of attachment of the group to the carbon atom of the –C(O)– group.

[0444] Each optional substituent of a group in Formula (ID) (e.g., an optional substituent 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 the substituents described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0445] –R in formula (ID) 5 The group may be a moiety selected from the group consisting of

[0446] in Represents R 5 The point of attachment of the group to the carbon atom of the –C(O)– group.

[0447] The compound of formula (I) or formula (II) may be a compound of formula (IE):

[0448]

[0449] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

[0450] R 6 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, —OC(O)-alkyl, —C(O)O-alkyl, —OC(O)-heteroalkyl, —C(O)O-heteroalkyl, —N, —SH, or —S-alkyl (e.g., —S-Me), wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and

[0451] R A and R B Each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[0452] R in formula (IE) 6 The group may be a moiety selected from the group consisting of

[0453]

[0454] in

[0455] R G3 and R G4 are each independently hydrogen, alkyl, or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted;

[0456] or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0457] R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted;

[0458] and Represents R 6 Group and –C(R A )(R B ) – point of attachment to a carbon atom of a group.

[0459] Each optional substituent of a group in Formula (IE) (e.g., an optional substituent 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 the substituents described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0460] R in formula (IE) 6 The group may be a moiety selected from the group consisting of

[0461] in Represents R 6 Group and –C(R A )(R B ) – point of attachment to a carbon atom of a group.

[0462] The compound of the present disclosure may be a compound of formula (I-II):

[0463]

[0464] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein:

[0465] Indicates a single bond or a double bond;

[0466] Y 1 is alkylene (e.g., methylene), alkenylene, alkynylene, heteroalkylene, -C(O)-, -OC(O)-, -C(O)O-, -NR 1 -, -O-, or -S-, wherein the alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted;

[0467] 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 =0, wherein the heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0468] R 1 and R 2each is 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0469] or R 1 and R 2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted;

[0470] 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, heterocyclyl-alkyl, or heterocyclyl-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkylene, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0471] 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, heterocyclyl, aryl or heteroaryl is optionally substituted;

[0472] R 7A and R 7B are each independently hydrogen or optionally substituted alkyl, or R 7A and R 7B One of them is bonded to Y through one or more carbon atoms or heteroatoms 1 to form a cyclic moiety (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl, e.g., pyrrole), and R 7A and R 7B The other of the groups is hydrogen or optionally substituted alkyl;

[0473] R 7C and R 7Dare 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

[0474] R 7E and R 7F Each independently does not exist, is hydrogen, alkyl, heteroalkyl, -NR 1 R 2 、–OR 3 or -SR4, wherein the alkyl or heteroalkyl group is optionally substituted, provided that when When it is a double bond, R 7E and R 7F One of them does not exist, or R 7E and R 7F Each is bonded to the same oxygen to form an oxo group.

[0475] In some embodiments, Y of formula (I-II) 1 For –O– or –N(R 1 )— (e.g., —N(H)—, —N(alkyl)—, or —N(heteroalkyl)—). For example, Y of formula (I-II) 1 Alternatively, Y in formula (I-II) 1 It can be –N(Me)–, –N(Et)–, –N(EtOH)– or –N( n PrOH)–.

[0476] The compound of formula (I-II) may be a compound of formula (I-IIa):

[0477] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein Y 2 、R 1 、R 7C 、R 7D 、R 7E and R 7F As defined above.

[0478] The compound of formula (I-II) may be a compound of formula (I-IIb):

[0479] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein Y 2 、R 7C 、R 7D 、R 7E and R 7F As defined above.

[0480] The compound of formula (I-II) may be a compound of formula (I-IIc):

[0481] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein Y 2 、R 1 、R 7C 、R 7D and R 7E As defined above.

[0482] The compound of formula (I-II) may be a compound of formula (I-IId):

[0483] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein Y 2 、R 7C 、R 7D and R 7E As defined above.

[0484] The compound of formula (I-II) may be a compound of formula (I-IIe):

[0485] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein Y 2 As defined above.

[0486] Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId) or (I-IIe) 2 , or when When it is a double bond, R 7E , which may be an optionally substituted heteroalkyl, -NR 1 R 2 (e.g., –NH2, –NHMe, or –NMe2), –OR 3 (e.g., –OH, –OMe, –OEt, or –O t Bu) or =O. For example, Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId) or (I-IIe) 2 , or when When it is a double bond, R 7E , which can be –NH2, –NHMe or –OH.

[0487] Alternatively, Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId) or (I-IIe) 2 , or when When it is a double bond, R 7E, may be an optionally substituted heteroalkyl, for example, a substituted or unsubstituted heteroalkyl selected from the group consisting of:

[0488]

[0489]

[0490]

[0491]

[0492] For example, Y of formula (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId) or (I-IIe) 2 may be selected from the group consisting of: –OH, –NH2, –NHMe, –NMe2,

[0493]

[0494] R 7A and R 7B Formula (I-II) may each independently be hydrogen.

[0495] R of formula (I-II), (I-IIa), (I-IIb), (I-IIc) or (I-IId) 7C and R 7D R is independently hydrogen or methyl, or R 7C and R 7D Each may be bonded to the same oxygen atom to form an oxo group.

[0496] R of formula (I-II), (I-IIa), (I-IIb), (I-IIc) or (I-IId) 7E and R 7F R is independently hydrogen or methyl, or R 7C and R 7D Each may be bonded to the same oxygen atom to form an oxo group.

[0497] R in formula (I-II), (I-IIa) and (I-IIc) 1 It can be hydrogen, alkyl or heteroalkyl. For example, R 1 It can be hydrogen, methyl, ethyl, –MeOH, –EtOH or – n PrOH.

[0498] Each optional substituent of a group in one of Formulas (I-II), (I-IIa), (I-IIb), (I-IIc), (I-IId), or (I-IIe), such as an optional substituent on an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, or heteroaryl group, can be any suitable substituent, for example, a substituent described herein.For example, the optional substituents can be alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., C1-C6 heteroalkyl), haloalkyl (e.g., C1-C6 haloalkyl, e.g., -CH2Cl, -CH2I, -(CH2)2Cl, -(CH2)2I, or -CF3), cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-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), hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., –OMe, –OEt, or –OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino (e.g., –NH2, –NHMe, or –NMe2), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imine alkyl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)O-alkyl, –C(O)O-heteroalkyl, –C(O)O-alkylaryl, –C(O)NH, –C(O)NH-alkyl, –C(O)NH-heteroalkyl, –C(O)NH-alkylaryl, –NHC(O)O-alkyl -alkyl), -NHC(O)O-alkyl, -NHC(O)O-alkylaryl, -NH-Cbz, -C(O)N(alkyl), -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl), -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), -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl), -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl.Cyclic groups (eg, 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.

[0499] The 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 the structure provided in Table 1, or a pharmaceutically 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 hydrochloric acid (HCl) salt. In some embodiments, a compound disclosed herein is a hydrochloric acid (HCl) salt of a compound provided in Table 1. 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 trifluoroacetic acid (TFA) salt. In some embodiments, a compound disclosed herein is a trifluoroacetic acid (TFA) salt of a compound provided in Table 1.

[0500] It should be understood that certain compounds can form salts with more than one counterion, for example, two chloride ions to form a bis-HCl salt. Thus, it should be understood that references to HCl salts herein can refer to either mono- or di-HCl salts. Similarly, references to TFA salts herein can refer to either mono- or di-trifluoroacetic acid salts.

[0501] Table 1. Exemplary compounds.

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528] In some embodiments, the compound of formula (I), (II) and (IA) is compound 100 or a pharmaceutically 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 101 or a pharmaceutically 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 102 or a pharmaceutically 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 103 or a pharmaceutically 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 104, or a pharmaceutically 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 105, or a pharmaceutically 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 106, or a pharmaceutically 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), and (I-IIa) is compound 107 or a pharmaceutically acceptable salt thereof (e.g., HCl salt or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 108 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 109 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer.In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa) and (I-IIc) is compound 110 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA) and (IA-a) is compound 111 or a pharmaceutically acceptable salt thereof (e.g., 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 112 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 113 or a pharmaceutically acceptable salt thereof (e.g., HCl salt or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (IA) is compound 114 or a pharmaceutically acceptable salt thereof (e.g., 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 115 or a pharmaceutically acceptable salt thereof (e.g., HCl salt or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (IA) is compound 116 or a pharmaceutically acceptable salt thereof (e.g., 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 117 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 118 or a pharmaceutically acceptable salt thereof (e.g., HCl salt or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (IA) is compound 119 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer.In some embodiments, the compound of Formula (I), (II), (IA), (IA-a), (IA-b), (I-II), (I-IIa), and (I-IIc) is Compound 120, or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of Formula (I), (II), and (IA) is Compound 121, or a pharmaceutically acceptable salt thereof (e.g., 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 122, or a pharmaceutically acceptable salt thereof (e.g., HCl salt or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), and (IA) is compound 123 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 124 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is compound 125 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa) and (I-IIc) is compound 126 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa) and (I-IIc) is compound 127 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (I-II), (I-IIa) and (I-IIc) is compound 128 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of Formula (I), (II), (IA), (I-II), (I-IIa), and (I-IIc) is Compound 129 or a pharmaceutically acceptable salt (e.g., 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 pharmaceutically acceptable salt (e.g., 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 131, or a pharmaceutically acceptable salt (e.g., 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 pharmaceutically acceptable salt (e.g., 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 pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 134, or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is compound 135, or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of Formula (I), (II), (IA), (IA-a), (I-II), and (I-IIa) is Compound 136, or a pharmaceutically 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 137, or a pharmaceutically acceptable salt (e.g., 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 pharmaceutically acceptable salt (e.g., 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 pharmaceutically acceptable salt (e.g., 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 pharmaceutically acceptable salt (e.g., 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 141, or a pharmaceutically 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) and (I-IIa) is compound 142 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 143 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 pharmaceutically acceptable salt thereof (e.g., HCl salt 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 pharmaceutically acceptable salt thereof (e.g., HCl salt 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 146 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 147 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 148 or a pharmaceutically acceptable salt (e.g., HCl salt 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 149 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 150 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 151 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 152 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 153 or a pharmaceutically acceptable salt thereof (e.g., HCl salt 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 154 or a pharmaceutically acceptable salt thereof (e.g., HCl salt or TFA salt), solvate, hydrate, tautomer, or stereoisomer.

[0529] In some embodiments, the compound of formula (I), (II), (IB), (I-II), and (I-IIb) is compound 200, or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 203, or a pharmaceutically 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 204, or a pharmaceutically 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 205, or a pharmaceutically 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 pharmaceutically 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 207, or a pharmaceutically 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 208, or a pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt (eg, 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 211 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II) and (I-IIb) is compound 212 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 213 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II) and (I-IIb) is compound 214 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II) and (I-IIb) is compound 215 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II) and (I-IIb) is compound 216 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), and (IB) is compound 217 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 218 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 219 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of Formula (I), (II), and (IB) is Compound 220 or a pharmaceutically acceptable salt (eg, HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.In some embodiments, the compound of formula (I), (II) and (IB) is compound 221 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (IB) is compound 222 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 223 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 224 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 225 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 226 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 227 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 228 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 229 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of Formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is Compound 230 or a pharmaceutically 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 231 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 232 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 233 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 234 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 235 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 236 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 237 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 238 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 239 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer.In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 240 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 241 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 242 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), and (I-IIe) is compound 243 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), and (I-IIb) is compound 244 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb), (I-IIe) is compound 245 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II), (I-IIb) and (I-IIe) is compound 246 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (IB), (I-II) and (I-IIb) is compound 247 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer.

[0530] In some embodiments, the compound of formula (I), (II), (IC) and (I-II) is compound 300 or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC) and (I-II) is compound 301 or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC) and (I-II) is compound 302 or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC) and (I-II) is compound 303 or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), and (IC) is compound 304, or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC), and (I-II) is compound 305, or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC), and (I-II) is compound 306, or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC), and (I-II) is compound 307, or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC), and (I-II) is compound 308, or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC), and (I-II) is compound 309, or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of formula (I), (II), (IC), and (I-II) is compound 310, or a pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0531] In some embodiments, the compound of formula (I), (II) and (ID) is compound 400 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 401 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 402 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 403 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 404 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 405 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 406 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 407 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 408 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 409 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 410 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 411 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer.In some embodiments, the compound of formula (I), (II) and (ID) is compound 412 or its pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 413 or its pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 414 or its pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 415 or its pharmaceutically acceptable salt (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (ID) and (I-II) is compound 416 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 417 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II), (ID) and (I-II) is compound 418 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of formula (I), (II) and (ID) is compound 419 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer or stereoisomer. In some embodiments, the compound of Formula (I), (II), and (ID) is Compound 420 or a pharmaceutically acceptable salt (eg, HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0532] In some embodiments, the compound of formula (I), (II), and (IE) is compound 500 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), and (IE) is compound 501 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), and (IE) is compound 502 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of formula (I), (II), and (IE) is compound 503 or a pharmaceutically acceptable salt thereof (e.g., HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer. In some embodiments, the compound of Formula (I), (II), and (IE) is Compound 504 or a pharmaceutically acceptable salt (eg, HCl or TFA salt), solvate, hydrate, tautomer, or stereoisomer thereof.

[0533] Pharmaceutical compositions and kits

[0534] The present 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 listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof), and optionally a pharmaceutically acceptable excipient.

[0535] In some aspects, the pharmaceutical compositions described herein comprise a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.

[0536] In some aspects, the pharmaceutical compositions described herein comprise a compound of Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.

[0537] In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (IA) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, and an optional pharmaceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (IA-a) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, and an optional pharmaceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (IA-b) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, and an optional pharmaceutically acceptable excipient.

[0538] In some aspects, the pharmaceutical compositions described herein comprise a compound of Formula (IB) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.

[0539] In some aspects, the pharmaceutical compositions described herein comprise a compound of Formula (IC) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.

[0540] In some aspects, the pharmaceutical compositions described herein comprise a compound of Formula (ID) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.

[0541] In some aspects, the pharmaceutical compositions described herein comprise a compound of Formula (IE) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.

[0542] In some aspects, the pharmaceutical compositions described herein include a compound of formula (I-II) or a pharmaceutically acceptable salt thereof, a solvate, a hydrate, a tautomer or a stereoisomer, and an optional pharmaceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein include a compound of formula (I-IIa) or a pharmaceutically acceptable salt thereof, a solvate, a hydrate, a tautomer or a stereoisomer, and an optional pharmaceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein include a compound of formula (I-IIb) or a pharmaceutically acceptable salt thereof, a solvate, a hydrate, a tautomer or a stereoisomer, and an optional pharmaceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein include a compound of formula (I-IIc) or a pharmaceutically acceptable salt thereof, a solvate, a hydrate, a tautomer or a stereoisomer, and an optional pharmaceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (I-IId) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient. In some aspects, the pharmaceutical compositions described herein comprise a compound of formula (I-IIe) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.

[0543] In some aspects, the pharmaceutical compositions described herein comprise a compound listed in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient. The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof can be provided in the pharmaceutical composition in an effective amount.

