Dimethyltryptamine prodrugs and derivatives

Abstract

Provided herein are compounds of Formula (IA), Formula (IB), Formula (II-A), Formula (II-B), their pharmaceutically acceptable salts, and compositions thereof, wherein R, R, R, R, R, R, R 10 , R 11 , R 12 , R 13 , R 14 , A, B, E, W, X, and n are defined herein. The disclosed compounds are useful for treating a variety of disorders, including depression and related conditions. [Formula 1] JPEG2025539560000060.jpg50163

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 387,679, filed December 15, 2022, the entire contents of which are incorporated herein by reference.

[0002] N,N-Dimethyltryptamine (DMT), a naturally occurring compound found in many plant species and botanical preparations (such as the hallucinogenic infusion known as ayahuasca), is classified as a classic serotonergic hallucinogen that induces potent alterations in perception, emotion, and cognition in humans. At high doses, DMT has a rapid onset, strong hallucinogenic effects, and a relatively short duration of action, with an estimated half-life of less than 15 minutes. Like other hallucinogens in the tryptamine family, DMT binds to serotonin receptors to produce euphoric and hallucinogenic effects. Unfortunately, DMT is metabolically unstable and is readily converted by monoamine oxidase (MAO) to indole acetic acid and N-oxidized metabolites, resulting in poor oral bioavailability.

[0003] Serotonergic hallucinogens have also demonstrated promising antidepressant, anti-anxiety, and anti-addiction properties.

[0004] There remains a need for improved prodrugs of tryptamine, such as N,N-dimethyltryptamine (DMT). Summary of the Invention

[0005] In one aspect, the present disclosure provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or C-VR 16 and B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; V, X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, R5, and R 16 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or —P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 11 and R 12 are each independently an alkyl, a deuterated alkyl, -O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, or R 11 and R 12together with the atom to which they are attached form a heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are each optionally substituted; R 13 is H, D, halogen, deuterated alkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, —C(O)-(alkylene-optionally substituted aryl), or —OC(O)—NHR 15 or R 11 and R 13 together with the atom to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms; R 14 is H, D, halogen, haloalkyl, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and R 15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0006] In one aspect, the present disclosure provides a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or CH; B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, and R5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or -P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 11 and R 12 are each independently O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, or R 11 and R 12 together with the atom to which they are attached form a heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are each optionally substituted; R 13is H, D, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, —C(O)-(alkylene-optionally substituted aryl), or —OC(O)—NHR 15 or R 11 and R 13 together with the atom to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms; R 14 is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and R 15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0007] In one aspect, the present disclosure provides a compound of formula (II-A): Compound of formula (II-A) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or C-VR 16 and B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; V, X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, R5, and R 16are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or —P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 12 -O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, wherein M is a pharmaceutically acceptable cation, and alkyl, cycloalkyl, and aryl are each optionally substituted; R 14 is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and n is 0, 1, or 2.

[0008] In one aspect, the present disclosure provides a compound of formula (II-B): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or CH; B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, and R5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or -P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 12 O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, and alkyl, cycloalkyl, and aryl are optionally substituted; R 14is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and n is 0, 1, or 2.

[0009] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (IB) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (II-A) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0012] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (II-B) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [Brief explanation of the drawings]

[0013] [Figure 1] Figure 1 shows PK studies of N-phosphonooxymethyl prodrug Compound 1 (VLS-02-23-0; 6-1-2) and metabolite (VLS-02-023-10) after intravenous (1 mg / kg) and oral administration (30 mg / kg) to male CD1 mice (in plasma). [Figure 2] Figure 2 shows PK studies of N-phosphonooxymethyl prodrug Compound 1 (VLS-02-23-0; 6-1-2) and metabolite (VLS-02-023-10) after intravenous (1 mg / kg) and oral administration (30 mg / kg) to male CD1 mice (intracerebrospinal). DETAILED DESCRIPTION OF THE INVENTION

[0014] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of a conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0015] definition For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0016] The terms "administer," "administering," or "administration," as used herein, refer to administering a compound or a pharmaceutically acceptable salt of the compound, or a composition or formulation comprising a compound or a pharmaceutically acceptable salt of the compound, to a patient.

[0017] The term "pharmaceutically acceptable salts" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include salts obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., acids that form salts containing pharmaceutically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, acetate, tartrate, oleate, fumarate, formate, benzoate, glutamate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate. Base addition salts include, but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine dicyclohexylamine, etc. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc. Examples of ammonium salts and alkylated ammonium salts include ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts, ethylammonium salts, hydroxyethylammonium salts, diethylammonium salts, butylammonium salts, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, and the like.Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compound with the appropriate inorganic or organic acid via any of a number of known methods.

[0018] The term "treating," as used herein with respect to a patient, refers to improving at least one symptom of the patient's disorder. In embodiments, treating can be improving or at least partially reversing the disorder or one or more symptoms of the disorder.

[0019] The term "preventing" as used herein with respect to a patient or subject refers to preventing the onset of a disease where the disease has not yet occurred, preventing the disease or disorder from occurring in a subject or patient who is susceptible to the disorder or disease but has not yet been diagnosed with the disorder or disease, and / or preventing further progression of the disease / disorder where the disorder or disease is already present.

[0020] The term "therapeutically effective" as applied to a dose or amount refers to that amount of a compound or pharmaceutical preparation that is sufficient to result in a desired clinical benefit following administration to a patient in need thereof.

[0021] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" means C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0022] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain having from 1 to 12 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing any number of carbon atoms from 1 to 12 is included. Alkyl containing up to 12 carbon atoms is C 1- C 12 Alkyl, and alkyl containing up to 10 carbon atoms is C 1- C 10 Alkyl, and alkyl containing up to 6 carbon atoms is C 1- C6 alkyl, and alkyl containing up to 5 carbon atoms is C 1- C5 alkyl. 1- C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). 1- C6 alkyl is C 1- Includes all of the moieties listed above for C5 alkyl, but also includes C6 alkyl. 1- C 10 Alkyl is C 1- C5 alkyl and C 1- Includes all of the moieties listed above for C6 alkyl, but also includes C7, C8, C9, and C 10 Also includes alkyl. 1- C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Also includes alkyl. 1- C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0023] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, attached to the rest of the molecule by a single bond. For purposes of this disclosure, aryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Aryl includes, but is not limited to, aryls derived from acentrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, "aryl" may be optionally substituted.

[0024] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon, consisting solely of carbon and hydrogen atoms, attached to the rest of the molecule by a single bond, which may include fused, bridged, or spirocyclic ring systems having from 3 to 20 carbon atoms (e.g., having from 3 to 10 carbon atoms). Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified in the specification, cycloalkyl groups can be optionally substituted.

[0025] "Heterocyclyl," "heterocycle," or "heterocycle" refers to a stable, saturated, unsaturated, or aromatic 3- to 20-membered ring consisting of 2 to 19 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, attached to the remainder of the molecule by a single bond. Heterocyclyl or heterocycle includes heteroaryl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless stated otherwise in the specification, a heterocyclyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused, bridged, or spirocyclic ring systems; the nitrogen, carbon, or sulfur atoms in a heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, heterocyclyl groups may be optionally substituted.

[0026] "Heteroaryl" refers to a 5- to 20-membered ring system containing a hydrogen atom, 1-19 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, at least one aromatic ring, and attached to the remainder of the molecule by a single bond. For purposes of this disclosure, heteroaryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthlanyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, and indolyl. nyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0027] As used herein, the term "substituted" means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, including, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms of various other groups. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher order bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" refers to any group in which one or more hydrogen atoms have been replaced by a higher order bond (e.g., a double or triple bond) to a heteroatom, such as -NR g R h , ‐NR g C(=O)R h , ‐NR g C(=O)NR g R h , ‐NR g C(=O)OR h , ‐NR g SO2R h , -OC(=O)NR g R h , -OR g , ‐SR g , ‐SOR g , ‐SO2R g , ‐OSO2R g ,‐SO2OR g , =NSO2R g , and SO2NRg R h "Substituted" also refers to any of the above groups substituted with -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R h are the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

[0028] compound The present disclosure provides compounds that are prodrugs of tryptamine and related scaffolds, such as N,N-dimethyltryptamine (DMT), and pharmaceutical compositions thereof.

[0029] DMT is metabolically unstable and is easily converted by monoamine oxidase (MAO) to indole acetic acid and N-oxidized metabolites, resulting in reduced oral bioavailability. In embodiments, the compounds of the present disclosure enable controlled release of DMT. Advantages of the compounds of the present disclosure may include increased metabolic stability, increased absorption, reduced maximum plasma concentration of the parent drug DMT over time, and reduced dosing frequency. In embodiments, the compounds of the present disclosure prevent or inhibit N-oxidation, promoting increased oral bioavailability and exposure.

[0030] In embodiments, the DMT compounds of the present disclosure include a phosphate moiety, a phosphonate moiety, or derivatives thereof. Without being bound by theory, such compounds may increase bioavailability by active transport of the prodrug in the small intestine by high-capacity nutrient transporters, including, for example, monocarboxylate transporter 1 (MCT-1). The DMT prodrugs disclosed herein may also reduce the potential for abuse by preventing absorption via nasal inhalation or insufflation.

[0031] Compounds of formula (IA) and (II-A) In embodiments, the present disclosure provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or C-VR 16 and B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; V, X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, R5, and R 16 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or —P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 11 and R 12 are each independently an alkyl, a deuterated alkyl, O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, or R 11 and R 12 together with the atom to which they are attached form a heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are each optionally substituted; R 13is H, D, halogen, deuterated alkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, —C(O)-(alkylene-optionally substituted aryl), or —OC(O)—NHR 15 or R 11 and R 13 together with the atom to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms; R 14 is H, D, halogen, haloalkyl, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and R 15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0032] In embodiments, the present disclosure provides a compound of formula (II-A): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or C-VR 16 and B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; V, X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, R5, and R 15are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or —P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 12 O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, and alkyl, cycloalkyl, and aryl are optionally substituted; R 14 is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and n is 0, 1, or 2.

[0033] In embodiments, A is N. In embodiments, A is C-VR 16 is.

[0034] In embodiments, B is N. In embodiments, B is C-YR4.

