Phenylalkylamine prodrugs

Abstract

Provided herein are prodrugs of phenylalkylamines (e.g., psychedelic phenethylamines) that incorporate a vitamin B6-based promoiety (e.g., pyridoxal). Also provided are methods of making such compounds, pharmaceutical compositions thereof, and methods of their use, such as in the treatment of mental health disorders, neurodegenerative conditions, pain disorders, and inflammation, including as part of psychedelic-assisted therapy. (I)

Description

PHENYLALKYLAMINE PRODRUGSINVENTOR: Nicholas V. CozziCROSS-REFERENCE

[0001] Priority is claimed under PCT Art. 8(1) and Rule 4.10 to U.S. Provisional App. Nos. 63 / 449,511 , filed March 2, 2023, and 63 / 468,956, filed May 25, 2023, both fully incorporated by reference for all purposes.TECHNICAL FIELD

[0002] This disclosure relates in some aspects to compounds that are prodrugs of phenylalkylamines (e.g., psychedelic phenethylamines). The disclosure also relates to methods of making the compounds and pharmaceutical compositions thereof, and methods of using disclosed compounds and compositions for treating medical conditions, such as mental, behavioral, and neurodevelopmental disordersBACKGROUND OF THE INVENTION

[0003] The significant impact of mental health disorders on public health, coupled with the limitations of existing therapies, underscores an urgent need for improved treatment options. This includes the development of effective interventions with minimal adverse effects. Psychedelics have demonstrated promising efficacy in addressing various mental health conditions like depression, post-traumatic stress disorder, addiction, and anxiety. Developing prodrugs of psychedelics for therapeutic applications presents an opportunity to modulate their pharmacokinetic profiles and enhance their safety and efficacy for clinical use, leading to greater utility in treating mental health disorders, among other conditions. Provided herein are therapeutic prodrug compounds as well as compositions, kits, and methods of use that meet this need, and that have such other benefits and advantages as will become apparent in view of the disclosure below.INCORPORATION BY REFERENCE

[0004] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated individually, and as if each is fully set forth herein. However, no such citation should be construed as an admission that a cited reference comes from an area that is analogous or directly applicable to the invention, nor should any citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or part of the common general knowledge in the art.BRIEF SUMMARY OF THE INVENTION

[0005] The following is a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. It is not an extensive overview of the invention, nor intended to identify key or critical elements of the invention or to delineate the scope thereof. Its sole purpose is to present some embodiments and aspects of the invention in a simplified form as a prelude to the more detailed description.

[0006] In a first aspect, provided is a compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein:X is H or PO3H2;Rais H or CrC6alkyl;Rpis H, OH, or CpCg alkoxy;R2, R3, R4, and R5are each independently H, Br, F, Cl, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or -SONH; andR6is H; or any of R2and R3, R3and R4, R4and R5, and R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R2, R3, R4, R5, and R6as defined above; provided that at least two of R2, R3, R4, R5, and R6are not H.

[0007] In another aspect, provided is a compound of Formula (A):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein:X is H or PO3H2;Rais H or CrC6alkyl;Rpis H, OH, or C^Ce alkoxy;R2, R3, R4, and R5are each independently H, Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, CrCg alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^-Cg alkoxy, C^-Cg alkylthio, C^-Cg haloalkyl, C^-Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or -SONH; and R6is H; or any of R2and R3, R3and R4, R4and R5, and R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R2, R3, R4, R5, and R6as defined above.

[0008] In some embodiments, the compound has the structure of Formula (I A), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IA-6), (IA-7), (IB), (IC), (ID), (IE), or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:wherein R1, R2, R3, R4, R5, R6, Ra, Rp, and X are as defined for Formula (I)

[0009] In some embodiments, the compound has the structure of Formula (AA), (AA-1), (AA-2), (AA-3), (AA-4), (AA-5), (AA-6), (AA-7), (AB), (AC), (AD), (AE), or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:wherein R1, R2, R3, R4, R5, R6, Ra, Rp, and X are as defined for Formula (I)

[0010] In some embodiments, R4is Br. In some embodiments, R4is CrCg alkyl. In some embodiments, R4is — CH3. In some embodiments, R4is CrCg alkylthio. In some embodiments, R4is — SCH2CH2CH3.

[0011] In some embodiments, R2Ais CrCg alkyl. In some embodiments, R2Ais — CH3.

[0012] In some embodiments, R3Ais CrCg alkyl. In some embodiments, R3Ais — CH3.

[0013] In some embodiments, R4Ais C^Cg alkyl. In some embodiments, R4Ais — CH3. In some embodiments, R4Ais — CH2CH3.

[0014] In some embodiments, R5Ais C^Cg alkyl. In some embodiments, R5Ais — CH3.

[0015] In some embodiments, Rais H. In embodiments, Rais C^Cg alkyl. In embodiments, Rais — CH3.

[0016] In some embodiments, Rpis H.

[0017] In some embodiments, X is H. In some embodiments, X is PO3H2.

[0018] In some embodiments, the compound is selected from Table IA, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. In some embodiments, the compound is selected from TableIB, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0019] In some embodiments, the compound is:or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0021] In some embodiments, the compoundpharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0022] In some embodiments, the compoundor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0023] In some embodiments, the compound ispharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0024] In some embodiments, the compoundpharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0025] In some embodiments, the compoundpharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0026] In some embodiments, the compoundpharmaceuticallyacceptable salt, stereoisomer, hydrate, or solvate thereof.

[0027] In some embodiments, the compoundor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0028] In some embodiments, the compoundor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0029] In some embodiments, the compoundpharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0030] Also provided is a pharmaceutical composition comprising a therapeutically effective amount of the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration. In some embodiments, the composition is provided in unit dosage form. In some embodiments, the composition comprises the compound in a total amount of between 1 and 200 mg, or between 5 and 100 mg. In some embodiments, the composition comprises the compound in a total amount of between 10 and 75 mg, or between 15 and 50 mg. In some embodiments, the unit dosage form is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

[0031] In some embodiments, the composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. In some embodiments, the additional active compound is selected from the group consisting of: amino acids,antioxidants, anti-inflammatory agents, analgesics, anti neuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins. In some embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, or alter pharmacokinetics or pharmacodynamics. In some embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, anti neuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

[0032] Also provided is a method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or composition of any of the disclosed embodiments.

[0033] In some embodiments, the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission. In some embodiments, the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission. In some embodiments, the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of serotonergic, dopaminergic, or noradrenergic neurotransmission.

[0034] In some embodiments, the medical condition is a mental health disorder. In some embodiments, the mental health disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, alcohol or drug abuse or dependence disorders, a substance use disorder, substance-induced mood disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, and dissociative disorders. In some embodiments, depression is major depressive disorder (MDD) or treatment-resistant depression (TRD). In some embodiments, anxiety is generalized anxiety disorder (GAD). In embodiments, the mental health disorder is PTSD. In embodiments, the substance use disorder is alcohol use disorder (AUD), nicotine dependence or tobacco use disorder, opioid use disorder (OLID), stimulant use disorder, or sedative, hypnotic, or anxiolytic use disorder.

[0035] In some embodiments, the medical condition is a neurodegenerative disorder, pain or a paindisorder, or inflammation or an inflammatory disorder.

[0036] In some embodiments, the compound is administered together with one or more sessions of psychotherapy or psychological support.

[0037] Also provided is a method of modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of the compound or composition of any of the disclosed embodiments. In some embodiments, modulating neurotransmission comprises activating a monoamine neurotransmitter receptor and / or modulating the uptake activity of a monoamine transporter. In some embodiments, the monoamine neurotransmitter receptor is any of a serotonin receptor (HTR), a dopamine receptor, and a norepinephrine receptor. In some embodiments, the monoamine transporter is any of a serotonin transporter (SERT), a dopamine transporter (DAT), or a norepinephrine transporter (NET). In some embodiments, the HTR is any of HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, and HTR6. In some embodiments, modulating neurotransmission comprises agonizing HTR^.

[0038] Also provided is the compound or composition of any of the disclosed embodiments for use in the treatment of a medical condition.

[0039] Also provided is the use of the compound or composition of any of the disclosed embodiments for the manufacture of a medicament for the treatment of a mental health disorder patient according to the method of any of the following claims.

[0040] The foregoing has outlined broadly and in summary certain pertinent features of the disclosure so that the detailed description of the invention that follows may be better understood, and so that the present contribution to the art can be more fully appreciated. Hence, this summary is to be considered as a brief and general synopsis of only some of the objects and embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are lawfully entitled. Additional features of the invention are described hereinafter. It should be appreciated by those in the art that all disclosed specific compositions and methods are only exemplary, and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods will be appreciated to be also within the scope and spirit of the invention as set forth in the claims.

[0041] The headings in this document are utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner.DETAILED DESCRIPTION OF THE INVENTION

[0042] While various aspects and features of certain embodiments are summarized above, the following detailed description illustrates several exemplary embodiments in further detail to enable one of skill in the art to practice such embodiments, and to make and use the full scope of the invention claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications. It will be understood that many modifications, substitutions, changes, andvariations in the described examples, embodiments, applications, and details of the invention illustrated herein can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as described in the appended claims. Furthermore, where possible, any element of an embodiment is meant to be combined with any elements from any other embodiment to describe an additional embodiment. It also will be appreciated that the headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner.

[0043] The scope of the invention includes all embodiments and formulations thereof, not only those expressly described below, and it will be understood that many modifications, substitutions, changes, and variations in the described embodiments, applications, and details of the invention can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as claimed.A. General Definitions and Terms

[0044] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an active agent” includes reference to a combination of two or more active agents, and reference to “an excipient” includes reference to a combination of two or more excipients. While the term “one or more” may be used, its absence (or its replacement by the singular) does not signify the singular only, but simply underscores the possibility of multiple agents or ingredients in particular embodiments.

[0045] The terms “comprising,” “including,” “such as,” and “having” are intended to be inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). Thus, the term “including” means, and is used interchangeably with, the phrase “including but not limited to.” The term “or” is used to mean, and is used interchangeably with, the term “and / or,” unless context clearly indicates otherwise.

[0046] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. The term “substantially,” where it is applied to modify a feature or limitation herein, will be read in the context of the invention and in light of the knowledge in the art to provide the appropriate certainty, e.g., by using a standard that is recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the art.

[0047] In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely aspracticable. The numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0048] A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations; the current list as of the date of this filing is hereby incorporated by reference as if fully set forth herein.

[0049] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs, who as a shorthand may be referred to simply as “one of skill.” Further definitions that may assist the reader in understanding the disclosed embodiments are as follows; however, it will be appreciated that such definitions are not intended to limit the scope of the invention, which shall be properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill in the relevant art) in view of the language used in the appended claims. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0050] Generally, the nomenclature used and procedures performed herein are those known in fields relating to one or more aspects of the invention, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or medicinal chemistry, and are those that will be well known and commonly employed in such fields. Standard techniques and procedures will be those generally performed according to conventional methods in the art.

[0051] “Alkyl” will be understood to include straight or branched radicals having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” can also be used. Preferably, an alkyl group comprises from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, and most preferably from 1 to 3 carbon atoms. For any alkyl, the alkyl may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, -OC(O)NH2, or — SONH2.

[0052] “Alkanyl” refers to saturated branched, straight-chain, or cyclic alkyl radicals derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include methanyl; ethanyl; propanyls such as propan-1 -yl, propan-2-yl (isopropyl), and cyclopropan-1-yl; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1 -yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), and cyclobutan-1-yl; etc.

[0053] “Alkenyl” refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include ethenyl; propenyls such as prop-1 -en-1-yl, prop-1 -en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1 -en-1-yl, and cycloprop-2-en-1-yl; butenyls such as but-1 -en-1-yl, but-1 -en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2yl, buta-1 ,3-dien-1-yl, buta-1 ,3-dien-2-yl, cyclobut-1 -en-1 -yl, cyclobut-1-en-3-yl, and cyclobuta-1 ,3-dien-1 -yl; and the like.

[0054] “Alkynyl” refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include ethynyl; propynyls such as prop-1 -yn-1-yl, and prop-2-yn-1 -yl; butynyls such as but-1 -yn-1 -yl, but-1 -yn-3-yl, and but-3-yn-1 -yl; and the like.

[0055] “Aryl” refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen (H) atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. Preferably, an aryl group comprises from 6 to 20 carbon atoms, more preferably, between 6 to 12 carbon atoms.

[0056] “Amino” refers to — NR2, wherein each R is independently H, OH, or C^Cg alkyl, wherein the C^Cg alkyl is optionally substituted. An amino group can be a primary amino group (— NH2) a secondary amino group (— NHR), a tertiary amino group (— NR2), or a quaternary amino group (— NR3+), wherein R is independently H or C^Cg alkyl, wherein the C^Cg alkyl is optionally substituted.

[0057] “Cycloalkyl” refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to12 carbon atoms. Monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compoundsand bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decahydronaphthalene and adamantane. When cycloalkyl is a monocyclic C3.8cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a monocyclic C3.6cycloalkyl, exemplary groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0058] “Cycloalkenyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring. However, if there is more than one double bond, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. Cycloalkenyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Representative cycloalkenyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1 ,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1 ,3-, 1 ,4- and 1 ,5-isomers), norbornene, and norbornadiene. A cycloalkenyl group may be unsubstituted or substituted.

[0059] “Halogen” refers to fluorine, chlorine, bromine, and iodine.

[0060] “Heterocycloalkyl” and “heterocyclyl” both refer to a cycloalkyl as defined above, having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Heterocycloalkyl and heterocyclyl include bicyclic compounds which include a heteroatom. Bicyclic compounds includes spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds The heteroatoms can also be oxidized, such as, but not limited to, — S(O)— and — S(O)2— . Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 , or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1 , 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1 ,2-, 1 ,3- and 1 ,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but notlimited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with alkyl or oxo (=0), among many others.

[0061] “Heterocycloalkenyl” refers to cycloalkenyl as defined above, having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, 0 and S. The heteroatoms can also be oxidized, such as, but not limited to, — S(0)— and — S(0)2— . Heterocycloalkenyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 , or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkenyl groups, such as 1 , 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Exemplary heterocycloalkenyl groups include dihydrofuran, dihydropyran, dihydropyridine, tetrahydropyridine, dihydrothiazole, and dihydrothiophene.

[0062] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, 0 or S. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1 , 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1 ,2,3-, 1 ,2,4- and 1 ,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0063] “Alkoxy” refers to the formula —OR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0064] “Acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, connected via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0001] Deuterium (2H or D), also called “heavy hydrogen,” is a stable isotope of hydrogen (1H) with a natural abundance in the Earth’s oceans of approximately one atom per 6,500 of hydrogen ("154 ppm). Deuterium thus accounts for approximately 0.0154% (alternately, on a mass basis, 0.0308%) of all naturally occurring hydrogen in the oceans. “Mon-substituted,” “non-deuterated,” and “undeuterated” may refer tocompounds having no greater than the amount of deuterium expected as a percentage of naturally occurring hydrogen in a compound.

[0001] “Deuteroalkyl” will be understood to include any alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a deuterium (i.e.,2H, or D). Where an alkyl radical is substituted by more than one deuterium, it may be referred to using a prefix corresponding to the number of deuterium substitutions. For example, trideuteroalkyl refers to an alkyl in which three hydrogens have been replaced by deuteriums. A deuteroalkyl can be fully deuterated (i.e., all of the hydrogens have been replaced by deuteriums) or partially deuterated (i.e., only some of the hydrogens have been replaced by deuteriums). For example, a deuteromethyl (i.e., a C! deuteroalkyl) group refers to — CH2D, — CHD2, or — CD3. A deuteroethyl (i.e., a C2deuteroalkyl) group refers to — CH2CH2D, — CHDCH2D, — CD2CH2D, — CH2CHD2, — CHDCHD2, — CD2CHD2, — CH2CD3, — CHDCD3, or — CD2CD3. A deuteropropyl group (i.e., a C3deuteroalkyl) refers to any partially or fully substituted n-propyl or isopropyl group.

[0065] “Haloalkyl” will be understood to include any alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen (e.g., a fluorine, a chlorine, a bromine, or an iodine). Where an alkyl radical is substituted by more than one halogen, it may be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkyl refers to an alkyl substituted by two halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl groups include difluoromethyl (— CHF2), bromofluoromethyl (— CHBrF), trifluoromethyl (— CF3), and 2-fluoroethyl (— CH2CH2F). Additional examples of haloalkyl groups include — CHF2, — CH2F, — CH2CF3, — CH2CHF2, -CH2CH2F, -CH(CH3)(CF3), -CH(CH3)(CHF2), and -CH(CH3)(CH2F).

[0066] “Hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include, for example, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0067] “Haloalkoxy” refers to an — O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). The halogens may be the same or different in each instance. Such groups include chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0068] “Alkylthio” refers to the formula —SR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein. A non-limiting list of alkylthio are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio. An alkylthio may be substituted or unsubstituted.

[0069] “Sulfenyl” refers to an —SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A sulfenyl may be substituted or unsubstituted.

[0070] “Sulfinyl” refers to an — S(=O)— R group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0071] “Sulfonyl” refers to an — SO2R group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0072] “O-carboxy” refers to a — RC(=O)O— group in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carboxy may be substituted or unsubstituted.

[0073] “Ester” and “C-carboxy” refer to a — C(=O)OR group in which R can be the same as defined with respect to O-carboxy. Ester and C-carboxy groups may be substituted or unsubstituted.

[0074] “Thiocarbonyl” refers to a — C(=S)R group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0075] “Trihalomethanesulfonyl” refers to an X3CSO2— group wherein each X is a halogen.

[0076] “Trihalomethanesulfonamido” refers to an X3CS(O)2N(RA)— group wherein each X is a halogen, and RAis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0077] “S-sulfonamido” refers to a — SO2N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An S-sulfonamido may be substituted or unsubstituted.

[0078] “N-sulfonamido” refers to a RSO2N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-sulfonamido may be substituted or unsubstituted.

[0079] “Oxo” refers to =0.

[0080] “O-carbamyl” refers to a — 0C(=0)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carbamyl may be substituted or unsubstituted.

[0081] “N-carbamyl” refers to an R0C(=0)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-carbamyl may be substituted or unsubstituted.

[0082] “O-thiocarbamyl” refers to a — 0C(=S)— N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-thiocarbamyl may be substituted or unsubstituted.

[0083] “N-thiocarbamyl” refers to an R0C(=S)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-thiocarbamyl may be substituted or unsubstituted.

[0084] “C-amido” group refers to a — C(=0)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A C-amido may be substituted or unsubstituted.

[0085] “N-amido” refers to a RC(=0)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-amido may besubstituted or unsubstituted.

[0086] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. If no substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl (alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, oxo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group.B. Prodrugs

[0087] In some aspects, provided herein are compounds that are prodrugs of psychedelic phenethylamines. A prodrug is an inactive derivative of a pharmacologically active drug that is designed to undergo chemical or enzymatic activation in vivo, for example by the action of a metabolic process, an enzymatic process or a degradative process that removes the prodrug moiety (i.e., the “promoiety”) to form the drug. Through selection of a particular promoiety and linking chemistry to connect the promoiety to the drug, prodrugs can be engineered to modulate how a drug is absorbed, distributed, metabolized, and excreted by the body. Beyond simply releasing a drug in vivo, prodrugs can also enhance pharmacokinetic properties of a drug by targeting specific tissues or cells, increasing the solubility across biological barriers, and prolonging drug release. Moreover, prodrugs can improve therapeutic efficacy by minimizing side effects, increasing drug potency, and reducing the required dosage (Jana et al. Current Medicinal Chemistry. 2010. 17(32), 3874-3908). These advantages make prodrugs a promising strategy in drug development, especially for drugs with poor bioavailability, low solubility, and high toxicity.

[0088] Prodrug modifications have been explored for the delivery of psychedelic phenethylamines previously. For example, WO 2022 / 235587 describes the use of lipid structures in prodrugs of psychedelic tryptamines and phenethylamines. Prodrugs containing fat-soluble lipid moieties can be useful in drug design by increasing the ability of hydrophilic drugs to cross cell lipid bilayers (Markovic et al. Med Res Rev. 2019. 39, 579-607). However, even lipid-based prodrugs may not be capable of crossing tight cellular barriers such as the blood-brain barrier. Prodrug strategies that employ a promoiety that can bind to specifictransporters on cellular barriers can be more likely to reach the active compound target within the tissue (Jornada et al. Molecules. 2016. 21 (1):42).

[0089] There is a need for diverse prodrugging strategies that are effective over the wide array of tissue, cellular, and subcellular targets in the human body, and which can be applied to a diverse array of phenethylamines with therapeutic potential. For example, mescaline is a phenethylamine with pharmacodynamic mechanisms similar to other psychedelic molecules (Agin-Liebes et al. ACS Pharmacol Transl Sci. 2021. 4(2), 543-552). However, it does not readily cross the blood-brain barrier (Palenicek et al. Psychopharmacology. 2007. 196(1), 51-62). Thus, this drug requires a higher dose for pharmacological activation, which may lead to unnecessary accumulation of mescaline metabolites in other tissues and can increase the chance / severity of non-target effects (Dinis Oliviera et al. Curr Mol Pharmacol. 2019. 12(3), 184-194). A prodrugging strategy that increases bioavailability of mescaline and other phenylalkylamines to the brain would allow for a lower dose, among other advantages associated with improved pharmacokinetics and higher central nervous system (CNS) penetration.

[0090] In some aspects, provided herein are prodrugs of phenethylamines that incorporate a vitamin B6 moiety. Vitamin B6 has six chemically distinct forms, including pyridoxine, pyridoxal, pyridoxamine, and their respective phosphorylated derivatives:

[0091] Pyridoxal 5’-phosphate has the highest biological activity, but other forms of vitamin B6 can be converted to pyridoxal 5’-phosphate in vivo (Bachmann, et al. Molecules 2018, 23(9), 2117). Humans cannot synthesize any of the forms of vitamin B6, and must therefore obtain it by dietary means (Calderon-Ospina, et al. CNS Neurosci. Ther. 2020, 26(1), 5-13). As vitamin B6 plays an essential role in neurotransmitter production, it must be transported into the CNS (Id.). Transporters, such as SLC19A2 and SLC19A3, also known as thiamine transporters (THTR) 1 and 2, have been shown to transport pyridoxine (Yamashiro et al., J Biol Chem. 2020, 295(50), 16998-17008). Various vitamin B6 conjugates have been synthesized and evaluated for their ability to act as prodrugs by enabling the transport of a therapeutically active component across cellular membranes (see, e.g., Araujo de Oliveira, et al. ACS Omega 2022, 7(14), 11678-11687; Day,et al. Mol Pharm. 2011 , 8(1), 297-301 ; Wu, et al. FASEB J. 2011 , 25(7), 2109-2122; Zhang, et al. Proc. Natl. Acad. Sci. USA 1991 , 88(23), 10407-10410). However, Applicant is unaware of any examples of vitamin B6 prodrugs of psychedelic compounds.