[0544] The pharmaceutical compositions of the present disclosure may be prepared by any suitable method known in the art. Such methods may involve the steps of associating 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 a compound of Table 1) with one or more pharmaceutically acceptable excipients (e.g., a carrier or a binding agent), and may also involve the steps of molding and / or packaging the composition into a single dose unit or multiple dose units.

[0545] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose or multiple single unit doses. A single unit dose describes a pharmaceutical composition comprising a discrete amount of 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 a compound of Table 1). The amount of active ingredient is generally equal to the dose of the active ingredient to be administered to a subject, or a convenient fraction of such a dose.

[0546] The relative amounts of the active ingredient and one or more pharmaceutically acceptable excipients in the pharmaceutical compositions of the present disclosure will vary depending on the characteristics, size and / or condition of the subject to be treated and also on the route by which the composition is to be administered. For example, the pharmaceutical composition may contain between about 0.1% to about 100% by weight of the 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).

[0547] The compositions of the present disclosure can be administered orally, parenterally (including but not limited to subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation (e.g., oral inhalation), topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some embodiments, the compositions of the present disclosure are administered orally. In some embodiments, the compositions of the present disclosure are administered intravenously.

[0548] The pharmaceutical compositions of the present disclosure can 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 can include pharmaceutically acceptable excipients (e.g., pharmaceutically acceptable excipients disclosed herein), such as carriers, lubricants, diluents, emulsifiers, suspending agents, flavorings, colorants, disintegrants, and the like. For example, oral dosage forms disclosed herein can contain lactose, corn starch, magnesium stearate, sweeteners, dyes, polyethers (e.g., polyethylene glycol, such as PEG-300), cyclodextrins (e.g., ) or polysorbates (e.g. For example )

[0549] The pharmaceutical compositions of the present disclosure may be administered intravenously in any acceptable dosage form, including but not limited to aqueous solutions. The intravenous dosage form may include a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable excipient disclosed herein), such as a carrier, a diluent, and the like. For example, the intravenous dosage form disclosed herein may contain a polyether (e.g., polyethylene glycol, such as PEG-300), a cyclodextrin (e.g., ) or polysorbates (e.g. For example )

[0550] The pharmaceutical compositions or dosage forms disclosed herein (e.g., intravenous dosage forms) may be formulated without solubilizing agents such as cyclodextrins (e.g., For example, a pharmaceutical composition or dosage form disclosed herein (e.g., an intravenous dosage form) may include a cyclodextrin-free formulation disclosed herein (e.g., ) or compounds with relatively low amounts of cyclodextrin, such as a compound:cyclodextrin ratio of less than 1:1, for example, 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.

[0551] Pharmaceutical compositions or dosage forms (e.g., intravenous dosage forms) disclosed herein may contain relatively small amounts of solubilizing agents (e.g., cyclodextrins, such as ), or does not include a solubilizing agent. For example, a pharmaceutical composition or dosage form (e.g., an intravenous dosage form) disclosed herein may not include a cyclodextrin (e.g., ), or containing relatively small amounts of cyclodextrin (e.g., ), such as less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% cyclodextrin by weight of the composition.

[0552] Although the descriptions of pharmaceutical compositions provided herein are 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 fully understood that modifications of the pharmaceutical compositions are possible to render the compositions suitable for administration to a variety of animals, and that such modifications can be designed and / or performed by a person of ordinary skill in the art using ordinary experimentation.

[0553] The compounds disclosed herein are generally formulated in dosage unit form, such as a single unit dosage form, for ease of administration and uniform dosage. However, it should be understood that the total daily dose of the compounds or compositions disclosed herein will be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend 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 administration time, route of administration and excretion or metabolic rate of the specific compound or composition being administered; the duration of treatment, drugs used in combination or concurrently with the specific compound or composition being administered; and similar factors known in the art.

[0554] The amount of compound or composition required to achieve an effective amount will vary from subject to subject, depending on various factors, including, for example, the species, age, and general condition of the subject; the severity of the side effects or disorders; the characteristics of the specific compound or composition; the mode of administration, etc. The desired dose may be delivered once or more per day, for example, once a day, twice a day, three times a day, etc., or may be delivered less frequently, for example, every other day, every three days, every week, every two weeks, every three weeks, monthly, etc. The desired dose may be delivered as needed. Multiple administrations, for example, two, three, four, five, or more administrations may also be used to deliver the desired dose.

[0555] The effective amount of the compound for administration will vary according to the body weight of the experimenter.For example, the effective amount of the compound administered to an adult of 70 kg body weight once or repeatedly every day can include about 0.0001 mg to about 3 g per unit dosage form, such as 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 compound.

[0556] It will be understood that the dosage ranges described herein provide guidance for administration to adults, and that the amount to be administered to, for example, pediatric subjects can be determined by a practitioner or person skilled in the art and may be less than or equal to that administered to adults.

[0557] The compounds and compositions described herein can be administered in combination with one or more additional agents. The compounds and compositions disclosed herein can be administered in combination with additional agents that improve their bioavailability, improve therapeutic effectiveness, reduce or alter the metabolism of the compound, or inhibit excretion and / or alter the distribution of the compound in the body. It should be understood that the additional agents employed can achieve the desired effect of the compound or composition on the same disorder, and / or can achieve different effects.

[0558] The compound or composition can be used simultaneously with, before or after one or more additional agents that can be used as, for example, combination therapy. Medicaments include therapeutic agents. Medicaments also include preventive agents. Each additional agent can be administered at a dose and / or time determined by the agent. Additional agents can also be administered together with each other and / or with the compounds or compositions described herein in a single dose or separately in different doses. The specific combination used in the scheme will take into account the compatibility of the compounds of the invention with the additional agents and / or the desired treatment and / or preventive effect to be achieved. Generally, it is expected that the additional agents used in combination will be used at a level that does not exceed the level at which they are used alone. In some aspects, the level used in combination will be lower than the level used alone.

[0559] The present disclosure also encompasses kits (e.g., pharmaceutical packs). The kit can be used to prevent and / or treat diseases or disorders disclosed herein, such as neurological disorders (e.g., epilepsy). The kit may comprise 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 kit may also include a second container comprising, for example, a pharmaceutical excipient 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 a unit dosage form or multiple unit dosage forms.

[0560] Pharmacokinetics

[0561] The compounds and pharmaceutical compositions disclosed herein can provide, for example, enhanced pharmacokinetic and pharmacodynamic profiles relative to ganaxolone. In particular, the compounds and pharmaceutical compositions disclosed herein have superior oral bioavailability compared to ganaxolone. Following administration (e.g., oral administration or intravenous administration), the compounds disclosed herein can be converted to ganaxolone in vivo (e.g., through metabolic processes). The compounds disclosed herein can be referred to as ganaxolone prodrugs. Thus, administration of the compounds disclosed herein can provide higher amounts of serum ganaxolone (e.g., as measured by ganaxolone C) compared to administration of ganaxolone. maxWithout wishing to be bound by theory, it is believed that the increased bioavailability of the compounds disclosed herein ultimately increases ganaxolone exposure and / or improves maintenance of ganaxolone steady state following administration (e.g., by oral administration) relative to the amount achieved by administration of ganaxolone itself. 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 through metabolic processes.

[0562] Similarly, the compounds and pharmaceutical compositions disclosed herein, upon administration to a subject (e.g., by intravenous or oral administration), can provide higher concentrations of ganaxolone in the CNS relative to the concentration achieved when ganaxolone is administered to the subject in an equivalent amount and by the same route of administration.

[0563] The compounds and pharmaceutical compositions disclosed herein can have bioavailability, e.g., oral bioavailability, with respect to serum concentrations of ganaxolone that is comparable to the bioavailability of administered ganaxolone itself (e.g., as measured by ganaxolone C max or AUC). About 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, about 325%, 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.

[0564] Because the compounds disclosed herein can be converted to ganaxolone in situ (e.g., by metabolic processes), in addition to measuring the C max In addition to the AUC levels, the enhanced bioavailability achieved by the compounds disclosed herein can also be seen through the C max In some embodiments, the ganaxolone-containing composition is administered orally relative to the C level achieved after oral administration of the composition. max and / or AUC, the compounds and pharmaceutical compositions disclosed herein can increase the Cmax and / or AUC.

[0565] The compounds and pharmaceutical compositions described herein can produce a maximum ganaxolone plasma concentration (C ) of about 100 ng / mL to about 1200 ng / mL. maxFor example, the compound can achieve 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, / mL, about 330ng / mL, about 340ng / mL, about 350ng / mL, about 360ng / mL, about 370ng / mL, about 380ng / mL, about 390ng / mL, about 400ng / mL, about 410ng / mL, about 420ng / mL, about 430ng / mL, about 440ng / mL, about 450ng / mL, about 460ng / mL, about 470ng / mL, about 480ng / mL, about 490ng / mL, about 500ng / mL, about 510ng / mL, about 520ng / mL, about 530ng / mL, about 540ng / mL, about 550ng / mL, about 5 60 ng / mL, 570 ng / mL, about 580 ng / mL, about 590 ng / mL, about 600 ng / mL, about 610 ng / mL, about 620 ng / mL, about 630 ng / mL, about 640 ng / mL, about 650 ng / mL, about 660 ng / mL, about 670 ng / mL, about 680 ng / mL, about 690 ng / mL, about 700 ng / mL, about 710 ng / mL, about 720 ng / mL, about 730 ng / mL, about 740 ng / mL, about 750 ng / mL, about 760 ng / mL, about 770 ng / mL, about 780 ng / mL, about 790 ng / mL , 800 ng / mL, about 810 ng / mL, about 820 ng / mL, about 830 ng / mL, about 840 ng / mL, about 850 ng / mL, about 860 ng / mL, about 870 ng / mL, about 880 ng / mL, about 890 ng / mL, about 900 ng / mL, about 910 ng / mL, about 920 ng / mL, about 930 ng / mL, 940 ng / mL, about 950 ng / mL, about 960 ng / mL, about 970 ng / mL, about 980 ng / mL, about 990 ng / mL, about 1000 ng / mL, about 1100 ng / mL or about 1200 ng / mL or more. max .

[0566] The compounds and pharmaceutical compositions described herein may increase the ganaxolone C max An increase of 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.

[0567] The compounds and pharmaceutical compositions disclosed herein can increase the AUC of ganaxolone relative to the AUC achieved following oral administration of another composition comprising ganaxolone. For example, oral administration of a compound or pharmaceutical composition disclosed herein can result in an AUC of ganaxolone 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, about 900 ng / mL / hr to about 1,200 ng / mL / hr. AUC can refer to the AUC calculated to the last measured concentration (AUC 0.t ) such as within a 24-hour period (AUC 0-24 )’s AUC.

[0568] The compounds and pharmaceutical compositions disclosed herein can produce a mean ganaxolone plasma concentration (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 ) dose.

[0569] The compounds and pharmaceutical compositions disclosed herein can be administered at doses that produce plasma ganaxolone concentrations 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.

[0570] How to use

[0571] The present disclosure also relates to methods of treating a disease or disorder.The methods disclosed herein may comprise administering (eg, orally or intravenously) a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof.

[0572] These methods can be applicable to treating any type of seizure disorder, epilepsy disorder, genetic epilepsy disorder, epilepsy-related disorder, central nervous system disorder, neurological disorder, neurodegenerative disorder, and the like.

[0573] The types of disorders (including epilepsy disorders and / or epilepsy-related disorders) for which the methods disclosed herein may be useful include, but are not limited to, focal seizures, essential tremor, generalized seizures, acute recurrent seizures, pediatric epilepsy, reflex epilepsy, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, ultra-refractory status epilepticus, SCN8 A epilepsy, catamenial epilepsy, Angelman syndrome, benign epilepsy with centro-temporal spikes (BECTS), CDKL5 deficiency disorder (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 (Western t) syndrome), Landau-Kleffner syndrome, Lennox-Gestohl syndrome (LGS), myoclonic absence epilepsy, frontal lobe epilepsy, juvenile myoclonic epilepsy (JME), Lyfora's progressive myoclonic epilepsy, Ohtahara syndrome, Rett syndrome, refractory childhood epilepsy (ICE), Panayiotopoulos syndrome, Rasmussen's n) 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 pediatric epilepsy, combined tuberous sclerosis, Dup15q syndrome, Jeavons syndrome, fever-related epilepsy syndrome (FIRES), anti-LGI1, anti-NMDAR, anti-Gaba-B receptor, or anti-GAD65 Antibody-induced autoimmune encephalitis / encephalopathy, FOXG1-related epilepsy, Syngap1-related epilepsy, Aicardi syndrome, sleep-related hyperkinetic epilepsy, epileptic encephalopathy with sustained spike-wave complexes during sleep (CSWS), myoclonic epilepsy of infancy, Rasmussen syndrome, developmental and epileptic encephalopathy (unclassified), focal epilepsy, juvenile absence epilepsy, post-traumatic epilepsy, epilepsy due to abnormal cortical development and catamenial epilepsy, increased seizure activity, breakthrough seizures, and infantile spasms.

[0574] Epilepsy disorders and / or epilepsy-related disorders suitable for treatment by the methods disclosed herein include CDKL5 deficiency disorder, combined tuberous sclerosis and PCDH19-related disorders. Another disorder suitable for treatment by the methods disclosed herein is Lennox-Gastaut syndrome (LGS).

[0575] The methods disclosed herein can also be used to treat other neurological disorders, such as anxiety, agitation, or depression (eg, postpartum depression).

[0576] Other medical conditions that can be treated with the methods disclosed herein that manifest as seizures include, but are not limited to, pre-eclampsia / eclampsia, medication-related seizures (including prescription medications used as prescribed, such as antihistamines, antibiotics, antidepressants, antipsychotics, and illicit substances such as PCP, cocaine, and amphetamines), medication withdrawal (e.g., withdrawal from THC, opioids, alcohol, or barbiturates), or anti-epileptic medication (AED) non-compliance.

[0577] 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 / 02815 1, PCT / US2018 / 060037, PCT / US2019 / 064850, PCT / US2020 / 044843, PCT / US2020 / 063648, PCT / US2021 / 060459, and PCT / US2021 / 061937; U.S. Patent No. 10,391,105; and U.S. Patent Publication No. 2019 / 0111059, each of which is incorporated herein by reference in its entirety.

[0578] The methods disclosed herein are applicable to the treatment of epileptic seizures. For example, the methods disclosed herein are applicable to the treatment of status epilepticus (SE). The methods disclosed herein are applicable to any form of SE. For example, early status epilepticus, established 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, latent non-convulsive status epilepticus), generalized convulsive status epilepticus, complex partial status epilepticus; systemic periodic epileptiform discharges and lateralized periodic epileptic discharges. The method can also be used to treat subjects who have failed first-line treatment (e.g., benzodiazepine), second-line treatment (e.g., fosphenytoin, valproic acid or levetiracetam) and / or third-line treatment (thiopental, midazolam, pentobarbital or propofol).