[0035] In an embodiment, E is N. In an embodiment, E is C-ZR5.

[0036] In embodiments, W is NR6 or O. In embodiments, W is NR6 or S. In embodiments, W is O or S. In embodiments, W is NR6. In embodiments, W is O. In embodiments, W is S.

[0037] In embodiments, V, X, Y, and Z are each independently absent, O, S, or N(C 1‐5 ) alkyl. In embodiments, V, X, Y, and Z are each independently absent or O. In embodiments, V, X, Y, and Z are each independently absent or NH. In embodiments, V, X, Y, and Z are each independently absent or S. In embodiments, V, X, Y, and Z are each absent.

[0038] In an embodiment, X is O, and V, Y, and Z are absent. In an embodiment, Y is O, and V, X, and Z are absent. In an embodiment, Z is O, and V, X, and Y are absent. In an embodiment, V is O, and X, Y, and Z are absent. In an embodiment, X is S, and V, Y, and Z are absent. In an embodiment, Y is S, and V, X, and Z are absent. In an embodiment, Z is S, and V, X, and Y are absent. In an embodiment, V is S, and X, Y, and Z are absent. In an embodiment, X is NH, and V, Y, and Z are absent. In an embodiment, Y is NH, and V, X, and Z are absent. In an embodiment, Z is NH, and V, X, and Y are absent. In an embodiment, V is NH, and X, Y, and Z are absent. In an embodiment, X is N(C 1‐5 ) alkyl, and V, Y, and Z are absent. In embodiments, Y is N(C 1‐5 ) alkyl, and V, X, and Z are absent. In embodiments, Z is N(C 1‐5 ) alkyl, and V, X, and Y are absent. In embodiments, V is N(C 1‐5) alkyl, and X, Y, and Z are absent.

[0039] In embodiments, R1 and R2 are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl. In embodiments, R1 and R2 are each independently H, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted C 1-5 In some embodiments, R1 and R2 are each independently H or alkyl. In some embodiments, R1 and R2 are each independently alkyl or deuterated alkyl. In some embodiments, R1 and R2 are each independently H or deuterated alkyl. In some embodiments, R1 and R2 are each independently H or C 1-5 In embodiments, R and R are each independently H or deuterated C. 1-5 In an embodiment, R and R are each independently alkyl or deuterated C 1-5 In an embodiment, R1 and R2 are each alkyl. In an embodiment, R1 and R2 are each deuterated alkyl. In an embodiment, R1 and R2 are each C 1-5 In embodiments, R1 and R2 are each alkyl. In embodiments, R1 and R2 are each deuterated C1-5 alkyl. In embodiments, R1 and R2 are each independently methyl, ethyl, or isopropyl. In embodiments, R1 and R2 are each independently deuterated methyl, deuterated ethyl, or deuterated isopropyl. In embodiments, R1 and R2 are each methyl. In embodiments, R1 and R2 are each deuterated methyl. In embodiments, R1 and R2 together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, e.g., azetidine, pyrrolidine, or piperidine.

[0040] In embodiments, R3, R4, R5, and R 16are each independently H, D, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-5 Heteroalkyl, -P(O)(OC 1-5 In an embodiment, R, R, R, and R are -P(O)(OH), -P(O)(OH), -P(O)(OH), or -P(O)(OH). 16 are each independently H, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-5 Heteroalkyl, -P(O)(OC 1-5 In an embodiment, R, R, R, and R are -P(O)(OH), -P(O)(OH), -P(O)(OH), or -P(O)(OH). 16 are each independently H, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 Cycloalkyl, -P(O)(OC 1-5 In an embodiment, R, R, R, and R are -P(O)(OH), -P(O)(OH), -P(O)(OH), or -P(O)(OH). 16 are each independently H, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, or —P(O)(OH). In embodiments, R, R, R, and R 16 are each independently H, optionally substituted C 1-5 alkyl, or —P(O)(OH). In embodiments, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. In embodiments, R, R, R, and R 16 are each H.

[0041] In embodiments, R3 is an optionally substituted C 1-5 alkyl or -P(O)(OH)2, and R4, R5, and R 16are each H. In an embodiment, R4 is optionally substituted C 1-5 alkyl or -P(O)(OH)2, and R3, R5, and R 16 are each H. In an embodiment, R5 is optionally substituted C 1-5 alkyl or -P(O)(OH)2, and R3, R4, and R 16 are each H. In an embodiment, R 16 is optionally replaced by C 1-5 alkyl or —P(O)(OH), and R, R, and R are each H. In embodiments, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. 1-5 Alkyl is methyl, ethyl, or isopropyl.

[0042] In embodiments, X is absent and R3 is H, halogen, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 In embodiments, Y is absent and R is H, halogen, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 In embodiments, Z is absent and R is H, halogen, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 In embodiments, V is absent and R 16 is H, halogen, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, or —P(O)(OH). In embodiments, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. In embodiments, halogen is F, Cl, or Br.

[0043] In embodiments, R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocyclyl, or optionally substituted alkylene-aryl. In embodiments, R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkylene-cycloalkyl. In embodiments, the optionally substituted alkyl is optionally substituted C 1-5 In embodiments, the optionally substituted cycloalkyl is an optionally substituted C alkyl. 3-6 In embodiments, the optionally substituted aryl is an optionally substituted phenyl. In embodiments, the optionally substituted heterocyclyl is an optionally substituted 4- to 6-membered heterocyclyl, such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, or piperazine, each of which is optionally substituted. In embodiments, the optionally substituted alkylene is an optionally substituted C 1‐3 In an embodiment, the optionally substituted alkylene is an optionally substituted methylene. In an embodiment, R6 is H, C 1-5 Alkyl, C 3-6 Cycloalkyl, or C(=O)(C 1-5 In an embodiment, R6 is H, C 1-5 Alkyl, or C 3-8 In an embodiment, R6 is H or C 1-5 In an embodiment, R6 is H. In an embodiment, R6 is C 1-5 In embodiments, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, optionally substituted C 1-5 Alkyl is -C(O)-C 1-4 Alkyl, -C(O)-N(H)(C 1-4 alkyl), or -C(O)-OC 1-4 It is alkyl.

[0044] In embodiments, R7 and R8 are each independently H, halogen, optionally substituted alkyl, -OH, optionally substituted -O-alkyl, or optionally substituted -O-cycloalkyl. In embodiments, R7 and R8 are each independently H, halogen, optionally substituted C 1-5 Alkyl, -OH, optionally substituted -OC 1-5 alkyl, or optionally substituted -OC 3-6 In an embodiment, R7 and R8 are each independently H or optionally substituted C 1-5 In an embodiment, R7 and R8 are each H. In an embodiment, R7 and R8 are each optionally substituted C 1-5 In an embodiment, R7 and R8 are each halogen. In an embodiment, halogen is F. In an embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. 1-5 Alkyl is methyl. In embodiments, C 1-5 The alkyl is ethyl.

[0045] In embodiments, R7 and R8 together with the atom to which they are attached form an oxo or optionally substituted cycloalkyl ring. In embodiments, R7 and R8 together with the atom to which they are attached form an oxo. In embodiments, R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted C 3-6 In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted cyclopropyl. In embodiments, R7 is H and R8 is an optionally substituted C 1-5In an embodiment, R7 is H and R8 is F. In an embodiment, R7 is H and R8 is -OH. In an embodiment, R7 is H and R8 is -OCH3. In an embodiment, R7 is F and R8 is F. In an embodiment, R7 and R8 are each optionally substituted C 1-5 In embodiments, C 1-5 Alkyl is methyl.

[0046] In embodiments, R and R 10 are each independently H, halogen, optionally substituted alkyl, -OH, optionally substituted -O-alkyl, or optionally substituted -O-cycloalkyl. In an embodiment, R and R 10 are each independently H, halogen, optionally substituted C 1-5 Alkyl, -OH, optionally substituted -OC 1-5 alkyl, or optionally substituted -OC 3-6 In an embodiment, R and R are cycloalkyl. 10 are each independently H or optionally substituted C 1-5 In an embodiment, R and R are alkyl. 10 are each H. In an embodiment, R and R 10 are each optionally substituted C 1-5 In an embodiment, R and R are alkyl. 10 are each halogen. In an embodiment, the halogen is F. In an embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. 1-5 Alkyl is methyl. In embodiments, C 1-5 The alkyl is ethyl.

[0047] In embodiments, R and R 10 together with the atoms to which they are attached form an optionally substituted cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted C 3-6In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted cyclopropyl. In embodiments, R is H and R 10 is optionally replaced by C 1-5 In an embodiment, R is H and R is alkyl. 10 is F. In an embodiment, R is H and R 10 is —OH. In an embodiment, R is H and R 10 is —OCH. In an embodiment, R and R 10 are each F. In an embodiment, R and R 10 are each optionally substituted C 1-5 In embodiments, C 1-5 Alkyl is methyl.

[0048] In embodiments of Formula (IA), R 11 and R 12 are each independently an alkyl, a deuterated alkyl, O - , -OH, optionally substituted -O-alkyl, optionally substituted -O-cycloalkyl, optionally substituted -O-alkylene-cycloalkyl, optionally substituted -O-aryl, or -OM, where M is a pharmaceutically acceptable cation. In embodiments, the optionally substituted -O-alkyl is an optionally substituted -O-haloalkyl, hemiaminal, acetal, or amino acid residue. In embodiments, R 11 and R 12 are each independently O - , -OH, optionally substituted -OC 1-5 Alkyl, optionally substituted -OC 1-5 Haloalkyl, optionally substituted -OC 3-6 In embodiments, R 11 and R 12 are each independently O - , -OH, optionally substituted -OC 1-5 Alkyl, optionally substituted -OC 1-5haloalkyl, or -OM. In embodiments, R 11 O - and R 12 is -OH, optionally substituted -OC 1-5 Alkyl, optionally substituted -OC 1-5 haloalkyl, or -OM. In embodiments, R 11 and R 12 are each optionally replaced by -OC 1-5 In embodiments, R 11 and R 12 are each optionally replaced by -OC 1-3 In embodiments, R 11 and R 12 are each independently -OMe, -OEt, -OiPr, or -OtBu. 11 and R 12 are each optionally replaced by -OC 1-5 In embodiments, -OC is haloalkyl. 1-5 Haloalkyl is -OCH3, -OCH2F, -OCHF2, or -OCH2CF3. In embodiments, -OC 1-5 Haloalkyl is —OCH2CF3. In embodiments, R 11 and R 12 are each independently an alkyl, a deuterated alkyl, O - , —OH, —OD, —O-alkyl, or —O-cycloalkyl. 11 and R 12 are each independently alkyl or deuterated alkyl. In embodiments, M is Na+, K+, NH4+, or Ca+2. In embodiments, M is Na+, K+, or NH4+.

