Phenylalkylamine prodrugs

Abstract

Provided herein are prodrugs of phenylalkylamines (e.g., psychedelic phenethylamines) incorporating 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. [Formula 1] JPEG2026508371000104.jpg3673

Description

[Technical Field]

[0001] cross reference Priority is claimed under PCT Article 8(1) and Rule 4.10 to U.S. Provisional Patent Application No. 63 / 449,511, filed March 2, 2023, and U.S. Provisional Patent Application No. 63 / 468,956, filed May 25, 2023, both of which are incorporated by reference in their entireties for all purposes.

[0002] Technical Field The present 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 the disclosed compounds and compositions to treat medical conditions, such as psychiatric, behavioral, and neurodevelopmental disorders.

[0003] Background of the Invention The significant impact of mental health disorders on public health, coupled with the limitations of existing therapies, highlights the urgent need for improved treatment options. This includes the development of effective interventions with minimal side effects. Psychedelic drugs have shown promising efficacy in addressing various mental health conditions, such as depression, post-traumatic stress disorder, addiction, and anxiety. The development of prodrugs of psychedelic drugs for therapeutic use offers the opportunity to tailor pharmacokinetic profiles and enhance safety and efficacy for clinical use, leading to greater utility in the treatment of mental health disorders, among other conditions. Provided herein are therapeutic prodrug compounds, as well as compositions, kits, and methods of use, that fulfill this need and have other benefits and advantages that will become apparent in light of the following disclosure.

[0004] Incorporation by Reference Each of the cited patents, publications, and non-patent literature is incorporated by reference in its entirety as if each were individually incorporated and as if each were fully set forth herein. However, such citation should not be construed as an admission that the cited references are from areas of similar or direct applicability to the present invention, nor should any citation be construed as an admission that the documents or underlying information in any jurisdiction are part of the prior art or common general knowledge in the art.

[0005] Brief Summary of the Invention The following is a simplified summary of some embodiments of the invention in order to provide a basic understanding of the invention. It is not an extensive overview of the invention, nor is it intended to identify key or critical elements of the invention or to delineate its scope. 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, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, compound is provided, During the ceremony: X is H or PO3H2; R α is H or C1-C6 alkyl; R β is H, OH, or C1-C6 alkoxy; R 2 , R 3 , R 4 and R 5are each independently H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino. heterocycloalkyl or amino is optionally substituted independently 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; R 6 is H; or R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and the remaining R 2 , R 3 , R 4 , R 5 , and R 6 is as defined above; However, R 2 , R 3 , R 4 , R 5 , and R 6 At least two of them are not H.

[0007] In another embodiment, a compound of formula (A): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, During the ceremony: X is H or PO3H2; R α is H or C1-C6 alkyl; R β is H, OH, or C1-C6 alkoxy; R 2 , R 3 , R 4 and R 5 are each independently H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino. heterocycloalkyl or amino is optionally substituted independently 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; R 6 is H; or R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6are taken together to form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and the remaining R 2 , R 3 , R 4 , R 5 , and R 6 is as defined above.

[0008] In some embodiments, the compound has the structure of formula (IA), (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: [Table 1-1] [Table 1-2] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R α , R β and X is 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: [Table 2-1] [Table 2-2] (In the formula, R 1, R 2 , R 3 , R 4 , R 5 , R 6 , R α , R β and X is as defined for formula (I).

[0010] In some embodiments, R 4 is Br. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is C1-C6 alkylthio. In some embodiments, R 4 is -SCH2CH2CH3.

[0011] In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is -CH3.

[0012] In some embodiments, R 3A is C1-C6 alkyl. In some embodiments, R 3A is -CH3.

[0013] In some embodiments, R 4A is C1-C6 alkyl. In some embodiments, R 4A is -CH3. In some embodiments, R 4A is -CH2CH3.

[0014] In some embodiments, R 5A is C1-C6 alkyl. In some embodiments, R 5A is -CH3.

[0015] In some embodiments, R α is H. In various embodiments, R α is C1-C6 alkyl. In various embodiments, R αis -CH3.

[0016] In some embodiments, R β is 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 Table IB, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

[0020] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0021] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

[0023] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0024] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0025] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0026] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

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

[0029] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

[0030] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, which may be any of the disclosed embodiments, 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 a unit dosage form. In some embodiments, the composition comprises the compound in a total amount of 1 mg to 200 mg, or 5 mg to 100 mg. In some embodiments, the composition comprises the compound in a total amount of 10 mg to 75 mg, or 15 mg to 50 mg. In some embodiments, the unit dosage form is an immediate release formulation, a controlled release formulation, a sustained release formulation, an extended release formulation, or a 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, hi some embodiments, the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathic and anti-nociceptive agents, anti-migraine agents, anti-anxiety agents, antidepressants, antipsychotics, anti-PTSD agents, dissociative agents, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, appetite stimulants, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotective agents, cognitive enhancers, 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, reduce an undesirable effect, increase stability or shelf life, improve bioavailability, induce a synergistic effect, or alter pharmacokinetics or pharmacodynamics. In some embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anti-cancer, antiemetic, appetite stimulant, 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 thereof, comprising administering to the subject a therapeutically effective amount of a compound or composition, which can be any of the disclosed embodiments.

[0033] In some embodiments, the medical condition is a disorder associated with dysregulated or improper functioning of neurotransmission. In some embodiments, the disorder associated with dysregulated or improper functioning of neurotransmission is a disorder of monoaminergic neurotransmission. In some embodiments, the disorder associated with dysregulated or improper functioning of neurotransmission is a disorder 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, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety disorder, phobic disorder, bulimia, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance use disorder, substance-induced mood disorder, mood disorder associated with another health condition, disruptive behavior disorder, eating disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, and dissociative disorder. In some embodiments, the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD). In some embodiments, the anxiety disorder is generalized anxiety disorder (GAD). In various embodiments, the mental health disorder is PTSD. In various embodiments, the substance use disorder is alcohol use disorder (AUD), nicotine dependence or tobacco use disorder, opioid use disorder (OUD), stimulant use disorder, or sedative, hypnotic, or anxiolytic use disorder.

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

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

[0037] Also provided are methods of modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of a compound or composition, which may be 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 may be any of a serotonin receptor (HTR), a dopamine receptor, and a norepinephrine receptor. In some embodiments, the monoamine transporter may be any of a serotonin transporter (SERT), a dopamine transporter (DAT), or a norepinephrine transporter (NET). In some embodiments, the HTR may be an HTR 1A , HTR 1B , HTR 2A , HTR 2B , HTR 2C In some embodiments, modulating neurotransmission may be HTR6. 2A This includes agonizing the

[0038] Also provided is a compound or composition, which may be any of the disclosed embodiments, for use in treating a medical condition.

[0039] Also provided is the use of a compound or composition, which may be any of the disclosed embodiments, for the manufacture of a medicament for treating a patient with a mental health disorder, according to any of the methods claimed below.

[0040] The foregoing has outlined, in a broad and concise manner, certain pertinent features of the present disclosure so that the detailed description of the invention that follows may be better understood, and so that the present contributions to the art may be more fully appreciated. This summary, therefore, should be considered a brief, general overview of only some of the objects and embodiments disclosed herein, and is provided solely for the benefit and convenience of the reader. It is not intended to limit in any way the scope or equivalents to which the claims are lawfully entitled. Additional features of the present invention are described below. It should be understood by those skilled in the art that all disclosed specific compositions and methods are merely illustrative 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 should also be understood to be within the scope and spirit of the invention as set forth in the claims.

[0041] The headings in this document are used solely to facilitate the reader's review. They should not be construed as limiting the invention in any way. DETAILED DESCRIPTION OF THE INVENTION

[0042] While various aspects and features of certain embodiments have been summarized above, the following detailed description sets forth several exemplary embodiments in further detail to enable those skilled in the art to implement such embodiments and to make and use the full scope of the invention as claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its application. It will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention shown herein may be made by those skilled in the art without departing from the spirit of the invention or the scope of the invention as set forth in the appended claims. Furthermore, where possible, any element of an embodiment is meant to be combined with any element from any other embodiment to describe additional embodiments. It will also be understood that the headings within this document are utilized solely to facilitate the reader's review and should not be construed as limiting the invention in any way.

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

[0044] A. General Definitions and Terminology 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 a reference to a combination of two or more active agents, and reference to "an excipient" includes a reference to a combination of two or more excipients. While the term "one or more" may be used, its absence (or its replacement with the singular) does not mean exclusively the singular, but merely highlights the possibility of multiple agents or ingredients in a particular embodiment.

[0045] The terms "comprising," "including," "such as," and "having" are intended to be inclusive and not exclusive (i.e., other elements may be present in addition to the listed elements). Accordingly, 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 dictates otherwise.

[0046] Unless otherwise indicated, all numbers expressing properties such as quantities and concentrations of ingredients, reaction conditions, and the like, used to describe and claim particular embodiments of the present invention should be understood to be modified in some cases by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the desired properties sought to be obtained by a particular embodiment. In some embodiments, "about" refers to plus or minus 5 percent (±5%) of the recited unit of measure. The term "substantially," when applied to modify a feature or limitation herein, should be read in light of the knowledge in the art to provide an appropriate degree of certainty in the context of the present invention, for example, by using art-recognized standards for measuring the meaning of "substantially" as a term of degree, or by ascertaining ranges as would be done by one of ordinary 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 as practicable. The numerical values ​​set forth in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0048] A comprehensive list of abbreviations utilized by organic chemists of ordinary skill in the art appears in Issue 1 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 application is incorporated herein by reference as if fully set forth herein.