[0092] Moreover, Applicant is unaware of the specific compounds and compositions disclosed herein having been synthesized, formulated, and / or used in the compositions and methods of the invention. In some embodiments, Applicant’s disclosed compounds are particularly advantageous. For example, by improving the ability of certain drugs to cross cellular membranes and reach their receptor targets, compounds disclosed herein may produce fewer species or lower concentrations of metabolites responsible for adverse effects, resulting in improved side-effect profiles, and may provide other advantages compared to the corresponding drug compounds alone.

[0093] In a first aspect, provided is a compound of Formula (I),or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein:X is H or PO3H2;Rais H or CrC6alkyl;Rpis H, OH, or C^Cg alkoxy;R2, R3, R4, and R5are each independently H, Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or -SONH; andR6is H; or any of R2and R3, R3and R4, R4and R5, and R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R2, R3, R4, R5, and R6as defined above.

[0094] In some embodiments (or equivalently, and as shorthand, “in embodiments”), X is H or PO3H2. Insome embodiments, X is H. In some embodiments, X is PO3H2.

[0095] In some embodiments, Rais H or C^Cg alkyl. In some embodiments, Rais H. In some embodiments, Rais C^Cg alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, Rais methyl (— CH3). In some embodiments, Rais ethyl (— CH2CH3).

[0096] In some embodiments, Rpis H, OH, or C^Cg alkoxy. In some embodiments, Rpis H. In some embodiments, Rpis OH. In some embodiments, Rpis C^Cg alkoxy (e.g., methoxy, ethoxy, n-propoxy, / so-propoxy). In some embodiments, Rpis methoxy. In some embodiments, Rpis oxo (=0).

[0097] In some embodiments, R2, R3, R4, and R5are each independently H, Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each CrCg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, CrCg alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, or -SONH; and R6is H; or any of R2and R3, R3and R4, R4and R5, and R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R2, R3, R4, R5, and R6as defined above; provided that at least two of R2, R3, R4, R5, and R6are not H.

[0098] In some embodiments, R2is H, Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, CrCg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, CrCg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or —SONH. In some embodiments, R2is H. In some embodiments, R2is halogen (i.e., F, Cl, Br, I). In some embodiments, R2is F. In some embodiments, R2is Cl. In some embodiments, R2is Br. In some embodiments, R2is I. In some embodiments, R2is CrCg alkyl. In some embodiments, R2is methyl (— CH3). In some embodiments, R2is ethyl (— CH2CH3). In some embodiments, R2is C2-C8alkenyl. In some embodiments, R2is C2-C8alkynyl. In some embodiments, R2is CrCg alkoxy. In some embodiments, R2is methoxy. In some embodiments, R2is ethoxy. In some embodiments, R2is propoxy. In some embodiments, R2is isopropoxy. In some embodiments, R2is CrCg alkylthio. In some embodiments, R2is — SCH3. In some embodiments, R2is — SCH2CH3. In some embodiments, R2is — SCH2CH2CH3. In some embodiments, R2is C^Cg haloalkyl. In some embodiments, R2is C^Cg haloalkoxy.In some embodiments, R2is 3- to 6-membered cycloalkyl. In some embodiments, R2is 4- to 6-membered heterocycloalkyl. In some embodiments, R2is cyano. In some embodiments, R2is nitro. In embodiments, R2is amino (i.e., -NR2, wherein each R is independently H, OH, or C^Cs alkyl, wherein the CrC6alkyl is optionally substituted according to embodiments described below).

[0099] In some embodiments, wherein R2is C^Cs alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cs alkoxy, C^Cs alkylthio, C^Cs haloalkyl, C^Cs haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each C^Cs alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, C^Cs haloalkyl, C^Cs haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or — SONH. In some embodiments, R2is unsubstituted CrC6alkyl, unsubstituted C2-C8alkenyl, unsubstituted C2-C8alkynyl, unsubstituted CrC6alkoxy, unsubstituted CrC6alkylthio, unsubstituted CrC6haloalkyl, unsubstituted CrC6haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH2). In some embodiments, R2is substituted CrC6alkyl, substituted C2-C8alkenyl, substituted C2-C8alkynyl, substituted CrC6alkoxy, substituted CrC6alkylthio, substituted CrC6haloalkyl, substituted CrC6haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR2, wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, or -SONH).

[0100] In some embodiments, R3is H, Br, F, Cl, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or —SONH. In some embodiments, R3is H. In some embodiments, R3is halogen (i.e., F, Cl, Br, I). In some embodiments, R3is F. In some embodiments, R3is Cl. In some embodiments, R3is Br. In some embodiments, R3is I. In some embodiments, R3is CrC6alkyl. In some embodiments, R3is methyl (— CH3). In some embodiments, R3is ethyl (— CH2CH3). In some embodiments, R3is C2-C8alkenyl. In some embodiments, R3is C2-C8alkynyl. In some embodiments, R3is CrC6alkoxy. In some embodiments, R3is methoxy. In some embodiments, R3is ethoxy. In some embodiments, R3is propoxy. In some embodiments, R3is isopropoxy. In some embodiments, R3is CrC6alkylthio. In someembodiments, R3is — SCH3. In some embodiments, R3is — SCH2CH3. In some embodiments, R3is — SCH2CH2CH3. In some embodiments, R3is CrC6haloalkyl. In some embodiments, R3is CrC6haloalkoxy. In some embodiments, R3is 3- to 6-membered cycloalkyl. In some embodiments, R3is 4- to 6-membered heterocycloalkyl. In some embodiments, R3is cyano. In some embodiments, R3is nitro. In embodiments, R3is amino (i.e., -NR2, wherein each R is independently H, OH, or CrC6alkyl, wherein the CrC6alkyl is optionally substituted according to embodiments described below).

[0101] In some embodiments, wherein R3is CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or — SONH. In some embodiments, R3is unsubstituted CrCg alkyl, unsubstituted C2-C8alkenyl, unsubstituted C2-C8alkynyl, unsubstituted CrCg alkoxy, unsubstituted CrCg alkylthio, unsubstituted CrCg haloalkyl, unsubstituted CrCg haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH2). In some embodiments, R3is substituted CrC6alkyl, substituted C2-C8alkenyl, substituted C2-C8alkynyl, substituted CrC6alkoxy, substituted CrC6alkylthio, substituted CrC6haloalkyl, substituted CrC6haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR2, wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, or -SONH).

[0102] In some embodiments, R4is H, Br, F, Cl, I, C Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrCg alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or —SONH. In some embodiments, R4is H. In some embodiments, R4is halogen (i.e., F, Cl, Br, I). In some embodiments, R4is F. In some embodiments, R4is Cl. In some embodiments, R4is Br. In some embodiments, R4is I. In some embodiments, R4is CrCg alkyl. In some embodiments, R4is methyl (— CH3). In some embodiments, R4is ethyl (— CH2CH3). In some embodiments, R4is C2-C8alkenyl. In some embodiments, R4is C2-C8alkynyl. In some embodiments, R4is CrC6alkoxy. Insome embodiments, R4is methoxy. In some embodiments, R4is ethoxy. In some embodiments, R4is propoxy. In some embodiments, R4is isopropoxy. In some embodiments, R4is CrC6alkylthio. In some embodiments, R4is — SCH3. In some embodiments, R4is — SCH2CH3. In some embodiments, R4is — SCH2CH2CH3. In some embodiments, R4is CrC6haloalkyl. In some embodiments, R4is CrC6haloalkoxy. In some embodiments, R4is 3- to 6-membered cycloalkyl. In some embodiments, R4 is 4- to 6-membered heterocycloalkyl. In some embodiments, R4is cyano. In some embodiments, R4is nitro. In embodiments, R4is amino (i.e., -NR2, wherein each R is independently H, OH, or CrC6alkyl, wherein the CrC6alkyl is optionally substituted according to embodiments described below).

[0103] In some embodiments, wherein R4is CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each CrCg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, CrCg alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or — SONH. In some embodiments, R4is unsubstituted CrCg alkyl, unsubstituted C2-C8alkenyl, unsubstituted C2-C8alkynyl, unsubstituted CrC6alkoxy, unsubstituted CrC6alkylthio, unsubstituted CrC6haloalkyl, unsubstituted CrC6haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH2). In some embodiments, R4is substituted CrC6alkyl, substituted C2-C8alkenyl, substituted C2-C8alkynyl, substituted CrC6alkoxy, substituted CrC6alkylthio, substituted CrC6haloalkyl, substituted CrC6haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR2, wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, or -SONH).

[0104] In some embodiments, R5is H, Br, F, Cl, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, C Cg alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each CrCg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, CrCg alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or —SONH. In some embodiments, R5is H. In some embodiments, R5is halogen (i.e., F, Cl, Br, I). In some embodiments, R5is F. In some embodiments, R5is Cl. In some embodiments, R5is Br. In some embodiments, R5is I. In some embodiments, R5is CrC6alkyl. In someembodiments, R5is methyl (— CH3). In some embodiments, R5is ethyl (— CH2CH3). In some embodiments, R5is C2-C8alkenyl. In some embodiments, R5is C2-C8alkynyl. In some embodiments, R5is CrC6alkoxy. In some embodiments, R5is methoxy. In some embodiments, R5is ethoxy. In some embodiments, R5is propoxy. In some embodiments, R5is isopropoxy. In some embodiments, R5is CrC6alkylthio. In some embodiments, R5is — SCH3. In some embodiments, R5is — SCH2CH3. In some embodiments, R5is — SCH2CH2CH3. In some embodiments, R5is CrC6haloalkyl. In some embodiments, R5is CrC6haloalkoxy. In some embodiments, R5 is 3- to 6-membered cycloalkyl. In some embodiments, R5is 4- to 6-membered heterocycloalkyl. In some embodiments, R5is cyano. In some embodiments, R5is nitro. In embodiments, R5is amino (i.e., -NR2, wherein each R is independently H, OH, or C^Cs alkyl, wherein the CrC6alkyl is optionally substituted according to embodiments described below).

[0105] In some embodiments, wherein R5is CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or — SONH. In some embodiments, R5is unsubstituted CrC6alkyl, unsubstituted C2-C8alkenyl, unsubstituted C2-C8alkynyl, unsubstituted CrC6alkoxy, unsubstituted CrC6alkylthio, unsubstituted CrC6haloalkyl, unsubstituted CrC6haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH2). In some embodiments, R5is substituted CrC6alkyl, substituted C2-C8alkenyl, substituted C2-C8alkynyl, substituted CrC6alkoxy, substituted CrC6alkylthio, substituted CrC6haloalkyl, substituted CrC6haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR2, wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, or -SONH).

[0106] In some embodiments, R6is H.

[0107] In some embodiments, any of R2and R3, R3and R4, R4and R5, and R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R2, R3, R4, R5, and R6as defined above.

[0108] In some embodiments, R2and R3are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, and R4, R5, and R6are as defined above. In some embodiments, R2and R3are taken together to form a 3- to 6-membered cycloalkyl (e.g., a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl). In someembodiments, R2and R3are taken together to form a 3- to 6-membered cycloalkenyl (e.g., a cyclobutenyl, cyclopentenyl, or cyclohexenyl). In some embodiments, R2and R3are taken together to form a 4- to 6-membered heterocycloalkyl. For example, in some embodiments, R2and R3are taken together to form a dihydrofuran ring. In other embodiments, R2and R3are taken together to form a dihydropyran ring. In some embodiments, R2and R3are taken together to form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R2and R3are taken together to form a furanyl.

[0109] In some embodiments, R3and R4are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, and R2, R5, and R6are as defined above. In some embodiments, R3and R4are taken together to form a 3- to 6-membered cycloalkyl. In some embodiments, R3and R4are taken together to form a 3- to 6-membered cycloalkenyl. In some embodiments, R3and R4are taken together to form a 4- to 6-membered heterocycloalkyl. For example, in some embodiments, R3and R4are taken together to form a dihydrofuran ring. In other embodiments, R3and R4are taken together to form a dihydropyran ring. In some embodiments, R3and R4are taken together to form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R3and R4are taken together to form a furanyl. In some embodiments, R3and R4are taken together to form a 3,4-methylenedioxy ring.

[0110] In some embodiments, R4and R5are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, and R2, R3, and R6are as defined above. In some embodiments, R4and R5are taken together to form a 3- to 6-membered cycloalkyl. In some embodiments, R4and R5are taken together to form a 3- to 6-membered cycloalkenyl. In some embodiments, R4and R5are taken together to form a 4- to 6-membered heterocycloalkyl. For example, in some embodiments, R4and R5are taken together to form a dihydrofuran ring. In other embodiments, R4and R5are taken together to form a dihydropyran ring. In some embodiments, R4and R5are taken together to form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R4and R5are taken together to form a furanyl.

[0111] In some embodiments, R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, and R2, R3, and R4are as defined above. In some embodiments, R5and R6are taken together to form a 3- to 6-membered cycloalkyl. In some embodiments, R5and R6are taken together to form a 3- to 6-membered cycloalkenyl. In some embodiments, R5and R6are taken together to form a 4- to 6-membered heterocycloalkyl. For example, in some embodiments, R5and R6are taken together to form a dihydrofuran ring. In other embodiments, R5and R6are taken together to form a dihydropyran ring. In some embodiments, R5and R6are taken together to form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R5and R6are taken together to form a furanyl.

[0112] In some embodiments, R2and R3are taken together to form a 3- to 6-membered cycloalkyl, 4- to6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl; R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl; and R4is H, Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, CrCg alkylthio, CrCg haloalkyl, CrC6haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, or -SONH.

[0113] In some embodiments, at least one of R2, R3, R4, R5, and R6is not H. In some embodiments, at least two of R2, R3, R4, R5, and R6are not H. In embodiments, at least three of R2, R3, R4, R5, and R6are not H.

[0114] In some embodiments, the compound has the structure of Formula (IA):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R24and R5Aare each independently CrC6alkyl, CrC6haloalkyl, or CrC6deuteroalkyl; and R4, Ra, Rp, and X are as defined above for Formula (I).

[0115] In some embodiments, R2Ais CrC6alkyl. In some embodiments, R24is methyl. In some embodiments, R2Ais CrCg haloalkyl. In some embodiments, R2Ais trifluoromethyl (i.e., — CF3). In some embodiments, R24is trideuteromethyl (i.e., — CD3).

[0116] In some embodiments, R5Ais CrCg alkyl. In some embodiments, R5Ais methyl. In some embodiments, R5Ais CrCg haloalkyl. In some embodiments, R5Ais trifluoromethyl (i.e., — CF3). In some embodiments, R5Ais trideuteromethyl (i.e., — CD3).

[0117] In some embodiments, the compound has the structure of Formula (IA-1):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4, Ra, Rp, and X are as defined above for Formula (I).

[0118] In some embodiments, the compound has the structure of Formula (IA-2):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4, Ra, Rp, and X are as defined above for Formula (I).

[0119] In some embodiments, the compound has the structure of Formula (IA-3):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4, Ra, Rp, and X are as defined above for Formula (I).

[0120] In some embodiments, the compound has the structure of Formula (IA-4):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4, Ra, Rp, and X are as defined above for Formula (I).

[0121] In some embodiments, the compound has the structure of Formula (IA-5):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4, Ra, Rp, and X are as defined above for Formula (I).

[0122] In some embodiments, the compound has the structure of Formula (IA-6):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4, Ra, Rp, and X are as defined above for Formula (I).

[0123] In some embodiments, the compound has the structure of Formula (IA-7):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4, Ra, Rp, and X are as defined above for Formula (I).

[0124] In some embodiments, the compound has the structure of Formula (IB):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein: R3A, R4A, and R5Aare each independently CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, or CrC6haloalkyl, wherein the CrC6alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl, and wherein Ra, Rp, and X are as defined above for Formula (I).

[0125] In some embodiments, R3Ais CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, or CrC6haloalkyl, wherein the CrC6alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl. In some embodiments, R3Ais CrC6alkyl. In some embodiments, R3Ais CrC6alkyl, C2-C8alkenyl. In some embodiments, R3Ais C2-C8alkynyl. In some embodiments, R3AisrC6haloalkyl. In some embodiments, R3Ais unsubstituted. In some embodiments, R3Ais CrC6alkyl, wherein the CrC6alkyl is substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl. In some embodiments, R3Ais C^Cg alkyl, wherein the CrCg alkyl is substituted by 3- to 6-membered cycloalkyl (e.g., cyclopropyl). In some embodiments, R3Ais CrCg alkyl, wherein the C^Cg alkyl is substituted by 6- to 10-membered aryl (e.g., phenyl).

[0126] In some embodiments, R4Ais C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, or C^Cg haloalkyl, wherein the CrCg alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl. In some embodiments, R4Ais C^Cg alkyl. In some embodiments, R4Ais C^Cg alkyl, C2-C8alkenyl. In some embodiments, R4Ais C2-C8alkynyl. In some embodiments, R4AisrC6haloalkyl. In some embodiments, R4Ais unsubstituted. In some embodiments, R4Ais C^Cg alkyl, wherein the C^Cg alkyl is substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl. In some embodiments, R3Ais CrCg alkyl, wherein the CpCg alkyl is substituted by 3- to 6-membered cycloalkyl (e.g., cyclopropyl). In some embodiments, R4Ais CpCg alkyl, wherein the CrCg alkyl is substituted by 6- to 10-membered aryl (e.g., phenyl).

[0127] In some embodiments, R5Ais CrCg alkyl, C2-C8alkenyl, C2-C8alkynyl, or CrCg haloalkyl, wherein the CrCg alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl. In some embodiments, R5Ais CrCg alkyl. In some embodiments, R5Ais CrCg alkyl, C2-C8alkenyl. In some embodiments, R5Ais C2-C8alkynyl. In some embodiments, R5AisrC6haloalkyl. In some embodiments, R5Ais unsubstituted. In some embodiments, R5Ais CrCg alkyl, wherein the CrCg alkyl is substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl. In some embodiments, R5Ais CrC6alkyl, wherein the C C6alkyl is substituted by 3- to 6-membered cycloalkyl (e.g., cyclopropyl). In some embodiments, R5Ais C C6alkyl, wherein the CrCg alkyl is substituted by 6- to 10-membered aryl (e.g., phenyl).

[0128] In some embodiments, the compound has the structure of Formula (IC):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein n is independently at each occurrence 1 or 2; and R4, Ra, Rp, and X are as defined above for Formula (I).

[0129] In some embodiments, the compound has the structure of Formula (ID):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4, Ra, Rp, and X are as defined above for Formula (I).

[0130] In some embodiments, the compound has the structure of Formula (IE):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R’ and R” are independently H, D, or F, and wherein Ra, Rp, and X are as defined above for Formula (I). In some embodiments, R’ and R” are both H. In some embodiments, R’ and R” are both D. In some embodiments, R’ and R” are both F. In some embodiments, R’ is H and R” is D. In some embodiments, R’ is H and R” is F.

[0131] In embodiments, a disclosed compound comprises a compound of Applicant’s Int’l Application Nos. PCT / US2022 / 041279 (Pub. No. W02023 / 028091A1), PCT / US2022 / 041283 (Pub. No. W02023 / 028092A2), and PCT / US2022 / 044771 (Pub. No. W02023 / 049480A1), each of which is fully incorporated herein by reference, bound to a vitamin B6 promoiety according to various embodiments described herein.

[0132] In embodiments, a disclosed compound comprises any suitable phenylalkylamine, phenethylamine, or tryptamine drug (e.g., a phenylalkylamine, phenethylamine, or tryptamine drug that comprises a primary amine moiety) bound to a vitamin B6 promoiety according to various embodiments described herein. Such compounds include, for example, 2C-x, DOx, Ariadne-type, cathinone, and amphetamine compounds. In some embodiments, the drug is a compound disclosed in PiHKAL (Shulgin & Shulgin. 1992. PiHKAL. A chemical love story, Transform Press, Berkeley, CA). In some embodiments, the drug is a compound disclosed in TiHKAL (Shulgin & Shulgin. 1997. TiHKAL: The Continuation, Transform Press, Berkeley, CA).

[0133] In some embodiments, Ra, Rp, and R4are selected from Table I, and R2, R3, R5, and R6are as defined in Formula (I) or any subformula thereof.Table I. Representative combinations of Ra, Rp, and R4

[0134] In some embodiments, the compound is a compound of Formula (IA) selected from Table IA, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:Table IA. Representative compounds of Formula (IA)

[0135] In some embodiments, the compound is a compound of Formula (IB) selected from Table IB, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:Table IB. Representative compounds of Formula (IB)aCp = cyclopropyl; '’Ph = phenyl.

[0136] In some embodiments, the compound is a compound of Formula (IE) selected from Table IE, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:Table IE. Representative compounds of Formula (IE)

[0137] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0138] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0139] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0140] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0141] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0142] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0143] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0144] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0145] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0146] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0147] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof

[0148] In some embodiments, the compound is selected from the group consisting ofor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0149] Herein, “a single compound of” will mean that the specified compound (e.g., by structural formula or description) is the only disclosed compound in the embodiment, i.e., that a compound, composition, or method consists of, consists essentially of, or comprises no further disclosed compound(s) (i.e., compound(s) having a different structural formula or description). It does not mean the embodiment has only a single molecule or single instance of the specified compound. For instance, embodiments “consisting of a single compound of Formula (I)” will include embodiments of “a compound of Formula (I),” or the use of “a compound of Formula (I),” and such embodiments, as well as embodiments of a composition “consisting essentially of a single compound of Formula (I),” each may comprise for example 5 mg, 10 mg, 50 mg, 100 mg, and other disclosed or known mass amounts or molar amounts of the compound of Formula (I).

[0150] Accordingly, and for example, in some embodiments one or more compounds may be excluded from a claim to a group of compounds, such as a Markush group of compounds, such as “a compound of Formula (I).” In some embodiments, one or more compounds also may be excluded from a claim to a composition consisting essentially of a group of compounds. In some embodiments, one or more compounds also may be excluded from a claim to a composition comprising a group of compounds. In some embodiments, one or more compounds also may be excluded from a claim to a use of a group of compounds. In some embodiments, one or more compounds also may be excluded from a claim to a use of a composition consisting essentially of a group of compounds. In some embodiments, one or more compounds also may be excluded from a claim to a use of a composition comprising a group of compounds. In some embodiments, one or more compounds may be excluded from all claims to a group of compounds.

[0151] In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, but are not excluded from a claim to a use of a group of compounds or compositions thereof. In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, andalso may be excluded from a claim to a composition comprising a group of compounds, but are not excluded from a claim to a use of a group of compounds or compositions thereof.