[0049] In embodiments of Formula (IA), R 11 and R 12 together with the atoms to which they are attached form a heterocyclyl. In embodiments, R 11 and R 12together with the atom to which they are attached form a 5- to 12-membered heterocyclyl. In embodiments, the heterocyclyl has the structure: [ka]

[0050] In embodiments of Formula (II-A), R 12 O - , -OH, optionally substituted -O-alkyl, optionally substituted -O-cycloalkyl, optionally substituted -O-alkylene-cycloalkyl, optionally substituted -O-aryl, or -OM, where M is a pharmaceutically acceptable cation. In embodiments, the optionally substituted -O-alkyl is an optionally substituted -O-haloalkyl, hemiaminal, acetal, or amino acid residue. In embodiments, R 12 O - , —OH, —O-alkyl, —O-haloalkyl, —O-cycloalkyl, or —OM. 12 O - , —OH, optionally substituted —O-alkyl, optionally substituted —O-haloalkyl, or —OM. 12 O - , optionally substituted —O-alkyl, or optionally substituted —O-haloalkyl. In embodiments, R 12 is an optionally substituted -O-alkyl. In embodiments, the optionally substituted -O-alkyl is an optionally substituted -OC 1-5 In embodiments, -O-alkyl is -OMe, -OEt, -OiPr, or -OtBu. In embodiments, R 12 is -O-haloalkyl. In embodiments, optionally substituted -O-haloalkyl is optionally substituted -OC 1-5 In some embodiments, the —O-haloalkyl is —OCH2CF3. In some embodiments, R 12 O - , -OH, -OC1-5 Alkyl, -OC 1-5 Haloalkyl, -OC 3-6 In embodiments, M is Na, K, NH, or Ca. In embodiments, M is Na, K, or NH. In embodiments, -O-alkyl is -OMe, -OEt, -OiPr, or -OtBu. In embodiments, -OC 1-5 Haloalkyl is -OCH3, -OCH2F, -OCHF2, or -OCH2CF3. In embodiments, -OC 1‐5 Haloalkyl is -OCH2CF3.

[0051] In embodiments, R 13 is H, D, or C 1-5 In embodiments, R 13 is H or -C 1-5 In embodiments, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or butyl. In embodiments, R 13 is H, methyl, ethyl, or isopropyl.

[0052] In embodiments of Formula (I), R 11 and R 13 together with the atoms to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms. 11 and R 13 together with the atoms to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring. 11 and R 13 together with the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocyclic ring.

[0053] In embodiments, R 14 is H, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl. 14is H, halogen, or optionally substituted alkyl. In embodiments, R 14 is H or alkyl. In some embodiments, R 14 is H. In an embodiment, R 14 is alkyl. In embodiments, alkyl is C1-C5 alkyl. In embodiments, C1-C5 alkyl is methyl, ethyl, or isopropyl. In embodiments, R 14 is a halogen. In embodiments, the halogen is Cl, Br, or F. In embodiments, the cycloalkyl is a C-C cycloalkyl. In embodiments, the cycloalkyl is cyclopropyl. In embodiments, the optionally substituted heteroalkyl is -CH-OC 1-5 In embodiments, the optionally substituted heteroalkyl is —CH—N—(H)(C 1-5 alkyl) or -CH2-N-(C 1-5 alkyl)2.

[0054] Compounds of formula (IB) and (II-B) In embodiments, the present disclosure provides a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or CH; B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, and R5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or -P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 11 and R 12 are each independently O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, or R 11 and R 12 together with the atom to which they are attached form a heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are each optionally substituted; R 13 is H, D, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, —C(O)-(alkylene-optionally substituted aryl), or —OC(O)—NHR 15 or R 11 and R 13together with the atom to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms; R 14 is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and R 15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0055] In embodiments, the present disclosure provides a compound of formula (II-B): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or CH; B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, and R5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or -P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 12 O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, and alkyl, cycloalkyl, and aryl are optionally substituted; R 14 is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and n is 0, 1, or 2.

[0056] In embodiments, A is N. In embodiments, A is CH.

[0057] In embodiments, B is N. In embodiments, B is C-YR4.

[0058] In an embodiment, E is N. In an embodiment, E is C-ZR5.

[0059] In an embodiment of Formula (I), W is NR6 or O. In an embodiment, W is NR6 or S. In an embodiment, W is O or S. In an embodiment, W is NR6. In an embodiment, W is O. In an embodiment, W is S.

[0060] In embodiments, X, Y, and Z are each independently absent, O, S, or N(C 1‐5 ) alkyl. In embodiments, X, Y, and Z are each independently absent or O. In embodiments, X, Y, and Z are each independently absent or NH. In embodiments, X, Y, and Z are each independently absent or S. In embodiments, X, Y, and Z are each absent.

[0061] In an embodiment, X is O and Y and Z are not present. In an embodiment, Y is O and X and Z are not present. In an embodiment, Z is O and X and Y are not present. In an embodiment, X is S and Y and Z are not present. In an embodiment, Y is S and X and Z are not present. In an embodiment, Z is S and X and Y are not present. In an embodiment, X is NH and Y and Z are not present. In an embodiment, Y is NH and X and Z are not present. In an embodiment, Z is NH and X and Y are not present. In an embodiment, X is N(C 1‐5 ) alkyl, and Y and Z are absent. In embodiments, Y is N(C 1‐5 ) alkyl, and X and Z are absent. In embodiments, Z is N(C 1‐5 ) alkyl, and X and Y are absent.

[0062] In embodiments, R1 and R2 are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl. In embodiments, R1 and R2 are each independently H, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted C 1-5 In some embodiments, R and R are each independently H or alkyl. In some embodiments, R and R are each independently H or C. 1-5In an embodiment, R1 and R2 are each alkyl. In an embodiment, R1 and R2 are each C 1-5 In embodiments, R1 and R2 are each independently methyl, ethyl, or isopropyl. In embodiments, R1 and R2 are each methyl. In embodiments, R1 and R2 together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, e.g., azetidine, pyrrolidine, or piperidine.

[0063] In embodiments, R3, R4, and R5 are each independently selected from H, D, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1‐5 Heteroalkyl, -P(O)(OC 1-5 In embodiments, R, R, and R are each independently H, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-5 Heteroalkyl, -P(O)(OC 1-5 In embodiments, R, R, and R are each independently H, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 Cycloalkyl, -P(O)(OC 1-5 In embodiments, R, R, and R are each independently H, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 In embodiments, R, R, and R are each independently H, optionally substituted C 1-5 alkyl, or —P(O)(OH). In embodiments, C 1-5Alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. In an embodiment, R3, R4, and R5 are each H.

[0064] In embodiments, R3 is an optionally substituted C 1-5 alkyl or —P(O)(OH), and R and R are each H. In an embodiment, R is an optionally substituted C 1-5 alkyl or —P(O)(OH), and R and R are each H. In an embodiment, R is an optionally substituted C 1-5 alkyl or —P(O)(OH), and R and R are each H. In an embodiment, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. 1-5 Alkyl is methyl, ethyl, or isopropyl.

[0065] In embodiments, X is absent and R3 is H, halogen, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 In embodiments, Y is absent and R is H, halogen, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 In embodiments, Z is absent and R is H, halogen, optionally substituted C 1-5 Alkyl, optionally substituted C 3-6 cycloalkyl, or —P(O)(OH). In embodiments, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. In embodiments, halogen is F, Cl, or Br.

[0066] In embodiments, R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocyclyl, or optionally substituted alkylene-aryl. In embodiments, R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkylene-cycloalkyl. In embodiments, the optionally substituted alkyl is optionally substituted C 1-5 In embodiments, the optionally substituted cycloalkyl is an optionally substituted C alkyl. 3-6 In embodiments, the optionally substituted aryl is an optionally substituted phenyl. In embodiments, the optionally substituted heterocyclyl is an optionally substituted 4- to 6-membered heterocyclyl, such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, or piperazine, each of which is optionally substituted. In embodiments, the optionally substituted alkylene is an optionally substituted C 1‐3 In an embodiment, the optionally substituted alkylene is an optionally substituted methylene. In an embodiment, R6 is H, C 1-5 Alkyl, C 3-6 Cycloalkyl, or C(=O)(C 1-5 In an embodiment, R6 is H, C 1-5 Alkyl, or C 3-8 In an embodiment, R6 is H or C 1-5 In an embodiment, R6 is H. In an embodiment, R6 is C 1-5 In embodiments, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, optionally substituted C 1-5 Alkyl is -C(O)-C 1-4 Alkyl, -C(O)-N(H)(C 1-4 alkyl), or -C(O)-OC 1-4 It is alkyl.

[0067] In embodiments, R7 and R8 are each independently H, halogen, optionally substituted alkyl, -OH, optionally substituted -O-alkyl, or optionally substituted -O-cycloalkyl. In embodiments, R7 and R8 are each independently H, halogen, optionally substituted C 1-5 Alkyl, -OH, optionally substituted -OC 1-5 alkyl, or optionally substituted -OC 3-6 In an embodiment, R7 and R8 are each independently H or optionally substituted C 1-5 In an embodiment, R7 and R8 are each H. In an embodiment, R7 and R8 are each optionally substituted C 1-5 In an embodiment, R7 and R8 are each halogen. In an embodiment, halogen is F. In an embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. 1-5 Alkyl is methyl. In embodiments, C 1-5 The alkyl is ethyl.