[0049] Unless otherwise defined, all technical and scientific terms herein have the meanings commonly understood by those of ordinary skill in the art to which this invention belongs (who may be referred to simply as "persons of ordinary skill in the art" for short). Additional definitions that may aid the reader in understanding the disclosed embodiments are provided below. However, it will be understood that such definitions are not intended to limit the scope of the invention, but should be properly interpreted and understood by reference to the entire specification (and any clear meaning known to those skilled in the art) in light of the language used in the appended claims. The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

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

[0051] "Alkyl" is understood to include straight-chain or branched radicals having any degree or level of saturation, i.e., groups having only a single carbon-carbon bond, 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 contains 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms. For any alkyl, the alkyl is optionally substituted at one or more positions with 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, —O—S—O—H, or —S—O—H.

[0052] "Alkanyl" refers to a saturated branched, straight-chain, or cyclic alkyl radical obtained by removing one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include methanyl; ethanyl; propanyl, such as propan-1-yl, propan-2-yl (isopropyl), and cyclopropan-1-yl; butanyl, 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.

[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; propenyl, 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; butenyl, 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.

[0054] "Alkynyl" refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon triple bond derived by removing one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include ethynyl; propynyl, e.g., prop-1-yn-1-yl and prop-2-yn-1-yl; butynyl, e.g., 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 removing one hydrogen (H) atom from a single carbon atom of a parent aromatic ring system. Representative 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, the aryl group contains 6 to 20 carbon atoms, more preferably 6 to 12 carbon atoms.

[0056] "Amino" refers to -NR2, where each R is independently H, OH, or C1-C6 alkyl, which is optionally substituted. An amino group may be a primary amino group (-NH2), a secondary amino group (-NHR), a tertiary amino group (-NR2), or a quaternary amino group (-NR3). + ), where R is independently H or C1-C6 alkyl, which is optionally substituted.

[0057] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can be any number of carbon atoms, e.g., 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, 10 to 12 carbon atoms, 11 to 12 carbon atoms, 12 to 12 carbon atoms, 13 to 13 carbon atoms, 14 to 14 carbon atoms, 15 to 15 carbon atoms, 16 to 16 carbon atoms, 17 to 17 carbon atoms, 18 to 18 carbon atoms, 19 to 20 carbon atoms, 20 to 21 carbon atoms, 21 to 22 carbon atoms, 22 to 23 carbon atoms, 23 to 24 carbon atoms, 24 to 25 carbon atoms, 25 to 26 carbon atoms, 26 to 27 carbon atoms, 27 to 28 carbon atoms, 28 to 29 carbon atoms, 29 to 30 carbon atoms, 30 to 31 carbon atoms, 31 to 32 carbon atoms, 32 to 33 carbon atoms, 33 to 34 carbon atoms, 34 to 35 carbon atoms, 35 to 36 carbon atoms, 36 to 37 carbon atoms, 37 to The cycloalkyl ring may contain 0 carbon atoms, 9-10 carbon atoms, 3-11 carbon atoms, 4-11 carbon atoms, 5-11 carbon atoms, 6-11 carbon atoms, 7-11 carbon atoms, 8-11 carbon atoms, 9-11 carbon atoms, 10-11 carbon atoms, 3-12 carbon atoms, 4-12 carbon atoms, 5-12 carbon atoms, 6-12 carbon atoms, 7-12 carbon atoms, 8-12 carbon atoms, 9-12 carbon atoms, 10-12 carbon atoms, and 11-12 carbon atoms. Examples of monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Examples of bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. Examples of bicyclic and polycyclic cycloalkyl rings include norbornane, bicyclooctane, decahydronaphthalene, and adamantane. When the cycloalkyl is a monocyclic C 3-8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When it is cycloalkyl, exemplary groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0058] "Cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring. However, if more than one double bond is present, the double bonds cannot form a completely delocalized π-electron system across all rings (otherwise the group would be an "aryl" as defined herein). When composed of more than one ring, the rings can be joined together in a fused fashion. Cycloalkenyl can be any number of carbon atoms, e.g., 3-6 carbon atoms, 4-6 carbon atoms, 5-6 carbon atoms, 3-8 carbon atoms, 4-8 carbon atoms, 5-8 carbon atoms, 6-8 carbon atoms, 7-8 carbon atoms, 3-9 carbon atoms, 4-9 carbon atoms, 5-9 carbon atoms, 6-9 carbon atoms, 7-9 carbon atoms, 8-9 carbon atoms, 3-10 carbon atoms, 4-10 carbon atoms, 5-10 carbon atoms, 6-10 carbon atoms, 7-10 carbon atoms, 8-10 carbon atoms, 9-10 carbon atoms, 10-10 carbon atoms, 11-10 carbon atoms, 12-10 carbon atoms, 13-10 carbon atoms, 14-10 carbon atoms, 15-10 carbon atoms, 16-10 carbon atoms, 17-10 carbon atoms, 18-10 carbon atoms, 19-20 carbon atoms, 20-21 carbon atoms, 21-22 carbon atoms, 22-23 carbon atoms, 23-24 carbon atoms, 24-25 carbon atoms, 25-26 carbon atoms, 26-27 carbon atoms, 27-28 carbon atoms, 28-29 carbon atoms, 29-30 carbon atoms, 30-31 carbon atoms, 31-32 carbon atoms, 32-33 carbon atoms, 33-34 carbon atoms, 34-35 carbon atoms, 35-36 carbon atoms, 36-37 carbon The alkyl group may include 0 carbon atoms, 9-10 carbon atoms, 3-11 carbon atoms, 4-11 carbon atoms, 5-11 carbon atoms, 6-11 carbon atoms, 7-11 carbon atoms, 8-11 carbon atoms, 9-11 carbon atoms, 10-11 carbon atoms, 3-12 carbon atoms, 4-12 carbon atoms, 5-12 carbon atoms, 6-12 carbon atoms, 7-12 carbon atoms, 8-12 carbon atoms, 9-12 carbon atoms, 10-12 carbon atoms, and 11-12 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. Cycloalkenyl groups can be unsubstituted or substituted.

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

[0060] Both "heterocycloalkyl" and "heterocyclyl" refer to cycloalkyl, as defined above, having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Heterocycloalkyl and heterocyclyl include bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. The heteroatoms can be oxidized (such as, but not limited to, -S(O)- and -S(O)-). Heterocycloalkyl groups can contain any number of ring atoms, for example, 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 a heterocycloalkyl group, 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. Heterocycloalkyl groups 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. Heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be, among others, C 1-6 It can be substituted with alkyl or oxo (=O).

[0061] "Heterocycloalkenyl" refers to a cycloalkenyl, as defined above, having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. The heteroatoms may be oxidized (such as, but not limited to, -S(O)- and -S(O)-). A heterocycloalkenyl group can contain any number of ring atoms, for example, 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 may be included in a heterocycloalkenyl group, 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, dihydropyrane, 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, wherein 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. A heteroaryl group 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 a heteroaryl group, 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 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused to an aromatic ring system, 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, benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), benzopyridazines, such as phthalazine and cinnoline, benzothiophenes, and benzofurans. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridines. Heteroaryl groups can be substituted or unsubstituted.

[0063] "Alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxy can be substituted or unsubstituted.

[0064] "Acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl bonded as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[01] Deuterium ( 2 H or D), also known as "deuterium," is a hydrogen atom with a natural abundance of approximately 1 atom per 6,500 hydrogen atoms (about 154 ppm) in the Earth's oceans. 1 Deuterium is a stable isotope of hydrogen (H). Deuterium therefore accounts for approximately 0.0154% (or 0.0308% by mass) of all naturally occurring hydrogen in the oceans. "Unsubstituted," "non-deuterated," and "under-deuterated" can refer to compounds having no more than the amount of deuterium expected as a percentage of naturally occurring hydrogen in the compound.

[01] A "deuteroalkyl" refers to a group in which one or more hydrogen atoms are replaced with deuterium (i.e., 2Deuteroalkyl is understood to include any alkyl group defined above where two or more hydrogens are replaced by deuterium (H or D). When an alkyl radical is substituted with 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 are replaced by deuterium. A deuteroalkyl can be fully deuterated (i.e., all hydrogens replaced by deuterium) or partially deuterated (i.e., only some of the hydrogens replaced by deuterium). For example, a deuteromethyl (i.e., C1 deuteroalkyl) group refers to -CH2D, -CHD2, or -CD3. A deuteroethyl (i.e., C2 deuteroalkyl) group refers to -CH2CH2D, -CHDCH2D, -CD2CH2D, -CH2CHD2, -CHDCHD2, -CD2CHD2, -CH2CD3, -CHDCD3, or -CD2CD3. A deuteropropyl group (ie, C3 deuteroalkyl) refers to any partially or fully substituted n-propyl or isopropyl group.