[0152] In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, but are not excluded from a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds. In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, and also may be excluded from a claim to a use of a group of compounds or compositions consisting essentially thereof, but are not excluded from a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds, or a use of a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds. In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, and also may be excluded from a claim to a use of a group of compounds or compositions consisting essentially thereof, and further may be excluded from a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds, but are not excluded from a claim to a use of a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds.

[0153] The individual compounds of the disclosed compositions will be understood to also encompass pharmaceutically acceptable salts of such compounds. The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, and which may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate,glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc and the like. (See Berge et al. (1977) “Pharmaceutical Salts,” J. Pharm. Sci. 66:1-19.) In embodiments, preferred pharmaceutically acceptable salts employ a hydrochloride anion.

[0154] Generally, the disclosed compounds are administered as part of a pharmaceutical composition or formulation, but will be prepared for inclusion in such composition or formulations as isolated or purified compounds. The terms “isolated,” “purified,” or “substantially pure,” as used herein, refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced. An “isolated,” “purified,” or “substantially pure” preparation of a compound is accordingly defined as a preparation having a chromatographic purity (of the desired compound) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method.

[0155] Preferably the substantially pure compound used in the invention is substantially free of any other active compounds which are not intended to be administered to a subject. In this context “substantially free” can be taken to mean that no active compound(s) other than the active compound intended to be administered to a subject are detectable by HPLC or other similar detection method, or are below a desired threshold of detection such as defined above.

[0156] It should be understood that any reference to a disclosed compound or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, will include all amorphous and polymorphic forms. In the case of solid compositions, in particular, it is understood that the compounds used in the disclosed compositions and methods may exist in different forms. For example, the compounds may exist in stable and metastable crystalline forms, isotropic and amorphous forms, milled forms and nano-particulate forms, all of which are intended to be within the scope of the invention. In addition, disclosed compounds may include crystalline forms, known as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0157] The disclosed compounds now generally described will be more readily understood by reference to the following description and examples, which are included for the purposes of illustration of certain aspects of the embodiments of the present invention. The following is not intended to limit the invention, as one of skill in the art would recognize from the teachings and examples herein that other techniques and methods can satisfy the claims and be employed without departing from the scope of the invention. Indeed, while this invention has been particularly shown and described with reference to certain exemplary embodiments, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope or spirit of the invention encompassed by the appended claims. a. Deuterated and / or Fluorinated Compounds

[0158] In some embodiments, a disclosed compound having deuterium substitution (e.g., a deuteroalkyl group), has a deuterium isotopic purity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%. In some embodiments, the compound has an isotopic purity of at least 50%. In an embodiment, the compound has an isotopic purity of at least 55%. In another embodiment, the compound has an isotopic purity of at least 60%. In yet another embodiment, the compound has an isotopic purity of at least 65%. In another embodiment, the compound has an isotopic purity of at least 70%. In another embodiment, the compound has an isotopic purity of at least 75%. In another embodiment, the compound has an isotopic purity of at least 80%. In another embodiment, the compound has an isotopic purity of at least 85%. In another embodiment, the compound has an isotopic purity of at least 90%. In another embodiment, the compound has an isotopic purity of at least 91 %. In another embodiment, the compound has an isotopic purity of at least 92%. In another embodiment, the compound has an isotopic purity of at least 93%. In another embodiment, the compound has an isotopic purity of at least 94%. In another embodiment, the compound has an isotopic purity of at least 95%. In another embodiment, the compound has an isotopic purity of at least 96%. In another embodiment, the compound has an isotopic purity of at least 97%. In another embodiment, the compound has an isotopic purity of at least 98%. In another embodiment, the compound has an isotopic purity of at least 99%. In another embodiment, the compound has an isotopic purity of at least 99.5%. In another embodiment, the compound has an isotopic purity of at least 99.6%. In another embodiment, the compound has an isotopic purity of at least 99.7%. In another embodiment, the compound has an isotopic purity of at least 99.8%. In another embodiment, the compound has an isotopic purity of at least 99.9%. For such isotopically-labeled molecules, isotopic enrichment may be described as a percentage indicating the percent of isotopic atoms at a particular site on the molecule. The percentage can be referredto as the “isotopic purity” of the isotopically-labeled compound.

[0159] In some embodiments, a disclosed compound having deuterium substitution (e.g., a deuteroalkyl group) is a mixture of the deuterated compound and a corresponding non-deuterated compound (i.e., the corresponding compound wherein none of the hydrogens are substituted by a deuterium, e.g., at no position of the compound will the presence of deuterium be higher than the natural abundance of deuterium isotope). In such mixtures, at least 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100% are deuterium-substituted compounds (wherein the other compounds in such mixtures are the corresponding non-substituted compounds). In an embodiment, at least 1 % of the compounds are deuterium-substituted. In an embodiment, at least 2% of the compounds are deuterium-substituted. In an embodiment, at least 3% of the compounds are deuterium-substituted. In an embodiment, at least 4% of the compounds are deuterium-substituted. In an embodiment, at least 5% of the compounds are deuterium-substituted. In an embodiment, at least 10% of the compounds are deuterium-substituted. In an embodiment, at least 20% of the compounds are deuterium-substituted. In an embodiment, at least 30% of the compounds are deuterium-substituted. In an embodiment, at least 40% of the compounds are deuterium- and / or fluorine- substituted. In an embodiment, at least 50% of the compounds are deuterium-substituted. In an embodiment, at least 60% of the compounds are deuterium-substituted. In an embodiment, at least 70% of the compounds are deuterium-substituted. In an embodiment, at least 80% of the compounds are deuterium-substituted. In an embodiment, at least 90% of the compounds are deuterium-substituted. In an embodiment, at least 95% of the compounds are deuterium-substituted. In an embodiment, at least 96% of the compounds are deuterium-substituted. In an embodiment, at least 97% of the compounds are deuterium-substituted. In an embodiment, at least 98% of the compounds are deuterium-substituted. In an embodiment, at least 99% of the compounds are deuterium- and / or fluorinesubstituted. In an embodiment, at least 99.5% of the compounds are deuterium-substituted. In an embodiment, at least 99.8% of the compounds are deuterium-substituted. In an embodiment, at least 99.9% of the compounds are deuterium-substituted.

[0160] In some embodiments, a disclosed composition comprises a mixture of one or more deuterium-substituted compounds and corresponding non-substituted compounds in a fixed ratio, and will contain a ratio of deuterium-substituted to non-substituted compounds (as mole ratio or mass ratio), including a pharmaceutically acceptable salt, hydrate, or solvate thereof, of 1 :1 , at least 1 :1, at least 1.1 :1 , at least 1.2:1, at least 1.3:1 , at least 1.4:1 , at least 1.5:1 , at least 1.6:1 , at least 1.7:1 , at least 1.8:1 , at least 1.9:1 , at least 2.0:1 , at least 2.5:1 , at least 3.0:1 , at least 4.0:1, at least 5.0:1 , at least 6.0:1 , at least 7.0:1, at least 8.0:1, at least 9.0:1, and at least 10:1 , at least 11 :1 , at least 12:1 , at least 13:1 , at least 14:1 , at least 15:1 , at least 16:1, at least 17:1 , at least 18:1 , at least 19:1 , at least 20:1, at least 25:1 , at least 30:1 , at least 40:1 , at least 50:1, at least 60:1 , at least 70:1 , at least 80:1 , at least 90:1 , and at least 100:1 , including theexact above-listed ratios themselves.

[0161] In some embodiments, a disclosed composition comprises a disclosed compound having fluorine substitution (e.g., a fluoroalkyl group) and corresponding non-substituted compounds in a fixed ratio, and contains a ratio of fluorine-substituted to non-substituted compounds (as mole ratio or mass ratio) of 1 :1 , at least 1 :1, at least 1 .1:1, at least 1.2:1, at least 1.3:1 , at least 1 .4:1, at least 1.5:1 , at least 1.6:1 , at least 1 .7:1, at least 1.8:1 , at least 1.9:1 , at least 2.0:1 , at least 2.5:1 , at least 3.0:1 , at least 4.0:1, at least 5.0:1 , at least 6.0:1 , at least 7.0:1 , at least 8.0:1 , at least 9.0:1 , and at least 10:1, at least 11 :1 , at least 12:1 , at least 13:1 , at least 14:1 , at least 15:1 , at least 16:1 , at least 17:1 , at least 18:1 , at least 19:1 , at least 20:1 , at least 25:1, at least 30:1 , at least 40:1 , at least 50:1 , at least 60:1 , at least 70:1 , at least 80:1 , at least 90:1 , and at least 100:1 , including the exact above-listed ratios themselves. b. Stereoisomers and Enantiomeric Mixtures

[0162] In some embodiments, a disclosed compound may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms.

[0163] Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard tests described herein and other similar tests which are well known in the art. Examples of methods that can be used to obtain optical isomers of the compounds according to the present disclosure include the following: i) physical separation of crystals whereby macroscopic crystals of the individual enantiomers are manually separated. This technique may particularly be used if crystals of the separate enantiomers exist (i.e., the material is a conglomerate), and the crystals are visually distinct; ii) simultaneous crystallization whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis, a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations whereby diastereomers from the racemateequilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomers; viii) kinetic resolutions comprising partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; and xiii) transport across chiral membranes whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0164] In some embodiments, a disclosed compound may be provided in a composition that is not enantiomerically enriched (i.e., a composition comprising the disclosed compound(s) as a racemic mixture). In other embodiments, a disclosed compound may be provided in a composition that is enantiomerically enriched, such as a mixture of enantiomers in which one enantiomer is present in excess, in particular to the extent of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%, and up to (and including) 100%.

[0165] In embodiments, a disclosed compound is provided in a composition enantiomerically enriched with the R-isomer, comprising the R-isomer in enantiomeric excess of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0166] In embodiments, a disclosed compound is provided in a composition enantiomerically enriched with the S-isomer, comprising the S-isomer in enantiomeric excess of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%,at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0167] In some embodiments, a disclosed compound is provided in a composition comprising the R-isomer and the S-isomer in a R:S ratio of about 20:1 to about 1 :20. In some embodiments, the R:S ratio is greater than about 20:1 , or about 20:1 , 15:1 , 12:1 , 10:1 , 9:1, 8:1 , 7:1 , 6:1, 5:1 , 4:1 , 3:1 , or 2:1. In some embodiments, a disclosed compound is provided as the R-isomer in an enantiomerically pure composition. In some embodiments, the R:S ratio is about 1 :1 , 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :12, 1 :15, 1 :20, or greater than about 1 :20. In some embodiments, a disclosed compound is provided as the S-isomer in an enantiomerically pure composition.

[0168] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, tautomeric forms are included. c. Mixtures of Pyridoxal-Amine and Pyridoxal-lmine Prodrugs

[0169] As described below, in some embodiments, disclosed compounds are synthesized according to a reaction sequence that produces an compound of Formula (A),also referred to herein as a “pyridoxal-imine,” wherein R1, R2, R3, R4, R5, R6, Ra, Rp, and X are as defined for Formula (I).

[0170] In some embodiments, pyridoxal-imine compounds of Formula (A) are also useful as prodrugs for phenethylamine psychedelics. In some embodiments, pyridoxal-imine compounds of Formula (A) are used in place of a compound of Formula (I) in any embodiment described herein, such as an embodiment describing a pharmaceutical composition, method of treatment, or use of a compound of Formula (I).

[0171] In some embodiments, the compound of Formula (A) is a compound of Formula (AA), (AA-1), (AA-2), (AA-3), (AA-4), (AA-5), (AA-6), (AA-7), (AB), (AC), (AD), (AE), or a pharmaceutically acceptable salt,wherein R1, R2, R3, R4, R5, R6, Ra, Rp, and X are as defined for Formula (I).

[0172] In some aspects, also provided are mixtures of pyridoxal-imine compounds of Formula (A) and pyridoxal-amine compounds of Formula (I). In some embodiments, a disclosed compound is provided in a composition comprising a pyridoxal-imine of Formula (A) and a pyridoxal-amine compound of Formula (I) in an (A):(l) ratio of about 20:1 to about 1 :20. In some embodiments, the (A):(l) ratio is greater than about 20:1 , or about 20:1 , 15:1 , 12:1 , 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1, 3:1, or 2:1. In some embodiments, a disclosed compound is provided as the compound of Formula (A) in a pure composition. In some embodiments, the(A):(l) ratio is about 1 :1 , 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :12, 1 :15, 1 :20, or greater than about 1 :20. In embodiments, a disclosed compound is provided as the compound of Formula (I) in a pure composition. Exemplary Features of Disclosed Compounds

[0173] In some aspects, features of disclosed compounds provide various advantages. Such advantages may be related to modulation of neurotransmission, pharmacokinetics, such as properties related to absorption, distribution, metabolism, and excretion of a disclosed compound, and subjective effects, such as upon administration to a subject. In some embodiments, such advantages are determined relative to a comparator. In some embodiments, the comparator for a disclosed compound is the corresponding component drug that is not bound to a pyridoxal promoiety.

[0174] For example, in some embodiments wherein the compound of Formula (I) is the compound

[0175] The permeability, such as apparent permeability, of a compound describes how effectively it can pass through a membrane. A medium permeability compound may have an in vitro apparent permeability of 50-150 nm / s, wherein the range is inclusive. A high permeability compound may have an in vitro apparent permeability in excess of 150 nm / s, wherein the range is inclusive. Measures of permeability, such as in vitro methods, are available to one of skill in the art and include, e.g., a Madin-Darby canine kidney cell line (MDCK) permeability assay and a parallel artificial membrane permeation assay (PAMPA). For example, PAMPA is an in vitro model of passive diffusion, which has shown a high degree of correlation with permeation across a variety of barriers, including Caco-2 cultures, the gastrointestinal tract, blood-brain barrier, and skin. See, e.g., Chavda & Shah, Chapter 25 - Self-emulsifying delivery systems: one step ahead in improving solubility of poorly soluble drugs, In Micro and Nano Technologies, Nanostructures for Cancer Therapy, Elsevier, 2017, pages 653-718.

[0176] In some embodiments, a disclosed compound has medium permeability. In some embodiments, a disclosed compound has high permeability. In some embodiments, a disclosed compound has increased permeability relative to its corresponding component drug compound. In some embodiments, a disclosed compound has increased permeability relative to a comparator. In embodiments, permeability of a disclosed compound is increased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200% relative to a comparator.

[0177] In some embodiments, a disclosed compound is actively transported across a barrier (such as a mucosal barrier, e.g., a gastrointestinal (Gl) barrier; or the blood-brain barrier (BBB)). In some embodiments,a disclosed compound is actively transported across the Gl barrier. In some embodiments, a disclosed compound is actively transported across the BBB. Without being bound by theory, the bioavailability of a disclosed compound may higher than a comparator compound, or higher than a phenylalkylamine drug lacking a vitamin B6-derived promoiety as disclosed in embodiments herein, because the disclosed compound may be actively transported across a barrier, whereas the phenylalkylamine drug may only diffuse passively across the same barrier. In some embodiments, a disclosed compound is actively transported by epithelial cells, such as intestinal enterocytes or renal proximal tubular cells. In some embodiments, a disclosed compound is actively transported across a barrier by a transporter (e.g., carrier) protein. In some embodiments, a disclosed compound is actively transported across a barrier by a transporter protein for which vitamin B6 is a substrate. Without being bound by theory, vitamin B6 transporters in humans are still not fully characterized, but may include human solute carriers SLC19A2 and SLC19A3, also known as thiamine transporters (THTR) 1 and 2, and ABC transporters; and may be similar in structure and / or function to transporters that have been characterized for yeasts and plants, which include Tpnlp, Bsu1 , members of the plant purine permease (PUP) family, and Mtmlp (Parra et al. Cells. 2018;7(7):84).

[0178] In some embodiments, a disclosed compound has reduced clearance relative to a comparator. In some embodiments, clearance refers to intrinsic clearance. In some embodiments, pharmacokinetic parameters, including intrinsic clearance and half-life, are determined using an in vitro metabolic stability study comprising human liver microsomes. Methods for assessing metabolic stability, such as in vitro clearance and half-life, are described in, e.g., Gajula et al., Drug Metab Rev. 2021 ;53(3):459-477 and Knights et al., Curr Protoc Pharmacol. 2016;74:7.8.1 -7.8.24. Pharmacokinetic parameters may also be determined in vivo, such as in a human, e.g., according to the paradigm described by Brown et al., Clin Pharmacokinet. 2017;56(12):1543-1554. Additionally, identification of metabolites and interactions with CYP enzymes may be performed as described in, e.g., Caspar et al., Drug Test Anal. 2018; 10(1): 184-195. In some embodiments, the half-life of a disclosed compound is increased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200% relative to the comparator.

[0179] In some embodiments, disclosed compounds are not substrates for monoamine oxidase enzymes. In some embodiments, disclosed compounds do not inhibit the activity of monoamine oxidase enzymes. In some embodiments, disclosed compounds do not irreversibly inhibit the activity of monoamine oxidase enzymes. In some embodiments, disclosed compounds do not reversibly inhibit the activity of monoamine oxidase enzymes. Monoamine oxidase enzymes include isoenzymes MAO-A and MAO-B. In some embodiments, disclosed compounds are not substrates for monoamine oxidase A (MAO-A). In some embodiments, disclosed compounds do not inhibit the activity of MAO-A. In some embodiments, disclosed compounds do not irreversibly inhibit the activity of MAO-A. In some embodiments, disclosed compounds donot reversibly inhibit the activity of MAO-A. In some embodiments, disclosed compounds are not reversible inhibitors of MAO-A (RIMAs). In some embodiments, the IC50of disclosed compounds at MAO-A is greater than 10 pM. Herein, a threshold of greater than or equal to 10 pM (EC50or IC50) may be used to determine an absence of activity. In some embodiments, the MAO enzymes are of mammalian origin. In some embodiments, the MAO enzymes are of human origin.

[0180] In embodiments, disclosed compounds are orally bioavailable. In embodiments, disclosed compounds have an oral bioavailability (%F) of about or at least 50%, 60%, 70%, 80%, or 90%. Bioavailability studies, both in vitro measures and in vivo determinations, are described in, e.g., Kim et al., Pharm Res. 2014; 31 (4): 1002-1014, EP2007397, EP3565550, and US20200009067.

[0181] In some embodiments, a disclosed compound has reduced adverse events relative to a comparator. Examples of adverse events include those related to neurotoxicity, cardiotoxicity, and renal toxicity, among others. In some embodiments, the reduction for at least one adverse event is at least a 5% reduction, at least a 10% reduction, at least a 15% reduction, at least a 25% reduction, at least a 50% reduction, at least a 75% reduction, at least a 90% reduction, at least a 95% reduction, at least a 99% reduction, or a reduction beyond the threshold of measurement, whether determined within-patient or across patients or patient groups, or in a rodent or other suitable animal model, or determined in vitro, in silico, or otherwise measured using a standard such as one known to those of ordinary skill for the determination or quantification of the adverse event(s) in question, such as relating to anxiety, cardiovascular effects such as blood pressure and heart rate, hyperthermia, hyperhidrosis, jaw tightness and bruxism, muscle tightness, psychostimulation, appetite, nausea, concentration, and balance, as well as markers for or correlated with potential neurotoxicity, and including such exemplary tests and procedures that are in silico (e.g., computer analysis or simulation, including by Al, machine learning, or deep learning), in vitro (e.g., biochemical assays, tissue culture), and in vivo (e.g., behavioral assessment; functional observational batteries; tests of motor activity, schedule-controlled operant behavior, neurological function, neurophysiological function, nerve-conduction, evoked-potential; neurochemical, neuroendocrine, or neuropathological measures; EEG; imaging), as well as the use of physiological biomarkers (body temperature; heart rate; respiratory rate; blood oxygenation; systolic blood pressure (SBP); diastolic blood pressure (DBP); mean arterial pressure (MAP); pulse pressure (PP); Continuous Beat-by-Beat Blood Pressure (CNIBP); heart rate variability (HRV); hemodynamic response (HR); glucose; cortisol; serotonin; dopamine; and brain derived neurotrophic factor (BDNF)), and patient assessments.

[0182] In some embodiments, administration of a disclosed compound or composition thereof does not cause a neurotoxic effect, such as in an in vitro assay or upon administration to a subject. In some embodiments, a disclosed compound or composition thereof causes a reduced neurotoxic effect, such as in an in vitro assay or upon administration to a subject. In some embodiments, the reduction of a neurotoxic effect is at least a 5% reduction, at least a 10% reduction, at least a 15% reduction, at least a 25% reduction,at least a 50% reduction, at least a 75% reduction, at least a 90% reduction, or at least a 95% reduction, or at least a 99% reduction, relative to a comparator. In some embodiments, the comparator is the disclosed compound’s corresponding component drug compound.

[0183] In some embodiments, a neurotoxic effect is determined by measuring one or more of: a) oxidative stress and dopamine-based quinones; b) mitochondrial dysfunction; and c) activation of glial cells. In some embodiments, neurotoxicity or a reduction thereof is determined by evaluating mitochondrial dysfunction. Mitochondrial dysfunction may be evaluated by measuring one or more of mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the mitochondrial cytochrome c release, and ADP / ATP ratio. See, e.g., Taghizadeh et al., Free Radic Biol Med. 2016;99: 11-19, in which markers of mitochondrial dysfunction include a significant increase in ROS formation, collapse of MMP, mitochondrial swelling, outer membrane damage, cytochrome c release from the mitochondria, and increased ADP / ATP ratio.

[0184] In some embodiments, neurotoxicity or a reduction thereof is determined by assessing the activation of glial cells. Activation of quiescent glial cells has been described, e.g., by Herndon et al., Toxicological Sciences. 2014; 138(1): 130-138. Reactive astrogliosis can be measured with glial fibrillary acidic protein (GFAP) staining, and microglia reactivity can be visualized by immunostaining complement type 3 receptor (CD11 b). See, e.g., Frau et al., J Neurochem. 2013; 124(1 ):69-78 and Frau et al., Neurotoxicol. 2016;56:127-138. In embodiments, neurotoxicity or a reduction thereof is determined in vitro. In embodiments, neurotoxicity or a reduction thereof is determined in vivo.