[0068] In embodiments, R7 and R8 together with the atom to which they are attached form an oxo or optionally substituted cycloalkyl ring. In embodiments, R7 and R8 together with the atom to which they are attached form an oxo. In embodiments, R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted C 3-6 In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted cyclopropyl. In embodiments, R7 is H and R8 is an optionally substituted C 1-5In an embodiment, R7 is H and R8 is F. In an embodiment, R7 is H and R8 is -OH. In an embodiment, R7 is H and R8 is -OCH3. In an embodiment, R7 is F and R8 is F. In an embodiment, R7 and R8 are each optionally substituted C 1-5 In embodiments, C 1-5 Alkyl is methyl.

[0069] In embodiments, R and R 10 are each independently H, halogen, optionally substituted alkyl, -OH, optionally substituted -O-alkyl, or optionally substituted -O-cycloalkyl. In an embodiment, R and R 10 are each independently H, halogen, optionally substituted C 1-5 Alkyl, -OH, optionally substituted -OC 1-5 alkyl, or optionally substituted -OC 3-6 In an embodiment, R and R are cycloalkyl. 10 are each independently H or optionally substituted C 1-5 In an embodiment, R and R are alkyl. 10 are each H. In an embodiment, R and R 10 are each optionally substituted C 1-5 In an embodiment, R and R are alkyl. 10 are each halogen. In an embodiment, the halogen is F. In an embodiment, C 1-5 Alkyl is methyl, ethyl, or isopropyl. 1-5 Alkyl is methyl. In embodiments, C 1-5 The alkyl is ethyl.

[0070] In embodiments, R and R 10 together with the atoms to which they are attached form an optionally substituted cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted C 3-6In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted cyclopropyl. In embodiments, R is H and R 10 is optionally replaced by C 1-5 In an embodiment, R is H and R is alkyl. 10 is F. In an embodiment, R is H and R 10 is —OH. In an embodiment, R is H and R 10 is —OCH. In an embodiment, R and R 10 are each F. In an embodiment, R and R 10 are each optionally substituted C 1-5 In embodiments, C 1-5 Alkyl is methyl.

[0071] In embodiments of Formula (I), R 11 and R 12 are each independently O - , -OH, optionally substituted -O-alkyl, optionally substituted -O-cycloalkyl, optionally substituted -O-alkylene-cycloalkyl, optionally substituted -O-aryl, or -OM, where M is a pharmaceutically acceptable cation. In embodiments, the optionally substituted -O-alkyl is an optionally substituted -O-haloalkyl, hemiaminal, acetal, or amino acid residue. In embodiments, R 11 and R 12 are each independently O - , -OH, optionally substituted -OC 1-5 Alkyl, optionally substituted -OC 1-5 Haloalkyl, optionally substituted -OC 3-6 In embodiments, R 11 and R 12 are each independently O - , -OH, optionally substituted -OC 1-5 Alkyl, optionally substituted -OC 1-5 haloalkyl, or -OM. In embodiments, R11 O - and R 12 is -OH, optionally substituted -OC 1-5 Alkyl, optionally substituted -OC 1-5 haloalkyl, or -OM. In embodiments, R 11 and R 12 are each optionally replaced by -OC 1-5 In embodiments, R 11 and R 12 are each optionally replaced by -OC 1-3 In embodiments, R 11 and R 12 are each independently -OMe, -OEt, -OiPr, or -OtBu. 11 and R 12 are each optionally replaced by -OC 1-5 In embodiments, -OC is haloalkyl. 1-5 Haloalkyl is -OCH3, -OCH2F, -OCHF2, or -OCH2CF3. In embodiments, -OC 1-5 Haloalkyl is -OCH2CF3. In embodiments, M is Na+, K+, NH4+, or Ca+2. In embodiments, M is Na+, K+, or NH4+.

[0072] In embodiments of Formula (I), R 11 and R 12 together with the atoms to which they are attached form a heterocyclyl. In embodiments, R 11 and R 12 together with the atom to which they are attached form a 5- to 12-membered heterocyclyl. In embodiments, the heterocyclyl has the structure: [ka]

[0073] In embodiments of Formula (II), R 12 O -, -OH, optionally substituted -O-alkyl, optionally substituted -O-cycloalkyl, optionally substituted -O-alkylene-cycloalkyl, optionally substituted -O-aryl, or -OM, where M is a pharmaceutically acceptable cation. In embodiments, the optionally substituted -O-alkyl is an optionally substituted -O-haloalkyl, hemiaminal, acetal, or amino acid residue. In embodiments, R 12 O - , —OH, —O-alkyl, —O-haloalkyl, —O-cycloalkyl, or —OM. 12 O - , —OH, optionally substituted —O-alkyl, optionally substituted —O-haloalkyl, or —OM. 12 O - , optionally substituted —O-alkyl, or optionally substituted —O-haloalkyl. In embodiments, R 12 is an optionally substituted -O-alkyl. In embodiments, the optionally substituted -O-alkyl is an optionally substituted -OC 1-5 In embodiments, -O-alkyl is -OMe, -OEt, -OiPr, or -OtBu. In embodiments, R 12 is -O-haloalkyl. In embodiments, optionally substituted -O-haloalkyl is optionally substituted -OC 1-5 In some embodiments, the —O-haloalkyl is —OCH2CF3. In some embodiments, R 12 O - , -OH, -OC 1-5 Alkyl, -OC 1-5 Haloalkyl, -OC 3-6 In embodiments, M is Na, K, NH, or Ca. In embodiments, M is Na, K, or NH. In embodiments, -O-alkyl is -OMe, -OEt, -OiPr, or -OtBu. In embodiments, -OC 1-5Haloalkyl is -OCH3, -OCH2F, -OCHF2, or -OCH2CF3. In embodiments, -OC 1‐5 Haloalkyl is -OCH2CF3.

[0074] In embodiments, R 13 is H, D, or C 1-5 In embodiments, R 13 is H or -C 1-5 In embodiments, C 1-5 Alkyl is methyl, ethyl, propyl, isopropyl, or butyl. In embodiments, R 13 is H, methyl, ethyl, or isopropyl.

[0075] In embodiments of Formula (I), R 11 and R 13 together with the atoms to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms. 11 and R 13 together with the atoms to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring. 11 and R 13 together with the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocyclic ring.

[0076] In embodiments, R 14 is H, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl. 14 is H, halogen, or optionally substituted alkyl. In embodiments, R 14 is H or alkyl. In some embodiments, R 14 is H. In an embodiment, R 14 is alkyl. In embodiments, alkyl is C1-C5 alkyl. In embodiments, C1-C5 alkyl is methyl, ethyl, or isopropyl. In embodiments, R 14is a halogen. In embodiments, the halogen is Cl, Br, or F. In embodiments, the cycloalkyl is a C-C cycloalkyl. In embodiments, the cycloalkyl is cyclopropyl. In embodiments, the optionally substituted heteroalkyl is -CH-OC 1-5 In embodiments, the optionally substituted heteroalkyl is —CH—N—(H)(C 1-5 alkyl) or -CH2-N-(C 1-5 alkyl)2.

[0077] In embodiments of Formula (I), R 15 is H, optionally substituted C 1-5 alkyl, or optionally substituted phenyl.

[0078] In embodiments of Formula (II), n is 0 or 1. In embodiments, n is 0. In some embodiments, n is 1. In embodiments, n is 2.

[0079] In embodiments, provided herein is one or more compounds of Formula (IA) or (IB) selected from Table 1, or a pharmaceutically acceptable salt thereof. [Table 1] JPEG2025539560000013.jpg203163

[0080] In embodiments, provided herein is one or more compounds of Formula (IA) or (IB) selected from Table 2, or a pharmaceutically acceptable salt thereof. [Table 2] JPEG2025539560000015.jpg225163

[0081] In embodiments, provided herein is one or more compounds of Formula (II-A) or (II-B) selected from Table 3, or a pharmaceutically acceptable salt thereof. [Table 3]

[0082] In embodiments, provided herein is one or more compounds of Formula (II-A) or (II-B) selected from Table 4, or a pharmaceutically acceptable salt thereof. [Table 4]

[0083] In embodiments, provided herein are compounds of Formula (IA), (IB), (II-A), or (II-B), as described herein, wherein Formulas (IA), (IB), (II-A), and (II-B) exclude compounds described in International Patent Application No. PCT / US2022 / 032918.

[0084] composition In an embodiment of the disclosure, a pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the disclosure (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound of Table 1, Table 2, Table 3, or Table 4), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0085] Pharmaceutically acceptable excipients and adjuvants are added to compositions or formulations for various purposes. In embodiments, pharmaceutical compositions containing one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, further comprise a pharmaceutically acceptable carrier. In embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable excipient, binder, and / or diluent. In embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents, and sterile aqueous or organic solutions. In embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, etc.

[0086] For the purpose of this disclosure, the compound of the present disclosure can be formulated as a preparation containing pharmaceutically acceptable carrier, adjuvant and vehicle for administration by various means, including oral, parenteral, by inhalation spray, topical or rectal.As used herein, the term parenteral includes subcutaneous injection, intravenous injection, intramuscular injection and intraarterial injection using various injection techniques.As used herein, intraarterial and intravenous injection include administration through a catheter.

[0087] How to use In one aspect, the disclosure provides a method of treating or preventing a neuropathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound in Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0088] In embodiments, the neurological disorder is a mood disorder. In several embodiments, the mood disorder is clinical depression, postnatal or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, major depressive disorder, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, treatment-refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In embodiments, the methods described herein provide a therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In embodiments, the mood disorder is associated with neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), or women's health disorders or conditions. In embodiments, the mood disorder is depression. In embodiments, the mood disorder is treatment-resistant depression or major depressive disorder. In embodiments, the mood disorder is major depressive disorder. In embodiments, the mood disorder is treatment-resistant depression.

[0089] In embodiments, the present disclosure provides methods for treating or preventing PTSD, mood disorders, generalized anxiety disorders, addictive disorders, and / or substance dependence in a subject in need of such treatment or prevention, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound in Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0090] In embodiments, the present disclosure provides a method of treating or preventing PTSD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound in Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0091] In embodiments, the method includes treating PTSD via induction and maintenance therapy by administering a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the compounds of the present disclosure are used in induction and maintenance therapy for treating PTSD with an improved safety profile when compared to treatment with an entactogenic, oneirophrenic, or psychedelic compound (e.g., dimethyltryptamine or related compounds, psilocybin, or MDMA) alone.