[0065] "Haloalkyl" is understood to include any alkyl group as defined above in which one or more hydrogen atoms have been replaced with a halogen (e.g., fluorine, chlorine, bromine, or iodine). When an alkyl radical is substituted with more than one halogen, it can be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkyl refers to an alkyl substituted with two halo groups, which are not necessarily the same halogen. Examples of haloalkyl groups include difluoromethyl (-CHF), bromofluoromethyl (-CHBrF), trifluoromethyl (-CF), and 2-fluoroethyl (-CHCHF). Further examples of haloalkyl groups include -CHF, -CHF, -CHCF, -CHCHF, -CH(CH)(CF), -CH(CH)(CHF), and -CH(CH)(CHF).

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

[0067] "Haloalkoxy" refers to an -O-alkyl group in which one or more of the hydrogen atoms has been replaced with 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, trifluoro-methoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. The haloalkoxy may be substituted or unsubstituted.

[0068] "Alkylthio" refers to a group of formula -SR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. A non-limiting list of alkylthio groups is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio. Alkylthio groups can be substituted or unsubstituted.

[0069] "Sulfenyl" refers to the group -SR, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. Sulfenyl can be substituted or unsubstituted.

[0070] "Sulfinyl" refers to the group -S(=O)-R, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0071] "Sulfonyl" refers to the group -SO2R, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0072] "O-carboxy" refers to the group -RC(=O)O-, where R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. The O-carboxy can be substituted or unsubstituted.

[0073] "Ester" and "C-carboxy" refer to the group -C(=O)OR, where R can be the same as defined for O-carboxy. The ester and C-carboxy groups can be substituted or unsubstituted.

[0074] "Thiocarbonyl" refers to the group -C(=S)R, where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted.

[0075] "Trihalomethanesulfonyl" refers to a X3CSO2- group where each X is a halogen.

[0076] "Trihalomethanesulfonamide" is X3CS(O)2N(R A )-group, where each X is a halogen and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein.

[0077] "S-sulfonamide" is -SO2N(R A R B ) group, wherein R A and R B can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. The S-sulfonamide can be substituted or unsubstituted.

[0078] "N-sulfonamide" is RSO2N(R A )-group, wherein R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-sulfonamides can be substituted or unsubstituted.

[0079] "Oxo" refers to =O.

[0080] "O-carbamyl" is -OC(=O)N(R A R B ) group, wherein R A and R B can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. O-carbamyl can be substituted or unsubstituted.

[0081] "N-carbamyl" is ROC(=O)N(R A )-group, wherein R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-carbamyl can be substituted or unsubstituted.

[0082] "O-thiocarbamyl" is -OC(=S)-N(R A R B ) group, wherein R A and R B can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. O-thiocarbamyl can be substituted or unsubstituted.

[0083] "N-thiocarbamyl" is ROC(=S)N(R A )-group, wherein R and R Acan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-thiocarbamyl can be substituted or unsubstituted.

[0084] A "C-amido" group is a -C(=O)N(R A R B ) group, wherein R A and R B can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. The C-amide can be substituted or unsubstituted.

[0085] "N-amide" is RC(=O)N(R A )-group, wherein R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-amidos can be substituted or unsubstituted.

[0086] Unless otherwise specified, "optionally substituted" means that a group can be unsubstituted or substituted with one or more of the substituents listed for that group. Similarly, when a group is described as "unsubstituted or substituted," if substituted, the substituents can be selected from one or more of the listed substituents. When multiple substituents are present, the substituents can 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, the indicated "optionally substituted" or "substituted" group can be any of 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, It means that the amino group can be substituted with one or more groups individually and independently selected from 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, amino, monosubstituted amino group, disubstituted amino group, and trisubstituted amino group.

[0087] B. Prodrugs In some embodiments, compounds that are prodrugs of psychedelic phenethylamines are provided herein. Prodrugs are inactive derivatives of pharmacologically active drugs designed to undergo chemical or enzymatic activation in vivo, for example, by the action of metabolic, enzymatic, or degradative processes that remove the prodrug moiety (i.e., "promoiety") and form the drug. Depending on the selection of a particular promoiety and the linking chemistry used to connect the promoiety to the drug, prodrugs can be engineered to modulate how the drug is absorbed, distributed, metabolized, and excreted by the body. In addition to simply releasing the drug in vivo, prodrugs can also enhance the pharmacokinetic properties of the drug by targeting specific tissues or cells, increasing solubility across biological barriers, and prolonging drug release. Furthermore, prodrugs can improve therapeutic efficacy by minimizing side effects, increasing drug potency, and reducing required dosages (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, poor solubility, and high toxicity.

[0088] Prodrug modifications have previously been investigated for the delivery of psychedelic phenethylamines. For example, International Publication No. 2022 / 235587 describes the use of lipid structures in prodrugs of psychedelic tryptamine and phenethylamine. Prodrugs containing lipid-soluble lipid moieties may be useful in drug design by enhancing the ability of hydrophilic drugs to cross cellular lipid bilayers (Markovic et al. Med Res Rev. 2019.39, 579-607). However, even lipid-based prodrugs may be unable to cross tough cellular barriers such as the blood-brain barrier. Prodrug strategies using promoieties that can bind to specific transporters on cellular barriers may be more likely to reach the active compound target in tissues (Jornada et al. Molecules. 2016.21(1):42).

[0089] There is a need for diverse prodrug strategies that are effective across a wide range of tissues, cells, and intracellular targets in the human body and can be applied to a wide variety of phenethylamines with therapeutic potential. For example, mescaline is a phenethylamine with a pharmacodynamic mechanism 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). Therefore, this drug requires higher doses for pharmacological activation, which may lead to unnecessary accumulation of mescaline metabolites in other tissues, increasing the chance and severity of non-target effects (Dinis Oliviera et al. Curr Mol Pharmacol. 2019.12(3),184-194). Prodrugging strategies that increase the bioavailability of mescaline and other phenylalkylamines to the brain allow for lower doses, among other benefits related to improved pharmacokinetics and greater central nervous system (CNS) penetration.

[0090] In some embodiments, provided herein are phenethylamine prodrugs incorporating a vitamin B6 moiety. Vitamin B6 has six chemically distinct forms, including pyridoxine, pyridoxal, pyridoxamine, and their respective phosphorylated derivatives: [ka]

[0091] Although pyridoxal 5'-phosphate has the highest biological activity, 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 through dietary means (Calderon-Ospina, et al. CNS Neurosci. Ther. 2020, 26(1), 5-13). Vitamin B6 plays an essential role in neurotransmitter production and therefore must be transported to the CNS (ibid.). 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 transport of therapeutically active components across cell 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] Furthermore, applicants are not aware of the specific compounds and compositions disclosed herein that have been synthesized, formulated, and / or used in the compositions and methods of the present invention. In some embodiments, applicants' disclosed compounds are particularly advantageous. For example, by improving the ability of certain drugs to cross cell membranes and reach their receptor targets, the compounds disclosed herein may result in fewer species or concentrations of metabolites responsible for adverse effects, resulting in an improved side effect profile, and may provide other advantages compared to the corresponding drug compound alone.

[0093] In a first aspect, there is provided a compound of formula (I) [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein: X is H or PO3H2; R α is H or C1-C6 alkyl; R β is H, OH, or C1-C6 alkoxy; R 2 , R 3 , R 4 and R 5are each independently H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino. heterocycloalkyl or amino is optionally substituted independently 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; R 6 is H; or R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and the remaining R 2 , R 3 , R 4 , R 5 , and R 6 is as defined above.

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

[0095] In some embodiments, R α is H or C1-C6 alkyl. In some embodiments, R α is H. In some embodiments, R α is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, R α is methyl (—CH). In some embodiments, R α is ethyl (-CH2CH3).

[0096] In some embodiments, R β is H, OH, or C1-C6 alkoxy. In some embodiments, R β is H. In some embodiments, R β is OH. In some embodiments, R β is C1-C6 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy). In some embodiments, R β is methoxy. In some embodiments, R β is oxo (=O).

[0097] In some embodiments, R 2 , R 3 , R 4 and R 5are each independently H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; R is optionally substituted, independently, 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), -OC(O)H, -OSOOH, -OC(O)NH, or -SONH; ... 6 is H; or R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and the remaining R 2 , R 3 , R 4 , R 5 , and R 6 is as defined above; provided that R 2 , R 3 , R 4 , R 5 , and R 6 At least two of them are not H.

[0098] In some embodiments, R 2is H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; In some embodiments, R is optionally substituted with 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, or —O—S—O—H. 2 is H. In some embodiments, R 2 is halogen (i.e., F, Cl, Br, I). In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is methyl (—CH). In some embodiments, R 2 is ethyl (-CH2CH3). In some embodiments, R 2 is C2-C8 alkenyl. In some embodiments, R 2 is C2-C8 alkynyl. In some embodiments, R 2 is C1-C6 alkoxy. In some embodiments, R 2 is methoxy. In some embodiments, R2 is ethoxy. In some embodiments, R 2 is propoxy. In some embodiments, R 2 is isopropoxy. In some embodiments, R 2 is C1-C6 alkylthio. In some embodiments, R 2 is -SCH3. In some embodiments, R 2 is -SCH2CH3. In some embodiments, R 2 is -SCH2CH2CH3. In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C6 haloalkoxy. In some embodiments, R 2 is a 3- to 6-membered cycloalkyl. In some embodiments, R 2 is a 4-6 membered heterocycloalkyl. In some embodiments, R 2 is cyano. In some embodiments, R 2 is nitro. In various embodiments, R 2 is amino (i.e., —NR, where each R is independently H, OH, or C-C alkyl, which is optionally substituted according to embodiments described below).