[0185] In some embodiments, a subject administered a disclosed compound does not experience serotonin syndrome. In some embodiments, a subject administered a disclosed compound experiences reduced incidence and / or severity of serotonin syndrome, e.g., relative to administration of a comparator compound. Co-administration of agents that increase serotonin levels, such as SERT inhibitors and MAOIs have been shown to potentiate serotonin neuromodulation, a potential complication of which is serotonin syndrome. See, e.g., Izumi et al., Eur J Pharmacol. 2006;532(3):258-64, Nakagawasai et al., Neurotoxicol. 2004;25(1-2):223- 32, and Tadano et al., J Pharmacol Exp Ther. 1989;250(1 ):254-60. Serotonin syndrome ranges in severity from mild to fatal, and clinical presentations include autonomic dysfunction, neuromuscular excitation, and altered mental status, as described in, e.g., Boyer & Shannon, N Engl J Med. 2005;352(11 ):1112-20 and Wang et al., Cleve Clin J Med. 2016 Nov;83(11):810-817.

[0186] In some embodiments, a subject administered a disclosed compound does not experience delirium. In some embodiments, a subject administered a disclosed compound experiences reduced incidence and / or severity of delirium, e.g., relative to administration of a comparator compound. Signs of delirium, such as drug-induced delirium, include disturbances of consciousness, attention, cognition, and perception. The severity of delirium may be assessed using available tools, e.g., the Memorial Delirium Assessment Scale (MDAS) subitems and Karnofsky Performance Status scale (KPS). See, e.g., Boettger et al., J Geriatrics.2014:247042; Carter et al. Drug Saf. 1996; 15(4):291 -301 ; Karlsson, Dement Geriatr Cogn Disord. 1999; 10(5):412-5. Delirium has been described following ingestion of 5-MeO-DALT, e.g., in Jovel et al., J Forensic Sciences. 59(3), 844-846.

[0187] In some embodiments, a disclosed compound does not cause cardiotoxicity following administration to a subject. In some embodiments, reduced severity and / or incidence of cardiotoxicity is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator compound. In some embodiments, disclosed compounds do not cause irregular heartbeat, e.g., tachycardia. In some embodiments, disclosed compounds show reduced inhibition of a cardiac ion channel, such as by at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200% relative to a comparator. In some embodiments, disclosed compounds do not inhibit the function of, such as block, cardiac ion channels. In embodiments, disclosed compounds do not block calcium channel CAV1.2. In embodiments, disclosed compounds do not block potassium channel hERG. In embodiments, disclosed compounds do not block sodium channel NAV1.5. In embodiments, a disclosed compound has an IC50of greater than 10 pM for any one or more of CAV1.2, hERG, and NAV1.5. In embodiments, CAV1.2, hERG, and NAV1.5 are of human origin.

[0188] In some embodiments, a disclosed compound does not cause rhabdomyolysis following administration to a subject. In some embodiments, reduced severity and / or incidence of rhabdomyolysis is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator compound. In some embodiments, disclosed compounds do not cause kidney injury, such as acute kidney injury, following administration to a subject. In some embodiments, reduced severity and / or incidence of kidney injury is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator compound. In embodiments, disclosed compounds do not elevate serum levels of rhabdomyolysis markers and / or kidney injury markers, e.g., muscular enzymes and creatinine phosphokinase. In embodiments, administration of a disclosed compound results in reduced markers of rhabdomyolysis and / or kidney injury, such as reductions by at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200%, relative to a comparator. In embodiments administration of disclosed compounds to a subject does not result in a reduction of any one or more of renal vasoconstriction, intraluminal cast formation, and direct myoglobin toxicity.

[0189] In some embodiments, administering a disclosed compound to a subject causes a psychoactive effect in the subject. In some embodiments, psychoactive effects are assessed using one or more of a Peak Experience Scale (PES), e.g., as described in Reckweg et al., Front Pharmacol. 2021 ;12:760671 , the Mystical Experience Questionnaire (MEQ), the Ego Dissolution Inventory (EDI), the Challenging Experience Questionnaire (CEQ), and the 5-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). In some embodiments, onset and duration of psychoactive effects may be determined by observing and / or interviewing the subject, such as by using a self-report symptom questionnaire, or by asking the subject to document subjective psychoactive effects, i.e., the subject’s experience. In some embodiments, theself-report symptom questionnaire is the Subjective Drug Effects Questionnaire (SDEQ), a 272-item questionnaire measuring perceptual, mood, and somatic changes caused by psychedelics (Katz et al. J Abnorm Psych, 1968;73:1-14). In some embodiments, the self-report symptom questionnaire is the List of Complaints (LC), a 66-item questionnaire that reliably measures physical and general discomfort (see, e.g., Holze et al. 2022. Psychopharmacol, 239:1893-1905). Psychoactive effects and onset and duration of such effects may additionally be determined according to methods known to one of skill in the art.C. Methods of Synthesis

[0190] In some aspects, provided herein are methods of preparing disclosed compounds. In embodiments, compounds of Formula (I) are prepared according to the following general reaction sequence. Briefly, in a first reaction step, a phenethylamine precursor is reacted with a pyridoxal precursor. A condensation reaction between the phenethylamine primary amine (— NH2) and the pyridoxal aldehyde (— COH) reversibly forms the imine compound of Formula (A), along with water (H2O) as a reaction byproduct.

[0191] The imine compound of Formula (A) may be isolated from the reaction mixture. In some embodiments, the compound of Formula (A) can be isolated, purified, and used as a pyridoxal-imine prodrug as described in various embodiments herein.

[0192] Alternatively, the compound of Formula (A) can be used as a synthetic intermediate (with or without being isolated from the reaction mixture) in the synthesis of compounds of Formula (I). In some embodiments, the compound of Formula (A) is reduced with a suitable reducing agent (e.g., NaBH4) to irreversibly form a pyridoxal-amine prodrug of Formula (I):

[0193] In these exemplary reaction schemes, pyridoxal is depicted generically with X being H or PO3H2. The skilled artisan understands that pyridoxal (wherein X is H) or pyridoxal 5'-phosphate (wherein X is PO3H2) can both be used to produce compounds of Formula (A) and Formula (I) according to disclosed methods of synthesis. Moreover, while the reaction schemes above depict exemplary synthetic routes usefulfor the synthesis of compounds of Formula (I), they may also be used to synthesize compounds of Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IA-3), Formula (IA-4), Formula (IA-5), Formula (IA-6), Formula (IA-7), Formula (IB), Formula (IC), or Formula (ID).

[0194] Methods for the condensation of pyridoxal with an amine to form an imine, and the reduction of such an imine to form an amine, are known to those of skill in the art (see, e.g., Araujo de Oliveira, et al. ACS Omega 2022, 7(14), 11678-11687; Day, et al. Mol Pharm. 2011 , 8(1), 297-301 ; Wu, et al. FASEB J. 2011 , 25(7), 2109-2122; Zhang, et al. Proc. Natl. Acad. Sci. USA 1991 , 88(23), 10407-10410; Bowers-Komro, et al. Bioorg. Chem. 1987, 15(3), 224-236).

[0195] Methods for synthesis of the phenethylamine drug compounds described herein as the component drugs of a disclosed prodrug, and any necessary starting materials, are either described in the art or will be readily apparent to the skilled artisan in view of general references well-known in the art (see, e.g., Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed. 1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1-17, Wiley Interscience; Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991 ; “Theilheimer’s Synthetic Methods of Organic Chemistry,” Volumes 1-45, Karger, 1991 ; March, “Advanced Organic Chemistry,” Wiley Interscience, 1991; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995) and may be used to synthesize the disclosed compounds.

[0196] In general, the approaches used for similar compounds (Shulgin & Shulgin. 1992. PiHKAL. A chemical love story, Transform Press, Berkeley CA; Glennon et al. 1986. J. Med. Chem., 29(2), 194-199; Nichols et al. 1991. J. Med. Chem., 34(1), 276-281 ; Kedrowski et al. 2007. Organic Letters, 9(17), 3205-3207; Heravi & Zadsirjan. 2016. Current Organic Synthesis, 13(6), 780-833; Keri et al. 2017. European J. Med. Chem., 138, 1002-1033; Perez-Silanes et al. 2001. J. Heterocyclic Chem, 38(5), 1025-1030; and references therein), such adaptation being that known and understood to those of ordinary skill.C. Pharmaceutical Compositions

[0197] In some aspects, provided herein are compositions, such as pharmaceutical compositions, comprising a disclosed compound, such as a compound of any disclosed Formulae or subformula thereof. “Pharmaceutical compositions” are compositions comprising disclosed compound(s) together in an amount (for example, in a unit dosage form) with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments will not have a single carrier, diluent, or excipient alone, but will include multiple carriers, diluents, and / or excipients. Compositions can be prepared by standard pharmaceutical formulation techniques as disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th ed., Academic Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, N.J.; Pharm. Principles of Solid Dosage Forms (1993), Technomic Pub. Co., Inc., Lancaster, Pa.; and Ansel& Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; & Poznansky et al. Drug Delivery Systems (1980), R.L. Juliano, ed., Oxford, N.Y., pp. 253-315).

[0198] “Pharmaceutically acceptable” used in connection with an excipient, carrier, diluent, or other ingredient means the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with cells of humans and animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk / benefit ratio.

[0199] In some embodiments, pharmaceutical compositions comprising a disclosed compound can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal. In some embodiments, the compounds employed in the methods of this disclosure are effective as oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. (See, e.g., Remington, 2020.)

[0200] The disclosed compositions are preferably formulated in a unit dosage form, each dosage containing a therapeutically effective amount of the active ingredients, for example in the dosage amounts disclosed below. The term “unit dosage form” refers to a physically discrete unit suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect(s), in association with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are often used for ease of administration and uniformity of dosage. Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof (e.g., one half a “full” dose for a “booster” dose as described below), of the pharmaceutical composition administered.

[0201] Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Unit dosage forms also include ampules and vials with liquid compositions disposed therein. Unit dosage forms further include compounds for transdermal administration, such as “patches” that contact the epidermis (including the mucosa) of a subject for an extended or brief period of time.

[0202] In some embodiments, the disclosed compositions are formulated in a pharmaceutically acceptable oral dosage form. Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like) and oral solid dosage forms. The disclosed pharmaceutical compositions also may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0203] In some embodiments, a disclosed composition is formulated as an oral solid dosage form. Oralsolid dosage forms may include but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combinations thereof. Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations. Accordingly, in some embodiments, the disclosed oral solid dosage forms may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-melt tablet. Additionally, pharmaceutical formulations may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.

[0204] Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof. Oral solid dosage forms also can comprise one or more pharmaceutically acceptable additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).

[0205] Supplementary active compounds include preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents. Preservatives can be used to inhibit microbial growth or increase stability of the active ingredient thereby prolonging the shelf life of the formulation. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate. Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as alpha lipoic acid.

[0206] In some embodiments, a disclosed composition is formulated as an oral liquid dosage form. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients. Solvents may be, for example, water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.

[0207] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. Liquid formulations also may be prepared as single dose or multi-dose beverages. Suspensions may include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include carrier oils such as MCT and long chain triglyceride (LCT) oils. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations may include alcohols, (such as ethanol, isopropyl alcohol, hexadecyl alcohol), glycerol, and propylene glycol. Ethers, such as polyethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations. Suspension can thus include an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion, or a water-in-oil emulsion.

[0208] In some embodiments, formulations are provided comprising the disclosed compositions and at least one dispersing agent or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained. The aqueous dispersion can comprise amorphous and non-amorphous particles consisting of multiple effective particle sizes such that a drug is absorbed in a controlled manner over time.

[0209] Dosage forms for oral administration can be aqueous suspensions selected from the group including pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, e.g., Singh et al., Encyclopedia of Pharm. Tech., 2nd Ed., 754-757 (2002). In addition to the disclosed compounds, the liquid dosage forms may comprise additives, such as one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, or (g) flavoring agents.

[0210] Disclosed compositions also may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0211] In other embodiments, disclosed pharmaceutical compositions may be formulated into a topical dosage form. Topical dosage forms include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. For such formulations, penetrants and carriers can be included in the pharmaceutical composition. Penetrants are known in the art, and include, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. For transdermal administration, carriers which may be used include Vaseline®, lanolin, PEG, alcohols, transdermal enhancers, and combinations thereof.D. Pharmaceutical Combinations

[0212] It should be readily appreciated that the disclosed compositions are not limited to combinations of a single compound, or (when formulated as a pharmaceutical composition) limited to a single carrier, diluent, and / or excipient alone, but may also include combinations of multiple compounds (including additional active compounds), and / or multiple carriers, diluents, and excipients. Pharmaceutical compositions of this disclosure thus may comprise a disclosed compound together with one or more other active agents (or their derivatives and analogs) in combination, together with one or more pharmaceutically-acceptable carriers, diluents, and / or excipients, and additionally with one or more other active compounds.

[0213] In some embodiments, a formulation of the disclosure will be prepared so as to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects.

[0214] “Therapeutic effects” that may be increased or added in embodiments of the disclosure include, but are not limited to, antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, and stimulant effects.

[0215] “Synergistic effects” should be understood to include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect, that are greater than the additive contributions of the components acting alone. Numerous methods known to those of skill in the art exist to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby producing “1 +1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol. 2019; 10:1222), or the equation of Loewe additivity (Loewe & Muischnek, Arch Exp Pathol Pharmacol. 1926; 114: 313-326). A synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, Clin Pharmacokinet. 1981 ;6: 429-453) and the median-effect equation (Chou & Talalay, Adv Enzyme Regul. 1984;22:27-55). The corresponding graphs associated with the equations referred to above are the concentration-effect curve and combination index curve, respectively. Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.

[0216] In some embodiments, a disclosed pharmaceutical composition comprises an additional active compound. In some embodiments, the additional active compound is selected from the group consisting of: amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives,cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents (e.g., psychoplastogens), monoamine oxidase inhibitors, tryptamines, terpenes, phenylalkylamines, sedatives, stimulants, serotonergic agents, and vitamins. In some embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, increase plasticity (e.g., neural plasticity), or alter pharmacokinetics or pharmacodynamics. In some embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

[0217] In embodiments, an additional active compound is a tryptamine. As will be understood by those in the art, tryptamines are compounds having the general structure below, wherein RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7are as defined herein and as generally understood in the art:

[0218] In some embodiments, RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7are each independently hydrogen, deuterium, halogen (F, Cl, Br, or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Additionally, any two of RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7and the intervening atoms can be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In embodiments, the tryptamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0219] In some embodiments, the additional active compound is a tryptamine selected from the group consisting of O-Phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 6-allyl-N,N-diethyl- norlysergamide (AL-LAD), N,N-dibutyltryptamine (DBT), N,N-diethyltryptamine (DET), N,N-diisopropyl- tryptamine (DiPT), 5-methoxy-a-methyltryptamine (a,O-DMS), N,N-dimethyl-tryptamine (DMT),2,a-dimethyltryptamine (2,a-DMT), a,N-dimethyltryptamine (a,N-DMT), N,N-dipropyltryptamine (DPT), N-ethyl-N-isopropyltryptamine (EiPT), a-ethyltryptamine (AET), 6,N,N-triethylnorlysergamide (ETH-LAD), 3,4-dihydro-7-methoxy-1- methylcarboline (Harmaline), 7-methoxy-1 -methylcarboline (Harmine), N,N-dibutyl-4-hydroxy-tryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl-4-hydroxytryptamine (4-HO-DiPT), 4-hydroxy-N,N,N-trimethyltryptamine (4-HO-TMT), N,N-dimethyl-4-hydroxytryptamine (4-HO-DMT), N,N-dimethyl-5-hydroxytryptamine (5-HO-DMT, bufotenine), N,N-dipropyl-4-hydroxytryptamine (4-HO-DPT), N-ethyl-4-hydroxy- N-methyltryptamine (4-HO-MET),4-hydroxy-N-isopropyl-N-methyltryptamine (4-HO-MiPT), 4-hydroxy-N-methyl-N-propyl-tryptamine(4-HO-MPT), 4-hydroxy-N,N-tetramethylene- tryptamine (4-HO-pyr-T), 12-methoxyibogamine (Ibogaine), N-butyl-N-methyltryptamine (MBT), N,N-diisopropyl-4,5-methylenedioxytryptamine (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylenedioxytryptamine (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxy- tryptamine (4,5-MDO-DMT), N,N-dimethyl-5,6-methylenedioxytryptamine (5,6-MDO-DMT), N-isopropyl- N-methyl-5,6-methylenedioxytryptamine (5,6-MDO-MiPT), N,N-diethyl-2-methyltryptamine (2-Me-DET), 2,N,N-trimethyltryptamine (2-Me-DMT), N-acetyl-5-methoxytryptamine (melatonin), N,N-diethyl-5-methoxytryptamine (5-MeO-DET), N,N-diisopropyl-5-methoxy-tryptamine (5-MeO-DiPT), N,N,diallyl- 5-methoxytryptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-isopropyl-4-methoxy-N-methyltryptamine (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyltryptamine (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyltryptamine (5,6-MeO-MiPT), 5-methoxy-N-methyl-tryptamine (5-MeO-NMT), 5-methoxy-N,N-tetramethylenetryptamine (5-MeO-pyr-T), 6-methoxy-1 -methyl-1 ,2,3,4-tetra- hydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl-tryptamine (5-MeO-TMT), N,N-dimethyl-5-methylthiotryptamine (5-MeS-DMT), N-isopropyl-N-methyltryptamine (MiPT), a-methyltryptamine (a-MT), N-ethyltryptamine (NET), N-methyltryptamine (NMT), 6-propylnorlysergamide (PRO-LAD), N,N-tetra- methylenetryptamine (pyr-T), tryptamine (T), 7-methoxy-1 -methyl-1, 2, 3, 4-tetrahydrocarboline (THH), or a,N-dimethyl-5-methoxytryptamine (a,N,O-TMS), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.

[0220] In some embodiments, an additional tryptamine will be a “complex tryptamine” or other indolamine and including such examples as iboga alkaloids such as ibogaine, and their analogs, metabolites, and derivatives, and beta-carbolines.

[0221] In some embodiments, the additional active compound is a phenylalkylamine. In some embodiments, and as will be understood by those in the art, a phenylalkylamine may be a phenylalkylamine having the structure of Formula (A), wherein RN1, RN2, Ra, Rp, and each of R2-R6are as defined herein and as generally understood in the art.