[0092] In embodiments, the present disclosure provides a method of treating or preventing a behavioral or mood disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound in Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the behavioral or mood disorder comprises anxiety, such as social anxiety in autistic subjects (e.g., adults with autism) and anxiety associated with a life-threatening illness. In embodiments, the behavioral or mood disorder comprises stress (the relief of which is measured, for example, by an effect on amygdala response). In embodiments, the anxiety disorder is panic disorder, obsessive-compulsive disorder, and / or generalized anxiety disorder. In embodiments, the subject suffers from deficits in motivation, attention, accuracy of memory recall, response speed, perseveration, and / or cognitive engagement. Further examples include depression (e.g., MDD or TRD), attention disorders, disorders of executive function and / or cognitive engagement, obsessive-compulsive disorder, bipolar disorder, panic disorder, phobias, schizophrenia, psychopathy, antisocial personality disorder, and / or neurocognitive disorders.

[0093] In embodiments, the present disclosure provides a method of treating an addictive disorder in a subject in need of treatment for the addictive disorder, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound in Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the addictive disorder is alcohol abuse, drug abuse, smoking, obesity, or a mixture thereof. In embodiments, the disorder is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, etc.) or an auditory disorder.

[0094] In embodiments, the present disclosure provides a method of treating an impulsive disorder in a subject in need of treatment for the impulsive disorder, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound in Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the impulsive disorder is attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Tourette's syndrome, autism, or a combination thereof.

[0095] In embodiments, the present disclosure provides a method of treating obsessive-compulsive disorder in a subject in need of treatment for obsessive-compulsive disorder, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound in Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the obsessive-compulsive disorder is obsessive-compulsive disorder (OCD), gambling, aberrant sexual behavior, or a combination thereof.

[0096] In embodiments, the present disclosure provides a method of treating a personality disorder in a subject in need of treatment for the personality disorder, the method comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), or a compound in Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the personality disorder is conduct disorder, antisocial personality, aggressive behavior toward the subject, or a combination thereof. Numbered Embodiments 1. A compound of formula (IB), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or CH; B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, and R5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or -P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, F, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 11 and R 12 are each independently O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, or R 11 and R 12 together with the atom to which they are attached form a heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are each optionally substituted; R 13 is H, D, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, —C(O)-(alkylene-optionally substituted aryl), or —OC(O)—NHR 15 or R 11 and R 13 together with the atom to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms; R 14 is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and R 15is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof. 2. The compound of embodiment 1, wherein A is CH. 3. The compound of embodiment 1 or 2, wherein B is C-YR4. 4. The compound of any one of embodiments 1 to 3, wherein Y is absent. 5. The compound of any one of embodiments 1 to 3, wherein Y is O. 6. R4 is H, C 1-5 Alkyl, C 3-6 Cycloalkyl, alkylene-C 3-6 The compound of any one of embodiments 1-5, wherein the aryl group is cycloalkyl, or —P(O)(OH) 2 . 7. R4 is H, C 1-5 The compound of any one of embodiments 1-6, wherein the aryl group is alkyl, or —P(O)(OH) 2 . 8. The compound of any one of embodiments 1-7, wherein E is C-ZR5. 9. The compound of any one of embodiments 1 to 8, wherein Z is absent. 10. The compound of any one of embodiments 1-8, wherein Z is O. 11. R5 is H, C 1-5 Alkyl, C 3-6 Cycloalkyl, alkylene-C 3-6 The compound of any one of embodiments 1-10, wherein the aryl group is cycloalkyl, or —P(O)(OH) 2 . 12. R5 is H or C 1-5 The compound of any one of embodiments 1-10, wherein is alkyl. 13. The compound of any one of embodiments 1-10, wherein R5 is H. 14. The compound of any one of embodiments 1-7, wherein E is N. 15. The compound of any one of embodiments 1, 2, and 8-13, wherein B is N. 16. The compound of any one of embodiments 1-15, wherein X is absent. 17. The compound of any one of embodiments 1-15, wherein X is O. 18. The compound of any one of embodiments 1-17, wherein R3 is H, alkyl, cycloalkyl, alkylene-cycloalkyl, or -P(O)(OH)2. 19. R3 is H, C 1-5 The compound of any one of embodiments 1-18, wherein the aryl group is alkyl, or —P(O)(OH) 2 . 20. The compound of any one of embodiments 1-19, wherein R3 is H. twenty one. The compound of any one of embodiments 1 to 20, wherein W is NR6. twenty two. R6 is H, C 1-5 Alkyl, C 3-6 Cycloalkyl or alkylene-C 3-6 The compound of any one of embodiments 1-21, which is cycloalkyl. twenty three. R6 is H or C 1-5 The compound of any one of embodiments 1-22, wherein is alkyl. twenty four. The compound of any one of embodiments 1-23, wherein R6 is H. twenty five. The compound of any one of embodiments 1-24, wherein R1 and R2 are each independently H or alkyl. 26. The compound of any one of embodiments 1-25, wherein R1 and R2 are each alkyl. 27. Alkyl is C 1-5 The compound of embodiment 25 or 26, wherein is alkyl. 28. 27. The compound of embodiment 25 or 26, wherein alkyl is methyl, ethyl, or isopropyl. 29. The compound of any one of embodiments 1-28, wherein R7 and R8 are each independently H, F, or alkyl. 30. The compound of any one of embodiments 1-29, wherein R7 and R8 are each independently H or alkyl. 31. The compound of any one of embodiments 1-29, wherein R7 and R8 are each alkyl. 32. Alkyl is C 1-5 The compound of any one of embodiments 29-31, wherein is alkyl. 33. The compound of any one of embodiments 29-31, wherein alkyl is methyl. 34. The compound of any one of embodiments 1-29, wherein R7 and R8 are each independently H or F. 35. The compound of any one of embodiments 1-29, wherein R7 and R8 are each H. 36. The compound of any one of embodiments 1-29, wherein R7 is H and R8 is F. 37. R7 and R8, together with the atoms to which they are attached, are C 3-6 The compound of any one of embodiments 1 to 28, which forms a cycloalkyl. 38. The compound of any one of embodiments 1-28, wherein R7 and R8 together with the atom to which they are attached form a cyclopropyl. 39. R9 and R 10 are each independently H, F, or C 1-5 The compound of any one of embodiments 1-38, wherein is alkyl. 40. R9 and R 10 are each independently H or C 1-5 The compound of any one of embodiments 1-39, wherein is alkyl. 41. R9 and R 10 However, each C 1-5 The compound of any one of embodiments 1-39, wherein is alkyl. 42. R9 and R 10 However, each C 1-3 The compound of any one of embodiments 1-39, wherein is alkyl. 43. R9 and R 10 is, at each occurrence, independently, H or methyl. 44. R9 and R 10 is independently at each occurrence H or F. 45. R9 and R 10 and R are each H. 46. R9 is H and R 10 The compound of any one of embodiments 1-39, wherein is F. 47. R9 and R 10 together with the atom to which they are attached form oxo. 48. R 11 and R 12 However, each independently, O - , -OH, -OC 1-5 Alkyl, -OC 1-5 Haloalkyl, -OC 3-6The compound of any one of embodiments 1-47, wherein the aryl group is cycloalkyl, or -OM. 49. R 11 and R 12 However, each independently, O - , -OH, -OC 1-5 Alkyl, -OC 1-5 The compound of any one of embodiments 1-48, wherein the aryl group is haloalkyl, or -OM. 50. R 11 But, O - and R 12 -OH, -OC 1-5 Alkyl, -OC 1-5 The compound of any one of embodiments 1-49, wherein the aryl group is haloalkyl, or -OM. 51. R 11 and R 12 However, each -OC 1-5 The compound of any one of embodiments 1-49, wherein is alkyl. 52. R 11 and R 12 However, each -OC 1-3 The compound of any one of embodiments 1-49, wherein is alkyl. 53. R 11 and R 12 is each independently -OMe, -OEt, -OiPr, or -OtBu. 54. R 11 and R 12 However, each -OC 1-5 The compound of any one of embodiments 1-49, wherein the compound is haloalkyl. 55. -OC 1-5 The compound of any one of embodiments 48-50 and 54, wherein haloalkyl is -OCH2CF3. 56. The compound of any one of embodiments 1-50, wherein M is Na+, K+, or NH4+. 57. R 11 and R 12 together with the atom to which they are attached form a heterocyclyl. 58. R 11 and R 12 together with the atom to which they are attached form a 5- to 12-membered heterocyclyl. 59. The compound of embodiment 57 or 58, wherein heterocyclyl is: [ka] 60. R 13 But H, D, or C 1-5 The compound of any one of embodiments 1-59, wherein is alkyl. 61. R 13 But H or C 1-5 The compound of any one of embodiments 1-60, wherein is alkyl. 62. R 13 The compound of any one of embodiments 1-60, wherein is H, methyl, ethyl, or isopropyl. 63. R 14 The compound of any one of embodiments 1-60, wherein is H, F, Cl, Br, or methyl. 64. R 14 is H. 65. The following structure: [Table 5] 2. The compound of claim 1, having the formula JPEG2025539560000021.jpg161163 or a pharmaceutically acceptable salt thereof. 66. The following structure: [ka] or a pharmaceutically acceptable salt thereof. 67. A compound of formula (II-B), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or CH; B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, and R5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or -P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R10 form oxo together with the atom to which they are attached, R 12 O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, wherein M is a pharmaceutically acceptable cation, and alkyl, cycloalkyl, aryl, and heterocyclyl are each optionally substituted; R 14 is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and A compound of formula (II-B), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. 68. The compound of embodiment 67, wherein A is CH. 69. The compound of embodiment 67 or 68, wherein B is C-YR4. 70. 70. The compound of any one of embodiments 67-69, wherein Y is absent. 71. The compound of any one of embodiments 67-69, wherein Y is O. 72. R4 is H, C 1-5 Alkyl, C 3-6 Cycloalkyl, alkylene-C 3-6 The compound of any one of embodiments 67-71, wherein the aryl group is cycloalkyl, or —P(O)(OH) 2 . 73. R4 is H, C 1-5 The compound of any one of embodiments 67-72, wherein the aryl group is alkyl, or —P(O)(OH) 2 . 74. The compound of any one of embodiments 67-73, wherein E is C-ZR5. 75. The compound of any one of embodiments 67-74, wherein Z is absent. 76. The compound of any one of embodiments 67-74, wherein Z is O. 77. R5 is H, C 1-5 Alkyl, C 3‐6 Cycloalkyl, alkylene-C 3-6 The compound of any one of embodiments 67-76, wherein the aryl group is cycloalkyl, or —P(O)(OH) 2 . 78. R5 is H or C 1-5 The compound of any one of embodiments 67-76, wherein is alkyl. 79. The compound of any one of embodiments 67-76, wherein R5 is H. 80. The compound of any one of embodiments 67-73, wherein E is N. 81. The compound of any one of embodiments 67, 68, and 74-79, wherein B is N. 82. The compound of any one of embodiments 67-81, wherein X is absent. 83. The compound of any one of embodiments 67-81, wherein X is O. 84. R3 is H, C 1-5 Alkyl, C 3-6 Cycloalkyl, alkylene-C 3-6 The compound of any one of embodiments 67-83, wherein the aryl group is cycloalkyl, or —P(O)(OH) 2 . 85. R3 is H, C 1-5 The compound of any one of embodiments 67-84, wherein the aryl group is alkyl, or —P(O)(OH) 2 . 86. The compound of any one of embodiments 67-85, wherein R3 is H. 87. The compound of any one of embodiments 67-86, wherein W is NR6. 88. R6 is H, C 1-5 Alkyl, C3-6 Cycloalkyl or alkylene-C 3-6 The compound of any one of embodiments 67-87, which is cycloalkyl. 89. R6 is H or C 1-5 The compound of any one of embodiments 67-88, wherein is alkyl. 90. The compound of any one of embodiments 67-89, wherein R6 is H. 91. The compound of any one of embodiments 67-90, wherein R1 and R2 are each independently H or alkyl. 92. The compound of any one of embodiments 67-91, wherein R1 and R2 are each alkyl. 93. Alkyl is C 1-5 The compound of embodiment 91 or 92, wherein is alkyl. 94. 93. The compound of embodiment 91 or 92, wherein alkyl is methyl, ethyl, or isopropyl. 95. The compound of any one of embodiments 67-94, wherein R7 and R8 are each independently H, F, or alkyl. 96. The compound of any one of embodiments 67-95, wherein R7 and R8 are each independently H or alkyl. 97. The compound of any one of embodiments 67-95, wherein R7 and R8 are each alkyl. 98. Alkyl is C 1-5 The compound of embodiment 97, wherein is alkyl. 99. 99. The compound of embodiment 97 or 98, wherein alkyl is methyl. 100. The compound of any one of embodiments 67-95, wherein R7 and R8 are each independently H or F. 101. The compound of any one of embodiments 67-95, wherein R7 and R8 are each H. 102. The compound according to any one of embodiments 67-95, wherein R7 is H and R8 is F. 103. R7 and R8, together with the atoms to which they are attached, are C 3-6 The compound of any one of embodiments 67-94, which forms a cycloalkyl. 104. Compounds according to any one of embodiments 67-94, wherein R7 and R8 together with the atom to which they are attached form a cyclopropyl. 105. R9 and R 10 is, at each occurrence, independently, H, F, or alkyl. 106. R9 and R 10 The compound of any one of embodiments 67-105, wherein each is independently H or alkyl. 107. R9 and R 10 and R 1 and R 2 are each alkyl. 108. Alkyl is C 1-5 The compound of any one of embodiments 105-107, wherein is alkyl. 109. The compound of any one of embodiments 105-107, wherein alkyl is methyl. 110. R9 and R 10 is independently at each occurrence H or F. 111. R9 and R 10 and R are each H. 112. R9 is H and R 10The compound of any one of embodiments 67-105, wherein is F. 113. R9 and R 10 together with the atom to which they are attached form oxo. 114. R 12 But, O - , —OH, —O-alkyl, —O-haloalkyl, —O-cycloalkyl, or —OM. 115. R 12 But, O - , —OH, —O-alkyl, —O-haloalkyl, or —OM. 116. R 12 But, O - , —O-alkyl, —O-haloalkyl. 117. R 12 The compound of any one of embodiments 67-115, wherein is -O-alkyl. 118. -O-alkyl is -OC 1-5 The compound of any one of embodiments 113-117, wherein is alkyl. 119. The compound according to any one of embodiments 113-118, wherein -O-alkyl is -OMe, -OEt, -OiPr, or -OtBu. 120. R 12 The compound of any one of embodiments 67-115, wherein is -O-haloalkyl. 121. -O-haloalkyl is -OC 1-5 The compound of any one of embodiments 114-116 and 120, wherein the compound is haloalkyl. 122. The compound according to any one of embodiments 114-116 and 120, wherein -O-haloalkyl is -OCH2CF3. one two three. The compound of any one of embodiments 67-115, wherein M is Na+, K+, or NH4+. 124. R 14 is H, F, Cl, Br, or C 1-5 The compound of any one of embodiments 67-123, wherein is alkyl. 125. R 14 The compound of any one of embodiments 67-124, wherein is H. 126. The following structure: [ka] or a pharmaceutically acceptable salt thereof. 127. 67. The compound of any one of embodiments 1-66, wherein the compound of formula (I) excludes compounds described in International Application No. PCT / US2022 / 032918. 128. The compound according to any one of embodiments 67 to 126, wherein the compound of formula (II) excludes compounds described in International Application No. PCT / US2022 / 032918. 129. A compound of formula (IA), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or C-VR 16 and B is N or C-YR4; E is N or C-ZR5, where no more than two of A, B, and E are N; W is O, S, or NR6; V, X, Y, and Z are each independently absent, O, S, or NH; R1 and R2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R3, R4, R5, and R 16 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or —P(O)(OH); R6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R7 and R8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R7 and R8 together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R9 and R 10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R and R 10 form oxo together with the atom to which they are attached, R 11 and R 12 are each independently an alkyl, a deuterated alkyl, -O - , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, where M is a pharmaceutically acceptable cation, or R 11 and R 12 together with the atom to which they are attached form a heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are each optionally substituted; R 13is H, D, halogen, deuterated alkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, —C(O)-(alkylene-optionally substituted aryl), or —OC(O)—NHR 15 or R 11 and R 13 together with the atom to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms; R 14 is H, D, halogen, haloalkyl, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and R 15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein the compound is [ka] A compound of formula (IA) which is not: [Example]