[0099] In some embodiments, R2 is C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, and each C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is alkyl, or amino is independently optionally substituted with 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, R2 is unsubstituted C1-C6 alkyl, unsubstituted C2-C8 alkenyl, unsubstituted C2-C8 alkynyl, unsubstituted C1-C6 alkoxy, unsubstituted C1-C6 alkylthio, unsubstituted C1-C6 haloalkyl, unsubstituted C1-C6 haloalkoxy, unsubstituted 3-6 membered cycloalkyl, unsubstituted 4-6 membered heterocycloalkyl, or unsubstituted amino (i.e., -NH2).In some embodiments, R2 is substituted C1-C6 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 alkylthio, substituted C1-C6 haloalkyl, substituted C1-C6 haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., -NR2, where each R is independently deuterium, halogen, alkyl, alkylester, 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, R 3 is H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; In some embodiments, R is optionally substituted with 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, or —O—S—O—H. 3 is H. In some embodiments, R 3is halogen (i.e., F, Cl, Br, I). In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 is I. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl (—CH). In some embodiments, R 3 is ethyl (-CH2CH3). In some embodiments, R 3 is C2-C8 alkenyl. In some embodiments, R 3 is C2-C8 alkynyl. In some embodiments, R 3 is C1-C6 alkoxy. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is ethoxy. In some embodiments, R 3 is propoxy. In some embodiments, R 3 is isopropoxy. In some embodiments, R 3 is C1-C6 alkylthio. In some embodiments, R 3 is -SCH3. In some embodiments, R 3 is -SCH2CH3. In some embodiments, R 3 is -SCH2CH2CH3. In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is C1-C6 haloalkoxy. In some embodiments, R 3 is a 3- to 6-membered cycloalkyl. In some embodiments, R 3 is a 4-6 membered heterocycloalkyl. In some embodiments, R 3 is cyano. In some embodiments, R 3 is nitro. In various embodiments, R 3is amino (i.e., —NR, where each R is independently H, OH, or C-C alkyl, which is optionally substituted according to embodiments described below).

[0101] In some embodiments, R 3 is C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, and each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino R is independently optionally substituted with 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, —O—S—O—H, or —S—O—H. In some embodiments, R 3 is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C8 alkenyl, an unsubstituted C2-C8 alkynyl, an unsubstituted C1-C6 alkoxy, an unsubstituted C1-C6 alkylthio, an unsubstituted C1-C6 haloalkyl, an unsubstituted C1-C6 haloalkoxy, an unsubstituted 3- to 6-membered cycloalkyl, an unsubstituted 4- to 6-membered heterocycloalkyl, or an unsubstituted amino (i.e., —NH2). In some embodiments, R 3is a substituted C1-C6 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 alkylthio, substituted C1-C6 haloalkyl, substituted C1-C6 haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., —NR2, where 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, R 4 is H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; In some embodiments, R is optionally substituted with 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, or —O—S—O—H. 4 is H. In some embodiments, R 4is halogen (i.e., F, Cl, Br, I). In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is I. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is methyl (—CH). In some embodiments, R 4 is ethyl (-CH2CH3). In some embodiments, R 4 is C2-C8 alkenyl. In some embodiments, R 4 is C2-C8 alkynyl. In some embodiments, R 4 is C1-C6 alkoxy. In some embodiments, R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is propoxy. In some embodiments, R 4 is isopropoxy. In some embodiments, R 4 is C1-C6 alkylthio. In some embodiments, R 4 is -SCH3. In some embodiments, R 4 is -SCH2CH3. In some embodiments, R 4 is -SCH2CH2CH3. In some embodiments, R 4 is C1-C6 haloalkyl. In some embodiments, R 4 is C1-C6 haloalkoxy. In some embodiments, R 4 is a 3- to 6-membered cycloalkyl. In some embodiments, R is a 4- to 6-membered heterocycloalkyl. In some embodiments, R 4 is cyano. In some embodiments, R 4 is nitro. In various embodiments, R 4is amino (i.e., —NR, where each R is independently H, OH, or C-C alkyl, which is optionally substituted according to embodiments described below).

[0103] In some embodiments, R 4 is C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, and each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino R is independently optionally substituted with 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, —O—S—O—H, or —S—O—H. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C8 alkenyl, an unsubstituted C2-C8 alkynyl, an unsubstituted C1-C6 alkoxy, an unsubstituted C1-C6 alkylthio, an unsubstituted C1-C6 haloalkyl, an unsubstituted C1-C6 haloalkoxy, an unsubstituted 3- to 6-membered cycloalkyl, an unsubstituted 4- to 6-membered heterocycloalkyl, or an unsubstituted amino (i.e., —NH2). In some embodiments, R 4is a substituted C1-C6 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 alkylthio, substituted C1-C6 haloalkyl, substituted C1-C6 haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., —NR2, where 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, R 5 is H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; In some embodiments, R is optionally substituted with 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, or —O—S—O—H. 5 is H. In some embodiments, R 5is halogen (i.e., F, Cl, Br, I). In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is methyl (—CH). In some embodiments, R 5 is ethyl (-CH2CH3). In some embodiments, R 5 is C2-C8 alkenyl. In some embodiments, R 5 is C2-C8 alkynyl. In some embodiments, R 5 is C1-C6 alkoxy. In some embodiments, R 5 is methoxy. In some embodiments, R 5 is ethoxy. In some embodiments, R 5 is propoxy. In some embodiments, R 5 is isopropoxy. In some embodiments, R 5 is C1-C6 alkylthio. In some embodiments, R 5 is -SCH3. In some embodiments, R 5 is -SCH2CH3. In some embodiments, R 5 is -SCH2CH2CH3. In some embodiments, R 5 is C1-C6 haloalkyl. In some embodiments, R 5 is C1-C6 haloalkoxy. In some embodiments, R5 is 3-6 membered cycloalkyl. In some embodiments, R 5 is a 4-6 membered heterocycloalkyl. In some embodiments, R 5 is cyano. In some embodiments, R 5 is nitro. In various embodiments, R 5is amino (i.e., —NR, where each R is independently H, OH, or C-C alkyl, which is optionally substituted according to embodiments described below).

[0105] In some embodiments, R 5 is C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, and each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino R is independently optionally substituted with 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, —O—S—O—H, or —S—O—H. In some embodiments, R 5 is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C8 alkenyl, an unsubstituted C2-C8 alkynyl, an unsubstituted C1-C6 alkoxy, an unsubstituted C1-C6 alkylthio, an unsubstituted C1-C6 haloalkyl, an unsubstituted C1-C6 haloalkoxy, an unsubstituted 3- to 6-membered cycloalkyl, an unsubstituted 4- to 6-membered heterocycloalkyl, or an unsubstituted amino (i.e., —NH2). In some embodiments, R 5is a substituted C1-C6 alkyl, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 alkylthio, substituted C1-C6 haloalkyl, substituted C1-C6 haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., —NR2, where 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, R 6 is H.

[0107] In some embodiments, R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and the remaining R 2 , R 3 , R 4 , R 5 , and R 6 is as defined above.

[0108] In some embodiments, R 2 and R 3 together form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and R 4 , R 5 , and R 6is as defined above. In some embodiments, R 2 and R 3 taken together form a 3- to 6-membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 2 and R 3 taken together form a 3- to 6-membered cycloalkenyl (e.g., cyclobutenyl, cyclopentenyl, or cyclohexenyl). In some embodiments, R 2 and R 3 taken together form a 4- to 6-membered heterocycloalkyl. For example, in some embodiments, R 2 and R 3 taken together form a dihydrofuran ring. In another embodiment, R 2 and R 3 taken together form a dihydropyran ring. In some embodiments, R 2 and R 3 taken together form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R 2 and R 3 together to form furanyl.

[0109] In some embodiments, R 3 and R 4 together form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and R 2 , R 5 and R 6 is as defined above. In some embodiments, R 3 and R 4 taken together form a 3- to 6-membered cycloalkyl. In some embodiments, R 3 and R 4 taken together form a 3- to 6-membered cycloalkenyl. In some embodiments, R 3 and R 4 taken together form a 4- to 6-membered heterocycloalkyl. For example, in some embodiments, R3 and R 4 taken together form a dihydrofuran ring. In another embodiment, R 3 and R 4 taken together form a dihydropyran ring. In some embodiments, R 3 and R 4 taken together form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R 3 and R 4 taken together form a furanyl. In some embodiments, R 3 and R 4 together form a 3,4-methylenedioxy ring.