[0579] Other forms of epileptic seizures that the methods disclosed herein may be suitable for treating include epileptic seizures, acute recurrent seizures, cluster seizures, continuous seizures, persistent seizures, protracted seizures, recurrent seizures, refractory seizures, myoclonic seizures, tonic seizures, tonic-clonic seizures, simple partial seizures, combined partial seizures, secondarily generalized seizures, atypical absence seizures, absence seizures, atonic seizures, benign rolandic seizures, febrile seizures, and mood seizures. seizures, focal seizures, gelastic seizures, generalized onset seizures, infantile spasms, Jacksonian seizures, massive bilateral myoclonic seizures, multifocal seizures, neonatal onset seizures, nocturnal seizures, occipital lobe seizures, post-traumatic seizures, insidious seizures, Sylvan seizures, visual reflex seizures, seizures due to traumatic brain injury, seizures caused by exposure to chemical weapons (e.g., organophosphate nerve gas or withdrawal seizures).

[0580] Compounds and pharmaceutical compositions disclosed herein can also be used as a preventive agent for treating central nervous system disorders and / or neurological disorders. Exemplary central nervous system disorders and / or neurological disorders that may be suitable for treatment using formulations disclosed herein include autism spectrum disorders, Rett syndrome, Tourette syndrome, obsessive-compulsive disorder, insomnia, parasomnias, oppositional defiant disorder, behavioral disorders, disruptive mood dysregulation disorders, agitation, anxiety, generalized anxiety disorder, social anxiety disorder, panic disorder, anxiety or agitation caused by Alzheimer's dementia, schizophrenia, substance withdrawal syndrome (alcohol, benzodiazepines, barbiturates and cocaine), post-traumatic stress disorder (PTSD), tremor, essential tremor, spasticity caused by cerebral palsy, depression (including major depression, major depressive disorder, severe depression, unipolar depression, unipolar disorder, recurrent depression), postnatal or postpartum depression, atypical depression, melancholic depression, psychotic major depression (PMD), catatonic depression, seasonal affective disorder (SAD), dysthymia, double depression, depressive personality disorder (DPD), recurrent brief depression (RBD), mild depression, bipolar disorder or manic-depressive disorder, post-traumatic stress disorder, postmenopausal depression, depression caused by chronic medical conditions, refractory depression, suicidal tendencies, suicidal ideation, mood disorders or suicidal behavior, attention deficit hyperactivity disorder or neurocognitive disorders, including delirium. The compound or composition can also be used as a sedative or analgesic.

[0581] The present disclosure also includes methods for treating epileptic seizures caused by neurodegenerative disorders. Such neurodegenerative disorders include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. The present disclosure includes methods for treating epileptic seizures caused by inflammatory disorders such as multiple sclerosis. The present disclosure includes methods for treating epileptic seizure disorders caused by lysosomal storage disorders, including Neimann-Pick disease type C (NPS), Tay-Sachs disease, Batten disease, Sandhoff disease, and Gaucher disease.

[0582] Although the preferred subject is a human, any mammal, generally including domestic animals such as dogs, cats, and horses, may be treated according to the methods disclosed herein.

[0583] Modified forms of ganaxolone that are intended as prodrugs are expected to convert unpredictably to ganaxolone. For example, conventional methods for forming ganaxolone prodrugs have resulted in compounds that, while having improved aqueous solubility or oral absorption compared to ganaxolone, 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 long-term stable, 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 also efficiently converted to ganaxolone through metabolic processes (see, e.g., Example 121). The discovery that even minor modifications to the compound's structure can significantly reduce or eliminate the compound's ability to be converted to ganaxolone or adversely affect its stability demonstrates the high degree of unpredictability and difficulty in designing useful ganaxolone prodrugs.

[0584] Synthesis method

[0585] Compounds disclosed herein can be prepared according to known processes. The following schemes 1-3 represent general synthetic schemes for preparing 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 meant to limit the possible techniques that those skilled in the art may use to prepare compounds disclosed herein. Different methods are apparent to those skilled in the art. Those skilled in the art may envision various modifications to these methods to achieve similar results as described below. Optional protecting groups can be used as described in, for example, Protective Groups in Organic Synthesis (4th edition 2006) by Greene et al. It should be understood that, for clarity, additional steps and / or salt formation steps (e.g., by treating with acid) may be involved in the synthesis not depicted in the comprehensive scheme.

[0586] Compounds of formula (I) can generally be prepared, for example, according to Scheme 1:

[0587]

[0588] Scheme 1. Exemplary synthesis of compounds of formula (I).

[0589] wherein X, Z, and Y are as defined herein, and LG is a suitable leaving group (e.g., halogen, OSO2Me, OM, OT, OTf, or OH). The reaction can be catalyzed by heating and / or a reagent (e.g., an acid or base) or a catalyst, and can be carried out in any suitable solvent (e.g., an inert organic solvent).

[0590] Compounds of formula (II) can generally be prepared, for example, according to Scheme 2:

[0591]

[0592] Scheme 2. Exemplary synthesis of compounds of formula (II).

[0593] Among them, X, R 7A and R 7B As defined herein, and LG is a suitable leaving group (e.g., halogen, OSO2Me, OM, OT, OTf, or OH). The reaction can be catalyzed by heating and / or a reagent (e.g., an acid or base) or a catalyst, and can be carried out in any suitable solvent (such as an inert organic solvent).

[0594] Alternatively, compounds of formula (II) can generally be prepared, for example, according to Scheme 3:

[0595]

[0596] Scheme 3. Exemplary synthesis of compounds of formula (II).

[0597] Among them, X, R 7A and R 7B As defined herein, and LG is a suitable leaving group (e.g., halogen, OSO2Me, OM, OT, OTf, or OH). The reaction can be catalyzed by heating and / or a reagent (e.g., an acid or base) or a catalyst, and can be carried out in any suitable solvent (such as an inert organic solvent).

[0598] The base used, for example, in the synthesis of compounds disclosed herein according to one of Schemes 1-3 may include an inorganic base such as potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, and the like, or may include an organic base such as an amine base (e.g., triethylamine (TEA), diisopropylamine, diisopropylethylamine (DIPEA), pyrrolidine, or pyridine).

[0599] Acids used, for example, in the synthesis of compounds disclosed herein according to one of Schemes 1-3 can include hydrochloric acid, sulfuric acid, nitric acid, toluenesulfonic acid, trifluoroacetic acid, acetic acid, and the like.

[0600] Solvents used, for example, 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), dimethyl sulfoxide (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, alone or as a mixture with one or more other solvents (e.g., those described herein).

[0601] The reaction of preparing the compounds disclosed herein, for example according to one of Schemes 1-3, can be carried out at any suitable temperature. For example, the reaction of preparing the compounds disclosed herein can be carried out at room temperature, below room temperature or above room temperature. The reaction of preparing the compounds disclosed herein can be carried out at 0 ° C or lower, for example -5 ° C, -10 ° C, -25 ° C, -50 ° C, -78 ° C, -80 ° C, -100 ° C or lower temperatures. The reaction of preparing the compounds disclosed herein can be carried out at 25 ° C or higher, for example 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 higher temperatures.

[0602] The reactions described herein, for example according to one of Schemes 1-3, can be followed by further isolation and purification steps, such as chromatography (e.g., flash column chromatography, high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC) and the like), crystallization, trituration, filtration, lyophilization and the like.

[0603] Equivalent solutions

[0604] It will be apparent to those skilled in the art that other suitable modifications and adaptations of the compounds, compositions, kits, and methods of the present disclosure are readily apparent and may be made using suitable equivalents without departing from the scope of the present disclosure or embodiments. Having now described certain compounds, compositions, kits, and methods in detail, they will be more clearly understood by reference to the following examples, which are incorporated by reference only for purposes of illustration and are not intended to be limiting.

[0605] Example

[0606] Materials and methods

[0607] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without purification.

[0608] Preparation and analytical methods

[0609] LC / MS data (ESI+) were determined using 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) with a 2996 diode array detector from 210-400 nm; the solvent system was a linear gradient of 5%-95% acetonitrile (MeCN) in water (containing 0.1% trifluoroacetic acid (TFA)) over nine minutes, and retention times were reported in minutes. Mass spectra were performed on a Waters ZQ using electrospray in positive mode.

[0610] LC / MS data (ESI-) were determined using a Shimadzu Prominence HPLC / MS (Phenomenex Luna C18, 3.0×50 mm, 3 μm) with a 2996 diode array detector from 210–400 nm; the solvent system was a linear gradient from 5% to 95% MeCN in water (containing 0.1% formic acid) over five minutes, and retention times were reported 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 using a Waters Alliance 2695 HPLC / MS (Phenomenex C18, 4.6×75 mm, 3.0 μm) with a 2996 diode array detector from 210–400 nm; the solvent system was a linear gradient from 5% to 95% MeCN in water (containing 0.1% formic acid) over nine minutes, and retention times were reported in minutes. Mass spectra were performed on a Waters ZQ using electrospray in positive mode.

[0611] HRMS data were determined by the University of Notre Dame Mass Spectrometry & Proteomics Facility on a Bruker micrOTOF II.

[0612] Preparative reverse phase HPLC was performed on a Waters Sunfire column (19×50 mm, C18, 5 μm) with a 10 min mobile phase gradient from 10% acetonitrile / water to 90% acetonitrile / water with 0.1% TFA as buffer and detection wavelengths of 214 and 254 nm. Injection and fraction collection were performed using a Gilson 215 liquid handling device using Trilution LC software.

[0613] Unless otherwise stated, NMR spectra were recorded on a Varian Oxford 300 MHz in CDCl 3 . Chemical shifts (δ) are expressed in ppm downfield from tetramethylsilane (TMS).

[0614] Unless otherwise stated, purity as determined by NMR or LCMS was typically ≥95%.

[0615] Example 1. Synthesis of Compound 404.

[0616]

[0617] A 250 mL 3-necked 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. DMAP (0.74 g, 6.04 mmol) was added to the flask, and the reaction mixture was allowed to clarify. Et3N (2.55 mL, 13.28 mmol) was added to the flask, resulting in a clear solution that was stirred at ambient temperature for 15 min. A solution of chloroacetic anhydride (5.18 g, 30.3 mmol) dissolved in 35 mL of 1,2-DCE was added via the addition funnel over 15 min. Upon addition, the reaction immediately turned into a neon yellow solution, then a slurry, and finally a dark brown solution. The reaction was allowed to stir for 1 h, 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 dried over Na2SO4 for about 30 minutes, 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 on silica gel. The resulting brown solid was dried under high vacuum for 30 minutes. A 20 gram silica column was then prepared for use, running 10 volumes with a gradient of 0%-5% EtOAc / hexane, followed by maintaining 15 volumes at 5%. After maintenance, EtOAc was raised to 100% and then maintained for 5 volumes. Concentration of the product containing fractions gave compound 404 as a solid (1.1439 g). HRMS (ESI+): C 24 H 38 ClO3 m / z[M+H] + The calculated value is 409.2504, and the observed value is 409.2517; 1 H NMR 300MHz DMSO,d6δ: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).

[0618] Example 2. Synthesis of Compound 100

[0619]

[0620] To a solution of 1-(2-methoxyphenyl)-piperazine (12.9 mg, 0.07 mmol) and K2CO3 (10 mg, 0.07 mmol) in MeCN (0.55 mL) was added compound 404 (25 mg, 0.06 mmol), and the contents were stirred and heated to 50 ° C overnight. Once the reaction was considered complete by TLC, 0.5 M HCl (15 mL) was added, followed by ethyl acetate (15 mL). The organic layer was separated, washed with water (15 mL) and brine (15 mL), and dried over Na2SO4. The organic layer was decanted, and the solvent was removed in vacuo. The crude product was purified by column chromatography using ISCO TM The resulting free base was treated with 2.0 M HCl / diethyl ether (2 mL) and the solvent removed in vacuo to afford compound 100 as a solid (44.7 mg). LCMS (ESI+): RT = 5.55 min, (M+H)+ = 565.55; HRMS (ESI+): C 35 H 53 N2O4 m / z[M+H] + The calculated value is 565.4000 and the observed value is 565.4003; 1 H NMR 300 MHz CD3ODδ: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,coincident with solvent),2.54-2.63(br.s,1H),2.10-2.30(m,2H),2.09(s,3H),1.84-2.07(m,2H),1.57-1.77(m ,5H),1.55(s,3H),1.09-1.52(m,11H),0.85-1.06(m,1H),0.83(s,3H),0.74(m,1H),0.59(s,3H).

[0621] Example 3. Synthesis of Compound 101

[0622]

[0623] In a manner analogous to the procedure outlined in Example 2, substituting morpholine for 1-(2-methoxyphenyl)-piperazine, compound 101 was obtained as the HCl salt. LCMS (ESI) m / z (M+1)+ 460.36; HRMS (ESI+): C 28 H 46 NO4 m / z[M+H] + The calculated value is 460.3421, and the observed value is 460.3416; 1 H NMRδ:4.03-4.22(br.s,4H),3.77(s,2H),3.38-3.52(br.s,4H),2.48-2.57(br.s,1H),2.15-2.29(m,2H),2.11(s,3H),1.80-2. 06(m,2H),1.54-1.75(m,5H),1.53(s,3H),1.12-1.49(m,11H),0.82-1.11(m,1H),0.77(s,3H),0.69-0.75(m,1H),0.60(s,3H).

[0624] Example 4. Synthesis of Compound 102

[0625]

[0626] In a manner analogous to the procedure outlined in Example 2, substituting methylpiperazine for 1-(2-methoxyphenyl)-piperazine, compound 102 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 473.39; HRMS (ESI+): C 29 H 49 Calculated value of N2O3 m / z[M+H]+: 473.3738, observed value: 473.3732; 1 H NMR(CD3OD)δ:3.83(s,2H),3.12-3.62(m,8H,coincident with solvent),2.94(s,3H),2.54-2.62(br.s,1H),2.10-2.28(m,2H),2.08(s,3H),1.82-2.05(m,2H),1.52-1.7 5(m,5H),1.50(s,3H),1.08-1.48(m,11H),0.83-1.06(m,1H),0.81(s,3H),0.68-0.79(m,1H),0.58(s,3H).

[0627] Example 5. Synthesis of Compound 103

[0628]

[0629] In a manner analogous to the procedure outlined in Example 2, substituting glycine ethyl ester for 1-(2-methoxyphenyl)-piperazine, compound 103 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 476.45; HRMS (ESI+): C 28 H 46 NO5 m / z[M+H] + The calculated value is 476.3370, and the observed value is 476.3362; 1 H NMR CD3ODδ:4.30(q,J=7.4Hz,2H),4.00(s,2H),3.98(s,2H),2.59(t,J=8.4Hz,1H),2.10-2.25(m,2H),2.09(s,3H),1.85-2.06( m,2H),1.54-1.76(m,5H),1.52(s,3H),1.08-1.50(m,14H),0.84-1.02(m,1H),0.82(s,3H),0.64-0.80(m,1H),0.59(s,3H).