[0097] The compounds of the present disclosure can be synthesized using the exemplary methods below or other methods known to those skilled in the art.

[0098] General reaction conditions are provided, and reaction products can be purified by known methods, including silica gel chromatography using a variety of organic solvents, such as hexane, dichloromethane, ethyl acetate, methanol, or preparative reverse-phase high pressure liquid chromatography.

[0099] The preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by those skilled in the art. The chemistry of protecting groups is described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th Ed., Wiley & Sons, 2006, and Jerry March, Advanced Organic Chemistry, 4 th edition, John Wiley & Sons, publisher, New York, 1992, which are incorporated herein by reference in their entireties.

[0100] Example 1. Synthesis of compounds of the present disclosure

[0101] Compounds 1-10 in Table 5 were prepared by the methods described below. [Table 6] JPEG2025539560000028.jpg132163

[0102] Compounds 1-4 were synthesized from the commercially available intermediate tryptophan according to Scheme 1. [ka]

[0103] Compounds 5 and 6 were synthesized from commercially available intermediate 5-substituted tryptophan according to Scheme 2. [ka]

[0104] Salts of the disclosed compounds were synthesized in one step from compound 1 as shown in Scheme 3. [ka]

[0105] Synthesis of Compound 1 [ka]

[0106] Step 1: To a solution of tryptamine (200 mg, 1.25 mmol, 1.0 equiv.) in 3 mL of methanol was added sodium cyanoborohydride (197 mg, 3.13 mmol, 2.5 equiv.), acetic acid (0.15 mL), and formaldehyde (254 mg, 3.13 mol, 2.5 equiv., 37% aqueous solution) in methanol (1.5 mL) at 0 °C. The mixture was stirred at 25 °C overnight and then concentrated in vacuo. The resulting solution was diluted with 20 mL of saturated sodium bicarbonate and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting mixture was dissolved in 2 mL of acetonitrile, and then di-tert-butyl(chloromethyl)phosphate (274 mg, 1.06 mmol, 2.0 equiv.), Me5-piperidine (164.5 mg, 1.06 mmol, 2.0 equiv.), and sodium iodide (8.0 mg, 0.05 mmol, 0.1 equiv.) were added under a nitrogen atmosphere at 25° C. The mixture was stirred at 40° C. for 24 hours. The resulting solution was diluted with 20 mL of ethyl acetate and washed sequentially with saturated sodium bicarbonate solution (2×10 mL) and saturated sodium chloride solution (10 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product (120 mg) was used directly in the next step without further purification.

[0107] Step 2: To a solution of the intermediate from Step 1 above (120 mg, 0.29 mmol, 1.0 equiv) in dichloromethane (1.2 mL) under argon, trifluoroacetic acid (0.6 mL) was slowly added at RT. The resulting solution was stirred for 1 h and then concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography: column, C18 silica gel; mobile phase, water and methanol (20% to 100% methanol in 15 min, hold at 100% for 5 min); detector: 220 nm. Fractions were concentrated under reduced pressure. Compound 1 was obtained as a white solid (28 mg, 28%). MS m / z [M+H] + (ESI):299.05.1H NMR(300MHz,DMSO-d6)δ 11.11(s,1H),7.65(d,J=7.8Hz,1H),7.37(d,J=8.1Hz,1H),7.26(s,1H),7.11-6.98( m,2H),4.89(d,J=8.7Hz,2H),3.51-3.45(m,2H),3.18-3.13(m,2H),3.07(s,6H).31P NMR (121MHz, DMSO-d6) δ -1.88.