[0110] In some embodiments, R 4 and R 5 together form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and R 2 , R 3 and R 6 is as defined above. In some embodiments, R 4 and R 5 taken together form a 3- to 6-membered cycloalkyl. In some embodiments, R 4 and R 5 taken together form a 3- to 6-membered cycloalkenyl. In some embodiments, R 4 and R 5 taken together form a 4- to 6-membered heterocycloalkyl. For example, in some embodiments, R 4 and R 5 taken together form a dihydrofuran ring. In another embodiment, R 4 and R 5 taken together form a dihydropyran ring. In some embodiments, R 4 and R 5 taken together form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R 4 and R 5 together to form furanyl.

[0111] In some embodiments, R 5 and R 6 together form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and R 2 , R 3 and R 4 is as defined above. In some embodiments, R 5 and R 6 taken together form a 3- to 6-membered cycloalkyl. In some embodiments, R 5 and R 6 taken together form a 3- to 6-membered cycloalkenyl. In some embodiments, R 5 and R 6 taken together form a 4- to 6-membered heterocycloalkyl. For example, in some embodiments, R 5 and R 6 taken together form a dihydrofuran ring. In another embodiment, R 5 and R 6 taken together form a dihydropyran ring. In some embodiments, R 5 and R 6 taken together form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R 5 and R 6 together to form furanyl.

[0112] In some embodiments, R 2 and R 3 together form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, or a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl; R 5 and R 6 together form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, or a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl; R 4is H, Br, F, Cl, I, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each of C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; The alkyl, aryl, or amino is optionally substituted independently 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, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, —O—S—O—H, or —S—O—H.

[0113] In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 At least one of R is not H. In some embodiments, 2 , R 3 , R 4 , R 5 , and R 6 At least two of R are not H. In various embodiments, 2 , R 3 , R 4 , R 5 , and R 6 At least three of these are not H.

[0114] In some embodiments, the compound has the structure of formula (IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 2A and R 5A are each independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R 4 , R α , R β and X is as defined above for formula (I).

[0115] In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is methyl. In some embodiments, R 2A is C1-C6 haloalkyl. In some embodiments, R 2A is trifluoromethyl (i.e., —CF). In some embodiments, R 2A is trideuteromethyl (i.e., -CD3).

[0116] In some embodiments, R 5A is C1-C6 alkyl. In some embodiments, R 5A is methyl. In some embodiments, R 5A is C1-C6 haloalkyl. In some embodiments, R 5A is trifluoromethyl (i.e., —CF). In some embodiments, R 5A is trideuteromethyl (i.e., -CD3).

[0117] In some embodiments, the compound has the structure of formula (IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and R 4 , R α , R β and X is as defined above for formula (I).

[0118] In some embodiments, the compound has the structure of formula (IA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and R 4 , R α , R β and X is as defined above for formula (I).

[0119] In some embodiments, the compound has the structure of formula (IA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and R 4 , R α , R β and X is as defined above for formula (I).

[0120] In some embodiments, the compound has the structure of formula (IA-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and R 4 , R α , R β and X is as defined above for formula (I).

[0121] In some embodiments, the compound has the structure of formula (IA-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and R 4 , R α , R βand X is as defined above for formula (I).

[0122] In some embodiments, the compound has the structure of formula (IA-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and R 4 , R α , R β and X is as defined above for formula (I).

[0123] In some embodiments, the compound has the structure of formula (IA-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and R 4 , R α , R β and X is as defined above for formula (I).

[0124] In some embodiments, the compound has the structure of formula (IB): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein: R 3A , R 4A , and R 5A are each independently C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted with a 3- to 6-membered cycloalkyl or a 6- to 10-membered aryl; R α , R β and X is as defined above for formula (I).

[0125] In some embodiments, R 3A is C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted with a 3- to 6-membered cycloalkyl or a 6- to 10-membered aryl. 3A is C1-C6 alkyl. In some embodiments, R 3A is C1-C6 alkyl, C2-C8 alkenyl. In some embodiments, R 3A is C2-C8 alkynyl. In some embodiments, R 3A is C1-C6 haloalkyl. In some embodiments, R 3A is unsubstituted. In some embodiments, R 3A is a C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with a 3- to 6-membered cycloalkyl or a 6- to 10-membered aryl. 3A is a C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with a 3-6 membered cycloalkyl (e.g., cyclopropyl). 3A is a C1-C6 alkyl, and the C1-C6 alkyl is substituted with a 6- to 10-membered aryl (eg, phenyl).

[0126] In some embodiments, R 4A is C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted with a 3- to 6-membered cycloalkyl or a 6- to 10-membered aryl. 4A is C1-C6 alkyl. In some embodiments, R 4A is C1-C6 alkyl, C2-C8 alkenyl. In some embodiments, R 4A is C2-C8 alkynyl. In some embodiments, R 4A is C1-C6 haloalkyl. In some embodiments, R 4A is unsubstituted. In some embodiments, R 4Ais a C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with a 3- to 6-membered cycloalkyl or a 6- to 10-membered aryl. 3A is a C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with a 3-6 membered cycloalkyl (e.g., cyclopropyl). 4A is a C1-C6 alkyl, and the C1-C6 alkyl is substituted with a 6- to 10-membered aryl (eg, phenyl).

[0127] In some embodiments, R 5A is C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted with a 3- to 6-membered cycloalkyl or a 6- to 10-membered aryl. 5A is C1-C6 alkyl. In some embodiments, R 5A is C1-C6 alkyl, C2-C8 alkenyl. In some embodiments, R 5A is C2-C8 alkynyl. In some embodiments, R 5A is C1-C6 haloalkyl. In some embodiments, R 5A is unsubstituted. In some embodiments, R 5A is a C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with a 3- to 6-membered cycloalkyl or a 6- to 10-membered aryl. 5A is a C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with a 3-6 membered cycloalkyl (e.g., cyclopropyl). 5A is a C1-C6 alkyl, and the C1-C6 alkyl is substituted with a 6- to 10-membered aryl (eg, phenyl).

[0128] In some embodiments, the compound has the structure of formula (IC): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein n is independently 1 or 2 in each occurrence; R 4 , R α , R β and X is as defined above for formula (I).

[0129] In some embodiments, the compound has the structure of formula (ID): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and R 4 , R α , R β and X is as defined above for formula (I).

[0130] In some embodiments, the compound has the structure of formula (IE): [ka] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R′ and R″ are independently H, D, or F; and R α , R β 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 various embodiments, the disclosed compounds include compounds of Applicant's International Application No. PCT / US2022 / 041279 (published WO 2023 / 028091), International Application No. PCT / US2022 / 041283 (published WO 2023 / 028092), and International Application No. PCT / US2022 / 044771 (published WO 2023 / 049480), each of which is incorporated by reference herein in its entirety, conjugated to a vitamin B6 promoiety according to various embodiments described herein.

[0132] In various embodiments, the disclosed compounds include any suitable phenylalkylamine, phenethylamine, or tryptamine drug (e.g., a phenylalkylamine, phenethylamine, or tryptamine drug containing a primary amine moiety) linked to a vitamin B6 promoiety according to various embodiments described herein. Such compounds include, for example, 2C-x, DOx, ariadone-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, R α , R β , and R 4 is selected from Table I, and R 2 , R 3 , R 5 , and R 6 is as defined in formula (I) or any subformula thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13]

[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: [ka] [Table 4-1] [Table 4-2] [Table 4-3]

[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: [ka] [Table 5-1] [Table 5-2] [Table 5-3]

[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: [ka] [Table 6]

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

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

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

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

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

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

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

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

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

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

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

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

[0149] As used herein, "single compound" means that the compound specified (e.g., by structural formula or description) is the only disclosed compound in an embodiment, i.e., that the compound, composition, or method does not consist of, consist essentially of, or include additional disclosed compounds (i.e., compounds having a different structural formula or description). This does not mean that the embodiment has only a single molecule or single instance of the specified compound. For example, an embodiment "consisting of a single compound of Formula (I)" includes embodiments of "a compound of Formula (I)," or use of "a compound of Formula (I)," and such embodiments, as well as embodiments of compositions "consisting essentially of a single compound of Formula (I)," can each include, for example, 5 mg, 10 mg, 50 mg, 100 mg, and other disclosed or known mass or molar amounts of a compound of Formula (I).

[0150] Thus, 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 "compounds of Formula (I)." In some embodiments, one or more compounds may also be excluded from a claim to a composition consisting essentially of a group of compounds. In some embodiments, one or more compounds may also be excluded from a claim to a composition comprising a group of compounds. In some embodiments, one or more compounds may also be excluded from a claim to the use of a group of compounds. In some embodiments, one or more compounds may also be excluded from a claim to the use of a composition consisting essentially of a group of compounds. In some embodiments, one or more compounds may also be excluded from a claim to the 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 claims to a group of compounds and from claims to compositions consisting essentially of the group of compounds, but not from claims to uses of the group of compounds or compositions thereof. In some embodiments, one or more compounds may be excluded from claims to a group of compounds and from claims to compositions comprising the group of compounds, but not from claims to uses of the group of compounds or compositions thereof.