[0630] Example 6. Synthesis of Compound 104

[0631]

[0632] In a manner analogous to the procedure outlined in Example 2, substituting N-(2-methoxyethyl)methanamine 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 NO4 m / z[M+H] + The calculated value is 462.3578, and the observed value is 462.3566; 1 H NMR CD3ODδ:4.09-4.23(br.s.,2H),3.75(t,J=5.0Hz,2H),3.43-3.54(br.s.,2 H),3.41(s,3H),2.99(s,3H),2.60(t,J=9.08Hz,1H),2.12-2.29(m,2H),2 .10(s,3H),1.85-2.08(m,2H),1.55-1.79(m,5H),1.54(s,3H),1.11-1.53 (m,11H),0.86-1.05(m,1H),0.84(s,3H),0.65-0.82(m,1H),0.61(s,3H).

[0633] Example 7. Synthesis of Compound 105

[0634]

[0635] In a manner analogous to the procedure outlined in Example 2, substituting 1-(2-methoxyphenyl)-piperazine with ethyl sarcosinate, compound 105 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 490.41; 1 H NMR CD3ODδ:4.33(q,J=7.0Hz,2H),4.20(s,4H),3.05(s,3H),2.60(t,J=8.6Hz,1H),2.12-2.29(m,2H),2.10(s,3H),1.87-2.08( m,2H),1.56-1.82(m,5H),1.55(s,3H),1.13-1.54(m,14H),0.86-1.07(m,1H),0.84(s,3H),0.69-0.83(m,1H),0.60(s,3H).

[0636] Example 8. Synthesis of Compound 106

[0637]

[0638] In a manner similar to the procedure outlined in Example 2, substituting D-alanine methyl ester hydrochloride for 1-(2-methoxyphenyl)-piperazine, compound 106 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 476.31; HRMS (ESI+): C 28 H 46 NO5m / z[M+H] + The calculated value is 476.3370, and the observed value is 476.3376; 1 H NMR CD3ODδ:4.15(q,J=7.0Hz,1H),3.98(d,J=2.3Hz,2H),3.86(s,3H),2.60(t,J=8.8Hz,1H),2.12-2.28(m,2H),2.10(s,3H),1.87-2 .08(m,2H),1.55-1.78(m,8H),1.54(s,3H),1.12-1.53(m,11H),0.87-1.06(m,1H),0.84(s,3H),0.74-0.82(m,1H),0.60(s,3H).

[0639] Example 9. Synthesis of Compound 107

[0640]

[0641] In a manner analogous to the procedure 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 NO4 m / z[M+H] + The calculated value is 434.3265, and the observed value is 434.3258; 1 H NMR CD3ODδ:3.95(s,2H),3.81(t,J=5.2Hz,2H),3.18(t,J=5.0Hz,2H),2.60(t,J=8.8Hz,1H),2.12-2.28(m,2H),2.10(s,3H),1.88-2 .08(m,2H),1.55-1.77(m,5H),1.53(s,3H),1.11-1.52(m,11H),0.88-1.06(m,1H),0.84(s,3H),0.74-0.82(m,1H),0.60(s,3H).

[0642] Example 10. Synthesis of Compound 108

[0643]

[0644] In a manner similar to the procedure outlined in Example 2, substituting L-valine methyl ester for 1-(2-methoxyphenyl)-piperazine, compound 108 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 504.30; HRMS (ESI+): C 30 H 50 NO5 m / z[M+H] + The calculated value is 504.3684, and the observed value is 504.3695; 1H NMR CD3ODδ:4.03(d,J=3.5Hz,1H),3.98(s,2H),3.88(s,3H),2.61(t,J=8.8Hz,1H ),2.31-2.46(m,1H),2.13-2.30(m,2H),2.11(s,3H),1.86-2.09(m,2H),1.55- 1.79(m,5H),1.54(s,3H),1.17-1.53(m,11H),1.14(d,J=7.0Hz,3H),1.07(d, J=7.0Hz,3H),0.87-1.02(m,1H),0.84(s,3H),0.65-0.83(m,1H),0.60(s,3H).

[0645] Example 11. Synthesis of Compound 109

[0646]

[0647] In a manner similar to the procedure outlined in Example 2, substituting glycine tert-butyl ester for 1-(2-methoxyphenyl)-piperazine, compound 109 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 504.23; HRMS (ESI+): C 30 H 50 NO5 m / z[M+H] + The calculated value is 504.3684, and the observed value is 504.3673; 1 H NMRδ:3.39-3.50(m,4H),2.75-2.90(br.s,1H),2.51(t,J=9.1Hz,1H),2.11-2.26(m,2H),2.10(s,3H),1.82-2.09(m,2H),1.5 1-1.73(m,5H),1.49(s,3H),1.48(s,9H),1.04-1.46(m,11H),0.82-1.02(m,1H),0.76(s,3H),0.64-0.75(m,1H),0.59(s,3H).

[0648] Example 12. Synthesis of Compound 110

[0649]

[0650] In a manner analogous to the procedure outlined in Example 2, substituting glycine methyl ester for 1-(2-methoxyphenyl)-piperazine, compound 110 was obtained as the HCl salt. LCMS (ESI) m / z (M+1) + 462.29; HRMS (ESI+): C27 H 44 NO5 m / z[M+H] + The calculated value is 462.3214, and the observed value is 462.3207; 1 H NMRδ:4.03(s,2H),4.00(s,2H),3.86(s,3H),2.61(t,J=8.8Hz,1H),2.13-2.28(m,2H),2.11(s,3H),1.88-2.08(m,2H) ,1.56-1.80(m,5H),1.54(s,3H),1.14-1.54(m,11H),0.87-1.07(m,1H),0.84(m,3H),0.72-0.82(m,1H),0.60(s,3H).

[0651] Example 13. Synthesis of Compound 300

[0652]

[0653] Compound 404 (50 mg, 0.12 mmol) was added 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). The contents were stirred overnight at ambient temperature. Once the reaction was considered complete by TLC, a 1: 1 mixture (7 mL) of saturated NH4Cl aqueous solution and water was added, followed by dichloromethane (DCM) (9 mL). The organic layer was separated, washed with 1: 1NH4Cl: water (9 mL), dried over Na2SO4, and filtered through a phase separation column. The extracted aqueous phase was washed with DCM (9 mL), which was then separated, dried over Na2SO4, and filtered through the above-mentioned phase separation column. The organic layers were combined, and the solvent was removed in vacuo. The crude product was purified by column chromatography using ISCO TM Purification by chromatography afforded compound 300 as an oil (61.6 mg). LCMS (ESI+): RT = 7.91 min, (M+H)+ = 550.45; HRMS (ESI+): C 31 H 51 NNaO5S m / z[M+H] + The calculated value is 572.3380, and the observed value is 572.3371; 1H NMR 300MHzδ:4.92-5.05(br.s,1H),3.28-3.50(m,2H),3.18(s,2H),2.77(t ,J=6.1,2H),2.53(t,J=8.8,1H),2.13-2.25(m,2H),2.11(s,3H),1.88- 2.03(m,2H),1.49-1.74(m,5H),1.48(s,3H),1.45(s,9H),1.08-1.43(m ,11H),0.83-1.01(m,1H),0.77(s,3H),0.68-0.75(m,1H),0.60(s,3H).

[0654] Example 14. Synthesis of Compound 301

[0655]

[0656] To a solution of 2-mercaptoethanol (57.3 mg, 0.73 mmol) and K2CO3 (101 mg, 0.73 mmol) in MeCN (2 mL) was added compound 404 (200 mg, 0.49 mmol). The contents were stirred and heated to 50 ° C overnight. Once the reaction was considered complete by TLC, a 1: 1 mixture (7 mL) of saturated NH4Cl aqueous solution and water was added, followed by the addition of DCM (9 mL). The organic layer was separated, washed with 1: 1NH4Cl: water (9 mL), dried over Na2SO4, and filtered through a phase separation column. The extracted aqueous phase was washed with DCM (9 mL), which was then separated, dried over Na2SO4, and filtered through the above-mentioned phase separation column. The organic layers were combined, and the solvent was removed in vacuo. The crude product was purified by column chromatography using ISCO TM Purification by chromatography afforded compound 301 as a solid (177 mg). LCMS (ESI+): RT = 6.86 min, (M+H)+ = 451.25; HRMS (ESI+): C26H42NaO4S m / z [M+H] + The calculated value is 473.2696, and the observed value is 473.2692; 1H NMR 300MHzδ:3.78(t,J=5.5Hz,2H),3.22(s,2H),2.84(t,J=5.5Hz,2H),2.52(t,J=8.8Hz,1H),2.13-2.24(m,2H),2.11(s,3H),1.90- 2.07(m,2H),1.51-1.73(m,6H),1.48(s,3H),1.09-1.47(m,11H),0.83-1.00(m,1H),0.77(s,3H),0.66-0.76(m,1H),0.60(s,3H).

[0657] Example 15. Synthesis of Compound 302

[0658]

[0659] A solution of compound 300 (43.2 mg, 0.08 mmol) in 4N HCl / dioxane (1 mL) was stirred vigorously at ambient temperature for 10 min. The mixture was diluted with DCM (9 mL) followed by water (8 mL). The organic layer was separated, washed with brine (9 mL), dried over Na2SO4, and filtered through a phase separation column. The aqueous layer was washed with DCM (9 mL), then separated, dried over Na2SO4, and filtered through the above phase separation column. The organic layers were combined, and the solvent was removed in vacuo, followed by lyophilization 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 NO3S m / z[M+H] + The calculated value is 450.3036, and the observed value is 450.3042; 1 H NMR300MHz CD3ODδ:3.33(s,2H),3.15(t,J=6.7Hz,2H),2.91(t,J=6.7Hz,2H),2.61(t,J=9.1Hz,1H),2.13-2.24(m,2H),2.11(s,3H),1.87-2 .08(m,2H),1.49-1.83(m,5H),1.48(s,3H),1.13-1.48(m,11H),0.86-1.06(m,1H),0.83(s,3H),0.63-0.82(m,1H),0.60(s,3H).

[0660] Example 16. Preparation of Compound 303

[0661]

[0662] 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 at ambient temperature overnight. Once the reaction was considered complete by TLC, a 1: 1 mixture (18 mL) of saturated NH4Cl aqueous solution and water was added, followed by the addition of DCM (14 mL). The organic layer was separated, washed with 1: 1NH4Cl: water (18 mL), dried over Na2SO4, and filtered through a phase separation column. The extracted aqueous phase was washed with DCM (18 mL), which was then separated, dried over Na2SO4, and filtered through the above-mentioned phase separation column. The organic layers were combined, and the solvent was removed in vacuo. The crude product was purified by column chromatography using ISCO TM Purification by chromatography system, followed by Gilson TM Further purification by Semi Prep HPLC system gave 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 NO6S m / z[M+H] + The calculated value is 578.3510, and the observed value is 578.3504; 1 H NMR 300 MHz CD3ODδ: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,11 H),0.86-1.05(m,1 H),0.83(s,3 H),0.72-0.81(m,1 H), 0.60(s,3 H).

[0663] Example 17: Synthesis of Compound 200

[0664]

[0665] Anhydrous DMF (3mL) is added into compound 404 (75.6mg, 0.18mmol), 4-morpholineacetic acid (125mg, 0.95mmol) and sodium iodide (46.7mg, 0.31mmol), to produce a clear orange solution. The solution was stirred at ambient temperature for 15 minutes. After 15min, Cs was added CO (292mg, 0.90mmol) and the resulting mixture was heated to 70°C and stirred overnight. The reaction mixture was cooled and diluted with 25mL EtOAc, then quenched with 15mL water. Each layer was separated and the EtOAc layer was washed with 2x15 ml saturated NaHCO solution, and Na was used SO Drying for 30 minutes, filtered and concentrated to obtain 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 minutes, then loaded onto a 4 g column and eluted with EtOAc in hexanes, running isocratically at 25% EtOAc, then increasing to 50%, and then to 100% EtOAc. Compound 200 (free base; 81.1 mg) was obtained as an oil. HRMS (ESI+): C30H48NO6 m / z [M+H] + The calculated value is 518.3476, and the observed value is 518.3484; 1 H NMR 300MHzδ: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=11.14Hz,2.34Hz,1H),1.05-1.76(m,19H),0.71-1.03(m,4H),0.57-0.65(m,3H).

[0666] Compound 200 (free base; 42.4 mg, 0.08 mmol) was dissolved in 2 mL of Et2O to produce a clear solution and stirred for 5 minutes. 2M HCl in Et2O (50 μL, 0.1 mmol) was added and a white precipitate formed. The reaction was stirred for 10 minutes. The precipitate was isolated by filtration and washed with 5 mL of Et2O. The solid was then dried under high vacuum overnight to give compound 200 as the HCl salt. HRMS (ESI+): C 30 H 48 NO6 m / z[M+H] + The calculated value is 518.3476, and the observed value is 518.3484; 1H NMR 300MHzδ: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=8.76Hz,1H),2.08- 2.28(m,5H),1.95-2.07(m,1H),1.86(d,J=8.79Hz,1H),1.08-1.78(m,19H),0.74-1.04(m,4H),0.59-0.73(m,4H).

[0667] Example 18: Synthesis of Compound 202

[0668]

[0669] In a manner analogous to the procedure outlined in Example 17, substituting dimethylglycine for 4-morpholineacetic acid, compound 202 was obtained as the HCl salt. HRMS (ESI+): C 28 H 46 NO5 m / z[M+H] + The calculated value is 476.3370, and the observed value is 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).

[0670] Example 19: Synthesis of Compound 203

[0671]

[0672] In a manner analogous to the procedure outlined in Example 17 (excluding the HCl salt formation step), compound 203 was obtained by substituting 3-ethoxypropionic acid for 4-morpholinoacetic acid. HRMS (ESI+): C 29 H 46 NaNO6 m / z[M+H] + The calculated value is 513.3187, and the observed value is 513.3198; 1H NMRδ: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).

[0673] Example 20: Synthesis of Compound 204

[0674]

[0675] In a manner analogous to the procedure outlined in Example 17 (excluding the HCl salt formation step), compound 204 was obtained by substituting 2-(2-methoxyethoxy)acetic acid for 4-morpholinoacetic acid. HRMS (ESI+): C 29 H 46 NaNO7 m / z[M+H] + The calculated value is 529.3136, and the observed value is 529.3137; 1 H NMRδ: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).

[0676] Example 21: Synthesis of Compound 205

[0677]

[0678] In a manner analogous to the procedure outlined in Example 17 (excluding the step of forming the HCl salt), compound 205 was obtained by substituting 2-[2-(2-methoxyethoxy)ethoxy]acetic acid for 4-morpholinoacetic acid. HRMS (ESI+): C 31 H 50 NaO8 m / z[M+H] + The calculated value is 573.3398, and the observed value is 573.3399; 1H NMRδ: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,6 H), 1.97 (d, J = 11.72Hz, 1H), 1.86 (d, J = 11.14Hz, 2H), 1.09-1.73 (m, 18H), 0.71-1.01 (m, 4H), 0.57 (s, 3H).