[0108] Synthesis of compound 2 [ka]

[0109] To a solution of compound 1 (100 mg, 0.34 mmol, 1.00 equiv.) in N,N-dimethylformamide (1 mL) was added 2-iodopropane (171 mg, 1.00 mmol, 3.0 equiv.) and trimethylamine (101 mg, 1.00 mmol, 3.0 equiv.) at 25 °C. The resulting mixture was stirred at 50 °C overnight and then diluted with 20 mL of dichloromethane. The organic layer was washed with saturated aqueous sodium chloride (2 × 20 mL) and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure and purified by reverse phase: column, C18 silica gel; mobile phase, water (containing 0.05% NH4CO3), 10% to 100% gradient in 20 min; detector: UV 254 nm. Compound 2 was obtained as a white solid (20 mg, 17%). MS m / z [M+H] +(ESI):341.05.1H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),7.65(d,J=8.0Hz,1H),7.36(d,J=8.0Hz,1H),7.26(d,J=2.0Hz,1H),7.12-7.08(m,1H),7.03-6.99(m,1H) ),4.87(d,J=8.8Hz,2H),4.29-4.22(m,1H),3.50-3.45(m,2H),3.19-3.15(m,2H),3.08(s,6H),1.12(d,J=6.0Hz,6H).

[0110] Synthesis of compound 3 [ka]

[0111] Compound 3 was prepared from 100 mg of compound 1 and 156 mg of iodoethane in a manner similar to that described for compound 2, yielding compound 3 as a white solid (19 mg 17%). MS m / z [M+H] + (ESI):327.05.1H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),7.65(d,J=7.6Hz,1H),7.36(d,J=8.0Hz,1H),7.26-7.00(m,3H),4.88(d,J=8.8Hz ,2H),3.77-3.69(m,2H),3.50-3.44(m,2H),3.20-3.15(m,2H),3.08(s,6H),1.13-1.04(m,3H).

[0112] Synthesis of compound 4 [ka]

[0113] Compound 4 was prepared from 100 mg of compound 1 and 156 mg of iodomethane in a similar manner as described for compound 2. The reaction was purified by preparative HPLC: Column: YMC Triart C18 ExRS, 20 × 150 mm, 5 μm; Mobile phase A: 10 mmol NH4HCO3 + 0.05% NH3·H2O, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% B to 34% B, 34% B in 12 min; Wavelength: 220 nm. Compound 4 was obtained as a white solid (19 mg). MS m / z [M+H] + (ESI):313.10.1H NMR(300MHz,DMSO-d6)δ 11.00(s,1H),7.65(d,J=7.8Hz,1H),7.37(d,J=7.8Hz,1H),7.26(d,J=2.1Hz,1H),7.10 -7.02(m,2H),4.89(d,J=8.4Hz,2H),3.52(s,3H),3.42-3.40(m,2H),3.20-3.09(m,8H).

[0114] Synthesis of compound 5 [ka]

[0115] To a solution of 5-hydroxytryptamine (1 g, 5.2 mmol, 1.0 equiv.) in methanol (10 mL) was added sodium cyanoborohydride (0.83 mg, 13 mmol, 2.5 equiv.), acetic acid (0.5 mL), and formaldehyde (1.1 mL, 13 mol, 2.5 equiv., 40% in water) at 0° C. The mixture was stirred at 25° C. overnight and then concentrated under vacuum. The crude product was dissolved in 2 mL of acetonitrile, and then di-tert-butyl(chloromethyl)phosphate (480 mg, 1.9 mmol, 2.0 equiv.), Me5-piperidine (330 mg, 1.9 mmol, 2.0 equiv.), and sodium iodide (15 mg, 0.2 mmol, 0.1 equiv.) were added under nitrogen at 25° C. The mixture was stirred at 40° C. for 24 h. The resulting solution was diluted with ethyl acetate (20 mL) and washed with saturated sodium bicarbonate solution (2 × 10 mL) and saturated sodium chloride solution (10 mL), respectively. The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure and purified by preparative HPLC: Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: 10 mmol NH4HCO3 + 0.05% NH3·HO, Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 50% B, 50% B over 8 min; Wavelength: 254 nm. Compound 5 was obtained as a white solid (38 mg). MSm / z[M+H]+(ESI):371.15.1H NMR(300MHz,DMSO-d6)δ 10.79(s,1H),9.35(s,1H),7.16-7.09(m,3H),6.64-6.60(m,1H),4.92(d,J=8.1Hz,2H),3.50-3.48(m,2H),3.07-3.02(m,8H),1.33(s,9H).

[0116] Synthesis of compound 6 [ka]

[0117] To a solution of 5-methoxytryptamine (1 g, 5.2 mmol, 1.0 equiv.) in methanol (10 mL) was added sodium cyanoborohydride (0.83 mg, 13 mmol, 2.5 equiv.), acetic acid (0.5 mL), and formaldehyde (1.1 mL, 13 mol, 2.5 equiv., 40% in water) at 0° C. The mixture was stirred at 25° C. overnight and then concentrated under vacuum. The crude product was dissolved in 2 mL of acetonitrile, and then di-tert-butyl(chloromethyl)phosphate (480 mg, 1.9 mmol, 2.0 equiv.), Me5-piperidine (330 mg, 1.9 mmol, 2.0 equiv.), and sodium iodide (15 mg, 0.2 mmol, 0.1 equiv.) were added under a nitrogen atmosphere at 25° C. The mixture was stirred at 40° C. for 24 hours. The resulting solution was diluted with ethyl acetate (20 mL) and washed with saturated sodium bicarbonate solution (2 × 10 mL) and saturated sodium chloride solution (10 mL), respectively. The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure and purified by preparative HPLC: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O); Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 35% B in 9 min; 35% B; Wavelength: 220 nm. Compound 6 was obtained as a white solid (31 mg). MS m / z [M+H] + (ESI):385.20. 1 H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),7.27-7.15(m,3H),6.75-6.72(m,1H),4.86(d,J=8.7Hz,2H),3 .79(s,3H),3.48-3.43(m,2H),3.15-3.10(m,2H),3.08(s,6H),1.31(s,9H).

[0118] Synthesis of compound 7 [ka]

[0119] To a solution of compound 1 (40 mg, 0.13 mmol, 1.00 equiv) in water (1 mL) was added sodium hydroxide (5.3 mg, 0.13 mmol, 1.0 equiv) at 25° C. The mixture was stirred at 25° C. for 15 min, and the resulting solution was concentrated by lyophilization. Compound 7 was obtained as a white solid (30.0 mg, 70%). MS m / z [M+H] + (ESI):299.05. 1 H NMR (400MHz, deuterium oxide) δ 7.57-7.52(m,1H),7.43-7.39(m,1H),7.18-7.13(m,2H),7.11-7.06(m,1H) ,4.66(d,J=6.4Hz,2H),3.38-3.31(m,2H),3.07-3.01(m,2H),2.92(s,6H).

[0120] Synthesis of compound 8 [ka]

[0121] To a solution of compound 1 (40 mg, 0.13 mmol, 1.0 equiv.) in water (1 mL) was added potassium hydroxide (7 mg, 0.13 mmol, 1.0 equiv.) at 25° C. The mixture was stirred at 25° C. for 15 min, and the resulting solution was concentrated by lyophilization. Compound 8 was obtained as a white solid (32 mg, 71%). MS m / z [M+H] + (ESI):299.05. 1 H NMR (400MHz, deuterium oxide) δ 7.57-7.52(m,1H),7.43-7.39(m,1H),7.18-7.13(m,2H),7.11-7.06(m,1H) ,4.66(d,J=6.4Hz,2H),3.38-3.31(m,2H),3.07-3.01(m,2H),2.92(s,6H).

[0122] Synthesis of compound 9 [ka]

[0123] To a solution of compound 1 (40 mg, 0.13 mmol, 1.00 equiv.) in water (1 mL) was added ammonium hydroxide (23 mg, 0.13 mmol, 1.0 equiv.) at 25° C. The mixture was stirred at 25° C. for 15 min, and the resulting solution was concentrated by lyophilization. Compound 9 was obtained as a yellow solid (28 mg, 70%). MS m / z [M+H] + (ESI):299.05. 1 H NMR (400 MHz, methanol-d₄) δ 7.69-7.61 (m, 1H), 7.39-7.34 (m, 1H), 7.24 (s, 1H), 7.16-7.04 (m, 2H), 4.92-4.90 (m, 2H), 3.67-3.57 (m, 2H), 3.32-3.27 (m, 2H), 3.17 (s, 6H).

[0124] Synthesis of compound 10 [ka]

[0125] To a solution of compound 1 (40 mg, 0.13 mmol, 1.00 equiv.) in water (1 mL) was added calcium hydroxide (5 mg, 0.07 mmol, 0.5 equiv.) at 25° C. The mixture was stirred at 25° C. for 15 min, and the resulting solution was concentrated by lyophilization. Compound 10 was obtained as a white solid (33 mg, 72%). MS m / z [M+H] + (ESI):299.05. 1 H NMR (300MHz, deuterium oxide) δ 7.52-7.47(m,1H),7.38-7.33(m,1H),7.15-7.00(m,3H),4.62-4.61(m,2H),3.36-3.25(m,2H),3.06-2.94(m,2H),2.88(s,6H). [Table 7] JPEG2025539560000043.jpg235163JPEG2025539560000044.jpg92163

[0126] Example 2. Evaluation of the chemical stability of the disclosed compounds [ka]

[0127] Examples of prodrug strategies: [ka]

[0128] Compound 1 was synthesized as part of a novel prodrug strategy to improve the water solubility of tertiary amine-containing drugs. As shown in the scheme above, the tertiary amine DMT (parent) was converted to the polar intermediate prodrug 1 in a two-step reaction.

[0129] The intermediate prodrug 1 releases the parent DMT in vivo via a two-step bioreversion process. The rate-limiting first step is via an enzymatic process; bioreversion of the prodrug involves phosphatase-catalyzed dephosphorylation, resulting in a hydroxymethyl quaternary ammonium intermediate and inorganic phosphate. The second step involves chemical conversion of the hydroxymethyl quaternary ammonium intermediate to DMT and formaldehyde at physiological pH.