[0152] In some embodiments, one or more compounds may be excluded from claims to a group of compounds, or from claims to compositions consisting essentially of a group of compounds, but not from compositions comprising 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 claims to a group of compounds, or from claims to compositions consisting essentially of a group of compounds, or from claims to the use of a group of compounds or compositions consisting essentially of a group of compounds, but not from compositions comprising one or more compounds together with one or more additional disclosed compounds and / or additional active compounds, or from the use of compositions comprising 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 claims to the group of compounds, from claims to compositions consisting essentially of the group of compounds, from claims to the use of the group of compounds or compositions consisting essentially of them, and even from compositions comprising one or more compounds together with one or more additional disclosed compounds and / or additional active compounds, but not from claims to the use of compositions comprising one or more compounds together with one or more additional disclosed compounds and / or additional active compounds.

[0153] It is understood that each compound of the disclosed compositions also includes pharmaceutically acceptable salts of such compounds. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases and synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of these drugs with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, the salts of compounds are those in which the counterion is pharmaceutically acceptable. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-naphsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefirate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, tartrate, borate, butyrate, calcium edetate, calcium, camphorcarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavamate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, Dichloroacetate, Digluconate, Dodecyl Sulfate, Edentate, Edetate, Edisylate, Estolate, Esylate, Ethanesulfonate, Ethyl Sulfate, Fumarate, Furanate, Fusidate, Galactarate (Mucin Hydrochloride), Galactronate, Gallate, Gentisate, Gluceptate, Glucoheptanoate, Gluconate, Glucuronate, Glutamate, Glutarate, Glycerophosphate, Glycolate, Glycolylarsanilate, Hemisulfate, Heptanoate (Enanthate), Heptanoate, Hexafluorophosphate, Hexanoate, Hexylresorcinate, Hippurate, Hybenzate, Hydrabamine, Hydrobromide, Hydrobromide / Bromide, Hydrochloride, Hydroiodide, Hydroxide, Hydroxybenzoate, Hydroxynaphthoate, IodideIsethionate, Isothionate, L-Aspartate, L-Camsylate, L-Lactate, Lactate, Lactobionate, Laurate, Laurylsulfonate, Lithium, Magnesium, Malate, Maleate, Malonate, Mandelate, Meso-Tartrate, Mesylate, Methanesulfonate, Methyl Bromide, Methyl Nitrate, Methyl Sulfate, Mucate, Myristate, N-Methylglucamine Ammonium Salt, Napadisylate, Naphthylate, Napsylate, Nicotinate, Nitrate, Octanoate, Oleate, Orotate, Oxalate, p-Toluenesulfonate, Palmitate, Pamoate, Pantothenate Examples of suitable pharmaceutically acceptable salts include phosphate, pectinate, persulfate, phenylpropionate, phosphate, phosphate diphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, diacetate, succinate sulfate, sulfosaliculate, sulfosalicylate, sulamate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribulofenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc, and the like. (See Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.) In various embodiments, preferred pharmaceutically acceptable salts utilize the hydrochloride anion.

[0154] Generally, the disclosed compounds are administered as part of a pharmaceutical composition or formulation, but are prepared for inclusion in such compositions or formulations as isolated or purified compounds. As used herein, the terms "isolated," "purified," or "substantially pure" refer to a material that is substantially or essentially free from components that normally accompany the material when it is synthesized, manufactured, or otherwise produced. Thus, an "isolated," "purified," or "substantially pure" preparation of a compound is defined as one that has 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 compounds used in the present invention are substantially free of any other active compounds that are not intended to be administered to a subject. In this context, "substantially free" can be interpreted to mean that the active compound(s) other than the active compound(s) intended to be administered to a subject are not detectable by HPLC or other similar detection methods, or are below the desired detection threshold as defined above.

[0156] Any reference to the disclosed compounds or their pharmaceutically acceptable salts, stereoisomers, hydrates, or solvates should be understood to include all amorphous and polymorphic forms. In the case of solid compositions, it is understood that the compounds used in the disclosed compositions and methods, in particular, may exist in different forms. For example, the compounds may exist in stable and metastable crystalline forms, isotropic and amorphous forms, pulverized forms, and nanoparticulate forms, all of which are intended to be within the scope of the present invention. Additionally, the disclosed compounds may include crystalline forms known as polymorphs. Polymorphs include different crystalline packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors, such as the recrystallization solvent, crystallization rate, and storage temperature, may result in the predominance of a single crystalline form.

[0157] The disclosed compounds generally described herein will be more readily understood by reference to the following description and examples, which are included for the purpose of illustrating certain aspects of embodiments of the invention. The following is not intended to limit the invention, as one of ordinary skill in the art will recognize from the teachings and examples herein that other techniques and methods may be used to satisfy the claims and without departing from the scope of the invention. Indeed, while the invention has been specifically 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 can be made therein without departing from the scope or spirit of the invention as encompassed by the appended claims.

[0158] a. Deuterated and / or fluorinated compounds In some embodiments, disclosed compounds having deuterium substitutions (e.g., deuteroalkyl groups) have 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 compounds have an isotopic purity of at least 50%. In one embodiment, the compounds have an isotopic purity of at least 55%. In another embodiment, the compounds have an isotopic purity of at least 60%. In yet another embodiment, the compounds have an isotopic purity of at least 65%. In another embodiment, the compounds have an isotopic purity of at least 70%. In another embodiment, the compounds have 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, the isotopic enrichment can be described as a percentage indicating the percent of atoms of the isotope at a particular site on the molecule. The percentage can be referred to as the "isotopic purity" of the isotopically labeled compound.

[0159] In some embodiments, the disclosed compounds having deuterium substitutions (e.g., deuteroalkyl groups) are mixtures of deuterated and corresponding non-deuterated compounds (i.e., corresponding compounds in which none of the hydrogens are replaced with deuterium, e.g., the presence of deuterium at any position in the compound is not greater than the natural abundance of the 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 (the other compounds in such mixtures are the corresponding unsubstituted compounds). In one embodiment, at least 1% of the compounds are deuterium-substituted. In one embodiment, at least 2% of the compounds are deuterium-substituted. In one embodiment, at least 3% of the compounds are deuterium-substituted. In one embodiment, at least 4% of the compounds are deuterium-substituted. In one embodiment, at least 5% of the compounds are deuterium-substituted. In one embodiment, at least 10% of the compounds are deuterium-substituted. In one embodiment, at least 20% of the compounds are deuterium-substituted. In one embodiment, at least 30% of the compounds are deuterium-substituted. In one embodiment, at least 40% of the compounds are deuterium-substituted and / or fluorine-substituted. In one embodiment, at least 50% of the compounds are deuterium-substituted. In one embodiment, at least 60% of the compounds are deuterium-substituted. In one embodiment, at least 70% of the compounds are deuterium-substituted. In one embodiment, at least 80% of the compounds are deuterium-substituted. In one embodiment, at least 90% of the compounds are deuterium-substituted. In one embodiment, at least 95% of the compounds are deuterium-substituted. In one embodiment, at least 96% of the compounds are deuterium-substituted. In one embodiment, the compound is at least 97% deuterium substituted.In one embodiment, at least 98% of the compounds are deuterium-substituted. In one embodiment, at least 99% of the compounds are deuterium-substituted and / or fluorine-substituted. In one embodiment, at least 99.5% of the compounds are deuterium-substituted. In one embodiment, at least 99.8% of the compounds are deuterium-substituted. In one embodiment, at least 99.9% of the compounds are deuterium-substituted.

[0160] In some embodiments, the disclosed compositions comprise a fixed ratio mixture of one or more deuterium-substituted compounds and the corresponding unsubstituted compounds, wherein the ratio (by molar or mass) of deuterium-substituted compound to unsubstituted compound (including pharmaceutically acceptable salts, hydrates, or solvates thereof) is 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 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, 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 21:1, at least 22:1, at least 23:1, at least 24:1, at least 25:1, at least 26:1, at least 27:1, at least 28:1, at least 29:1, at least 30:1, at least 31:1, at least 32:1, at least 33:1, at least 34:1, at least 35:1, at least 36:1, at least 37:1, at least 38:1, at least 39:1, at least 40:1, at least 41:1, at least 42:1, at least 43:1, at least 44: 0.0:1, 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 above-listed ratios themselves.

[0161] In some embodiments, the disclosed compositions include a fixed ratio of the disclosed compounds having fluorine substitution (e.g., fluoroalkyl groups) to the corresponding unsubstituted compounds, where the ratio (as a molar or weight ratio) of the fluorine-substituted compounds to the unsubstituted compounds is 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, at least 10.0:1, at least 11.0:1, at least 12.0:1, at least 13.0:1, at least 14.0:1, at least 15.0:1, at least 16.0:1, at least 17.0:1, at least 18.0:1, at least 19.0:1, at least 20.0:1, at least 21.0:1, at least 22.0:1, at least 23.0:1, at least 24.0:1, at least 25.0:1, at least 26.0:1, at least 27.0:1, at least 28.0:1, at least 29.0:1, at least 30.0:1, at least 31.0:1, at least 32.0:1, at least 33.0:1, at least 34.0:1, at least 35.0:1, at least 36.0:1, at least 0.0:1, 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 above-listed ratios themselves.

[0162] b. Mixtures of stereoisomers and enantiomers In some embodiments, the disclosed compounds may contain one or more asymmetric centers and may 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 present invention is meant to include all such possible isomers and mixtures thereof, including racemic and optically pure forms.