[0222] In some embodiments, the additional active compound is a phenylalkylamine selected from the group consisting of a-ethyl-3,4,5-trimethoxy-phenethylamine (AEM), 4-allyloxy-3,5-dimethoxy- phenethylamine (AL), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH), 2,5-dimethoxy-4-ethylthio-amphetamine (ALEPH-2), 2,5-dimethoxy-4-isopropylthioamphetamine (ALEPH-4), 2,5-dimethoxy-4-phenyl- thioamphetamine (ALEPH-6), 2,5-dimethoxy-4-propylthioamphetamine (ALEPH-7), 2,5-dimethoxy- a-ethyl-4-methylphenethylamine (ARIADNE), 3,4-diethoxy-5-methoxy-phenethylamine (ASB), 4-butoxy-3,5- dimethoxyphenethylamine (B), 2,5-dimethoxy-4,N-dimethylamphetamine (BEATRICE), 2,5-bismethylthio-4- methylamphetamine (BIS-TOM), 4-bromo-2,5,B-trimethoxyphenethylamine (BOB), 2,5,B-trimethoxy-4- methylphenethylamine (BOD), B-methoxy-3,4-methylenedioxyphenethylamine (BOH), 2,5-dimethoxy-B- hydroxy-4-methylphenethylamine (BOHD), 3,4,5,B-tetramethoxyphenethylamine (BOM), 4-bromo-3,5- dimethoxyamphetamine (4-Br-3,5-DMA), 2-bromo-4,5-methylenedioxyamphetamine (2-Br-4,5-MDA),3.4-methylenedioxy-N-ethylamphetamine (MDEA), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-benzyloxy-3,5-dimethoxy- amphetamine (3C-BZ), 4-chloro-2,5-dimethoxyphenethylamine (2C-C),2.5-di methoxy- 4-methyl-phenethylamine (2C-D), 2,5-dimethoxy-4-ethyl-phenethylamine (2C-E),3.5-dimethoxy-4-ethoxyamphetamine (3C-E), 2,5-dimethoxy-4-fluorophenethylamine (2C-F),2.5-dimethoxy-3,4-dimethylphenethylamine (2C-G), 2,5-dimethoxy-3,4-trimethylene- phenethylamine (2C-G-3), 2,5-dimethoxy-3,4-tetramethylenephenethylamine (2C-G-4), 3,4-norbornyl-2,5-dimethoxy- phenethylamine (2C-G-5), 1 ,4-dimethoxynaphthyl-2-ethylamine (2C-G-N), 2,5-dimethoxyphenethylamine (2C-H), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), 2,5-dimethoxy-4-nitro-phenethylamine (2C-N),2.5-dimethoxy-4-isopropoxyphenethylamine (2C-O-4), 2,5-dimethoxy-4-propylphenethylamine (2C-P), 4-cyclopropylmethoxy- 3,5-dimethoxyphenethylamine (CPM), 2,5-dimethoxy-4-methylselenophenethylamine (2C-SE), 2,5-dimethoxy-4-methylthiophenethylamine (2C-T), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,6-dimethoxy-4- isopropylthiophenethylamine (psi-2C-T-4), 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), 4-cyclopropylmethylthio-2,5-dimethoxyphenethylamine (2C-T-8), 4-(t)-butylthio-2,5-dimethoxy- phenethylamine (2C-T-9), 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine (2C-T-13), 4-cyclopropylthio-2, 5-dimethoxyp henethylami ne (2C-T-15), 4-(s)-butylthio-2, 5- dimethoxyphenethylamine (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine (2C-T-21), 3,5-dimethoxy-4-trideuteromethyl- phenethylamine (4-D), B,B-dideutero-3,4,5-trimethoxyphenethylamine (B-D), 3,5-dimethoxy-4-methyl- phenethylamine (DESOXY), 2,4-dimethoxyamphetamine (2,4-DMA), 2,5-dimethoxyamphetamine (2,5-DMA),3.4-dimethoxyamphetamine (3,4-DMA), 2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine (DMCPA),3.4-dimethoxy-B-hydroxyphenethylamine (DME), 2,5-dimethoxy-3,4- methylenedioxyamphetamine (DMMDA), 2,3-dimethoxy-4,5-methylenedioxyamphetamine (DMMDA-2), 3,4-dimethoxyphenethylamine (DMPEA), 4-amyl-2,5-dimethoxyamphetamine (DOAM), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-butyl-2,5-dimethoxyamphetamine (DOBU), 4-chloro-2,5-dimethoxyamphetamine (DOC), 2,5-dimethoxy-4- (2-fluoroethyl)amphetamine (DOEF), 2,5-dimethoxy-4-ethylamphetamine (DOET), 4-iodo-2,5- dimethoxyamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM (STP)),2.6-dimethoxy-4-methylamphetamine (psi-DOM), 2,5-dimethoxy-4-nitroamphetamine (DON),2,5-dimethoxy-4-propylamphetamine (DOPR), 3,5-dimethoxy-4-ethoxyphenethylamine (E), 2,4,5-triethoxyamphetamine (EEE), 2,4-diethoxy-5-methoxyamphetamine (EEM), 2,5-diethoxy-4-methoxyamphetamine (EME),4.5-dimethoxy-2-ethoxyamphetamine (EMM), 2-ethylamino-1-(3,4-methylenedioxyphenyl)butane (ETHYL-J), 2-ethyl ami no-1 -(3,4- methylenedioxyphenyl)pentane (ETHYL-K), 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3- dihydrobenzofuran (F-2), 6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran (F-22), N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine (FLEA), 2,5-dimethoxy-3,4-(trimethylene) amphetamine (G-3), 2,5-dimethoxy-3,4-(tetramethylene)amphetamine (G-4), 3,6-dimethoxy-4-(2-amino- propyl)benzonorbornane (G-5), 2,5-dimethoxy-3,4-dimethyl-amphetamine (GANESHA), 1 ,4-dimethoxy- naphthyl-2-isopropylamine (G-N), 2,5-dimethoxy-4- ethylthio-N-hydroxyphenethylamine (HOT-2),2.5-dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine (HOT-7), 4-(s)-butylthio-2,5-dimethoxy-N-hydroxy- phenethylamine (HOT-17), 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA), 2,3,4-trimethoxy- phenethylamine (IM), 3,5-dimethoxy-4-isopropoxyphenethylamine (IP), 5-ethoxy-2-methoxy-4-methyl- amphetamine (IRIS), 2-amino-1-(3,4-methylenedioxyphenyl)butane (J, BDB), 3-methoxy-4,5-methylene- dioxyphenethylamine (LOPHOPHINE), 3,4,5-trimethoxyphenethylamine (M), 4-methoxyamphetamine (4-MA, PMA), 2,N-dimethyl-4,5-methylenedioxyamphetamine (MADAM-6), 3,5-dimethoxy-4-methallyloxy- phenethylamine (MAL), 3,4-methylenedioxyamphetamine (MDA), N-allyl-3,4-methylenedioxyamphetamine (MDAL), N-butyl-3,4-methylenedioxyamphetamine (MDBU), N-benzyl-3,4-methylenedioxy-amphetamine (MDBZ), N-cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM), N,N-dimethyl-3,4-methylene- dioxyamphetamine (MDDM), N-ethyl-3,4-methylenedioxy-amphetamine (MDE), N-(2-hydroxyethyl)-3,4-methylenedioxyamphetamine (MDHOET), N-isopropyl-3,4-methylenedioxy- amphetamine (MDIP), N-methyl-3,4-methylenedioxyamphetamine (MDMA), 3,4-ethylenedioxy-N-methyl- amphetamine (MDMC), N-methoxy-3,4-methylenedioxyamphetamine (MDMEO), N-(2-methoxyethyl)-3,4- methylenedioxyamphetamine (MDMEOET), 3,4-methylenedioxy-a,a,N-trimethylphenethylamine (MDMP), N-hydroxy-3,4- methylenedioxyamphetamine (MDOH), 3,4-methylenedioxyphenethylamine (MDPEA), a,a-dimethyl-3,4-methylenedioxyphenethylamine (MDPH), 3,4-methylenedioxy-N-propargyl- amphetamine (MDPL), 3,4-methylenedioxy-N-propyl-amphetamine (MDPR), 3,4-dimethoxy- 5-ethoxyphenethylamine (ME), 4,5-ethylenedioxy-3-methoxyamphetamine (MEDA), 4,5-diethoxy-2-methoxyamphetamine (MEE),2.5-dimethoxy-4-ethoxyamphetamine (MEM), 4-ethoxy-3-methoxyphenethylamine (MEPEA),5-bromo-2,4-dimethoxyamphetamine (META-DOB), 2,4-dimethoxy-5-methylthioamphetamine (META-DOT),2.5-di methoxy- N-methylamphetamine (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methylamphetamine (METHYL-DOB), 2-methylamino-1-(3,4-methylenedioxyphenyl)butane (METHYL-J, MBDB),2-methylamino-1-(3,4-methylenedioxyphenyl)pentane (METHYL-K), 4-methoxy-N-methyl- amphetamine (METHYL-MA, PMMA), 2-methoxy-N-methyl-4,5-methylenedioxyamphetamine (METHYL-MMDA-2),3-methoxy-4,5-methylenedioxyamphetamine (MMDA), 2-methoxy- 4,5-methylenedioxyamphetamine (MMDA-2), 2-methoxy-3,4-methylenedioxyamphetamine (MMDA-3a), 4-methoxy-2,3-methylenedioxy-amphetamine (MMDA-3b), 2,4-dimethoxy-5-ethoxyamphetamine (MME), 3,4-dimethoxy-5-(n)- propoxyphenethylamine (MP), 2,5-dimethoxy-4-(n)-propoxyamphetamine (MPM), 4,5-dimethoxy-2- methylthioamphetamine (ORTHO-DOT), 3,5-dimethoxy-4-propoxyphenethylamine (P), 3,5-dimethoxy-4- phenethyloxyphenethylamine (PE), phenethylamine (PEA), 3,5-dimethoxy-4-(2-propynyloxy) phenethylamine (PROPYNYL), 3,5-diethoxy-4-methoxyphenethylamine (SB), 2,3,4,5-tetra- methoxyamphetamine (TA), 4-ethoxy-3-ethylthio-5-methoxyphenethylamine (3-TASB),3-ethoxy-4-ethylthio-5-methoxyphenethylamine (4-TASB), 3,4-diethoxy-5-methylthio- phenethylamine (5-TASB), 4-(n)-butylthio-3,5-dimethoxyphenethylamine (TB), 4-ethoxy-5-methoxy-3-methylthio- phenethylamine (3-TE), 3,5-dimethoxy-4-ethylthiophenethylamine (TE, 4-TE), 3,4-dimethoxy-2- methylthiophenethylamine (2-TIM), 2,4-dimethoxy-3-methylthio- phenethylamine (3-TIM), 2,3-dimethoxy-4-methylthiophenethylamine (4-TIM), 3,4-dimethoxy- 5-methylthiophenethylamine (3-TM), 3,5-dimethoxy-4-methylthiophenethylamine (4-TM), 3,4,5-trimethoxyamphetamine (TMA), 2,4,5-trimethoxy- amphetamine (TMA-2), 2,3,4-trimethoxyamphetamine (TMA-3), 2,3,5-trimethoxyamphetamine (TMA-4), 2,3,6-trimethoxyamphetamine (TMA-5), 2,4,6-trimethoxyamphetamine (TMA-6), 4,5-dimethoxy-3-ethylthio- phenethylamine (3-TME), 3-ethoxy-5-methoxy-4-methylthiophenethylamine (4-TME), 3-ethoxy-4-methoxy- 5-methylthiophenethylamine (5-TME), 3,4-methylenedioxy-2-methylthioamphetamine (2T-MMDA-3a), 2-methoxy-4,5-methylene- thiooxyamphetamine (4T-MMDA-2), 2,4,5-trimethoxyphenethylamine (TMPEA),4-ethyl-5-methoxy-2-methylthioamphetamine (2-TOET), 4-ethyl-2-methoxy-5-methylthio- amphetamine (5-TOET), 5-methoxy-4-methyl-2-methylthioamphetamine (2-TOM), 2-methoxy-4-methyl-5-methylthio- amphetamine (5-TOM), 2-methoxy-4-methyl-5-methylsulfinylamphetamine (TOMSO), 3,5-dimethoxy-4- propylthiophenethylamine (TP), 3,4,5-triethoxyphenethylamine (TRIS), 3-ethoxy-5-ethylthio-4-methoxy- phenethylamine (3-TSB), 3,5-diethoxy-4-methylthiophenethylamine (4-TSB), 3,4-diethoxy-5-ethylthio- phenethylamine (3-T-TRIS), 3,5-diethoxy-4-ethylthiophenethylamine (4-T-TRIS), (R)-2,5-dimethoxy-4-iodo- amphetamine (R-DOI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.

[0223] In some embodiments, the additional active compound is an ergoline. In embodiments, the additional active compound is an ergot alkaloid. In embodiments, the additional active compound is a lysergamide. As will be understood by those in the art, lysergamides are compounds having the general structure below, wherein RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are as defined herein and as generally understood in the art:

[0224] In some embodiments, RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are each independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Additionally, any two of RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14and the intervening atoms can be taken together to form an optionally substituted optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In embodiments, the lysergamide is a quaternary salt, in which an additional R6Ais connected to the nitrogen to which R6is bound; wherein R6Ais optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0225] In some embodiments, the additional active compound is a lysergamide selected from the group consisting of lysergic acid diethylamide (i.e., LSD, LSD-25, LAD, Delysid), 6-ethyl-6-nor-lysergic acid diethylamide (ETH-LAD), 6-propynyl-6-nor-lysergic acid diethylamide (PARGY-LAD), 6-allyl-6-nor-lysergic acid diethylamide (AL-LAD), 6-propyl-6-nor-lysergic acid diethylamide (PRO-LAD), 6-isopropyl-6-nor-lysergic acid diethylamide (IP-LAD), 6-cylopropyl-6-nor-lysergic acid diethylamide (CIP-LAD), 6-butyl-6-nor-lysergic acid diethylamide (BU-LAD), 6-(2-fluoroethyl)-6-nor-lysergic acid diethylamide (FLUOROETH-LAD), 1 -acetyl-lysergic acid diethylamide (i.e., ALD, ALD-52, N-acetyl-LSD), 1 -propionyl-lysergic acid diethylamide (1 P-LSD), 1 -butyryl-lysergic acid diethylamide (1 B-LSD), 1 -valeryl-lysergic acid diethylamide (1V-LSD), 1 -(cyclopropyl- methanoyl)-lysergic acid diethylamide (1cP-LSD), 1-(1 ,2-dimethylcyclobutane- 1-carbonyl)-lysergic acid diethylamide (1 D-LSD), 1-propionyl-6-allyl-6-nor-lysergic acid diethylamide (1 P-AL-LAD), 1-(cyclopropylmethanoyl)-6-allyl-6-nor-lysergic acid diethylamide (1cP-AL-LAD), 1-propionyl- 6-ethyl-6-nor-lysergic acid diethylamide (1 P-ETH-LAD), lysergic acid 2,4-dimethylazetidide (i.e., LA-SS-Az, LSZ), lysergic acid piperidide (LSD-Pip), and lysergic acid methylisopropyl amide (MIPLA).

[0226] Other tryptamines, phenylalkylamines, and lysergamides useful as additional active compounds for purposes of the disclosure and thus contemplated for inclusion therein will be as generally known in the art(see, e.g., Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997); Grob & Grigsby, Handbook of Medical Hallucinogens, 2021 ; Luethi & Liechti, Arch Toxicol. 2020; 94, 1085-1133; Nichols, Pharmacol Reviews, 2016;68(2):264-355; Glennon, Pharmacol Biochem & Behav. 1999;64:251-256; each of which is incorporated by reference as if fully set forth herein).E. Dose and Dosage

[0227] In some embodiments, pharmaceutical compositions comprise a therapeutically effective amount or an effective amount of a disclosed compound, such as for administration to a subject. Administration of pharmaceutical compositions in a “therapeutically effective amount,” or an “effective amount” to a subject means administration of an amount of composition sufficient to achieve the desired effect. When an “effective amount” means an amount effective in treating the stated disorder or symptoms in a subject, “therapeutic effect” would be understood to mean the responses(s) in a subject after treatment that are judged to be desirable and beneficial. Hence, depending on the mental health disorder to be treated, or improvement in mental health or functioning sought, and depending on the particular constituent(s) in the disclosed compositions under consideration, those responses shall differ, but would be readily understood by those of ordinary skill, through an understanding of the disclosure herein and the general knowledge of the art (e.g., by reference to the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for the stated disorder).

[0228] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, as well as amounts within these ranges.

[0229] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient) between about 0.01 mg / kg and 0.1 mg / kg, such as about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg about 0.08 mg / kg about 0.09 mg / kg, and about 0.1 mg / kg, as well as ranges between these values. In some embodiments, a single dose is between about 0.1 mg / kg and 1.0 mg / kg, such as about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg about 0.8mg / kg about 0.9 mg / kg, and about 1 .0 mg / kg, as well as ranges between these values.

[0230] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, as well as amounts within these ranges.

[0231] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) between about 0.1 mg and 1.0 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, and about 1.0 mg, as well as ranges between these values. In embodiments, a single dose is between about 1 mg and 10 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg, as well as ranges between these values. In some embodiments, a single dose is between about 10 mg and 100 mg.

[0232] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a microgram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 pg / kg or less (including a dose of 0.10 pg / kg or less, 0.05 pg / kg or less, and 0.01 pg / kg or less), at least 0.50 pg / kg, at least 0.55 pg / kg, at least 0.60 pg / kg, at least 0.65 pg / kg, at least 0.70 pg / kg, at least 0.75 pg / kg, at least 0.80 pg / kg, at least 0.85 pg / kg, at least 0.90 pg / kg, at least 0.95 pg / kg, at least 1.0 pg / kg, at least 1.1 pg / kg, at least 1.2 pg / kg, at least 1.3 pg / kg, at least 1.4 pg / kg, at least 1 .5 pg / kg, at least 1 .6 pg / kg, at least 1 .7 pg / kg, at least 1 .8 pg / kg, at least 1.9 pg / kg, at least 2.0 pg / kg, at least 2.1 pg / kg, at least 2.2 pg / kg, at least 2.3 pg / kg, at least 2.4 pg / kg, at least 2.5 pg / kg, at least 2.6 pg / kg, at least 2.7 pg / kg, at least 2.8 pg / kg, at least 2.9 pg / kg, or at least 3.0 pg / kg, as well as amounts within these ranges.

[0233] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a microgram dosage amount calculated based on the kilogram weight of the patient) between about 0.01 pg / kg and 0.1 pg / kg, such as about 0.01 pg / kg, about 0.02 pg / kg, about 0.03 pg / kg, about 0.04 pg / kg, about 0.05 pg / kg, about 0.06 pg / kg, about 0.07 pg / kg about 0.08 pg / kg about 0.09 pg / kg, and about 0.1 pg / kg, as well as ranges between these values. In some embodiments, a single dose is between about 0.1 pg / kg and 3.0 pg / kg, such as about 0.1 pg / kg, about 0.2pg / kg, about 0.3 pg / kg, about 0.4 pg / kg, about 0.5 pg / kg, about 0.6 pg / kg, about 0.7 pg / kg about 0.8 pg / kg about 0.9 pg / kg, about 1.0 pg / kg, about 1.2 pg / kg, about 1.4 pg / kg, about 1.6 pg / kg, about 1.8 pg / kg, about 2.0 pg / kg, about 2.2 pg / kg, about 2.4 pg / kg, about 2.6 pg / kg, about 2.8 pg / kg, about 3.0 pg / kg, as well as ranges between these values.

[0234] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 pg or less (including a dose of 10 pg or less, 5 pg or less, and 1 pg or less), from about 25 to 1000 pg, 50 to 1000 pg, 100 to 1000 pg, 200 to 1000 pg, 300 to 1000 pg, 400 to 1000 pg, 500 to 1000 pg, or greater than 1000 pg.

[0235] In some embodiments, where a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenylalkylamine or tryptamine, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, as well as amounts within these ranges.

[0236] In some embodiments, where a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenylalkylamine or a tryptamine, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, as well as amounts within these ranges.

[0237] In some embodiments, a dose of a disclosed compound is in the range of about 1 mg to about 100 mg. For example, the dose may be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about100 mg. In some embodiments, a dose of a disclosed compound is between about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 30 mg. In some embodiments, a dose of a disclosed compound is about 1 mg, about 10 mg, or about 25 mg. In some embodiments, a dose of a disclosed compound is in the range of about 0.001 mg to about 1 g.ln some embodiments, a dose of a disclosed compound is in the range of about 100 mg to about 250 mg. In some embodiments, a dose of a disclosed compound is about 25 mg.

[0238] In some embodiments, a disclosed compound is administered daily. In embodiments, a disclosed compound is administered twice a day. In embodiments, a disclosed compound is administered three times a day. In embodiments, a disclosed compound is administered every other day. In embodiments, a disclosed compound is administered every third day. In embodiments, a disclosed compound is administered every fourth day. In embodiments, a disclosed compound is administered every fifth day. In embodiments, a disclosed compound is administered weekly. In embodiments, a disclosed compound is administered every other week. In embodiments, a disclosed compound is administered every third week. In embodiments, a disclosed compound is administered monthly.

[0239] In some embodiments, about 50 mg of a disclosed compound is administered daily. In some embodiments, about 50 mg of a disclosed compound is administered twice a day. In some embodiments, about 50 mg of a disclosed compound is administered three times a day. In some embodiments, about 50 mg of a disclosed compound is administered every other day. In some embodiments, about 50 mg of a disclosed compound is administered every third day. In some embodiments, about 50 mg of a disclosed compound is administered every fourth day. In some embodiments, about 50 mg of a disclosed compound is administered every fifth day. In some embodiments, about 50 mg of a disclosed compound is administered weekly. In some embodiments, about 50 mg of a disclosed compound is administered every other week. In some embodiments, about 50 mg of a disclosed compound is administered every third week. In some embodiments, about 50 mg of a disclosed compound is administered monthly.

[0240] In some embodiments, about 100 mg of a disclosed compound is administered daily. In some embodiments, about 100 mg of a disclosed compound is administered twice a day. In some embodiments, about 100 mg of a disclosed compound is administered three times a day. In some embodiments, about 100 mg of a disclosed compound is administered every other day. In some embodiments, about 100 mg of a disclosed compound is administered every third day. In some embodiments, about 100 mg of a disclosed compound is administered every fourth day. In some embodiments, about 100 mg of a disclosed compound is administered every fifth day. In some embodiments, about 100 mg of a disclosed compound is administered weekly. In some embodiments, about 100 mg of a disclosed compound is administered every other week. In some embodiments, about 100 mg of a disclosed compound is administered every third week. In some embodiments, about 100 mg of a disclosed compound is administered monthly.

[0241] In some embodiments, about 150 mg of a disclosed compound is administered daily. In someembodiments, about 150 mg of a disclosed compound is administered twice a day. In some embodiments, about 150 mg of a disclosed compound is administered three times a day. In some embodiments, about 150 mg of a disclosed compound is administered every other day. In some embodiments, about 150 mg of a disclosed compound is administered every third day. In some embodiments, about 150 mg of a disclosed compound is administered every fourth day. In some embodiments, about 150 mg of a disclosed compound is administered every fifth day. In some embodiments, about 150 mg of a disclosed compound is administered weekly. In some embodiments, about 150 mg of a disclosed compound is administered every other week. In some embodiments, about 150 mg of a disclosed compound is administered every third week. In some embodiments, about 150 mg of a disclosed compound is administered monthly.

[0242] In some embodiments, about 200 mg of a disclosed compound is administered daily. In some embodiments, about 200 mg of a disclosed compound is administered twice a day. In some embodiments, about 200 mg of a disclosed compound is administered three times a day. In some embodiments, about 200 mg of a disclosed compound is administered every other day. In some embodiments, about 200 mg of a disclosed compound is administered every third day. In some embodiments, about 200 mg of a disclosed compound is administered every fourth day. In some embodiments, about 200 mg of a disclosed compound is administered every fifth day. In some embodiments, about 200 mg of a disclosed compound is administered weekly. In some embodiments, about 200 mg of a disclosed compound is administered every other week. In some embodiments, about 200 mg of a disclosed compound is administered every third week. In some embodiments, about 200 mg of a disclosed compound is administered monthly.

[0243] In some embodiments, about 250 mg of a disclosed compound is administered daily. In some embodiments, about 250 mg of a disclosed compound is administered twice a day. In some embodiments, about 250 mg of a disclosed compound is administered three times a day. In some embodiments, about 250 mg of a disclosed compound is administered every other day. In some embodiments, about 250 mg of a disclosed compound is administered every third day. In some embodiments, about 250 mg of a disclosed compound is administered every fourth day. In some embodiments, about 250 mg of a disclosed compound is administered every fifth day. In some embodiments, about 250 mg of a disclosed compound is administered daily. In some embodiments, about 250 mg of a disclosed compound is administered weekly. In some embodiments, about 250 mg of a disclosed compound is administered every other week. In some embodiments, about 250 mg of a disclosed compound is administered every third week. In some embodiments, about 250 mg of a disclosed compound is administered monthly.

[0244] In some embodiments, an initial dose of a disclosed compound is administered, which is then boosted 30 minutes-4 hours later by administering a second dose of the disclosed compound. In some embodiments, the boosted dose is administered about 30 min after the initial dose. In some embodiments, the boosted dose is administered about 60 min after the initial dose. In some embodiments, the boosted dose is administered about 90 min after the initial dose. In some embodiments, the boosted dose isadministered about 120 min after the initial dose. In some embodiments, the boosted dose is administered about 150 min after the initial dose. In some embodiments, the boosted dose is administered about 180 min after the initial dose. In some embodiments, the boosted dose is administered about 210 min after the initial dose. In some embodiments, the boosted dose is administered about 240 min after the initial dose.

[0245] In some embodiments, the boosted dose is from about 10% to 100% of the amount of the initial dose. In some embodiments, the boosted dose is the same amount as the initial dose. In some embodiments, the boosted dose is about half of the amount of the initial dose. In some embodiments, this dosing schedule is performed daily. In some embodiments, this dosing schedule is performed twice a day. In some embodiments, this dosing schedule is performed three times a day. In some embodiments, this dosing schedule is performed every other day. In some embodiments, this dosing schedule is performed every third day. In some embodiments, this dosing schedule is performed every fourth day. In some embodiments this dosing schedule is performed every fifth day. In some embodiments, this dosing schedule is performed weekly. In some embodiments, this dosing schedule is performed every other week. In some embodiments, this dosing schedule is performed every third week. In some embodiments, this dosing schedule is performed monthly.

[0246] In some embodiments, a dose of a disclosed compound may be in the range of about 1 mg / kg to about 100 mg / kg. For example, the dose may be about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, the dose of a disclosed compound is between about 0.1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, or about 5 mg / kg to about 30 mg / kg. In some embodiments, the dose of a disclosed compound is about 1 mg / kg, about 10 mg / kg, or about 25 mg / kg. In some embodiments, the dose of a disclosed compound is in the range of about 0.001 mg / kg to about 1 g / kg. In some embodiments, the dose of a disclosed compound is in the range of about 100 mg / kg to about 250 mg / kg. In some embodiments, the dose of a disclosed compound is about 25 mg / kg.

[0247] In some embodiments, a disclosed compound is administered, e.g., as a single dose or one or more times per week (up to twice daily or even three times a days). In some embodiments, a disclosed compound is administered according to a dosing schedule provided herein. In some embodiments, a disclosed compound is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.