[0679] Example 22: Synthesis of Compound 206

[0680]

[0681] In a manner analogous to the procedure outlined in Example 17 (excluding the HCl salt formation step), replacing 4-morpholineacetic acid with N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucine, compound 206 was obtained. HRMS (ESI+): C 44 H 67 N2O8 m / z[M+H] + The calculated value is 751.489194, and the observed value is 751.489134; 1 H NMRδ:7.22-7.42(m,5H),6.52(d,J=7.62Hz,1H),5.35(d,J=8.21Hz,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).

[0682] Example 23: Synthesis of Compound 207

[0683]

[0684] In a manner similar to the procedure outlined in Example 17 (excluding the HCl salt formation step), substituting CBz-L-Ala-Gly-OH for 4-morpholineacetic acid, compound 207 was obtained. HRMS (ESI+): C 37 H 53 N2O8 m / z[M+H] + The calculated value is 653.379643, and the observed value is 653.378352; 1H NMRδ:7.28-7.45(m,5H),6.74(br.s.1H),5.44(d,J=6.45Hz,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).

[0685] Example 24: Synthesis of Compound 208

[0686]

[0687] In a manner similar to the procedure outlined in Example 17, 4-methyl-1-piperazineacetic acid was substituted for 4-morpholineacetic acid to afford compound 208 as a bis-HCl salt. HRMS (ESI+): C 31 H 51 N2O5 m / z[M+H] + The calculated value is 531.379249, and the observed value is 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=8.79Hz,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).

[0688] Example 25: Synthesis of Compound 201

[0689]

[0690] 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), 3 mL of anhydrous DMF was added to produce a clear orange solution. The solution was stirred at ambient temperature for 15 minutes. After 15 min, CsCO (278 mg, 0.85 mmol) was added and the resulting mixture was heated to 70 ° C. After stirring for 18 h, the reactant was cooled, diluted with 25 mL of EtOAc, and then quenched with 15 mL of water. After separating each layer, the EtOAc layer was washed with 2x15 ml of saturated NaHCO solution, dried, filtered and concentrated to obtain 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 30 minutes, then loaded onto a 4 g column and eluted with EtOAc in hexanes, running from 0% to 10% EtOAc over 10 volumes, holding at 10% for 10 volumes, then ramping to 50%, then finally ramping to 100% EtOAc. Compound 201 (73.3 mg) was obtained as a crystalline solid. HRMS (ESI+): C 24 H 38 NaNO4 m / z[M+H] + The calculated value is 413.2662, and the observed value is 413.2662; 1 HNMR 300MHz CDCl3δ:4.04-4.11(m,2H),2.52(t,J=9.08Hz,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).

[0691] Example 26: Synthesis of Compound 500

[0692]

[0693] 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 produce 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, followed by 75 mL of HO. The mixture was stirred and allowed to settle. The lower aqueous layer was discarded and the process was repeated four times. The washed organics were dried over sodium sulfate, filtered, and concentrated to give a clear, pale yellow oil, which was dried under vacuum. The crude reaction mixture was purified by column chromatography. The oil was loaded onto an 80 g column and eluted with 0.5% to 3% EtOAc / hexane. The desired fractions were combined and concentrated. Compound 500 was obtained as a solid (2.31 g) after drying under vacuum. HRMS(ESI+):C24H41O2S m / z[M+H] + The calculated value is 393.2822, and the observed value is 393.2830; 1 H NMR 300MHz CDC13δ: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).

[0694] Example 27: Synthesis of Compound 503

[0695]

[0696] 4A molecular sieves (0.25g) is added to a solution of compound 500 (107mg, 0.27mmol), 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (60.4mg, 0.34mmol) and 3mL dichloromethane to produce a thick white slurry. The reactant is cooled to 0°C in an ice bath and Bu4NBr (0.1mg, 0.31mmol) is added, followed by CuBr2 (68.5mg, 0.31mmol). After adding CuBr2, the reaction becomes dark purple. The reactant is warmed to ambient temperature. After stirring for 18h, the reactant is diluted with 25mL EtOAc and then filtered to remove the molecular sieve. The sieve is washed with 15ml EtOAc. The combined organic phase is then washed with 2x15 ml saturated NaHCO3 solution, followed by 15mL saturated NaCl solution. The washed organic phase is dried with Na2SO4, filtered and concentrated to obtain a clear orange oil. The crude mixture was purified by column chromatography. The oil was dissolved in CH2Cl2 and stripped onto silica gel. The silica gel was dried under high vacuum for 30 minutes and then loaded onto a 4 g column and eluted with EtOAc in hexane: 15% EtOAc, held for 10 volumes, then increased to 100 in 5 volumes, then held for 10 volumes. Compound 503 (57.3 mg) was obtained as an oil. HRMS (ESI+): C 30 H 50 NaO7 m / z[M+H] + The calculated value is 545.3449, and the observed value is 545.3448; 1 H NMR 300MHz CDCl3δ: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).

[0697] Example 28: Synthesis of Compound 502

[0698]

[0699] In a manner analogous to the procedure outlined in Example 27, substituting N-Cbz-glycine for 2-[2-(2-methoxyethoxy)ethoxy]acetic acid, compound 502 was obtained. HRMS (ESI+): C 33 H 47 NNaO6 m / z[M+H] +The calculated value is 576.3296, and the observed value is 576.3287; 1 H NMRδ: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).

[0700] Example 29: Synthesis of Compound 209

[0701]

[0702] In a manner analogous to the procedure outlined in Example 17 (excluding the HCl salt formation step), Cbz-L-valyl-glycine was substituted for 4-morpholineacetic acid to obtain compound 209. HRMS (ESI+): C 39 H 57 N2O8 m / z[M+H] + The calculated value is 681.410943, and the observed value is 681.411352; 1 H NMRδ:7.30-7.41(m,5H),6.81(d,J=4.69Hz,1H),5.53(d,J=9.38Hz,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,10 H),1.08-1.43(m,1)H),0.89-1.07(m,6H),0.71-0.84(m,3H),0.57(s,3H).

[0703] Example 30: Synthesis of Compound 210

[0704]

[0705] In a manner similar to the procedure outlined in Example 17 (excluding the HCl salt formation step), Cbz-D-proline was substituted for 4-morpholineacetic acid to obtain compound 210. HRMS (ESI+): C 37 H 52 NO7 m / z[M+H] +The calculated value is 644.355774, and the observed value is 644.355320; 1 H NMRδ: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 =8.79Hz,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).

[0706] Example 31: Synthesis of Compound 211

[0707]

[0708] In a manner analogous to the procedure outlined in Example 17, using (S)-2-morpholin-4-yl-propionic acid hydrochloride in place of 4-morpholineacetic acid, compound 211 was obtained. HRMS (ESI+): C 31 H 50 NO6 m / z[M+H] + The calculated value is 532.363265, and the observed value is 532.362510; 1 H NMRδ: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).

[0709] Example 32: Synthesis of Compound 212

[0710]

[0711] In a manner analogous to the procedure outlined in Example 17, (R)-2-morpholin-4-yl-propionic acid hydrochloride was substituted for 4-morpholineacetic acid to obtain compound 212 as the hydrochloride salt. HRMS (ESI+): C 31 H 50 NO6 m / z[M+H] + The calculated value is 532.363265, and the observed value is 532.363688; 1H NMRδ: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=8.79Hz,1H),2.08-2.29(m,5H),2.01(d,J=11 .14Hz,1H),1.85(d,J=4.69Hz,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).

[0712] Example 33: Synthesis of Compound 213

[0713]

[0714] In a manner similar to the procedure outlined in Example 17, replacing 4-morpholineacetic acid with α,α-dimethyl-4-morpholineacetic acid hydrochloride, compound 213 was obtained as the hydrochloride salt. HRMS (ESI+): C 32 H 52 NO6 m / z[M+H] + The calculated value is 546.378915, and the observed value is 546.378119; 1 H NMRδ:4.59-4.75(m,2H),4.42-4.58(m,2H),3.98(d,J=12.31Hz,2H),3.54(br.s 4H), 2.51 (t, J = 9.08Hz, 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).

[0715] Example 34: Synthesis of Compound 111

[0716]

[0717] Compound 404 (114 mg 0.28 mmol) was dissolved in 5 mL of DMSO, producing a clear, almost colorless solution after 10 minutes. Ammonium hydroxide 28-30 wt % (0.25 mL, 2.07 mmol) was added to the solution, causing the color to immediately turn orange-red. The reactants were stirred at ambient temperature. After stirring for 18 h, the reaction was post-processed as follows: diluted with 25 mL of EtOAc and then quenched with 15 mL of water. The mixture was transferred to a separatory funnel and the lower aqueous solution was discarded. 2 x 15 mL of H2O was extracted, with the lower aqueous solution discarded each time. The washed organic layer was then dried over Na2SO4 for 30 minutes, filtered and concentrated to give a clear orange oil after drying. The sample was dissolved in 2 mL of anhydrous EtOH to produce a clear light brown solution. 2N HCl in Et2O (0.2 mL, 0.4 mmol) was added thereto, and the solution darkened, but no solid was observed. After stirring for 30 minutes, the reaction was placed on a rotary evaporator and the solvent was removed. This resulted in the formation of a foam, which was dried under high vacuum to give compound 111 (91.2 mg) as a hydrochloride salt. HRMS (ESI+): C 24 H 41 ClNO3 m / z[M+H] + The calculated value is 390.300271, and the observed value is 390.300526; 1 H NMR(MeOD)δ:3.98(d,J=2.34Hz,1H),3.25-3.42(m,2H overlaps withsolvent), 2.61 (t, J = 8.50Hz, 1H), 1.89-2.28 (m, 6H), 1.15-1.79 (m, 24H), 0.75-1.06 (m, 4H), 0.60 (s, 3H).

[0718] Example 35: Synthesis of Compound 112

[0719]

[0720] DCM (4 mL) is added to compound 111 (from Example 34, 31.6 mg, 0.07 mmol) and 4-morpholineacetic acid (13.2 mg, 0.09 mmol). The mixture is 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) are added to produce a slurry that is clarified when diisopropylethylamine (40 μL, 0.23 mmol) is added. The resulting orange solution is heated to ambient temperature overnight. The reactant is diluted with 10 mL of DCM and quenched with 10 mL of H2O. The mixture is transferred to a separating funnel and each phase is separated. The organic matter is then washed with 10 mL of saturated NaHCO3, followed by 10 mL of NaCl. The washed organic matter is dried with Na2SO4, filtered and concentrated to give a crude product. The crude product is purified by column chromatography using ISCO TM Purification by chromatography system gave compound 112 (free base) as a solid (17.1 mg). HRMS (ESI+): C 30 H 49 N2O5 m / z[M+H] + The calculated value is 517.3636, and the observed value is 517.3635; 1 H NMRδ: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=12.89Hz,1H),1.04-1.75(m,27H),0.84-1.02(m,2H),0.68-0.81(m,5H),0.59(s,3H).

[0721] The resulting free base was treated with 2.0 M HCl / diethyl ether (2 mL) and the solvent removed in vacuo to afford compound 112 as a solid hydrochloride salt (19.8 mg). HRMS (ESI+): C 30 H 49 N2O5m / z[M+H] + The calculated value is 517.3636, and the observed value is 517.3635; 1H NMRδ: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 = 13.5hz, 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).

[0722] Example 36: Synthesis of Compound 114

[0723]

[0724] 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 produce a clear orange solution. The solution was stirred at ambient temperature for 15 minutes, then a 2M solution (150 μL, 0.30 mmol) of methylamine in tetrahydrofuran (THF) was added, followed by addition of CsCO (127.4 mg, 0.39 mmol) and the resulting mixture was heated to 70 ° C. After stirring for 2 h, the reactant was cooled, diluted with 25 mL of EtOAc, and then quenched with 15 mL of water. After separation of the layers, the EtOAc layer was washed with 2x15 ml of saturated NaHCO solution. The washed organic phase was dried with NaSO, filtered and concentrated to give a clear orange oil. The crude product was purified by column chromatography using ISCO TM Purification by chromatography system gave compound 114 (free base; 36.1 mg) as a solid. HRMS (ESI+): C 25 H 42 NO3 m / z[M+H] + The calculated value is 404.3159, and the observed value is 404.3159; 1 H NMRδ: 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).

[0725] Diethyl ether (Et2O; 2 mL) was added to the free base 114 (33.6 mg, 0.08 mmol) to produce a clear solution. The solution was allowed to stir for 5 minutes. 2M HCl in Et2O (50 μl 0.100 mmol) was added to the reaction flask and a precipitate formed. The reaction was stirred for an additional 10 minutes. The precipitate was isolated by filtration and washed with 5 mL Et2O and dried under vacuum to obtain compound 114 as the hydrochloride salt (31.4 mg). HRMS (ESI+): C25H42NO3 m / z [M+H] + The calculated value is 404.3159, and the observed value is 404.3159; 1 H NMRδ: 3.78(br.s.,2H),2.84(br.s.,3H),2.53(t,J=8.50Hz,1H),2.08-2.35(m,5H),2.00(d,J=11.14Hz, 1H), 1.89 (d, J = 8.21Hz, 1H), 1.07-1.78 (m, 23H), 0.97 (d, J = 8.21Hz, 1H), 0.72-0.85 (m, 4H), 0.60 (s, 3H).

[0726] Example 37: Synthesis of Compound 115

[0727]

[0728] In a manner analogous to the procedure outlined in Example 35, compound 114 was substituted for compound 404 to obtain compound 115 as a hydrochloride salt (18.7 mg). HRMS (ESI+): C 31 H 51 N2O5m / z[M+H] + The calculated value is 531.3792, and the observed value is 531.3782; 1 H NMRδ: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).

[0729] Example 38: Synthesis of Compound 218

[0730]

[0731] In a manner analogous to the procedure outlined in Example 17, substituting 2-aminoisobutyric acid for 4-morpholineacetic acid, compound 218 (101.6 mg) was obtained as a solid. HRMS (ESI+): C28H46NO5 m / z [M+H] + The calculated value is 476.3370, and the observed value is 476.3370; 1 HNMRδ: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).

[0732] Example 39: Preparation of Compound 125

[0733]

[0734] Anhydrous DMF (3mL) is added to compound 404 (150mg, 0.37mmol) and sodium iodide (96mg, 0.64mmol) to produce a clear orange solution. The solution is stirred at ambient temperature for 15 minutes and 2-aminoisobutyric acid methyl ester HCl (302mg, 1.96mmol) is added, followed by diisopropylethylamine (850 μL, 0.49mmol) and the resulting mixture is heated to 50 ° C. After 22h, the reactant is cooled. The reactant is diluted with 25mL EtOAc and then quenched with 15mL water. After separating the layers, the EtOAc layer is washed with 2x15 ml 1N HCl and then washed with 15mL brine. The washed organic matter is dried for 30 minutes with Na2SO4, filtered and concentrated to obtain a clear light brown oil. The crude product is purified by column chromatography using ISCO TM Purification by chromatography system gave compound 125 (85.1 mg) as an oil. HRMS (ESI+): C 29 H 48 NO5 m / z[M+H] + The calculated value is 490.3527, and the observed value is 490.3527; 1H NMRδ:3.71(s,3H),3.30(s,2H),2.52(t,J=8.8Hz,1H),2.30-2.08(m,6H),2.05-1.87(m,2H),1.7 4-1.38(m,20H),1.38-1.33(m,8H),0.92(dq,J=5.3,11.9Hz,1H),0.81-0.68(m,4H),0.60(s,3H).