[0163] Optically active (R)- and (S)-isomers, (-)- and (+)-isomers, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods for preparing optically active forms and determining activity are known in the art. Such methods include the standard tests described herein and other similar tests known in the art. Examples of methods that can be used to obtain optical isomers of compounds according to the present disclosure include: i) physical separation of macroscopic crystals of individual enantiomers by manual separation. This technique can be particularly used in the following cases: when crystals of the separate enantiomers exist (i.e., the material is a conglomerate) and the crystals are visually distinguishable; ii) simultaneous crystallization, in which individual enantiomers are crystallized separately from a solution of the racemate, which is only possible if the latter is a solid-state conglomerate; iii) enzymatic resolution, in which the racemate is partially or completely separated due to different reaction rates between the enantiomers and an enzyme; iv) enzymatic asymmetric synthesis (a synthetic technique in which 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, in which the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomeric separation, in which a racemate is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their now more distinct structural differences, with the chiral auxiliary later removed to give the desired enantiomer; vii) the diastereomers equilibrate from the racemate, with first and second order asymmetric transformations occurring predominantly in solution of the diastereomer from the desired enantiomer, or preferential crystallization of the diastereomer from the desired enantiomer disrupting the equilibrium until essentially all of the material is converted from the desired enantiomer to the crystalline diastereomer.The desired enantiomer is then released from the diastereomer; viii) kinetic resolution, which involves partial or complete resolution of the racemate (or further resolution of the partially resolved compound) by unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from a non-racemic precursor, in which the desired enantiomer is obtained from a non-chiral starting material and the stereochemical integrity is intact or only minimally compromised over the course of the synthesis; x) chiral liquid chromatography, in which the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with the stationary phase. The stationary phase can be made of a chiral material, or the mobile phase can contain an additional chiral material that causes differential interactions; xi) chiral gas chromatography, in which a column containing a fixed, non-racemic, chiral adsorbent phase is used to volatilize the racemate and separate the enantiomers through differential interactions in the gaseous mobile phase; xii) chiral solvent extraction, in which enantiomers are separated by preferential dissolution of one enantiomer in a particular chiral solvent; and xiii) chiral membrane transport, in which the racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one of which contains the racemate, and a driving force, such as a concentration or pressure difference, causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chirality of the membrane, which allows only one enantiomer of the racemate to pass through.

[0164] In some embodiments, the disclosed compounds can be provided in enantiomerically non-enriched compositions (i.e., compositions comprising the disclosed compound(s) as a racemic mixture). In other embodiments, the disclosed compounds can be provided in enantiomerically enriched compositions, e.g., mixtures of enantiomers in which one enantiomer is present in excess, particularly in ranges 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 various embodiments, the disclosed compounds are provided in compositions enantiomerically enriched in the R-isomer, comprising an enantiomeric excess of the R-isomer 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 various embodiments, the disclosed compounds are provided in compositions enantiomerically enriched in the S-isomer, comprising an enantiomeric excess of the S-isomer 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, the disclosed compounds are provided in compositions comprising an R:S ratio of the R-isomer to the S-isomer of about 20:1 to about 1:20. In some embodiments, the R:S ratio is greater than about 20:1, or is about 20:1, about 15:1, about 12:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1. In some embodiments, the disclosed compounds are provided as the R-isomer in an enantiomerically pure composition. In some embodiments, the R:S ratio is about 1:1, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:12, about 1:15, about 1:20, or greater than about 1:20. In some embodiments, the disclosed compounds are provided as S-isomers in enantiomerically pure compositions.

[0168] When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as tautomeric forms.

[0169] c. A mixture of pyridoxal-amine and pyridoxal-imine prodrugs As described below, in some embodiments, the disclosed compounds are synthesized according to a reaction sequence that produces a compound of formula (A): [ka] It is also referred to herein as a "pyridoxal imine" and has the formula: 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R α , R β and X are as defined for formula (I).

[0170] In some embodiments, the pyridoxal imine compounds of Formula (A) are also useful as prodrugs for phenethylamine psychedelic drugs. In some embodiments, the pyridoxal imine compounds of Formula (A) are used in place of the compounds of Formula (I) in any of the embodiments described herein, e.g., in pharmaceutical compositions, methods of treatment, or embodiments describing the use of compounds 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, stereoisomer, hydrate, or solvate thereof: [Table 7-1] [Table 7-2] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R α , R β and X is as defined for formula (I).

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

[0173] d. Exemplary Features of the Disclosed Compounds In some aspects, the characteristics of the disclosed compounds provide various advantages. Such advantages may relate to modulation of neurotransmission, pharmacokinetics, e.g., properties related to absorption, distribution, metabolism, and excretion of the disclosed compounds, and subjective effects upon administration to a subject. In some embodiments, such advantages are determined relative to a comparator. In some embodiments, the comparator for the disclosed compounds is the corresponding component drug not bound to a pyridoxal promoiety.

[0174] For example, the compound of formula (I) is [ka] In some embodiments, the comparator is [ka] (i.e., 2C-B).

[0175] Permeability, such as the apparent permeability of a compound, describes how effectively it can cross a membrane. A moderately permeable compound may have an in vitro apparent permeability of 50-150 nm / s, inclusive. A highly permeable compound may have an in vitro apparent permeability of greater than 150 nm / s, inclusive. In vitro methods for measuring permeability are available to those skilled in the art, including the Madin-Darby canine kidney cell line (MDCK) permeability assay and the parallel artificial membrane permeability assay (PAMPA). For example, PAMPA is an in vitro model of passive diffusion that has been shown to highly correlate with permeation across various barriers, including Caco-2 cultures, the gastrointestinal tract, the 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, the disclosed compounds have intermediate permeability. In some embodiments, the disclosed compounds have high permeability. In some embodiments, the disclosed compounds have increased permeability relative to their corresponding constituent drug compounds. In some embodiments, the disclosed compounds have increased permeability relative to a comparator. In various embodiments, the permeability of the disclosed compounds 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, the disclosed compounds are actively transported across a barrier (e.g., a mucosal barrier, such as the gastrointestinal (GI) barrier; or the blood-brain barrier (BBB)). In some embodiments, the disclosed compounds are actively transported across a GI barrier. In some embodiments, the disclosed compounds are actively transported across the BBB. Without being bound by theory, because the disclosed compounds may be actively transported across a barrier, while a phenylalkylamine drug may only passively diffuse across the same barrier, the bioavailability of the disclosed compounds may be higher than a comparable, or higher than a phenylalkylamine drug lacking a vitamin B6-derived promoiety as disclosed in embodiments herein. In some embodiments, the disclosed compounds are actively transported by epithelial cells, such as intestinal epithelial cells or renal proximal tubule cells. In some embodiments, the disclosed compounds are actively transported across a barrier by a transporter (e.g., carrier) protein. In some embodiments, the disclosed compounds are actively transported across a barrier by a transporter protein for which vitamin B6 is a substrate. Without being bound by theory, human vitamin B6 transporters have not yet been fully characterized but may include the human solute carriers SLC19A2 and SLC19A3, also known as thiamine transporters (THTR) 1 and 2, and ABC transporters; which may be similar in structure and / or function to transporters characterized in yeast and plants, including Tpn1p, Bsu1, members of the plant purine permease (PUP) family, and Mtm1p (Parra et al. Cells. 2018;7(7):84).

[0178] In some embodiments, the disclosed compounds have 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 in vitro metabolic stability studies involving human liver microsomes. Methods for assessing metabolic stability, such as clearance and half-life in vitro, are described, for example, in 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 can be determined in vivo, such as in humans, following the paradigm described, for example, by Brown et al., Clin Pharmacokinet. 2017;56(12):1543-1554. Further, identification of metabolites and interactions with CYP enzymes can be performed, for example, as described in Caspar et al., Drug Test Anal. 2018;10(1):184-195. In some embodiments, the half-life of the disclosed compounds 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 comparable compound.

[0179] In some embodiments, the disclosed compounds are not substrates of monoamine oxidase enzymes. In some embodiments, the disclosed compounds do not inhibit the activity of monoamine oxidase enzymes. In some embodiments, the disclosed compounds do not irreversibly inhibit the activity of monoamine oxidase enzymes. In some embodiments, the disclosed compounds do not reversibly inhibit the activity of monoamine oxidase enzymes. Monoamine oxidase enzymes include the isoenzymes MAO-A and MAO-B. In some embodiments, the disclosed compounds are not substrates of monoamine oxidase A (MAO-A). In some embodiments, the disclosed compounds do not inhibit the activity of MAO-A. In some embodiments, the disclosed compounds do not irreversibly inhibit the activity of MAO-A. In some embodiments, the disclosed compounds do not reversibly inhibit the activity of MAO-A. In some embodiments, the disclosed compounds are not reversible inhibitors of MAO-A (RIMA). In some embodiments, the IC of the disclosed compounds on MAO-A 50 is greater than 10 μM. Herein, a threshold value of 10 μM or greater (EC 50 or IC 50 ) can be used to determine the absence of activity. In some embodiments, the MAO enzyme is of mammalian origin. In some embodiments, the MAO enzyme is of human origin.