[0130] The chemical and plasma stability of prodrug Compound 1 was evaluated and the results are listed in Tables 7 and 8, respectively. PK studies of prodrug Compound 1 and a metabolite (VLS-02-23-10) in mice were also conducted and both plasma and brain exposure were analyzed as shown in Figures 1 and 2, respectively.

[0131] Chemical stability of N-phosphonooxymethyl prodrug compound 1 [Table 8]

[0132] Plasma stability of N-phosphonooxymethyl prodrug compound 1 Table 9

Claims

1. A compound of formula (IA), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or C-VR １６ and B is N or C-YR ４ and E is N or C-ZR ５ where no more than two of A, B, and E are N; W is O, S, or NR ６ and V, X, Y, and Z are each independently absent, O, S, or NH; R １ and R ２ are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R ３ , R ４ , R ５ , and R １６ are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or —P(O)(OH) ２ and R ６ is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R ７ and R ８ are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R ７ and R ８ together with the atoms to which they are attached form an optionally substituted cycloalkyl ring; R ９ and R １０ are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R ９ and R １０ form oxo together with the atom to which they are attached, R １１ and R １２ are each independently an alkyl, a deuterated alkyl, -O － , —OH, —OD, —O-alkyl, —O-cycloalkyl, —O-alkylene-cycloalkyl, —O-aryl, or —OM, where M is a pharmaceutically acceptable cation, or R １１ and R １２ together with the atom to which they are attached form a heterocyclyl, wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are each optionally substituted; R １３ is H, D, halogen, deuterated alkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, —C(O)—(alkylene-optionally substituted aryl), or —O—C(O)—NHR １５ or R １１ and R １３ together with the atom to which they are attached form an optionally substituted heterocycle containing 4 to 7 carbon atoms; R １４ is H, D, halogen, haloalkyl, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and R １５ is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof.

2. A is C-VR １６ 2. The compound of claim 1, wherein:

3. The compound of claim 2 , wherein V is absent.

4. R １６ The compound of claim 2 or 3, wherein is H.

5. B is C-YR ４ The compound according to any one of claims 1 to 4,

6. The compound of any one of claims 1 to 5, wherein Y is absent.

7. The compound of any one of claims 1 to 5, wherein Y is O.

8. R ４ is H, optionally substituted C １－５ Alkyl, or -P(O)(OH) ２ The compound according to any one of claims 1 to 7,

9. R ４ The compound according to any one of claims 1 to 8, wherein is methyl.

10. E is C-ZR ５ The compound according to any one of claims 1 to 9,

11. The compound of any one of claims 1 to 10, wherein Z is absent.

12. R ５ The compound of any one of claims 1 to 11, wherein is H.

13. The compound of any one of claims 1 to 12, wherein X is absent.

14. The compound of any one of claims 1 to 12, wherein X is O.

15. R ３ is H, optionally substituted C １－５ Alkyl, or -P(O)(OH) ２ The compound according to any one of claims 1 to 14,

16. W is NR ６ The compound according to any one of claims 1 to 15,

17. R ６ is H or optionally substituted C １－５ The compound of any one of claims 1 to 16, which is alkyl.

18. R ６ The compound of any one of claims 1 to 17, wherein is H.

19. R １ and R ２ are each independently H or optionally substituted C １－５ The compound of any one of claims 1 to 18, which is alkyl.

20. R １ and R ２ are each optionally substituted C １－５ The compound of any one of claims 1 to 19, which is alkyl.

21. R １ and R ２ 21. The compound of claim 19 or 20, wherein is methyl.

22. R ７ and R ８ are each independently H, F, or optionally substituted C １－５ The compound of any one of claims 1 to 21, which is alkyl.

23. R ７ and R ８ The compound of any one of claims 1 to 22, wherein each is H.

24. R ９ and R １０ are each independently H, F, or optionally substituted C １－５ The compound of any one of claims 1 to 23, which is alkyl.

25. R ９ and R １０ The compound of any one of claims 1 to 24, wherein each is H.

26. R ９ and R １０ 24. The compound of any one of claims 1 to 23, wherein together with the atom to which they are attached form an oxo.

27. R １１ and R １２ each independently represents -O － , —OH, —O—C １－５ The compound of any one of claims 1 to 26, wherein the aryl group is alkyl, or -OM.

28. R １１ But, O － and R １２ But -OH, -O-C １－５ The compound of any one of claims 1 to 27, wherein the aryl group is alkyl, or -OM.

29. R １１ and R １２ are -O-C １－５ The compound of any one of claims 1 to 27, which is alkyl.

30. R １１ and R １２ The compound of any one of claims 27 to 29, wherein each independently is -OMe, -OEt, -OiPr, or -OtBu.

31. R １１ and R １２ each independently represents —O—C １－５ The compound of any one of claims 27 to 29, which is haloalkyl.

32. R １１ and R １２ But, -OCH ２ CF ３ 32. The compound of any one of claims 27, 28, and 31, wherein:

33. M is Na+, K+, or NH ４ The compound according to any one of claims 1 to 28, wherein

34. R １１ and R １２ The compound of any one of claims 1 to 27, wherein each is -OH.

35. R １１ and R １２ together with the atom to which they are attached form an optionally substituted heterocyclyl.

36. R １１ and R １２ together with the atoms to which they are attached form an optionally substituted 5- to 12-membered heterocyclyl.

37. 37. The compound of claim 35 or 36, wherein said optionally substituted heterocyclyl is: 【Chemistry 2】

38. R １１ and R １２ The compound of any one of claims 1 to 26, wherein each is a deuterated alkyl.

39. R １１ and R １２ and each is deuterated methyl.

40. R １３ is H or optionally substituted C １－５ The compound of any one of claims 1 to 39, which is alkyl.

41. R １３ 41. The compound of claim 40, wherein is methyl, ethyl, or isopropyl.

42. R １４ is H, F, Cl, Br, or C １－５ The compound of any one of claims 1 to 41, which is alkyl.

43. R １４ The compound of any one of claims 1 to 42, wherein is H.

44. R １４ The compound of any one of claims 1 to 41, wherein is haloalkyl.

45. R １４ But CF ３ 45. The compound of any one of claims 1 to 41 or claim 44, wherein

46. The following structure: Table 1 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt thereof.

47. The following structure: Table 2 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt thereof.

48. The following structure: 【Transformation 3】 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt thereof.

49. The following structure: 【Chemistry 4】 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt thereof.

50. A compound of formula (II-A): 【Transformation 5】 or a pharmaceutically acceptable salt thereof, During the ceremony, A is N or C-VR １６ and B is N or C-YR ４ and E is N or C-ZR ５ where no more than two of A, B, and E are N; W is O, S, or NR ６ and V, X, Y, and Z are each independently absent, O, S, or NH; R １ and R ２ are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R ３ , R ４ , R ５ , and R １６ are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or —P(O)(OH) ２ and R ６ is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl; R ７ and R ８ are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R ７ and R ８ together with the atoms to which they are attached form an optionally substituted cycloalkyl ring; R ９ and R １０ are each independently H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R ９ and R １０ form oxo together with the atom to which they are attached, R １２ Is, -O － , -OH, -OD, -O-alkyl, -O-cycloalkyl, -O-alkylene-cycloalkyl, -O-aryl, or -OM, wherein M is a pharmaceutically acceptable cation, and said alkyl, cycloalkyl, and aryl are each optionally substituted; R １４ is H, D, halogen, —OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, and A compound of formula (II-A), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

51. A is C-VR １６ 51. The compound of claim 50, wherein:

52. 52. The compound of claim 51, wherein V is absent.

53. R １６ 53. The compound of claim 51 or 52, wherein is H.

54. B is Y-CR ４ 52. The compound of claim 50 or 51, wherein:

55. 55. The compound of any one of claims 50 to 54, wherein Y is absent.

56. 55. The compound of any one of claims 50 to 54, wherein Y is O.

57. R ４ The compound of any one of claims 50 to 55, wherein is H.

58. E is Z-CR ５ The compound according to any one of claims 50 to 53, wherein

59. 59. The compound of any one of claims 50 to 58, wherein Z is absent.

60. R ５ The compound of any one of claims 50 to 59, wherein is H.

61. 61. The compound of any one of claims 50 to 60, wherein X is absent.

62. 61. The compound of any one of claims 50 to 60, wherein X is O.

63. R ３ The compound of any one of claims 50 to 62, wherein is H.

64. W is NR ６ The compound according to any one of claims 50 to 63, wherein

65. R ６ The compound of any one of claims 50 to 64, wherein is H.

66. R １ and R ２ are each optionally substituted C １－５ 66. The compound of any one of claims 50 to 65, which is alkyl.

67. R １ and R ２ 67. The compound of claim 66, wherein is methyl.

68. R １ and R ２ and each is a deuterated alkyl.

69. R １ and R ２ and each is deuterated methyl.

70. R ７ and R ８ and each is H.

71. R ９ and R １０ The compound of any one of claims 50 to 70, wherein each is H.

72. R ９ and R １０ 71. The compound of any one of claims 50 to 70, wherein together with the atom to which they are attached form an oxo.

73. R １２ But, -O － , —OH, or —O—C １－５ 73. The compound of any one of claims 50 to 72, which is alkyl.

74. R １２ But, -O － or -O-C １－５ 74. The compound of any one of claims 50 to 73, which is alkyl.

75. R １２ 75. The compound of claim 73 or 74, wherein is -OMe.

76. R １４ is H, F, Cl, Br, or C １－５ 76. The compound of any one of claims 50 to 75, which is alkyl.

77. R １４ The compound of any one of claims 50 to 76, wherein is H.

78. The following structure: 【Transformation 6】 51. The compound of claim 50, wherein:

79. The following structure: 【Transformation 7】 51. The compound of claim 50, wherein:

80. 80. A composition comprising: (i) a compound according to any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient.

81. 81. An oral dosage form comprising the pharmaceutical composition of claim 80.

82. 81. A method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 79, or a pharmaceutical composition of claim 80.

83. 81. A method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 79, or a pharmaceutical composition of claim 80.

84. 84. The method of claim 83, wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

85. 81. A method of treating an anxiety disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 79, or a pharmaceutical composition of claim 80.

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