[0735] Example 40: Synthesis of Compound 126

[0736]

[0737] In a manner similar to the procedure outlined in Example 39, replacing methyl 2-aminoisobutyrate·HCl with tert-butyl 2-amino-2-methylpropanoate·HCl (302 mg, 1.96 mmol) gave compound 126 (188 mg) as a solid. HRMS (ESI+): C 32 H 54 NO5 m / z[M+H] + The calculated value is 532.3997, and the observed value is 532.3999; 1 H NMRδ:8.03(s,1H),3.79-3.56(m,2H),2.96(s,3H),2.89(s,3H),2.52(t,J=8.8Hz,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).

[0738] Example 41: Synthesis of Compound 305

[0739]

[0740] In a manner similar to the procedure outlined in Example 39, substituting methyl 2-mercapto-2-methylpropanoate 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 O5S m / z[M+H] + The calculated value is 507.313872, and the observed value is 507.313659; 1HNMRδ: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=5.3,11.9Hz,1H),0.82-0.71(m,4H),0.59(s,3H).

[0741] At room temperature, NaOH (1.0M, 1mL) aqueous solution is added in ester (62mg, 0.13mmol) in methanol (5mL).After 18hr, reactant is diluted with 25mL EtOAc, then quenched with 15mL H o.Separate each layer and acidify water layer to pH 1 with 2.0mL2N HCl.Water layer is extracted with 2x15 mL DCM.DCM is used mutually Na sO dry, filter and concentrate to obtain compound 305, which is an oily matter (10mg). 1 H NMRδ:3.42(s,2H),2.51(t,J=9.08Hz,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).

[0742] Example 42: Synthesis of Compound 307

[0743]

[0744] 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 about 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 light yellow solution was slowly warmed to ambient temperature overnight. After 21 h, the reactant was diluted with 25 mL of EtOAc and then quenched with 15 ml of H2O. The mixture was transferred to a separatory funnel and the lower aqueous solution was discarded. The organic matter was washed with 15 mL of saturated NaHCO3 solution and then with 15 ml of saturated brine. The organic layer was then dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography using ISCOTM Purification by chromatography system afforded 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 removed in vacuo to afford compound 307 as a solid hydrochloride salt (38.3 mg). HRMS (ESI+): C 32 H 55 N2O4S m / z[M+H] + The calculated value is 563.3863, and the observed value is 563.3877; 1 H NMRδ:8.10(br.s.,1H),3.76-3.53(m,3H),3.38(s,2H),3.21(t,J=5.0Hz,2H),2.88(s,6H),2.53(t J=9.1Hz,1H),2.25-2.06(m,6H),1.99(d,J=12.3Hz,1H),1.87(d,J=14.1Hz,1H),1.73-1.09(m,24H),1.02-0.70(m,5H),0.59(s,3H).

[0745] Example 43: Synthesis of Compound 124

[0746]

[0747] 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 stirred at ambient temperature. After 21 h, the reaction was diluted with 25 mL of EtOAc and then quenched with 15 ml of H2O. The mixture was transferred to a separatory funnel and the upper organic layer was discarded. The aqueous layer was then dried and acidified to pH 1 with 2.0 mL of 2N HCl. The aqueous layer was extracted with 2x15 mL of DCM. The organics were dried over Na2SO4, filtered and concentrated to give compound 124 as an oil (58.9 mg). HRMS (ESI+): C 26 H 42 NO5 m / z[M+H] + The calculated value is 448.3027, and the observed value is 448.3051; 1 H NMRδ: 4.01-3.88 (m, 2H), 3.68 (s, 2H), 2.62 (t, J = 8.8Hz, 1H), 2.30-1.86 (m, 7H), 1.78-1.10 (m, 19H), 1.07-0.69 (m, 7H), 0.60 (s, 3H).

[0748] Example 44: Synthesis of Compound 304

[0749]

[0750] Compound 404 (74 mg, 0.18 mmol) and sodium iodide (49 mg, 0.33 mmol) are suspended in 5 mL of 1,4-dioxane, thiourea (14.5 mg, 0.19 mmol) is added and the mixture is then heated to 85 ° C. After stirring for 18 h, the reactant is cooled, diluted with 25 mL of EtOAc, and then quenched with 15 mL of water. The EtOAc layer is washed with 1x15 ml of H2O, then washed with 15 mL of brine and dried with Na2SO4, then vacuum dried to obtain a yellow solid. The solid is then dissolved in 10 mL of 1,4-dioxane to obtain a clear yellow solution. 4N HCl in 1,4-dioxane (50 ul, 0.200 mmol) is added thereto. The solution is stirred for 15 minutes and then frozen in dry ice. The yellow solid is placed on a freeze dryer and freeze-dried to obtain compound 304 as a solid hydrochloride (77.8 mg). HRMS(ESI+):C25H41ClN2O3Sm / z[M+H] + The calculated value is 449.2832, and the observed value is 449.2827; 1 H NMRδ:9.63-8.79(bs.s.,3H),4.03-3.84(s,1H),3.77-3.58(m,3H),2.51(q,J=8.8Hz,1H),2.26-2.0 2(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).

[0751] Example 45: Synthesis of Compound 214

[0752]

[0753] Compound 209 (from Example 29; 97 mg, 0.14 mmol) was dissolved in 10 mL of anhydrous EtOH. The solution was degassed under vacuum and then backfilled with nitrogen. This was done three times. 5% wet Pd / C (98.1 mg, 0.05 mmol) was added to the solution. The black suspension was degassed under vacuum and then backfilled with hydrogen. This was done three times and the reactants were stirred overnight under a H2 balloon. After stirring for 18 h, the reactants were diluted with 25 mL of EtOAc and filtered through a Celite plug. The plug was rinsed with additional EtOAc and then concentrated to obtain a turbid residue. The flask containing the residue was dissolved in 2 mL of Et2O. 2M HCl in Et2O (100 μL, 0.2 mmol) was added to the reaction flask. After adding HCl, the resulting precipitate was separated by filtration and washed with 5 mL of Et2O. The solid was then dried under high vacuum overnight to afford compound 214 (57.3 mg) as a hydrochloride salt. HRMS (ESI+): C 31 H 51 ClN2O6m / z[M+H] + The calculated value is 547.3742, and the observed value is 547.3731; 1 H NMRδ: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).

[0754] Example 46: Synthesis of Compound 215

[0755]

[0756] In a manner analogous to the procedure outlined in Example 45, compound 206 (from Example 22) was substituted for compound 209 to obtain compound 215. HRMS (ESI+): C 36 H 61 ClN2O6m / z[M+H] + The calculated value is 617.4524, and the observed value is 617.4526; 1H NMRδ: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=8.5Hz,1H),2.30-2.0 6(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).

[0757] Example 47: Synthesis of Compound 216

[0758]

[0759] In a manner analogous to the procedure outlined in Example 45, compound 207 (from Example 23) was substituted for compound 209 to obtain compound 216. HRMS (ESI+): C 29 H 47 CN2O6m / z[M+H] + The calculated value is 519.3429, and the observed value is 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,3Hδ).

[0760] Example 48: Synthesis of Compound 128

[0761]

[0762] In a manner similar to the procedure outlined in Example 2, 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 NO5 m / z[M+H] + The calculated value is 578.3840, and the observed value is 578.3844; 1H NMRδ:7.45-7.19(m,5H),5.28-5.07(m,2H),3.77(dd,J=4.4,9.1Hz,1H),3.59-3.44(m,2H),3.23-3.08(m,1H),2.9 2(q,J=7.6Hz,1H),2.51(t,J=8.5Hz,1H),2.31-1.81(m,13H),1.76-1.06(m,16H),1.03-0.67(m,6H),0.60(s,3H).

[0763] Example 49: Synthesis of Compound 224

[0764]

[0765] In a manner similar to the procedure outlined in Example 17 (excluding the step of forming the HCl salt), 2-hydroxyisobutyric acid (166 mg, 1.60 mmol) was substituted for 4-morpholinoacetic acid to obtain compound 224 (91.3 mg) as a foam. HRMS (ESI+): C 28 H 44 NaO6 m / z[M+H] + The calculated value is 499.3030, and the observed value is 499.3027; 1 H NMRδ:4.63(s,2H),3.00(s,1H),2.60-2.46(m,1H),2.35-1.97(m,8H),1.85(d,J=1 1.7Hz,1H),1.75-1.07(m,21H),1.04-0.86(m,2H),0.83-0.68(m,5H),0.61(s,3H).

[0766] Example 50: Synthesis of Compound 504

[0767]

[0768] By compound 500 (from Example 26; 122mg, 0.31mmol), a solution of cyclohexene (0.5ml, 4.94mmol) in DCM is cooled to -78 DEG C in a dry ice acetone bath. After stirring for 5 minutes, thionyl chloride (22 μL, 0.30mmol) is added once, and the content is slowly warmed to ambient temperature overnight. After stirring for 18h, the reaction mixture is concentrated into residue. The residue is then dissolved in 5mL DMF and NaI (62.1mg, 0.41mmol) and 4-morpholineacetic acid (182mg, 1.25mmol) are added. The resulting mixture is stirred for 5 minutes, and cesium carbonate (430mg, 1.32mmol) is then added to cause bright yellow slurries. The slurries are heated to 70 DEG C. After stirring for 18h, the reactant is diluted with 25mL EtOAc and 15mL H o, to produce a clear two-phase solution. After separation, the EtOAc layer was washed with 2 x 15 mL of saturated NaHCO 3 and then with 15 mL of saturated NaCl solution. The organic phase was dried over Na 2 SO 4 , filtered and concentrated to produce an orange residue, which was then dried under high vacuum. The crude product was purified by column chromatography using an ISCO TM Purification by chromatography afforded compound 504 as a solid (47.1 mg). HRMS (ESI+): C 29 H 48 NO5 m / z[M+H] + The calculated value is 490.3527, and the observed value is 490.3527; 1 H NMRδ: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).

[0769] Example 51: Synthesis of Compound 217

[0770]

[0771] 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 produce a dark green solution. To this solution was added N-(2-isocyanatoethyl)-N,N-dimethylamine (23.4 mg, 0.21 mmol). The reactants were stirred at ambient temperature for 20 h, then diluted with 25 mL of EtOAc and washed with 3x15 ml of H2O, followed by 15 mL of brine. The washed aqueous solution was then dried over Na2SO4, filtered and concentrated to give the crude product as a clear oil. The crude product was purified by column chromatography using ISCO TM Purification by chromatography system afforded compound 217 (free base; 18.7 mg). 1 HNMRδ:5.71(br.s.,1H),4.65-4.41m,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).

[0772] The free base was treated with 2.0 M HCl / diethyl ether (200 uL) and the solvent removed in vacuo to afford compound 217 as a solid hydrochloride salt (21.9 mg). HRMS (ESI+): C 29 H 49 N2O5 m / z[M+H] + The calculated value is 505.3636, and the observed value is 505.3624; 1 H NMRδ: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=8.5Hz,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).

[0773] Example 52. Synthesis of Compound 407

[0774]

[0775] 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 dissolved the reagents. After 42 h, the reaction mixture was cooled to ambient temperature and poured into water (95 mL). The pH was adjusted to 3 with 1N HCl and the organic layer was extracted with ethyl acetate (75 mL, 2x). The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the organic extracts were concentrated and purified via silica gel chromatography using 0%-100% ethyl acetate / hexanes to give compound 404 as a solid, 225 mg. HRMS (ESI+): C 26 H 40 NaO5 m / z[M+Na] + The calculated value is 455.2768, and the observed value is 455.2762; 1 H NMRδ=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=11.7Hz,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=7.0Hz,5H),1.22-1.09(m,6H),0.89(s,1H),0.80-0.72(m,4H),0.59(s,3H).

[0776] Example 53: Synthesis of Compound 408

[0777]

[0778] In a manner analogous to the procedure 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 O5 m / z[M+H] + The calculated value is 445.2949, and the observed value is 445.2950; 1H NMR CDCl3δ:2.79(dd,J=2.6,8.5Hz,1H),2.59-2.45(m,1H),2.22(br d,J=2.9Hz,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=2.6,6.6,11.9Hz,2H) ,1.74-1.52(m,8H),1.47(s,4H),1.43-1.29(m,7H),1.26(t,J=7.0Hz,6H),0.90(s,1H),0.83-0.72(m,5H),0.60(s,3H).

[0779] Example 54: Synthesis of Compound 420

[0780]

[0781] In a manner analogous to the procedure 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 NMRδ:2.62(s,1H),2.60(d,J=2.9Hz,2H),2.52(br t,J=8.8Hz,2H),2.27-2.13(m,3H),2.11(s,6H),2.05-1.96(m,3H),1.90(brd,J=12.9Hz,2H),1.77-1.54(m,8H),1.45(d,J=1.2Hz,7H),1.39(br d,J=2.9Hz,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).

[0782] Example 55. Synthesis of Compound 410

[0783]

[0784] 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). The reaction mixture was stirred overnight at ambient temperature. The reactant was diluted with ethyl acetate and 1N HCl (aqueous solution) was added. Brine was added to destroy the resulting emulsion and separate the phases. 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 obtain impure material, which was purified by reverse phase preparative HPLC 5%-95% acetonitrile / water buffered with trifluoroacetic acid. The fractions containing the product were lyophilized to obtain compound 410 as a trifluoroacetate salt (53 mg). HRMS (ESI+): C 30 H 51 N2O4 m / z[M+H] + The calculated value is 503.3843, and the observed value is 503.3856; 1 H NMR(DMSO-d6)δ=3.42-3.29(m,3H),3.10(q,J=5.9Hz,3H),2.78(d,J=4.1Hz,7H),2.53(s,1H),2.45 (d,J=5.9Hz,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

[0785] -1.19(m,11H),1.12(br s,5H),0.73(s,4H),0.49(s,3H).

[0786] Example 56: Synthesis of Compound 409

[0787]

[0788] In a manner analogous 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 NO5 m / z[M+H] + The calculated value is 504.3684, and the observed value is 504.3690; 1H NMR DMSO-d6)δ=4.38-4.27(m,3H),3.36(br d,J=4.7Hz,2H),2.81(d,J=4.7Hz,5H),2.54(td,J=2.6,4.8Hz,4H),2.09(br s,1H),1.95(br d,J=11.7Hz,1H),1.80-1.70(m,1H),1.68-1.47(m,3H),1.40(br s,1H),1.38(s,3H),1.33-1.20(m,3H),1.12(br s,4H),0.99-0.78(m,1H),0.74(s,2H),0.71-0.62(m,1H),0.50(s,2H).