[0248] It will be readily appreciated that dosages may vary depending upon whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous,simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by the skilled artisan (e.g., medical or familial history).

[0249] Dose amount, frequency or duration may be increased or reduced, as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications. The skilled artisan with the teaching of this disclosure in hand will appreciate the factors that may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0250] It will be understood that, in some embodiments, the dose actually administered will be determined by a physician, in light of the relevant circumstances, including the disorder to be treated, the chosen route of administration, the actual composition or formulation administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms, and therefore any dosage ranges disclosed herein are not intended to limit the scope of the disclosure. In some instances, dosage levels below the lower limit of a disclosed range may be more than adequate, while in other cases doses above a range may be employed without causing any harmful side effects, provided for instance that such larger doses also may be divided into several smaller doses for administration, either taken together or separately.

[0251] In embodiments, especially where a formulation is prepared in single unit dosage form, such as a capsule, tablet, or lozenge, suggested dosage amounts may be known by reference to the format of the preparation itself. In embodiments, where a formulation is prepared in multiple dosage form, for instance liquid suspensions and topical preparations, suggested dosage amounts may be known by reference to the means of administration or by reference to the packaging and labeling, package insert(s), marketing materials, training materials, or other information and knowledge available to one of skill or the public.

[0252] Accordingly, another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefore, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers, pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.F. Kits

[0253] Another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefore, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers, pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0254] Kits generally comprise suitable packaging. The kits may comprise one or more containerscomprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub- unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and / or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0255] Preferably, information pertaining to dosing and proper administration (if needed) will be printed onto a multi-dose kit directly (e.g., on a blister pack or other interior packaging holding the compositions or formulations of the disclosure); however, kits of the disclosure can further contain package inserts and other printed instructions (e.g., on exterior packaging) for administering the disclosed compositions and for their appropriate therapeutic use.G. Methods of Use

[0256] In some aspects, provided herein are methods of using the disclosed compounds. In some embodiments, disclosed compounds are used to modulate neurotransmission. In some embodiments, disclosed compounds are used to treat a condition, such as a disease or a disorder. In some embodiments, disclosed compounds are used in the manufacture of a medicament for the therapeutic and / or the prophylactic treatment of a condition, such as a disease or a disorder. In some embodiments, disclosed compounds are administered as part of psychedelic-assisted therapy. In some embodiments, disclosed compounds are administered in a therapeutically effective amount to a subject having a condition, such as a disease or a disorder. In some embodiments, the condition is a mental health disorder. In some embodiments, the condition is a neurodegenerative disorder. In some embodiments, the condition is an inflammatory disorder. In some embodiments, the condition is pain and / or inflammation. In some embodiments, disclosed compounds are administered to a subject that is healthy.

[0257] As used herein, the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to any mammal, including murines, simians, mammalian farm animals, mammalian sport animals, and mammalian pets, such as canines and felines, although preferably humans. Such terms will be understood to include one who has an indication for which a compound, composition, or method described herein may be efficacious, or who otherwise may benefit by the invention. In general, all of the compounds, compositions, and disclosed methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood. The disclosed methods of treatment also can be modified to treat multiple patients at once, including couples or families. Hence, these terms will beunderstood to also mean two or more individuals.

[0258] In some embodiments, disclosed compounds or compositions thereof are orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation or transdermally administered to a subject. In some embodiments, when administered through one or more such routes, the disclosed compounds and the disclosed compositions and formulations comprising them are useful in methods for treating a patient in need of such treatment. a, Modulating Neurotransmission and Neuroplasticity

[0259] In some embodiments, administration of a disclosed compound modulates neurotransmission in a subject, such as following administration of a pharmacologically effective amount to said subject. In some embodiments, modulating neurotransmission comprises regulating levels of monoamines in, for example, the CNS and peripheral tissues. In some embodiments, modulating neurotransmission comprises increasing levels of monoamines in, for example, the CNS and peripheral tissues of a subject to whom a disclosed compound has been administered. In some embodiments, modulating neurotransmission comprises decreasing levels of monoamines in, for example, the CNS and peripheral tissues of a subject to whom a disclosed compound has been administered. In some embodiments, modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0260] In some embodiments, administration of a disclosed compound or composition thereof results in inhibiting the reuptake of one or more neurotransmitters. In some embodiments, administration of a disclosed compound or composition thereof results in increasing the extracellular concentration of one or more neurotransmitters, including the amount of extracellular serotonin, dopamine, or norepinephrine.

[0261] In some embodiments, the disclosed compounds are used to modulate neurotransmission, such as neurotransmission in a subject. In some methods herein, the disclosed compositions, when administered in a pharmacologically effective amount, thus affect monoaminergic neurotransmission, including serotonergic, dopaminergic, and noradrenergic neurotransmission. Accordingly, in some embodiments, the disclosed compositions, when administered in a pharmacologically effective amount, are used to treat a medical condition linked to dysregulation or inadequate functioning of neurotransmission, and in specific embodiments, are used to treat a medical condition linked to monoaminergic neurotransmission.

[0262] In embodiments, administration of a disclosed compound or composition thereof results in modulation of one or more monoamine receptors, such as a serotonin receptor, a dopamine receptor, or a norepinephrine receptor. In embodiments, administration of a disclosed compound or composition thereof results in agonism or partial agonism of a monoamine receptor, including any one or more of a serotonin receptor, a dopamine receptor, and a norepinephrine receptor.

[0263] In some embodiments, administration of a disclosed compound or composition thereof results in activation of a serotonin receptor. In some embodiments, administration of a disclosed compound or composition thereof results in agonism and / or antagonism of a serotonin receptor (HTR). In someembodiments, administration of a disclosed compound or composition thereof results in agonism or partial agonism of an HTR, such as any one or more of an HTRbsuch as HTR1Aand HTR1B, an HTR2, such as HTR2A, HTR2B, and HTR2C, and HTR6.

[0264] In some embodiments, a drug comprised in a disclosed compound has an in vitro EC50(agonist mode) for any one or more of HTR1A, HTR1B, HTR2AHTR2B, and HTR6that is less than 10 pM, less than 5 pM, less than 1 M, less than 0.5 pM, or less than 0.1 pM. In embodiments, a drug comprised in a disclosed compound has an in vitro EC50(agonist mode) for HTR^ that is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM.

[0265] In some embodiments, administration of a disclosed compound or composition thereof results in increased agonism of HTR2Arelative to other HTRs. In some embodiments, administration of a disclosed compound or composition thereof results in increased agonism of HTR2Arelative to any one or more of an HTR!, such as HTR1Aand HTR1B, another HTR2, such as HTR2Band HTR2C, an HTR5, e.g., HTR5A, HTR6, and an HTR7, e.g., HTR7D.

[0266] In some embodiments, a drug comprised in a disclosed compound modulates the activity of a dopamine receptor (DR), such as any one or more of DRD1 , DRD2, DRD3, DRD4, and DRD5. In some embodiments, a drug comprised in a disclosed compound agonizes or partially agonizes a dopamine receptor. In some embodiments, a drug comprised in a disclosed compound agonizes or partially agonizes DRD2. In some embodiments, a drug comprised in a disclosed compound agonizes or partially agonizes the DRD2 short isoform (DRD2S). In embodiments, a drug comprised in a disclosed compound has an in vitro EC50 for DRD2S that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM.

[0267] Determining agonism and antagonism, and measuring EC50and IC50, respectively, may be determined according to methods available to one of skill in the art. In one example, measuring Gq-mediated calcium flux is a known method for assessing modulation, e.g., activation, of HTR2A, a widely recognized target of psychedelic compounds. See, e.g., Klein et al., ACS Pharmacol Transl Sci. 2020 14;4(2):533-542; Flanagan et al., ACS Pharmacol Transl Sci. 2020;4(2):488-502; Toro-Sazo et al., PLoS One. 2019;14(1):e0209804; Halberstadt et al., Psychopharmacology (Bed). 2019;236(2):799-808. As would be recognized by one of skill, a partial agonist is one that shows reduced maximum efficacy (EMAX) relative to a full agonist (EMAX= 100%), e.g., serotonin in the example of an HTR.

[0268] In some embodiments, disclosed compounds or compositions thereof, when administered in a pharmacologically effective amount, result in modulation of one or more membrane monoamine transporters, including any one or more of a serotonin membrane transporter (SERT), a dopamine membrane transporter (DAT), a norepinephrine membrane transporter (NET), and a vesicular monoamine transporter. In some embodiments, a drug comprised in a disclosed compound blocks the uptake activity of monoamine transporters. In some embodiments, a drug comprised in a disclosed compound blocks theuptake activity of one or more of a serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).

[0269] In some embodiments, a drug comprised in a disclosed compound inhibits the uptake activity of any one or more of SERT, DAT, and NET. In some embodiments, a drug comprised in a disclosed compound inhibits the uptake activity of SERT, DAT, and NET. In embodiments, a drug comprised in a disclosed compound has an in vitro IC50of less than 10 pM for any one or more of SERT, DAT, and NET. In embodiments, a drug comprised in a disclosed compound does not inhibit the uptake activity of SERT. In embodiments, a drug comprised in a disclosed compound has an in vitro IC50of less than 10 pM for SERT. In embodiments, a drug comprised in a disclosed compound selectively inhibits the uptake activity of SERT. In embodiments, a drug comprised in a disclosed compound shows greater potency for inhibiting the uptake activity of SERT relative to DAT and NET.

[0270] Determining whether a disclosed compound results in inhibition of the uptake activity of a monoamine transporter, or whether such activity is lacking, may be determined according to available methods, which may include live-cell fluorescent assays or radioactive assays. In some examples, inhibition of monoamine uptake may be determined in rat synaptosomes or human platelets. See, e.g., Segonzac et al., J Neurochem. 1985;44(2):349-56; Cozzi et al., J Neural Transm (Vienna). 2009; 116(12):1591 -9. In some examples, inhibitory activity may be compared to uptake inhibitors having low nM potency, e.g., DAT inhibitor GBR 12909, NET inhibitor desipramine, and SERT inhibitor clomipramine.

[0271] In some embodiments, administration of a disclosed compound or composition according to the methods herein results in an improved pharmacological profile, such as a relative increase in agonism of serotonin receptors compared to dopamine and / or norepinephrine receptors, compared to a corresponding composition, which may be an increase of 5% or more, 10% or more, 25% or more, or 50% or more, and including amounts in between. Measurements of agonism of a receptor will be as understood by those in the art or by reference to the general knowledge in the art.

[0272] In some embodiments, an improved pharmacological profile of a disclosed compound or composition will be a relative increase in extracellular concentration of serotonin compared to dopamine and / or norepinephrine, compared to a corresponding non-substituted composition, which may be an increase of 5% or more, 10% or more, 25% or more, or 50% or more, and including amounts in between. Measurements of extracellular concentration of a neurotransmitter will be as understood by those in the art or by reference to the general knowledge in the art.

[0273] Detecting a change in monoamine levels in a subject, such as an increase or a decrease, can be achieved according to methods known to one of skill, for example, brain microdialysis (Chefer et al., Curr Protoc Neurosci. 2009; Chapter: Unit 7.1 ; Darvesh et al., Expert Opin Drug Discov. 2011 ;6(2):109-127) and brain imaging, for example, positron emission tomography (PET) and single photon emission computed tomography (SPECT) (see e.g., Wong & Gjedde, Encyclopedia Neurosci, 2009; 939-952 and Takano, FrontPsychiatry. 2018; 9:228).

[0274] In some embodiments, a disclosed compound is used to increase neuroplasticity. Neuroplasticity, also known as neural plasticity or brain plasticity, refers to the brain's ability to change and adapt in response to experiences, learning, and environmental factors. Neuroplasticity occurs through several mechanisms, including synaptic plasticity, which involves the strengthening or weakening of connections (synapses) between neurons. Synaptic plasticity is often associated with learning and memory processes. Another form of plasticity is called structural plasticity, which involves changes in the physical structure of neurons, such as the growth of new dendritic branches or the formation of new synapses. In some embodiments, increasing neuroplasticity contributes to the therapeutic effects of a disclosed compound in a subject. In some embodiments, increasing neuroplasticity by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0275] Neuroplasticity can be defined in terms of neuritogenesis, spinogenesis, and synaptogenesis in neurons. Neuritogenesis refers to the process by which neurons generate and extend their neurites (i.e., to form axons and dendrites). Neuritogenesis is a critical step in neural development and the formation of neuronal circuits. Spinogenesis refers to the formation of dendritic spines, which are small protrusions on the dendrites of neurons. Dendritic spines are crucial for synaptic connections and play a vital role in synaptic transmission and plasticity. Synaptogenesis refers to the formation of synapses, which is crucial for the establishment and refinement of neural circuits, and is a fundamental process underlying learning, memory, and information processing in the brain.

[0276] In some embodiments, administration of a disclosed compound or composition thereof increases neuritogenesis. Neuritogenesis can be measured in terms of total neurite length, maximum neurite length, number of neurite nodes, and / or number of neurite extremities. In some embodiments, administration of a disclosed compound or composition thereof increases total neurite length. In some embodiments, administration of a disclosed compound or composition thereof increases maximum neurite length. In some embodiments, administration of a disclosed compound or composition thereof increases the number of neurite nodes. In some embodiments, administration of a disclosed compound or composition thereof increases the number of neurite extremities.

[0277] In some embodiments, administration of a disclosed compound or composition thereof to a subject results in an increase in the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., number of synapses per neuron), or total dendritic length. These factors can be measured using a Sholl analysis and other techniques known to those of skill in the art (Ly et al. ACS Pharmacol Transl Sci. 2020;4(2):452-460). b. Treatment

[0278] In some embodiments, a disclosed compound is used to treat a medical condition, such as a disease or disorder. In embodiments, a disclosed compound is used in the manufacture of a medicament totreat a condition, such as a disease or disorder. Also provided are methods of administering disclosed compounds to a subject having a condition, such as a disease or disorder, thereby treating said condition.

[0279] In some embodiments, a disclosed compound or pharmaceutical composition comprising the disclosed compounds are administered to a subject by one or more routes of administration, including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes. When administered through one or more of such routes, the compound(s) of the disclosure and the disclosed compositions and formulations comprising them are useful in methods for treating a patient in need of such treatment.

[0280] In some embodiments are provided methods of treating and / or preventing a condition in a subject, the method comprising administering to the mammal a therapeutically effective amount of a disclosed compound or pharmaceutical composition. In some embodiments, “treating” or “treatment” refers to treating a disease or disorder in a subject, and preferably in a human, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e. arresting its development; (c) relieving a disorder, i.e., causing regression thereof; (d) protecting from or relieving a symptom or pathology caused by or related to a disorder; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a disorder; and (f) preventing or inhibiting of a worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder. In embodiments, treatment includes prevention. In other embodiments, treatment does not include prevention. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood to one of skill in view of the teachings herein and the knowledge in the art.

[0281] In embodiments, a disclosed compound is used to treat a central nervous system (CNS) disorder. Broadly, CNS disorders include diseases of the nervous system (e.g., movement disorders, neurodegenerative disorders) as well as mental, behavioral, and neurodevelopmental disorders, such as those in the DSM-5, Merck Manual, ICD-11 , or other such diagnostic resources known to one of skill. i. Mental, Behavioral, or Neurodevelopmental Disorders

[0282] In some embodiments, a disclosed compound is used to treat a mental, behavioral, or neurodevelopmental disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental, behavioral, or neurodevelopmental disorder, thereby treating said mental, behavioral, or neurodevelopmental disorder. In some methods herein, a disclosed composition, when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a mental, behavioral, or neurodevelopmental disorder.

[0283] The ICD-11 , which is incorporated by reference herein in its entirety, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant disturbance in anindividual's cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning. Such disorders include, but are not limited to, neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.

[0284] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or “mental health disorder”) generally refers to a disease condition that involves negative changes in emotion, mood, thinking, and / or behavior. In general, mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotion, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of suffering. Although the terms “mental disorder” and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11 , or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11 , ICD-10, DSM-5, or DSM-IV (each of which is incorporated by reference herein in its entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.

[0285] In some embodiments, a disclosed compound is used to treat a mental health disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating said mental health disorder. In some methods herein, a disclosed composition, when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a mental health disorder. In some embodiments, a compound or composition of the disclosure is used to reduce the symptoms of a mental health disorder. The symptoms of the mental health disorder to be treated shall be able to be determined by one of skill in the art, by reference to the general understanding of the art regarding that disorder.

[0286] In some embodiments, measures of therapeutic efficacy include reports by a subject or an observer. In some embodiments, measures of therapeutic efficacy include responses to a questionnaire. Non-limiting representative examples of applicable measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment ofFunctioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject- or observer-reported measures.

[0287] In some embodiments, a disclosed compound is used to treat a neurodevelopmental disorder. In some embodiments, a “neurodevelopmental disorder” is a neurological and / or cognitive disorder that arises during the developmental period that involves significant difficulties in the acquisition and execution of specific neurological functions (e.g., intellectual, motor, language, or social functions). In some embodiments, the neurodevelopmental disorder is a disorder of intellectual development, a developmental speech or language disorder, autism spectrum disorder, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.

[0288] In some embodiments, a disclosed compound is used to treat schizophrenia or another primary psychotic disorder. In general, these disorders are characterized by significant impairments in reality and alterations in behavior manifest in positive symptoms like persistent delusions, persistent hallucinations, disorganized thinking and speech, grossly disorganized behavior, as well as experience of negative symptoms such as blunted or flat affect and avolition and psychomotor disturbances. In some embodiments, a disclosed compound is used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder.

[0289] In some embodiments, a disclosed compound is used to treat catatonia. In some embodiments, “catatonia” refers to a category of syndromes characterized by the co-occurrence of several symptoms of decreased, increased, or abnormal psychomotor activity. In some embodiments, the catatonia is associated with another mental disorder. In some embodiments, the catatonia is induced by substances or medications.

[0290] In some embodiments, a disclosed compound is used to treat a mood disorder. As defined in the ICD-11 , mood disorders are categorized according to the specific type(s) of mood episodes, and their pattern over time. The primary types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. In some embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder), a depressive disorder, or a substance-induced mood disorder. In some embodiments, the mood disorder is a depressive disorder. In embodiments, the depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder (formally known as dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, seasonal affective disorder, mixed depressive and anxiety disorder, or an unspecified depressive disorder. In embodiments, depression is assessed through the Patient Health Questionnaire-9 (PHQ-9) screening tool, Montgomery-AsbergDepression Rating Scale (MADRS), Hamilton Depression Rating Scale, Beck Depression Inventory (BDI-II), Zung Self-Rating Depression Scales (SDS), Major Depression Inventory (MDI), Center for Epidemiologic Studies Depression Scale (CED-D), Rome Depression Inventory (RDI), Hamilton Rating Scale for Depression (HRSD), and Carroll Rating Scale (CRS).

[0291] In some embodiments, a disclosed compound is used to treat an anxiety or fear-related disorder. An “anxiety disorder” refers to a class of mental disorders that induce excessive or abnormal fear, dread, or worry. In some embodiments, the anxiety disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or a substance-induced anxiety disorder.

[0292] In some embodiments, a disclosed compound is used to treat an obsessive-compulsive or related disorder. In general, these disorders are characterized by repetitive thoughts and behaviors, such as cognitive phenomena (obsessions, intrusive thoughts and preoccupations). In some embodiments, the disorder is characterized by a compulsive need to accumulate possessions and distress related to discarding them (i.e., hoarding disorder). In some embodiments, the disorder is body-focused and can be characterized by recurrent and habitual actions (hair-pulling, skin-picking). In some embodiments, the disorder is obsessive-compulsive disorder, body dysmorphic disorder, olfactory reference disorder, hypochondriasis, hoarding disorder, a body-focused repetitive behavior disorder, or a substance-induced obsessive-compulsive disorder.

[0293] In some embodiments, a disclosed compound is used to treat a disorder associated with stress. In some embodiments, the disorder associated with stress has an identifiable stressor that is a causal factor, like exposure to a stressful or traumatic event, or a series of such events or adverse experiences. Stressors may be within the normal range of life experiences (e.g., divorce, socioeconomic problems), or from a threatening or traumatizing experience. In general, the nature and duration of the symptoms that arise in response to the stressor can distinguish the disorder from everyday stress. In embodiments, a disclosed compound is used to treat post-traumatic stress disorder, complex post-traumatic stress disorder, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder.

[0294] In some embodiments, a disclosed compound is used to treat a dissociative disorder. Dissociative disorders can be characterized by involuntary disruption or discontinuity in the normal integration of one or more of the following: identity, sensations, perceptions, affects, thoughts, memories, control over body movements, or behavior. In some subjects, dissociative disorder symptoms can be severe, and may result in impairment in personal, social, educational, occupational or other areas of functioning. In some embodiments, a disclosed compound is used to treat dissociative neurological symptom disorder, dissociative amnesia (including amnesia with dissociative fugue and without dissociative fugue), trance disorder, possession trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization- derealization disorder.

[0295] In some embodiments, a disclosed compound is used to treat a feeding or eating disorder. Feeding or eating disorders generally involve abnormal eating or feeding behaviors that are not explained by another health condition, and are not developmentally appropriate or culturally sanctioned. These disorders can involve preoccupation with food as well as body weight and shape concerns. In embodiments, a disclosed compound is used to treat anorexia nervosa (including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.

[0296] In some embodiments, a disclosed compound is used to treat an elimination disorder. Elimination disorders include, for example, the repeated voiding of urine into clothes or bed, and the repeated passage of feces in inappropriate places once the individual has reached a developmental age when continence is ordinarily expected. In embodiments, a disclosed compound is used to treat enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or encopresis (including both with encopresis constipation or overflow incontinence, and encopresis without constipation or overflow incontinence).

[0297] In some embodiments, a disclosed compound is used to treat a disorder of bodily distress or bodily experience. Disorders of bodily stress typically involve bodily symptoms that the subject finds distressing and to which the subject devotes excessive attention. Bodily integrity dysphoria typically involves a disturbance in the person’s experience of the body manifested by persistent discomfort or intense feelings of body configuration. In some embodiments, a disclosed compound is used to treat a bodily distress disorder (including mild, moderate, and severe bodily distress disorder) or body integrity dysphoria.

[0298] In some embodiments, a disclosed compound is used to treat a disorder due to substance use or addictive behaviors. Disorders due to substance use or addictive behaviors are mental and / or behavioral disorders that develop predominantly as a result of the use of psychoactive substances (including medications and illegal or illicit substances), or specific repetitive rewarding and reinforcing behaviors. In some embodiments, a disclosed compound is used to treat disorders due to substance use (i.e., a substance use disorder, or SUD). In some embodiments, the substance use disorder is associated with alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics or anxiolytics, cocaine, stimulants (e.g., amphetamines, methamphetamines, methcathinone, synthetic cathinones, caffeine), hallucinogens, nicotine, volatile inhalants, MDMA or MDA, dissociative drugs like ketamine and phencyclidine, or another substance (including medications and non-psychoactive substances). In some embodiments, the substance use disorder is selected from alcohol use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalants use disorder, opioids use disorder, sedatives use disorder, hypnotics use disorder, anxiolytics use disorder, stimulants use disorder, and tobacco use disorder. In some embodiments, the substance use disorder is alcohol use disorder. In some embodiments, the substance use disorder is cannabis use disorder. In some embodiments, the substance use disorder is caffeine use disorder. In some embodiments, the substance use disorder is phencyclidine use disorder. In someembodiments, the substance use disorder is inhalant use disorder. In some embodiments, the substance use disorder is opioids use disorder. In some embodiments, the substance use disorder is sedatives use disorder. In some embodiments, the substance use disorder is hypnotics use disorder. In some embodiments, the substance use disorder is anxiolytics use disorder. In some embodiments, the substance use disorder is stimulants use disorder. In some embodiments, the substance use disorder is tobacco use disorder. In some embodiments, the substance use disorder is alcohol use disorder, wherein said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism. In some embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder). In some embodiments, a substance use disorder can be screened using a Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), the Opioid Risk Tool - OLID (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).

[0299] In some embodiments, a disclosed compound is used to treat an impulse control disorder. In general, impulse control disorders are characterized by the repeated failure to resist an impulse, drive, or urge to perform an act that is rewarding to the subject despite negative long-term consequences, such as harm to the subject or a significant impairment in important areas of the subject’s functioning. In some embodiments, impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts. In some embodiments, a disclosed compound is used to treat pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.

[0300] In some embodiments, a disclosed compound is used to treat a disruptive behavior disorder or a dissocial disorder. Such disorders may be broadly characterized by persistent behavior problems that range from persistently defiant, disobedient, provocative or spiteful behaviors to behaviors that violate the rights of others or norms, rules, or laws. In some embodiments, a disclosed compound is used to treat oppositional defiant disorder (including oppositional defiant disorder with chronic irritability-anger and oppositional defiant disorder without chronic irritability-anger) or conduct-dissocial disorder (including childhood-onset conduct-dissocial disorder and adolescent-onset conduct-dissocial disorder).

[0301] In some embodiments, a disclosed compound is used to treat a personality disorder. Personality disorders may be generally characterized by problems in perceiving one’s identity, self-worth, accuracy of self-view, and self-discretion that is manifest in patterns of cognition, emotional experience, emotional expression, and maladaptive behavior. In some embodiments, a disclosed compound is used to treat a mild, moderate, or severe personality disorders. In some embodiments, a disclosed compound is used to treat a prominent personality trait or patterns (e.g., negative affectivity, detachment, dissociality, disinhibition, anankastia, borderline pattern). In some embodiments, the personality disorder is antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder,histrionic personality disorder, masochistic or sadistic behavior, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, psychopathy, sociopathy, schizoid personality disorder, or schizotypal personality disorder.

[0302] In some embodiments, a disclosed compound is used to treat a paraphilic disorder. Paraphilic disorders can be characterized by persistent and intense patterns of atypical sexual arousal, the focus of which involves others whose age or status renders them unwilling or unable to consent. In some embodiments, a disclosed compound is used to treat exhibitionistic disorder, voyeuristic disorder, pedophilic disorder, coercive sexual sadism disorder, frotteuristic disorder, other paraphilic disorders involving non-consenting individuals, or paraphilic disorders involving solitary behavior or consenting individuals.

[0303] In some embodiments, a disclosed compound is used to treat a factitious disorder. In general, factitious disorders may be characterized by intentionally feigning, falsifying, inducing or aggravating medical, psychological, or behavior signs and symptoms or injury to oneself or another person. Subjects with factitious disorders may seek treatment or otherwise present themselves or another person as ill, injured, or impaired. In embodiments, a disclosed compound is used to treat factitious disorder imposed on self or a factitious disorder imposed on another.

[0304] In some embodiments, a disclosed compound is used to treat a neurocognitive disorder. Neurocognitive disorders may be characterized by primary clinical defects in cognitive functioning that are acquired (rather than developmental), and therefore the subject experiences a decline from a previously attained level of functioning. In some embodiments, a disclosed compound is used to treat delirium. In some embodiments, the delirium is associated with another disease or disorder. In some embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat mild neurocognitive disorder. In some embodiments, a disclosed compound is used to treat an amnestic disorder. In some embodiments, the amnestic disorder is associated with another disease or disorder. In some embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat dementia. In some embodiments, the dementia is associated with Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, Lewy body disease, a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat a behavioral or psychological disturbance associated with dementia. In some embodiments, dementia is assessed using a Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).

[0305] In some embodiments, a disclosed compound is used to treat a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. In some embodiments, the syndrome associated with pregnancy or the puerperium involves significant mental and behavioral features, including a depressivesymptom. In some embodiments, the disorder includes psychotic symptoms. In some embodiments, a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, with psychotic symptoms. In embodiments, a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, without psychotic symptoms.

[0306] In embodiments, a disclosed compound is used to treat a sleep-wake disorder. In general, sleepwake disorders are associated with difficulty initiating or maintaining sleep (e.g., insomnia), excessive sleepiness (e.g., hypersomnolence disorders), respiratory disturbance during sleep (e.g., sleep-related breathing disorders (SRBDs), such as obstructive sleep apnea (OSA), central sleep apnea (CSA), sleep- related hypoventilation disorders, sleep-related hypoxemia disorder, snoring, catathrenia, Cheyne-Stokes breathing, and sleep-disordered breathing), disorders of the sleep-wake schedule (e.g., circadian rhythm sleep-wake disorders), abnormal movements during sleep, or problematic behavioral or psychological events that occur while falling asleep, during sleep, or upon arousal from sleep (e.g., parasomnia disorders). In embodiments, a disclosed compound is used to treat an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder.

[0307] In some embodiments, a disclosed compound is used to treat sexual dysfunction. Sexual dysfunctions can be defined as syndromes wherein a subject may have difficulty experiencing personally satisfying, non-coercive sexual activities. In some embodiments, a disclosed compound is used to treat hypoactive sexual desire dysfunction, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse.

[0308] In some embodiments, a disclosed compound or composition is administered together with psychotherapy, such as psychosocial or behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry. 1999;56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav. 2009;23(1):168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav. 2009;23(1):168-174; in J Consul Clin Psychol. 2005;73(2):354-59; or in Case Reports in Psychiatry. Vol. 2012, Article ID 731638), motivational interviewing based therapy (e.g., as described in J Consul Clin Psychol 2001 ; 69(5): 858-62), meditation based therapy, such as transcendental meditation based therapy (e.g., as described in J Consul Clin Psychol. 2000;68(3):515-52), or the therapeutic approach used by MAPS to treat patients with PTSD (e.g., as in Mithoefer, M (2017). Manual for MDMA-Assisted Psychotherapy in the Treatment of PTSD).

[0309] In some embodiments, a disclosed compound or composition may be administered in conjunction with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is neither necessitated nor desired, or no specific type of psychotherapy is necessitated or desired, however any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in specific therapies, as well as to choose between any such therapies (or to decide to forgo any specific therapy), while still receiving clinically significant therapeutic effects, is among the advantages of theinvention. Furthermore, a patient can participate in numerous other therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.

[0310] In some embodiments, “psychotherapy” is specifically “psychedelic-assisted psychotherapy.” Psychedelic-assisted psychotherapy, broadly, includes a range of related approaches that involve at least one session where the patient ingests a psychedelic and is monitored, supported, or otherwise engaged by one or more trained mental health professionals while under the effects of the psychedelic (see, e.g., Schenberg 2018). Protocols have been developed for the standardization of procedures which emphasize a high degree of care (see, e.g., Johnson 2008), such as the therapeutic approach used by MAPS to treat patients with PTSD using MDMA (e.g., as described in Mithoefer 2017).

[0311] In some embodiments, the psychotherapy conducted with a disclosed compound is conducted in widely spaced sessions. These sessions can be as frequently as weekly but are more often approximately monthly or less frequently. In most cases, a small number of sessions, on the order of one to three, is needed for a patient to experience significant clinical progress, as indicated, for example, by a reduction in the symptoms of the mental health disorder being treated. In some embodiments, psychotherapy comprises multiple sessions, during some of which a disclosed compound is administered (“drug-assisted psychotherapy”); in others, the patient participates in psychosocial or behavioral therapy without concomitant administration of a drug, or without administration of a disclosed compound.

[0312] In some embodiments, a disclosed compound or composition is administered together with standardized psychological treatment or support, which refers to any accepted modality of standard psychotherapy or counseling sessions, whether once a week, twice a week, or as needed; whether in person or virtual (e.g., over telemedicine or by means of a web program or mobile app); and whether with a human therapist or a virtual or Al “therapist.” As used herein, “therapist” refers to a person who treats a patient using the disclosed compositions and methods, whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, although it will be understood that certain requirements will be appropriate to certain aspects of the drug-assisted therapy (e.g., prescribing, dispensing, or administering a drug, offering psychotherapeutic support). In some embodiments, a “person” may also include an Al.

[0313] In some embodiments, a patient will participate in a treatment protocol or a disclosed method, or be administered a disclosed composition as part of such a method, if the patient meets certain specified inclusion criteria, does not meet certain specified exclusion criteria, does not meet any specified withdrawal criteria during the course of treatment, and otherwise satisfies the requirements of the embodiment of thedisclosure as claimed.

[0314] Preferably, where the disclosed pharmaceutical compositions are administered, such administration occurs without or with reduced risk of side effects that would require physician supervision, and therefore allow for treatment at home or otherwise outside of a clinic and without the need for such supervision, and / or additionally without the requirement of adjunctive psychotherapy (although it also may be provided in certain embodiments herein).

[0315] In some embodiments, a disclosed compound or composition may be administered in conjunction with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is neither necessitated nor desired, or no specific type of psychotherapy is necessitated or desired, however any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in specific therapies, as well as to choose between any such therapies (or to decide to forgo any specific therapy), while still receiving clinically significant therapeutic effects, is among the advantages of the invention. Furthermore, a patient can participate in numerous other therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.

[0316] In some instances, certain personalized approaches (i.e., “personalized” or “precision” medicine) may be utilized, based on individual characteristics, including drug metabolism (e.g., CYP2D6 or CYP3A4) or individual genetic variation. The term “genetic variation” refers to a change in a gene sequence relative to a reference sequence (e.g., a commonly-found and / or wild-type sequence). Genetic variation may be recombination events or mutations such as substitution / deletion / insertion events like point and splice site mutations. In some embodiments, the genetic variation is a genetic variation in one or more cytochrome P450 (CYP or CYP450) enzymes that affects drug metabolism, including metabolism of a disclosed composition, and including CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5. Other examples of CYP enzymes include CYP1A1 , CYP1 B1 , CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1 , CYP2G1 , CYP2J2, CYP2R1 , CYP2S1, CYP3A5P1 , CYP3A5P2, CYP3A7, CYP4A11 , CYP4B1 , CYP4F2, CYP4F3, CYP4F8, CYP4F11 , CYP4F12, CYP4X1 , CYP4Z1, CYP5A1 , CYP7A1 , CYP7B1, CYP8A1 , CYP8B1, CYP11A1 , CYP11 B1 , CYP11 B2, CYP17, CYP19, CYP21 , CYP24, CYP26A1, CYP26B1 , CYP27A1 , CYP27B1 , CYP39, CYP46, and CYP51.

[0317] In some embodiments, a disclosed compound or composition is taken together with a compound that is metabolized by the same CYP enzyme(s) as the disclosed compound, so as to permit a lower dose to be taken, increase the effective bioavailability of one or both, or otherwise affect drug metabolism or pharmacokinetics. In some embodiments, the dose of a disclosed composition is adjusted, such as reduced,when administered to a subject known to be a poor metabolizer of an active compound in the composition (e.g., having a genetic variation in CYP2D6 and / or CYP3A4), or increased when administered to a subject known to be a rapid metabolizer. In some embodiments, a patient is tested using ordinary means known to those of skill to determine if the patient is a poor or rapid metabolizer for one or more such CYP enzymes.

[0318] In some embodiments, the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which has been implicated in mood and anxiety symptoms in humans. In another embodiment, the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs. The FKBP5 gene has been implicated in responses to stress and trauma, and such SNPs are correlated with susceptibility to certain depression, PTSD, and anxiety disorders. In some embodiments, a genetic variation is an inclusion criteria for the administration of a disclosed compound. In some embodiments, a genetic variation is an exclusion criteria for the administration of a disclosed compound.

[0319] In some embodiments, the mammal being treated has altered epigenetic regulation of a gene, the expression of which is associated with a mental health condition or susceptibility to a mental health treatment, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor. ii. Neurodegenerative Disorders

[0320] In some embodiments, a disclosed compound is used to treat a neurodegenerative disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a neurodegenerative disorder. In some methods herein, a disclosed composition, when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a neurodegenerative disorder.

[0321] The term “neurodegenerative disorder” refers to a class of progressive, chronic, and debilitating conditions characterized by the gradual loss of structure and function of neurons within the central nervous system (CNS) or peripheral nervous system (PNS). These disorders involve the degeneration, impairment, or death of neuronal cells, leading to a decline in cognitive, motor, and / or sensory abilities.

[0322] Neurodegenerative disorders can be classified according to primary clinical features, e.g., dementia, parkinsonism, or motor neuron disease, anatomic distribution of neurodegeneration, e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations, or principal molecular abnormality (Dugger B, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology. 2017:9(7);a028035). These disorders may involve various etiologies, including but not limited to, presence of pathogenic proteins, age, environmental stressors, and genetic predisposition (Armstrong R. Folia Neuropathologica. 2020:58(2);93-112).

[0323] In some embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis or Charcot’s disease, chronic traumatic encephalopathy, corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodigdisease, mild cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease or Parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury. / . Pain and Inflammation

[0324] In some embodiments, a disclosed compound is used to treat pain and / or inflammation, such as a pain disorder and / or an inflammatory disorder. In some embodiments, a disclosed compound is administered, such as in a pharmacologically effective amount, to a subject having pain and / or inflammation, thereby treating said pain and / or inflammation. In some methods, a disclosed composition, when administered in a pharmacologically effective amount, provides beneficial therapeutic effects for the treatment of pain and / or inflammation.

[0325] In some embodiments, a disclosed compound is used to treat a pain disorder. In embodiments, the pain disorder is any of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesia, hyperalgesia, neuralgia, neuritis, neurogenic pain, phantom limb pain, analgesia, anesthesia dolorosa, causalgia, sciatic nerve pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorders, headache disorders, migraine headaches, chronic cluster headaches, concussion headache, short-lasting unilateral neuralgiform headache attacks, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, or pain associated with cancer.

[0326] In some embodiments, a disclosed compound is used to treat an inflammatory disorder. In some embodiments, the inflammatory disorder is characterized by inflammation of an organ or tissue. In embodiments, the inflammatory disorder comprises any one or more of skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, bladder inflammation, gastric inflammation, intestinal inflammation, neuroinflammation, and brain inflammation. In embodiments, the inflammatory disorder is a disorder that causes acute inflammation, or that exhibits chronic inflammation as a symptom. In some embodiments, the inflammatory disorder comprises chronic inflammation.

[0327] In some embodiments, a disclosed compound is used to reduce inflammation. In some embodiments, a disclosed compound is used in the manufacture of a medicament to reduce inflammation. In some embodiments, a disclosed compound, e.g., in a therapeutically effective amount, is administered to a subject to reduce inflammation.

[0328] The International Association for the Study of Pain (I ASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Although the mechanism for serotonin modulators, such as 5-HT2A agonists and 5-HT2A antagonists, to ameliorate pain remains unclear, the synaptic plasticity associated with such compounds may alter pathologic changes in neural connections seen in chronic pain states, potentially resulting in areduced pain intensity and duration (Castellanos et al., Reg Anesth Pain Med. 2020;45(7):486-494). Additionally, 5-HT2AR activation has been shown to promote anti-inflammatory effects, e.g., a reduction of TNF-a-induced inflammation. See, e.g., Pelletier & Siegel, Mol Interv. 2009;9(6):299-301 , Flanagan et al., Sci Rep. 2019;9(1 ):13444, Nichols et al., Clin Pharmacol Ther. 2017;101 (2):209-219; Int Rev Psychiatry. 2018;30(4):363-375, Okamoto et al., Neurosci. 2005; 130(2):465-74.

[0329] Pain, such as chronic pain, and improvements thereof, such as a reduction of symptoms, may be measured according to known methods, e.g., by subject reporting, pain diaries, pain scales, applicable questionnaires (assessments of chronic pain and its impact on physical, emotional and social functions), ecological momentary assessments and computerized versions thereof. See, e.g., Salaffi et al., Best Practice & Research Clinic Rheumatol, 2015;29(1): 164-186 and Hawker et al., Arthritis Care Res (Hoboken). 2011 ;63 Suppl 11 :S240-52. Exemplary questionnaires include the Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP), Migraine Diagnosis Questionnaire, the Migraine-Screen Questionnaire (MS-Q), the Fibromyalgia Survey Questionnaire (FSQ).

[0330] A reduction in inflammation, such as chronic systemic inflammation, may be measured according to various methods available to one of skill. Inflammatory biomarkers may be detected from biological specimens, for example, a subject’s blood, such as plasma or serum, or saliva. In one example, inflammation may be detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell count from a blood test. CRP may also be detected in a saliva sample. Salivary CRP is not synthesized locally in the mouth and may reflect more systemic levels of inflammation compared to other inflammatory biomarkers, such as cytokines (Szabo & Slavish, Psychoneuroendocrinology. 202; 124: 105069). Additionally clinical pathology data, e.g., hematology data on erythrocyte parameters, platelet count, total number of leukocytes, and leukocyte differentials and morphology, coagulation data on clotting times and fibrinogen, and clinical chemistry data on total protein, albumin and globulin, liver enzymes, renal parameters, electrolytes, and bilirubin can provide an initial indication of the presence and potentially the location of inflammation, in the absence of specific data on immune tissues. See, e.g., Germolec et al., Methods Mol Biol. 2018; 1803:57-79 and Luo et al., Clin Lab. 2019 1 ; 65(3) .H. Examples

[0331] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.Example 1 : Synthesis of 4-(((4-bromo-2,5-dimethoxyphenethyl)amino)methyl)-5-(hydroxy methyl)-2-methylpyridi n-3-ol HCI (Compound 1 A-1 )i: pyridoxal HCI, MeOH, 4 A molecular sieves; ii: NaBH4, MeOH; ill: MeOH, 1 M HCI in Et2O

[0332] Added 0.492 g (1.54 mmol) of 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine acetate and 0.313 g (1.54 mmol) of pyridoxal HCI to an Erlenmeyer flask containing 20 mL of methanol and 0.5 g 4 A molecular sieves. The reaction was shaken for 2 hours, during which time a yellow precipitate formed. Magnetic stirring was initiated and 20 mL of additional methanol was added. To the stirred mixture was added 0.464 g of NaBH4(12.3 mmol) in four portions over 10 minutes, waiting for effervescence to subside before adding the next portion. As the NaBH4was added to the reaction, the mixture became a light brown solution, which was filtered to remove the molecular sieves. The solvent was removed in vacuo to yield an orange oil. The oil was dissolved in 30 mL dichloromethane and shaken with 20 mL saturated NaHCO3in a separatory funnel. The organic layer was removed and the aqueous layer was washed once with 20 mL dichloromethane. The organic fractions were combined and dried over Na2SO4then filtered. The solvent was removed in vacuo to yield a sticky yellow oil.

[0333] Flash chromatography was performed on the oil. Five mL of oil was dissolved in a 1 :1 solution of methanokwater. Two mL of this solution was chromatographed using a Revelaris X2 fitted with a 40 g C18 column, eluting with a gradient solvent system of ethanol and water, starting with 0% ethanol and increasing to 100% ethanol over 20 minutes. The desired product eluted at 11.2 minutes as determined by thin layer chromatography (TLC), Rf = 0.33 (3:2:2; n-butanokacetic acid:water). Removal of solvent from the fractions containing the product caused the precipitation of a white solid, which was collected by filtration and dried overnight under vacuum at 50 °C. After drying, it weighed 0.07 g.

[0334] During the first run, the solution of methanokwater containing the oil began to precipitate a whitish- yellow solid. This solid was taken up in 20 mL of 33:67 methanokwater and filtered. This off-yellow precipitate was dried overnight in a vacuum oven at 50 °C, yielding 0.185 g of a yellow solid. The yellow solid was dissolved in 2 mL methanol and chromatographed using a Revelaris X2 fitted with a 40 g C18 column, gradient eluting as described above with a solvent system of EtOH and water, starting with 0% EtOH to 100% EtOH over 20 minutes. The desired product eluted at 11 .8 minutes as determined by TLC, Rf = 0.33 (3:2:2; n-butanokacetic acid:water). Removal of solvent from the fractions containing the product caused a white solid to precipitate. The solid was filtered and dried overnight under vacuum at 50 °C.

[0335] The combined white solids were dissolved in 2 mL methanol then 1 mL 1 M HCI in diethyl ether added. Subsequent dilution with 10 mL additional ether caused a fine white solid to form. The solid was collected by filtration and dried overnight under vacuum at 50 °C to yield 0.180 g of 4-(((4-bromo-2,5-dimethoxyphenethyl)amino)methyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol HCI (Compound 1 A-1)

[0336] HRMS calculated for C18H26NO4Br2+(M+2H+) = 412.0986; found = 412.1038.Example 2: In Vitro Metabolic Stability

[0337] Purpose: To determine the metabolic stability of a disclosed compound relative to its corresponding component drug. Metabolic stability assays measure the intrinsic clearance (CLint) of a compound, providing critical data needed to calculate other key pharmacokinetic parameters, e.g., bioavailability and half-life (t1 / 2).

[0338] Methods: A high-throughput assay is used to determine metabolic stability of disclosed compounds and any comparators therefore in human liver microsomes. LC / MS analysis is used to quantify the percent compound remaining after incubation. The half-life (t1 / 2) is estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) versus time, assuming first order kinetics.Example 3: In Vitro Metabolic Profiling

[0339] Purpose: To determine whether a disclosed compound is metabolized and to identify metabolites thereof.