[0789] Example 57: Synthesis of Compound 411

[0790]

[0791] In a manner analogous to the procedure outlined in Example 55, compound 408 (from Example 53) was substituted for compound 404 to obtain compound 411 as a trifluoroacetic acid salt. LCMS (ESI) m / z 515.75 (M+H)+; HRMS (ESI+): C 31 H 51 N2O4 m / z[M+H] + The calculated value is 515.3843, and the observed value is 515.3857; 1 H NMR(DMSO-d6)δ=8.23-8.13(m,2H),6.87(d,J=7.0Hz,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

[0792] -1.87(m,4H),1.82-1.68(m,1H),1.64-1.47(m,4H),1.34

[0793] -1.30(m,5H),1.21(s,2H),1.17-1.06(m,5H),0.75-0.68(m,4H),0.49(s,3H).

[0794] Example 58: Synthesis of Compound 412

[0795]

[0796] In a manner analogous to the procedure outlined in Example 55, compound 420 (from Example 54) was substituted for compound 404 to obtain compound 412 as a trifluoroacetic acid salt. LCMS (ESI) m / z 531.41 (M+H)+; HRMS (ESI+): C 32 H 55 N2O4 m / z[M+H] + The calculated value is 531.4156, and the observed value is 531.4150; 1 H NMR(DMSO-d6)δ=7.79(t,J=5.6Hz,1H),3.36(q,J=5.9Hz,3H),3.10(q,J=5.9Hz,2H),2.80(d,J=4.7Hz,6H),2.59-2.50(m,1H),2.02(br s,2H),1.73(br d,J=11.7Hz,1H),1.67-1.47(m,4H),1.36(s,7H),1.29-1.20(m,3H),1.1 4(s,7H),0.97-0.80(m,1H),0.73(s,3H),0.70-0.63(m,1H),0.49(s,3H).

[0797] Example 59: Synthesis of Compound 413

[0798]

[0799] In a manner analogous to the procedure outlined in Example 55, substituting compound 420 (from Example 54) for compound 404 and substituting 2-dimethylaminoethanol for dimethylaminoethylamine, compound 413 was obtained as a trifluoroacetic acid salt. LCMS (ESI) m / z 532.39 (M+H)+; HRMS (ESI+): C 32 H 54 NO5 m / z[M+H] + The calculated value is 532.3997, and the observed value is 532.3986; 1H 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=4.7Hz,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=10.5Hz,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).

[0800] Example 60. Synthesis of Compound 419

[0801]

[0802] To a solution of ganaxolone (83 mg, 0.25 mmol) and DMAP (37 mg, 0.3 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.174 mL, 1 mmol) at 0°C under a nitrogen atmosphere, followed by the dropwise addition of a solution of triphosgene (49 mg, 0.165 mmol) in dichloromethane (1.1 mL). The reaction was stirred at this temperature for 3.5 h, 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 while stirring overnight. The reaction was then diluted with water and 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 via silica gel chromatography using 0%-10% methanol / dichloromethane to give compound 419, which was converted to the hydrochloride salt (15 mg) with HCl. HRMS (ESI+): C 27 H 46 NO4 m / z[M+H] + The calculated value is 448.3421, and the observed value is 448.3421; 1H NMRδ=4.17(t,J=5.9Hz,2H),2.62(t,J=5.9Hz,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).

[0803] Example 61. Synthesis of Compound 220

[0804]

[0805] To a solution of bis(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 at ambient temperature overnight to give a 0.11 M solution of N', N'-dimethylaminoethyl O-succinimidyl carbonate, which was used directly in the next step without any purification. LCMS: m / z = 252.54 (M+Na) + .

[0806] To a mixture of compound 201 (from Example 25; 76 mg, 0.2 mmol) and DMAP (48 mg, 0.39 mmol) was added a 0.11 M solution of N', N'-dimethylaminoethyl O-succinimidyl carbonate in dichloromethane (5.6 mL) under nitrogen, followed by N, N-diisopropylethylamine (0.07 mL, 0.39 mmol). The reactants were stirred overnight at ambient temperature under nitrogen. 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 via silica gel chromatography with 0%-10% methanol / dichloromethane to give compound 220, which was converted into the hydrochloride salt (36 mg) using HCl. HRMS (ESI+): C 29 H 48 NO6 m / z[M+H] + The calculated value is 506.3476, and the observed value is 506.3486; 1H NMRδ=4.55(d,J=3.5Hz,2H),4.29(t,J=5.9Hz,2H),2.63(t,J=5.9Hz,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=2.6,11.4Hz,1H),1.51-1.46(m,4H),1.45-1.11(m,13 H), 0.97 (t, J = 7.3Hz, 1H), 0.94-0.85 (m, 1H), 0.82-0.73 (m, 4H), 0.59 (s, 3H).

[0807] Example 62. Synthesis of Compound 222

[0808]

[0809] To a solution of compound 201 (from Example 25, 78 mg, 0.2 mmol) in pyridine cooled to -20 ° C was added dropwise a solution of tert-butyl 3-[(chlorocarbonyl)oxy]azetidine-1-carboxylate (235 mg, 1.0 mmol) in dichloromethane (1 mL) under nitrogen. The reactant was slowly warmed to ambient temperature over 4 hours while stirring. The reactant was cooled to 0 ° C and quenched with 1N HCl (aqueous solution) and extracted with ethyl acetate (2x). The combined organic layers were washed with brine and dried over sodium sulfate. The extract was filtered, concentrated and purified via silica gel chromatography using 0%-25% ethyl acetate / hexane to give an intermediate compound containing Cbz, which was used immediately in the next step (109 mg). LCMS: m / z 612.37 (M+Na) + .

[0810] To the compound containing Cbz (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 via reverse phase preparative HPLC. The fractions containing the product were lyophilized to give compound 111 as a trifluoroacetate salt, 14 mg. HRMS (ESI+): C 28 H 44 NO6 m / z[M+H] + The calculated value is 490.3163, and the observed value is 490.3165; 1H NMR(DMSO-d6)δ=5.36-5.09(m,1H),4.68(s,2H),4.31(brdd,J=5.9,12.3Hz,2H),4.12-3.93(m,2H),2.71(quin,J=1.8Hz,1H),2.57-2.53(m ,2H),2.42(t,J=1.8Hz,1H),2.25(quin,J=1.9Hz,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=5.9Hz,4H),1.53(s,2H),1.41(s,3H),1.31(br d,J=8.2Hz,4H),1.22(s,1H),1.11(br d,J=2.9Hz,5H),0.76(s,1H),0.74(s,2H),0.49(s,3H).

[0811] Example 63. Synthesis of Compound 414

[0812]

[0813] To a solution of 1-benzyl N-(tert-butoxycarbonyl)aspartate (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, 1-benzyl N-(tert-butoxycarbonyl)aspartate 4-aspartic anhydride, was used in the next step without further purification.

[0814] 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 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 solution and diluted with dichloromethane, and the layers were separated. The organic layer was washed with 1N HCl (aq.) and dried over sodium sulfate. The extract was filtered, concentrated, and purified via silica gel chromatography using 0%-25% ethyl acetate to give the intermediate containing Boc and benzyl ester protecting groups (194 mg) as a solid, which was used directly in the next step without further purification. LCMS: m / z = 660.48 (M+Na) + .

[0815] To the solution of protected intermediate (190mg, 0.3mmol) in methanol (6.0mL), palladium carbon (35mg, 10% by mass) is added. Reactant mixture is purged and backfilled with hydrogen (3x), and vigorously stirred overnight. The consumption of starting material is found by LC / MS, and reactant mixture is filtered and concentrated filtrate, obtains the intermediate of Boc protection, which is directly used in the next step.

[0816] 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. After approximately 1 hour, the starting material was completely consumed by LC / MS 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 a trifluoroacetate salt, 20 mg. HRMS (ESI+): C 26 H 42 NO5 m / z[M+H] + The calculated value is 448.3057, and the observed value is 448.3050; 1 H NMR(DMSO-d6)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=11.7Hz,2H),1.76(br d,J=11.1Hz,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+).

[0817] Example 64: Synthesis of Compound 416

[0818]

[0819] In a manner similar to the procedure outlined in Example 63, replacing N-(tert-butyloxycarbonyl)-L-glutamic acid 1-benzyl ester with N-(tert-butyloxycarbonyl)-L-glutamic acid 1-benzyl ester, compound 416 was obtained as a trifluoroacetic acid salt. LCMS (ESI) m / z 484.21 (M+Na) + ; HRMS (ESI+): C 27 H 44 NO5 m / z[M+H] + The calculated value is 448.3057, and the observed value is 448.3050; 1H NMR(DMSO-d6)δ=3.80-3.65(m,2H),3.58(d,J=11.1Hz,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(m ,1H),2.15-2.06(m,2H),2.05(s,1H),2.04(s,3H),2.00-1.87(m,4H),1.8 0-1.67(m,2H),1.66-1.48(m,5H),1.39(s,5H),1.37-1.21(m,7H),1.12(br s,7H),0.96-0.86(m,1H),0.86-0.82(m,1H),0.74(s,4H),0.70-0.62(m,1H),0.49(s,3H).

[0820] Example 65. Synthesis of Compound 415

[0821]

[0822] To a solution of 2,5-dioxo-1-pyrrolidinepropionic acid (465 mg, 2.7 mmol) in dichloromethane (5.4 mL) was added a 1 M solution of N,N′-dicyclohexylcarbodiimide (1.35 mL, 1.35 mmol). The reaction was stirred at ambient temperature for 3 h, then filtered and the filtrate concentrated. The resulting oily residue, 2,5-dioxo-1-pyrrolidinepropionic anhydride, was used as is in the next step.

[0823] To a solution of ganaxolone (50 mg, 0.15 mmol) and DMAP (37 mg, 0.3 mmol) in dichloromethane (1.5 mL) under nitrogen was added N,N-diisopropylethylamine (0.12 mL, 0.66 mmol) followed by a solution of 2,5-dioxo-1-pyrrolidinepropionic anhydride (1.35 mmol) in dichloromethane (1.75 mL). The reaction was stirred overnight at ambient temperature under nitrogen. The reaction was quenched by the addition of 1N HCl (aq) and diluted with dichloromethane. The layers were separated and the organic layer was washed with brine and dried over sodium sulfate. The extract was filtered, concentrated and purified via silica gel chromatography using 0%-75% ethyl acetate / hexanes to give compound 415 as a solid (54 mg). HRMS (ESI+): C 29 H 43 NNaO5 m / z[M+Na] + The calculated value is 508.3033, and the observed value is 508.3035; 1H NMRδ=3.84-3.75(m,2H),2.72(s,4H),2.66-2.47(m,4H),2.25-2.13(m,1H),2. 11(s,3H),2.04-1.94(m,1H),1.93-1.82(m,1H),1.75-1.65(m,3H),1.65-1.62 (m,2H),1.57-1.56(m,1H),1.57(s,20H),1.53-1.49(m,1H),1.45(s,4H),1.43 -1.32(m,4H),1.30-1.14(m,9H),1.13-1.04(m,2H),0.76(s,4H),0.60(s,3H).

[0824] Example 66. Synthesis of Compound 417

[0825]

[0826] To a solution of 4-azidobutyric acid (387 mg, 3.0 mmol) in dichloromethane (3.0 mL) was added a 1 M solution of N,N′-dicyclohexylcarbodiimide (1.5 mL, 1.5 mmol). The reaction was stirred at ambient temperature for 1 h, then filtered and concentrated. The resulting oily residue, 4-azidobutyric anhydride, was used as is in the next step.

[0827] To a solution of ganaxolone (50 mg, 0.15 mmol) and DMAP (37 mg, 0.3 mmol) in dichloromethane (1.5 mL) under nitrogen was added N,N-diisopropylethylamine (0.12 mL, 0.66 mmol), followed by a solution of 4-azidobutyric anhydride (1.5 mmol) in dichloromethane (1.75 mL). The reaction was stirred overnight at ambient temperature under nitrogen. The reaction was quenched by the addition of 1N HCl (aq) and diluted with dichloromethane. The layers were separated and the organic layer was washed with brine and dried over sodium sulfate. The extract was filtered, concentrated, and purified via silica gel chromatography using 0%-25% ethyl acetate to give 43 mg of the azide-containing intermediate as a solid, which was used directly in the next step.

[0828] To a solution of the intermediate (24 mg, 0.054 mmol) containing azide in tetrahydrofuran (0.22 mL) was added dropwise a 1M solution of trimethylphosphine (0.07 mL, 0.07 mmol) in tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 3.5 h. Water (1.5 mL) was added and the mixture was stirred for 10 min, then diluted with dichloromethane (3 mL). The layers were separated and the organic phase was extracted with dichloromethane (3 mL, 2x). The combined organic layer was dried over sodium sulfate. The extract was filtered, concentrated and purified via silica gel chromatography using 0%-15% methanol / dichloromethane. The fraction containing the product was concentrated to give compound 417, which was converted into hydrochloride (36 mg) using HCl.

[0829] Example 67: Synthesis of Compound 418

[0830]

[0831] In a manner analogous to the procedure outlined in Example 66, substituting 5-azidopentanoic acid for 4-azidobutyric acid, compound 418 was obtained as the hydrochloride salt. LCMS (ESI) m / z 432.33 (M+H) + ; HRMS (ESI+): C 27 H 46 NO3 m / z[M+H] + The calculated value is 432.3472, and the observed value is 432.3471; 1 H NMRδ:3.43-3.14(m,1H),2.64-2.46(m,1H),2.42-2.25(m,8H),2.24-2.13(m,3H),2.11(s,3H),1.86(br d,J=11.7Hz,10H),1.79-1.55(m,14H),1.43(s,3H),1.29-1.03(m,16H),0.76(s,4H),0.59(s,3H).

[0832] Example 68: Synthesis of Compound 120 (Using Compound 125 as Precursor)

[0833]

[0834] The NaOH (1M, 250uL) aqueous solution was added to a solution of compound 125 (from Example 39, 119.5mg, 0.244mmol) and 2.5mL MeOH and the resulting solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was then concentrated to remove most of the MeOH using a rotary evaporator and diluted with 25mL EtOAc, then quenched with 5ml 1N NaOH. The mixture was transferred to a separating funnel and the upper organic layer was discarded. The water layer was then acidified to pH 1 with 3.0mL 2N HCl. The water layer was extracted with 2x15 mL DCM. Organic matter was dried using Na2SO4, filtered and concentrated to obtain a foam (30.1mg) containing compound 120 and compound 125 in a 9:1 ratio, as determined by LCMS. HRMS (ESI+): C 28 H 46 NO5 m / z[M+H] + The calculated value is 476.337050, and the observed value is 476.336738; 1 H NMRδ:3.84(br s,2H)2.52(br.s,1H),2.27-2.11(m,9H),2.01-1.98(m,2H),1.93-1.82(m,1 H),1.79-1.10(m,21H),1.06-0.92(m,1H),0.88-0.72(m,6H),0.60(2s,3H).