[0340] Methods: An in vitro study is conducted to evaluate metabolism and metabolites of disclosed compounds in human liver microsomes, such as S9 hepatocytes. Briefly, disclosed compounds are incubated with human liver microsomes and / or various recombinant enzymes to determine metabolism and formation of metabolites. Following incubation, the supernatant is analyzed directly by ultra-high performance liquid chromatography-mass spectrometry.

[0341] Phase I and / or Phase II metabolites are identified using mass spectrometry (MS). The % compound remaining and half-life of the disclosed compound (parent compound) are determined. MS data, such as extracted ion chromatograms, show parent and major metabolites. Metabolic transformation for each observed metabolite is elucidated, and metabolite masses, peak areas, and retention times are determined. Metabolic profiling may also be conducted according to the methods described in Muller & Rentsch, Anal Bioanal Chem. 2012;402:2141-2151 and Pedersen et al., Drug Metab Dispos. 2013;41 :1247-1255.

[0342] Results & Significance: Compounds that undergo metabolism in vivo may produce pharmacologically active or chemically reactive metabolites that produce unexpected effects or potential toxicities. The FDA Guidance for Industry on Safety Testing of Drug Metabolites highlights the relevance of in vitro metabolite profiling early in drug development, as metabolites which are unique to or disproportionate in humans may require additional toxicological studies.Example 4: In Vitro CYP Enzyme Inhibition

[0343] Purpose: To assess the interactions between disclosed compounds and cytochrome P450 (CYP450) enzymes. Such interactions will provide insight into metabolism-mediated drug-drug interactions, which can occur when a compound affects the pharmacokinetics, such as the absorption, distribution, metabolism, and excretion, of simultaneously administered drugs by altering the activities of drug metabolizing enzymes and / or drug transporters.no

[0344] Methods: An in vitro study is conducted to assess the inhibitory effect of the disclosed compound on recombinant human CYP450 isoenzymes. Recombinant human CYP450 isoenzymes are used to metabolize pro-fluorescent probe substrates to fluorescent products. Inhibition of human P450 isoforms is measured by reduced fluorescence following treatment with the disclosed compound at various concentrations.

[0345] Briefly, the disclosed compound is incubated in different concentrations in a mix containing buffer, enzymes, and substrate. Then, fluorescence is measured using a plate reader and percentage inhibition may be extrapolated out from the readings. Alternatively, the inhibitory effects of the disclosed compound on CYP enzymes may be assessed using high-performance liquid chromatography. Inhibition is evaluated using the Michaelis-Menten method. CYP enzyme inhibition may be conducted according to the methods described in Lin et al., J Pharm Sci. 2007;96(9):2485-95 and Wojcikowski et al., Pharmacol Rep. 2020;72(3):612-621.

[0346] Results & Significance: Metabolizing enzymes in the liver, such as CYP450 enzymes, are responsible for the majority of drug metabolism that occurs in the body. Six CYP450 class enzymes metabolize 90 percent of drugs, and two of the most significant metabolizers are CYP3A4 and CYP2D6 (Lynch & Price, Am Fam Physician. 2007;76(3):391 -6). Compounds can interact with such enzymes by inhibiting their enzymatic activity (CYP inhibition) or by inducing their gene expression (CYP induction).Example 5: In vitro evaluation of membrane permeability and interactions with P-glycoprotein (P-gp) in MDCKII MDR1 cells

[0347] Purpose: To assess the permeability and transport liability of disclosed compounds. Permeability is assessed using MDCK (Madin-Darby canine kidney) cells, and the effects of P-glycoprotein (P-gp) are evaluated to determine drug transport.

[0348] Methods: A bidirectional permeability study (apical to basolateral [AB] and basolateral to apical [BA]) is conducted to evaluate the apparent permeability of the disclosed compound. Additionally, the compound is evaluated to determine if it acts as a P-gp substrate in MDCKII-MDR1 and mock MDCKII cell lines.

[0349] Briefly, the disclosed compound and reference compounds are evaluated in two directions in the absence and presence of a P-gp inhibitor. The MDCKII and MDCKII-MDR1 cells are incubated in a transport buffer on both apical [A] and basolateral [B] sides. Then, the disclosed compound is added to each side of the cells and incubated. The rate of transport of the disclosed compound is determined in the absence or presence of a P-gp inhibitor. Following incubation, where the disclosed compound will permeate the cells in both AB and BA directions, the permeability of the cells is measured using a LC MS / MS system. The efflux ratio of the disclosed compound is calculated to determine if it is a P-gp substrate.

[0350] Results & Significance: This screening provides insight into the movement of the compound in a biological system. Compounds are classified as follows (Cambridge MedChem Consulting, ADME, 2019):

[0351] Mass balance as a percentage (%) is calculated using: %Recovery = 100 x (CD(t) + CR(t)) / Co

[0352] Where CD(t) is the measured concentration in the donor well at time t (expressed as IS ratio), CR(t) is the measured concentration in the receiver well at time t (expressed as IS ratio), Cois the initial concentration in the donor solution (expressed as IS ratio).

[0353] The percentage of cell integrity is calculated using the following equation:%l ntegrity = 100 x [1 -RFUbasolateral / RFUapical]

[0354] LY RFU values are normalized by background mean values. A test item is considered to be a P-gp substrate when the efflux ratio in the absence of the inhibitor is >2 and if the ratio is significantly reduced in the presence of a P-gp inhibitor.Example 6: In Vitro Activity at Trace Amine-Associated Receptor 1 (TAAR1)

[0355] Purpose: To assess the activity of disclosed compounds at trace amine-associated receptor 1, a target of psychoactive substances. See, e.g., Rickli et al., Neuropsychopharmacology, 2016;26(8), 1327-1337, Simmler et al., Br J Pharmacol. 2013 Jan; 168(2): 458-470, and Simmler et al., Journal of Pharmacology and Experimental Therapeutics, 2016;357(1):134-144.

[0356] Methods: A radioligand binding assay is performed according to previously described methods, for example, by Rickli et al., Neuropsychopharmacology, 2016;26(8), 1327-1337, using [3H] RO5166017 as a radiolabel and RO5166017 as a competitor. Briefly, membrane preparations of human embryonic kidney (HEK) 293 cells that overexpress TAAR1 receptors, for example, of human origin (Revel et al., PNAS, 2011 ;108:8485-8490) are incubated with the radiolabeled selective ligand at concentrations equal to Kd. Ligand displacement by the compounds is then measured. Specific binding of the radioligand to the target receptor is defined as the difference between the total binding and nonspecific binding that is determined in the presence of selected competitors in excess.

[0357] Results & Significance: Activation of TAAR1 has been shown to modulate monoaminergic neurotransmission. See, e.g., Revel et al., PNAS. 2011;108(20):8485— 8490. TAAR1 may be a promising target for the treatment of neuropsychiatric disorders. For example, the effects of TAAR1 activation on dopaminergic neurotransmission may provide therapeutic benefit for addiction, such as substance use disorders (Liu & Li, Front Pharmacol. 2018;9:279).Example 7: Prodrug Hydrolysis in Serum

[0358] Pooled mixed gender human plasma (2 ml), mouse plasma, rat plasma and dog plasma are equilibrated at 37 °C. A disclosed compound is added so as to achieve a concentration of 1.0 ug / mL. Aliquots (50 uL) of the mixture are withdrawn at timed intervals (0, 0.004, 0.5, 1 , 2 and 4 hours) andquenched with 200 uL of methanol / acetonitrile (1 :1). The samples are vortexed and stored at -80° C until analysis. Assays are done in triplicate. Control samples are done in phosphate buffered saline (PBS, pH 7.4) and simulated gastric fluid (SGF, pH 2). Analysis of samples is performed by HPLC-MS to determine the amounts of prodrug and drug in each sample tested. The mean concentrations of prodrug remaining at different time points of the experiment are determined.Example 8: Prodrug Absorption and Hydrolysis in an In Vitro Model of Human Intestinal Mucosa

[0359] Purpose: Caco-2 cells are derived from the human colon adenocarcinoma cell line, and are a valuable in vitro model for studying drug absorption in intestinal cells. In this assay, Caco-2 cells are cultured on transwell inserts with a semi-porous polycarbonate membrane, forming a continuous monolayer that closely mimics the morphology and function of human small intestinal epithelial cells, and compartments on either side to mimic the intestinal lumen and bloodstream. With marker enzyme expression, uptake, transport, and permeability characteristics akin to those of small intestinal epithelial cells, Caco-2 cells offer a robust model for understanding drug absorption processes. Research suggests in vitro cell experiments using Caco-2 cells can provide more accurate insights into drug absorption compared to animal experiments (Truffin et al. Future Pharmacol. 2023;3(1):229-237; Liu et al. Food Funct. 2020; 11 (5):4014-4025).

[0360] Methods: A Caco-2 permeability assay is performed using the CacoReady™ model (Readycell, Barcelona, Spain) consisting of Caco-2 cells seeded on polycarbonate filters (0.4 pm pore size, 6.5 mm diameter), in the apical chamber of 24-well high throughput screening plates (Corning Incorporated, NY, USA). Cells are seeded at a density of 1 x 105cells per mL in an appropriate medium and buffer solution. Cell culturing proceeds at 37 °C for 21 days, with culture medium changes every second day to allow the formation of a confluent monolayer. The apical chamber represents the intestinal lumen, and the basal chamber represents the bloodstream.

[0361] Prior to experimentation, the integrity of the monolayer is assessed by measuring the transepithelial electrical epithelial resistance (TEER), and the apparent permeability coefficient (Papp) of the monolayer is assessed by measuring the permeability of a fluorescent paracellular marker. Only wells with a TEER value >600 Q cm-2and Papp<0.8 x 10"6cm s-1are used in the transport experiments.

[0362] The culture media in the apical and basal chambers are removed and washed with the pre-warmed buffer solution (at 37 °C 15 min in an incubator) twice. 1.25 mL of prewarmed buffer is added in the basal chamber. Test compounds are dissolved in DMSO and properly diluted in buffer to obtain a final DMSO concentration of 0.1% (v / v). 0.25 mL of the test compound solution is then added into the apical chamber of the transwells. 0.5 mL aliquots of solution are taken from the basal chamber of the trans-wells at 0.5, 1 , 2, and 4 h intervals. The concentration of a test compound and its hydrolyzed metabolites in these samples is determined by HPLC. An equal volume of buffer solution is added to the transwells after taking a sample to compensate for the reduction in total volume. The TEER value of the monolayer is monitored throughout the whole experiment.

[0363] Results & Significance: Results can show that certain disclosed compounds having a drug bound to a vitamin B6 (e.g. pyridoxal) promoiety are likely to be absorbed and hydrolyzed by human intestinal mucosa cells. The absorption and hydrolysis rate is also evaluated and compared amongst compounds. Results can be represented as a concentration (pg / mL) per incubation time. Differences between the in vitro absorption and hydrolysis of disclosed compounds and suitable comparator compounds are also determined according to the described methods.Example 9: In Vivo Pharmacokinetics of Disclosed Compounds in Rats

[0364] Disclosed compounds are administered to rats by injection (intravenous and subcutaneous) with a sterile solution (2 mg / ml) at a rate of 1.4-2 mg / kg. Blood samples are taken at 15, 30, 45, 60, 120, 240 min and 360 min and analyzed by LC-MS for the disclosed compound (i.e., the prodrug) and its corresponding component drug. The pharmacokinetic (PK) profile for the prodrug and active species are obtained and relative bioavailability is determined for each of the routes of administration. PK-PD type curves can be generated to demonstrate the activity of disclosed compounds. PK parameters that can be determined according to this assay include Cmax, Tmax, t1 / 2, AUG, and bioavailability.Example 10: In Vivo Assessment Of The Behavioral Effects Of Disclosed Compounds Using A Head-Twitch Response (HTR) Assay

[0365] Purpose: The mouse head-twitch response (HTR) is a behavioral test that reflects S-HT^ receptor activation and can be predictive of psychedelic effects in humans (Halberstadt et al., J Psychopharmacol. 2011 ;25(11): 1548— 1561 ). The HTR is widely used as a behavioral surrogate for human psychedelic effects for its ability to reliably distinguish psychedelic from non-psychedelic 5-HT2Areceptor agonists (Halberstadt & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3).

[0366] Methods: An HTR assay is performed in accordance with the methods described in Klein et al., Neuropharmacol. 2018;142:231-239 to assess the effects of disclosed compounds in mice. Male C57BL / 6 J mice (6-8 weeks old) are obtained and housed in a vivarium that meets all requirements for care and treatment of laboratory animals. Mice are housed up to four per cage in a climate-controlled room on a reverse-light cycle (lights on at 1900 h, off at 0700 h) and are provided with ad libitum access to food and water, except during behavioral testing. Testing is conducted between 1000 and 1800 h. All animal experiments are conducted in accordance with applicable guidelines and are approved by an appropriate animal care committee.

[0367] A head-mounted magnet and a magnetometer detection coil is used to assess HTR, as previously described (Halberstadt & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3, Halberstadt & Geyer, Neuropharmacol, 2014;77:200-7; Nichols et al., ACS Chem Neurosci. 2015;6(7):1165— 1175). Briefly, mice are anesthetized and a small neodymium magnet is attached to the dorsal surface of the cranium using dental cement. Following a two-week recovery period, HTR experiments are carried out in a well-lit room with at least 7 days between sessions to avoid carryover effects.

[0368] Test compounds are dissolved in a suitable solvent, e.g., water containing 5% Tween 80, and administered IP at a volume of 5 or 10 mL / kg body weight immediately prior to testing. Different doses are tested to produce a dose-response curve. Mice are injected with drug or vehicle, and HTR activity is recorded in a glass cylinder surrounded by a magnetometer coil for 30 min. Coil voltage is low-pass filtered (2e10 kHz cutoff frequency), amplified, and digitized (20 kHz sampling rate) using a Powerlab / 8SP with LabChart v 7.3.2 (ADInstruments, Colorado Springs, CO, USA), then filtered off-line (40e200 Hz band-pass).

[0369] Head twitches are identified manually based on the following criteria: 1) sinusoidal wavelets; 2) evidence of at least two sequential head movements (usually exhibited as bipolar peaks) with frequency 40 Hz; 3) amplitude exceeding the level of background noise; 4) duration < 0.15 s; and 5) stable coil voltage immediately preceding and succeeding each response.

[0370] Head twitch counts are analyzed using one-way analyses of variance (ANOVA). Post hoc pairwise comparisons between selected groups are performed using Tukey’s studentized range method. The entire recordings are examined for head twitches. In some cases a shorter block of time is analyzed to accommodate compounds with a brief duration-of-action, as potency calculations can be confounded by extended periods of inactivity. ED50values and 95% confidence limits are calculated using nonlinear regression. Relationships between HTR potency and binding affinities are assessed using linear regression and ordinary least-squares regression. For all analyses, significance is demonstrated by surpassing an a-level of 0.05.

[0371] Results & Significance: Results can show that certain disclosed compounds having a psychedelic drug bound to a vitamin B6 (e.g. pyridoxal) promoiety are likely to produce psychedelic effects in humans. The magnitude of such effects is also evaluated and compared amongst compounds. Results can be represented as ED50(mg / kg). Differences between the mouse HTR of disclosed compounds and suitable comparator compounds are also determined according to the described methods.

[0372] The foregoing description, for purposes of explanation, uses specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that specific details are not required in order to practice the invention. Thus, the foregoing description of specific embodiments of the invention is presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise compositions, formulations, methods, or the like disclosed; many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, through the elucidation of specific examples, and to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated, when such uses are beyond the specific examples disclosed. Accordingly, the scope of the invention shall be defined solely by the following claims and their equivalents.

Claims

CLAIMSThe invention claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein:X is H or PO3H2;Rais H or CrCg alkyl;Rpis H, OH, or C^Cg alkoxy;R2, R3, R4, and R5are each independently H, Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or -SONH; andR6is H; or any of R2and R3, R3and R4, R4and R5, and R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R2, R3, R4, R5, and R6as defined above; provided that at least two of R2, R3, R4, R5, and R6are not H.

2. The compound of claim 1 , having the structure of Formula (IA):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R24and R5Aare each independently CrC6alkyl, CrC6haloalkyl, or CrC6deuteroalkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is Br.

4. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is CrCg alkyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is — CH3.

6. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is C^Cg alkylthio.

7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is — SCH2CH2CH3.

8. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R2Ais CrCg alkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R2Ais — CH3.

10. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4Ais C^Cg alkyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4Ais — CH3.

12. The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4Ais — CH2CH3.

13. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein Rais H.

14. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein Rpis H.

15. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein X is H.

16. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein X is PO3H2.

17. The compound of claim 1, having the structure of Formula (IB):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein: R3A, R4A, and R5Aare each independently CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, or CrC6haloalkyl, wherein the CrC6alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl.

18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R3Ais CrC6alkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R3Ais — CH3.

20. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4Ais CrC6alkyl.21 . The compound of claim 20, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4Ais — CH3.

22. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R5Ais CrC6alkyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R5Ais — CH3.

24. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein Rais CrC6alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein Rais — CH3.

26. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvatethereof, wherein Rais H.

27. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein Rpis H.

28. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein X is H.

29. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein X is PO3H2.

30. A compound selected from Table IA, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.31 . The compound of claim 30, having the structure of:or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

32. The compound of claim 31 , having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

33. The compound of claim 31 , having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

35. The compound of claim 31 , having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

36. The compound of claim 30, having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

37. The compound of claim 30, having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

38. The compound of claim 30, having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

39. The compound of claim 30, having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

40. A compound selected from Table IB, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

41. The compound of claim 40, having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

42. The compound of claim 40, having the structureor a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

43. The compound of claim 2, having the structure of Formula (I A- 1 ):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

44. The compound of claim 2, having the structure of Formula (I A-2) :or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

45. The compound of claim 2, having the structure of Formula (I A-3) :or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

46. The compound of claim 2, having the structure of Formula (I A-4) :or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

47. The compound of claim 2, having the structure of Formula (I A-5) :or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

48. The compound of claim 2, having the structure of Formula (I A-6) :or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

49. The compound of claim 2, having the structure of Formula (I A-7) :or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

50. The compound of any one of claims 43-49, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is Br.51 . The compound of any one of claims 43-49, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is C^Cg alkyl.

52. The compound of claim 51 , or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is — CH3.

53. The compound of any one of claims 43-49, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is CrC6alkylthio.

54. The compound of claim 53, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R4is — SCH2CH2CH3.

55. The compound of claim 1 , having the structure of Formula (IC):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein n is independently at each occurrence 1 or 2.

56. The compound of claim 55, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein n is 1.

57. The compound of claim 55, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein n is 2.

58. The compound of claim 1, having the structure of Formula (ID):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

59. The compound of claim 1, having the structure of Formula (IE):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R’ and R” are each independently H, F, or D.

60. The compound of claim 59, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R’ and R” are both H.61 . The compound of claim 59, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R’ and R” are both F.

62. The compound of claim 59, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R’ and R” are both D.

63. The compound of any one of claims 43-62, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein Rais H.

64. The compound of any one of claims 43-62, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein Rais — CH3.

65. The compound of any one of claims 43-64, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein Rpis H.

66. The compound of any one of claims 43-65, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein X is H.

67. The compound of any one of claims 43-65, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein X is PO3H2.

68. A compound of Formula (A):or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein:X is H or PO3H2;Rais H or CrC6alkyl;Rpis H, OH, or C^Cg alkoxy;R2, R3, R4, and R5are each independently H, Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, CrCg alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each CrCg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, CrCg alkylthio, CrCg haloalkyl, CrCg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, or -SONH; andR6is H; or any of R2and R3, R3and R4, R4and R5, and R5and R6are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R2, R3, R4, R5, and R6as defined above.

69. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-49, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

70. The pharmaceutical composition of claim 69, wherein the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.71 . The pharmaceutical composition of claim 69, wherein the composition is provided in unit dosage form.

72. The pharmaceutical composition of claim 71 , comprising the compound in a total amount of between 1 and 200 mg, or between 5 and 100 mg.

73. The pharmaceutical composition of claim 72, comprising the compound in a total amount of between 10 and 75 mg, or between 15 and 50 mg.

74. The pharmaceutical composition of claim 71 , wherein the unit dosage form is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

75. The pharmaceutical composition of claim 69, further comprising a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

76. The pharmaceutical composition of claim 75, wherein the additional active compound is selected from the group consisting of: amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, anti hypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins.

77. The pharmaceutical composition of claim 75, wherein the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, or alter pharmacokinetics or pharmacodynamics.

78. The pharmaceutical composition of claim 76, wherein the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

79. A method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-49, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

80. The method of claim 79, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission.81 . The method of claim 80, wherein the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission.

82. The method of claim 81, wherein the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of serotonergic, dopaminergic, or noradrenergic neurotransmission.

83. The method of claim 79, wherein the medical condition is a mental health disorder.

84. The method of claim 83, wherein the mental health disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, alcohol or drug abuse or dependence disorders, a substance use disorder, substance-induced mood disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, and dissociative disorders.

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

86. The method of claim 84, wherein anxiety is generalized anxiety disorder (GAD).

87. The method of claim 84, wherein the mental health disorder is PTSD.

88. The method of claim 84, wherein the substance use disorder is alcohol use disorder (AUD), nicotine dependence or tobacco use disorder, opioid use disorder (OLID), stimulant use disorder, or sedative, hypnotic, or anxiolytic use disorder.

89. The method of claim 79, wherein the medical condition is a neurodegenerative disorder, pain or a pain disorder, or inflammation or an inflammatory disorder.

90. The method of claim 79, wherein the compound is administered together with one or more sessions of psychotherapy or psychological support.91 . A method of modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 -47, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

92. The method of claim 91, wherein modulating neurotransmission comprises activating a monoamine neurotransmitter receptor and / or modulating the uptake activity of a monoamine transporter.

93. The method of claim 92, wherein the monoamine neurotransmitter receptor is any of a serotonin receptor (HTR), a dopamine receptor, and a norepinephrine receptor.

94. The method of claim 92, wherein the monoamine transporter is any of a serotonin transporter (SERT), a dopamine transporter (DAT), or a norepinephrine transporter (NET).

95. The method of claim 93, wherein the HTR is any of HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, and HTR6.

96. The method of claim 95, wherein modulating neurotransmission comprises agonizing HTR2A.

97. A method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-68, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

98. A method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 69-78.

99. .A method of modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 -68, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

100. A method of modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 69-78.

101. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, for use in the treatment of a medical condition.

102. A compound of any one of claims 1-68, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, for use in the treatment of a medical condition.

103. Use of the compound of any one of claims 1 -47, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, for the manufacture of a medicament for the treatment of a mental health disorder patient according to the method of any of the following claims.

104. Use of the compound of any one of claims 1 -68, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, for the manufacture of a medicament for the treatment of a mental health disorder patient according to the method of any of the following claims.

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