[0835] Example 69. Synthesis of Compound 127

[0836]

[0837] Compound 404 (from Example 1, 496 mg, 1.21 mmol) and sodium iodide (256 mg, 1.71 mmol) were dissolved in anhydrous DMF (8 mL) to produce a clear orange solution. After stirring for 15 minutes, benzyl-2-amino-2-propionic acid methyl ester HCl (1.35 g, 6.10 mmol) was added, followed by DiPEA (2.5 mL, 14.35 mmol) and the resulting mixture was heated to 50 ° C. After stirring for 22 hours, the reaction mixture was cooled, then diluted with 40 mL of EtOAc, and then quenched with 35 mL of water. The EtOAc phase was extracted with 2x25 mL of H2O and then with 25 mL of brine. The washed organic phase was dried with Na2SO4, filtered and concentrated to give an oily substance, which was purified by column chromatography using ISCO TM Purification by chromatography system gave compound 127 (375 mg) as an oil. HRMS (ESI+): C 28 H 44NaO6 m / z[M+H] + The calculated value is 499.3030, and the observed value is 499.3027; 1 H NMRδ:7.44-7.28(m,5H),5.20-5.11(m,2H),3.35-3.23(m,2H),2.55-2.50(t,J=8.8Hz,1H),2.22-2. 08(m,5H),2.06-1.87(m,3H),1.74-1.07(m,26H),1.02-0.83(m,1H),0.83-0.66(m,4H),0.60(m,3H).

[0838] Example 70. Synthesis of Compound 120 (Using Compound 127 as Precursor)

[0839]

[0840] Compound 127 (from Example 69; 257 mg, 0.45 mmol) was dissolved in EtOAc (10 mL) and 20 wt% Pd(OH)2 (27.6 mg, 0.0393 mmol) to produce a black slurry. The reaction was evacuated and then backfilled with H2. This was repeated 3 times and the reaction was then stirred und...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein Y is –C(O)– or –C(R A )(R B )– (e.g., –CH2–); 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, –N3, –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 each is 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 atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said 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, heterocyclyl, aryl or heteroaryl is optionally substituted; and R A and R B Each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

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

3. The compound of claim 1 or 2, wherein Z is a methylene group (e.g., an unsubstituted methylene group), in Z is absent, alkylene (e.g., methylene, e.g., unsubstituted methylene), alkenylene, alkynylene, heteroalkylene, cycloalkylene, heteroalkylene, arylene, or heteroarylene, wherein the alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted; R 2 is hydrogen or alkyl; R B and R C each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; and Each Indicates the point where Z is attached to X or Y.

4. A compound as claimed in any one of the preceding claims, wherein X is a moiety selected from the group consisting of in R 2 is hydrogen or alkyl; M is –C(H)(R D )– (e.g., –CH2–), –O–, or –N(R D )– (e.g., –N(Me)–); P is an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which can be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group), or P is a dipeptide moiety (e.g., a leucine-leucine moiety) which can comprise D-amino acids, L-amino acids, or combinations thereof and is optionally substituted (e.g., at one or more nitrogen atoms, e.g., at a terminal nitrogen atom, e.g., with a carbonate group such as a carboxybenzyl (Cbz) group); Q is heteroalkyl or heterocyclyl, wherein said heteroalkyl or heterocyclyl is optionally substituted; V is –O–, –N(H)–, or –N(Me)–; X2 and X3 are each independently -CH2-, -O-, -S- or -N(R G3 )– (e.g., –NH–); R A , R B , R C , R D , R E and R K each is 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 each independently is hydrogen, alkyl or an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which can be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group), or R G1 and R G2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R G3 and R G4 are each independently hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R G5 is hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted; R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted; R P is halo, –NH-alkyl, –NH-heteroalkyl, –N-(alkyl)2 (e.g., –N(Me)2), –N-(heteroalkyl)2 (e.g., –N(CH2CH2OH)2), or heterocyclyl (e.g., morpholinyl); R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, –OR J , –N(R G3 )(R G4 ), –NO2, –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 One of them, and R 13 and R 14 One of the following, together with the atoms to which they are attached, forms a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted; R 15 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, or halo; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl is optionally substituted; and m is an integer from 1 to 5; p is an integer between 0 and 4; and Represents the point of attachment of X and Z, or X and Y if Z is absent.

5. A compound as claimed in any one of the preceding claims, wherein X is a moiety selected from the group consisting of R B , R C and R K each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R G1 and R G2 each independently is hydrogen, alkyl or an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which can be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group), or R G1 and R G2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R G3 and R G4 are each independently hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R 2 is hydrogen or alkyl; and R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, –OR J , –N(R G3 )(R G4 ), –NO2, –CN or –NC.

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

7. A compound as claimed in any one of the preceding claims, wherein R 1 and R 2 Not all are hydrogen.

8. A compound of formula (I-II): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein: represents a single bond or a double bond; Y 1 is alkylene (e.g., methylene), alkenylene, alkynylene, heteroalkylene, -C(O)-, -OC(O)-, -C(O)O-, -NR 1 -, -O-, or -S-, wherein the alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted; Y 2 is heteroalkyl, heterocyclyl, heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, –NR 1 R 2 ,–OR 3 ,–SR 4 , =NR 1 or =0, wherein the heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R 1 and R 2 each is 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 atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said 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, heterocyclyl, 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 One of them is bonded to Y through one or more carbon atoms or heteroatoms 1 to form a cyclic moiety (e.g., cycloalkyl, heterocyclyl, aryl or heteroaryl, e.g., pyrrole), and R 7A and R 7B The other of the groups is hydrogen or optionally substituted alkyl; R 7C and R 7D are each independently hydrogen or optionally substituted alkyl, or R 7C and R 7D Each is bonded to the same oxygen atom to form an oxo group; and R 7E and R 7F 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 each bonded to the same oxygen to form an oxo group, provided that when When it is a double bond, R 7E and R 7F One of them does not exist.

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

10. The compound of claim 8 or 9, selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers and stereoisomers thereof, wherein Y 2 , R 1 , R 7C , R 7D , R 7E and R 7F As defined in claim 8.

11. A compound as described in any one of claims 8 to 10, wherein Y 2 or when When it is a double bond, R 7E is optionally substituted heteroalkyl, -NR 1 R 2 (e.g., –NH2, –NHMe, or –NMe2), –OR 3 (e.g., –OH, –OMe, –OEt, or –O t Bu) or =O, where R 1 , R 2 and R 3 As defined in claim 8.

12. A compound as described in any one of claims 8 to 11, wherein Y 2 or when When it is a double bond, R 7E Select from the group consisting of:

13. A compound of formula (IA) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 1 and R 2 each is 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 atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; and R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

14. The compound of claim 13, wherein the -N(R 1 )(R 2 ) group is a part selected from the group consisting of Where R 2 , M, Q, V, R A , R B , R C , R D , R E and R K As claimed in claim 1, and Indicates that the nitrogen atom is related to the –C(R 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

15. The compound of claim 13, wherein the -N(R 1 )(R 2 ) group is a part selected from the group consisting of Where R 2 , R 10 , R B , R C , R D , R E and R K As claimed in claim 1, and Indicates that the nitrogen atom is related to the –C(R 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

16. The compound of any one of claims 1-6 or 13-15, wherein the X group of formula (I) or the -N(R 1 )(R 2 ) group is a part selected from the group consisting of in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; or the point of attachment of the nitrogen atom and the -C(R 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

17. The compound of any one of claims 1-6 or 13-15, wherein the X group of formula (I) or the -N(R 1 )(R 2 ) group is a part selected from the group consisting of in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; or the point of attachment of the nitrogen atom and the -C(R 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

18. A compound as claimed in any one of the preceding claims, wherein the compound is a compound of formula (IA-a) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein G does not exist, is –C(O)– or –C(R 8A )(R 8B )– (e.g., –CH2–), K is alkylene, heteroalkylene, -C(O)-, -OC(O)-, -C(O)O-, -O-, -O-(CH2)-, or -(CH2)-O-, wherein the alkylene or heteroalkylene is optionally substituted; R 2 , R 7A , R 7B , R 8A and R 8B are each independently hydrogen or optionally substituted alkyl; and R 9 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

19. The compound of claim 18, wherein G is –C(R 8A )(R 8B )–; K is –OC(O)–; R 2 , R 7A , R 7B and R 9 are each hydrogen; and R 8A and R 8B are each independently hydrogen or alkyl (e.g., methyl), wherein the carbon atom of the carbonyl group in —OC(O)— is bonded to G.

20. A compound as claimed in any one of the preceding claims, wherein the compound is a compound of formula (IA-b) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 2 , R 8A and R 8B are each independently hydrogen or optionally substituted alkyl; and R 9 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

21. A compound as described in any one of claims 18 to 20, wherein R 2 is hydrogen; and R 8A and R 8B are each independently methyl.

22. A compound of formula (IB): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 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; and R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

23. The compound of claim 22, wherein the -O-(R 3 ) group is a part selected from the group consisting of in P is an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which can be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group), or P is a dipeptide moiety (e.g., a leucine-leucine moiety) which can comprise D-amino acids, L-amino acids, or combinations thereof and is optionally substituted (e.g., at one or more nitrogen atoms, e.g., at a terminal nitrogen atom, e.g., with a carbonate group such as a carboxybenzyl (Cbz) group); R B and R C each is 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 each independently is hydrogen, alkyl or an amino acid residue (e.g., glycine, alanine, valine, leucine or proline), which can be a D-amino acid residue or an L-amino acid residue and is optionally substituted (e.g., at the terminal nitrogen atom, for example, by a carbonate group such as a carboxybenzyl (Cbz) group), or R G1 and R G2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R G3 and R G4 are each independently hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said 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 K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R P is halo, –NH-alkyl, –NH-heteroalkyl, –N-(alkyl)2 (e.g., –N(Me)2), –N-(heteroalkyl)2 (e.g., –N(CH2CH2OH)2), or heterocyclyl (e.g., morpholinyl); m is an integer from 1 to 5; and Indicates that the oxygen atom is associated with the –C(R 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

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

25. The compound of any one of claims 1, 2 or 22-24, wherein the X group of formula (I) or the -OR of formula (IB) 3 A group is a part selected from the group consisting of in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; or the point of attachment of the oxygen atom and the -C(R) in formula (IB) 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

26. The compound of any one of claims 1, 2 or 22-24, wherein the X group of formula (I) or the -OR of formula (IB) 3 A group is a part selected from the group consisting of in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; or the point of attachment of the oxygen atom and the -C(R) in formula (IB) 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

27. A compound of formula (IC) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 4 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, or heteroalkylene-heteroaryl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R 7A and R 7B Each is independently hydrogen or optionally substituted alkyl.

28. The compound of claim 27, wherein the -S-(R 4 ) group is a part selected from the group consisting of in R B and R C each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R G3 and R G4 are each independently hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R G5 is hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted; R J is hydrogen, alkyl, alkylene-heterocyclyl, heteroalkyl or heterocyclyl, wherein the alkyl, alkylene, heteroalkyl or heterocyclyl is optionally substituted; R K is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted; R P is halo, -NH-alkyl, -NH-heteroalkyl, -N-(alkyl)2 (e.g., -N(Me)2), -N-(heteroalkyl)2 (e.g., -N(CH2CH2OH)2), or heterocyclyl (e.g., morpholinyl); and represents the sulfur atom and the –C(R 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

29. The compound of any one of claims 1, 2, 27 or 28, wherein the X group of formula (I) or the -SR of formula (IC) 4 A group is a part selected from the group consisting of in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; or the point of attachment of the sulfur atom and the -C(R 7A )(R 7B ) group is the point of attachment to a carbon atom of the group.

30. A compound of formula (ID) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, in R 5 is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, cycloalkylene-alkyl, cycloalkylene-heteroalkyl, heterocyclylene-alkyl, or heterocyclylene-heteroalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl or heteroaryl is optionally substituted.

31. The compound of claim 30, wherein R 5 including a portion selected from the group consisting of in X2 and X3 are each independently -CH2-, -O-, -S- or -N(R G3 )– (e.g., –NH–); R 10 is alkyl, alkenyl, alkynyl, haloalkyl, halo, –OR J , –N(R G3 )(R G4 ), –NO2, –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 One of them, and R 13 and R 14 One of the following, together with the atoms to which they are attached, forms a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group 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, wherein the alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said 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 Indicates the R 5 The point of attachment of the group to the carbon atom of the -C(O)- group.

32. A compound as described in any one of claims 1, 2, 30 or 31, wherein the X group of formula (I) or the R of formula (ID) 5 A group is a part selected from the group consisting of in represents the point of attachment of X and Z in formula (I) or X and Y when Z is absent; or R in formula (ID) 5 The point of attachment of the group to the carbon atom of the -C(O)- group.

33. A compound of formula (IE) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 6 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-aryl, alkylene-heteroaryl, heteroalkylene-cycloalkyl, heteroalkylene-heterocyclyl, heteroalkylene-aryl, heteroalkylene-heteroaryl, —OC(O)-alkyl, —C(O)O-alkyl, —OC(O)-heteroalkyl, —C(O)O-heteroalkyl, —N3, —SH, or —S-alkyl (e.g., —S-Me), wherein the alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, heteroalkylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; and R A and R B Each is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

34. The compound of claim 33, wherein R 6 is part of the group consisting of in R G3 and R G4 are each independently hydrogen, alkyl or heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted; or R G3 and R G4 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said 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 Indicates the R 6 The group is related to the –C(R A )(R B ) – the point of attachment of a carbon atom of a group.

35. A compound as described in any one of claims 1, 2, 33 or 34, wherein the X group of formula (I) or the R of formula (IE) 6 A group is a part selected from the group consisting of in represents the attachment point of X and Z or X and Y when Z is absent in formula (I); or said R 6 The group is related to the –C(R A )(R B ) – the point of attachment of a carbon atom of a group.

36. A compound as claimed in any one of the preceding claims, wherein the compound is a compound selected from Table 1.

37. A compound as described in any one of claims 1-26 or 36, wherein the compound is selected from the group consisting of and pharmaceutically acceptable salts, solvates, hydrates, tautomers and stereoisomers thereof.

38. A compound as described in any one of claims 1-26 or 36, wherein the compound is selected from the group consisting of and pharmaceutically acceptable salts, solvates, hydrates, tautomers and stereoisomers thereof.

39. A compound as described in any one of claims 1-4, 6, 13, 14, 16, 36 or 37, wherein the compound is or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

40. A compound as described in any one of claims 1-38, wherein the compound is not or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

41. The compound of any of the preceding claims, wherein the compound has greater water solubility and / or hydrophilicity relative to ganaxolone, e.g., as determined by logS, logP, logD, topological polar surface area (TPSA), acidic pKa, basic pKa, or a combination thereof.

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

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

44. The compound of any of the preceding claims, wherein the compound, e.g., upon administration to a subject, provides a higher serum concentration of ganaxolone (e.g., C max or AUC) and / or a longer ganaxolone half-life.

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

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

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

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

49. Use of a compound as described in any one of claims 1 to 44 or a pharmaceutical composition as described in claim 45 in the preparation of a medicament effective for treating a disease or disorder in a subject.

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

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

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

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

54. The method of claim 46 or 47, the composition for use of claim 48, or the use of claim 49, wherein the disease or disorder is tuberous sclerosis complex.

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

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

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