[0180] In various embodiments, the disclosed compounds are orally bioavailable. In various embodiments, the disclosed compounds have an oral bioavailability (%F) of about or at least 50%, about or at least 60%, about or at least 70%, about or at least 80%, or about or at least 90%. Bioavailability studies, both in vitro and in vivo, are described, for example, in Kim et al., Pharm Res. 2014;31(4):1002-1014, EP2007397, EP3565550, and U.S. 20200009067.

[0181] In some embodiments, the disclosed compounds exhibit reduced adverse events relative to a comparator. Examples of adverse events include those related to neurotoxicity, cardiotoxicity, and nephrotoxicity, among others. In some embodiments, the reduction in at least one adverse event is determined within a patient or across a patient or patient group, or in a rodent or other suitable animal model, or in vitro, in silico, or otherwise measured using standards such as those known to those of skill in the art for determining or quantifying the adverse event in question, such as those related to anxiety, cardiovascular effects such as blood pressure and heart rate, hyperthermia, hyperhidrosis, jaw pressure and teeth grinding, muscle tone, psychostimulation, appetite, nausea, concentration, and balance, and markers for or correlates of potential neurotoxicity (e.g., in silico (e.g., computational analysis or simulation, including AI, machine learning, or deep learning), in vitro (e.g., biochemical assays, tissue culture), and in vivo (e.g., behavioral assessments, functional observation batteries, motor activity, etc.). Exemplary such tests and procedures are: testing, schedule-controlled operant behavior; neurological function; neurophysiological function; nerve conduction; evoked potentials; neurochemical, neuroendocrine, or neuropathological measurements; EEG, imaging), as well as physiological biomarkers (body temperature; heart rate; respiratory rate; blood oxygenation; systolic blood pressure (SBP); diastolic blood pressure (DBP); mean blood pressure (MAP); pulse pressure (PP); continuous cardiac pressure (CNIBP); heart rate variability (HRV); hemodynamic response (HR); glucose; cortisol; serotonin; dopamine; and brain-derived neurotrophic factor (BDNF)), and including the use of patient assessments), 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 above the measurement threshold.

[0182] In some embodiments, administration of the disclosed compounds or compositions thereof does not cause neurotoxic effects, such as in in vitro assays, or when administered to a subject. In some embodiments, the disclosed compounds or compositions thereof cause a reduction in neurotoxic effects, such as in in vitro assays, or when administered to a subject. In some embodiments, the reduction in neurotoxic effects 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, or at least a 99% reduction, relative to a comparator. In some embodiments, the comparator is the corresponding component drug compound of the disclosed compound.

[0183] In some embodiments, neurotoxic effects are determined by measuring one or more of a) oxidative stress and dopamine quinones; b) mitochondrial dysfunction; and c) glial cell activation. In some embodiments, neurotoxicity or its reduction is determined by assessing mitochondrial dysfunction. Mitochondrial dysfunction can be assessed by measuring one or more of mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, mitochondrial cytochrome c release, and ADP / ATP ratio. See, e.g., Taghizadeh et al., Free Radic Biol Med. 2016;99:11-19 (markers of mitochondrial dysfunction include a significant increase in ROS formation, disruption of MMP, mitochondrial swelling, outer membrane damage, mitochondrial cytochrome c release, and an increased ADP / ATP ratio).

[0184] In some embodiments, neurotoxicity or its reduction is determined by assessing glial cell activation. Activation of quiescent glial cells is described, for example, by Herndon et al., Toxicological Sciences. 2014;138(1):130-138. Reactive astrogliosis can be measured using glial fibrillary acidic protein (GFAP) staining, and microglial reactivity can be visualized by immunostaining for complement receptor type 3 (CD11b). See, for example, Frau et al., J Neurochem. 2013;124(1):69-78 and Frau et al., Neurotoxicol. 2016;56:127-138. In various embodiments, neurotoxicity or its reduction is determined in vitro. In various embodiments, neurotoxicity or its reduction is determined in vivo.

[0185] In some embodiments, subjects administered a disclosed compound do not experience serotonin syndrome. In some embodiments, subjects administered a disclosed compound experience a reduced incidence and / or severity of serotonin syndrome, for example, compared to administration of a comparable compound. Co-administration of a SERT inhibitor and an agent that increases serotonin levels, such as an MAOI, has been shown to enhance 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 symptoms include autonomic dysfunction, neuromuscular agitation, and mental status changes, as described, for example, in 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, subjects administered a disclosed compound do not experience delirium. In some embodiments, subjects administered a disclosed compound experience a reduced incidence and / or severity of delirium, for example, compared to administration of a comparator compound. Symptoms of delirium, such as drug-induced delirium, include impaired consciousness, attention, cognition, and perception. The severity of delirium can be assessed using available tools, such as the Memorial Delirium Assessment Scale (MDAS) subitems and the 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 after ingestion of 5-MeO-DALT is described, for example, in Jovel et al., J Forensic Sciences. 59(3), 844-846.

[0187] In some embodiments, the disclosed compounds do not cause cardiotoxicity after administration to a subject. In some embodiments, after administration of the disclosed compounds to a subject, a reduction in the severity and / or incidence of cardiotoxicity is observed, e.g., compared to administration of a comparator compound. In some embodiments, the disclosed compounds do not cause irregular heartbeat, e.g., tachycardia. In some embodiments, the disclosed compounds exhibit reduced inhibition of cardiac ion channels relative to a comparator, e.g., at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200%. In some embodiments, the disclosed compounds do not inhibit (e.g., block) the function of cardiac ion channels. In various embodiments, the disclosed compounds do not block the calcium channel CAV1.2. In various embodiments, the disclosed compounds do not block the potassium channel hERG. In various embodiments, the disclosed compounds do not block the sodium channel NAV1.5. In various embodiments, the disclosed compounds have an IC of greater than 10 μM for any one or more of CAV1.2, hERG, and NAV1.5. 50 In embodiments, CAV1.2, hERG, and NAV1.5 are of human origin.

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

[0189] In some embodiments, administration of a disclosed compound to a subject produces a psychoactive effect in the subject. In some embodiments, the psychoactive effect is assessed using one or more of the 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, the onset and duration of the psychoactive effect can be determined by observing and / or questioning the subject, such as by using a self-report symptom questionnaire, or by asking the subject to record their subjective psychoactive effect, i.e., their experience. In some embodiments, the self-report symptom questionnaire is the Subjective Drug Effects Questionnaire (SDEQ), a 272-item questionnaire that measures perceptual, mood, and physical changes caused by psychedelic drugs (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 the onset and duration of such effects can further be determined according to methods known to those skilled in the art.

[0190] C. Synthesis method In some aspects, methods for preparing the disclosed compounds are provided herein. In various embodiments, compounds of formula (I) are prepared according to the following general reaction sequence: Briefly, in the first reaction step, a phenethylamine precursor is reacted with a pyridoxal precursor. The condensation reaction between the phenethylamine primary amine (-NH) and pyridoxal aldehyde (-COH) reversibly forms an imine compound of formula (A), with water (HO) as a reaction by-product. [ka]

[0191] The imine compound of Formula (A) can 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 (whether or not isolated from the reaction mixture) in the synthesis of the compound of formula (I). In some embodiments, the compound of formula (A) is reduced with a suitable reducing agent (e.g., NaBH4) to irreversibly form the pyridoxalamine prodrug of formula (I). [ka]

[0193] In these exemplary reaction schemes, pyridoxal is depicted generically, and X is H or PO3H2. One of skill in the art will understand that both pyridoxal (X is H) or pyridoxal 5'-phosphate (X is PO3H2) can be used to produce compounds of Formula (A) and Formula (I) according to the disclosed synthetic methods. Furthermore, while the above reaction schemes show exemplary synthetic routes useful for synthesizing compounds of Formula (I), they can 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 condensing pyridoxal with amines to form imines, and methods for reducing such imines to form amines, 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 synthesizing the phenethylamine drug compounds described herein as component drugs of the disclosed prodrugs, and any necessary starting materials, are described in the art or may be obtained by consideration of general references known in the art (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 1-17, Wiley Interscience). 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) will be readily apparent to one of ordinary skill in the art and can be used to synthesize the disclosed compounds.

[0196] Commonly used approaches 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. 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 adaptations are known and understood by those skilled in the art.

[0197] C. Pharmaceutical Compositions In some aspects, provided herein are compositions, e.g., pharmaceutical compositions, comprising the disclosed compounds, e.g., compounds of any of the disclosed formulas or subformulas thereof. A "pharmaceutical composition" is a composition comprising an amount (e.g., in unit dosage form) of a disclosed compound(s) together with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments do not have a single carrier, diluent, or excipient alone, but include multiple carriers, diluents, and / or excipients. The compositions can be prepared by standard pharmaceutical formulation techniques, e.g., as disclosed in Remington: The Science & Practice of Pharmacy (2020) 23rd ed., Academic Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, NJ; 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, NY, pp. 253-315).

[0198] "Pharmaceutically acceptable" as used with reference to an excipient, carrier, diluent, or other ingredient means that the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with human and animal cells without undue toxicity, irritation, allergic response, or other complications, commensurate with a reasonable risk / benefit ratio.

[0199] In some embodiments, pharmaceutical compositions containing the disclosed compounds can be administered by various routes, including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal. In some embodiments, the compounds used in the disclosed methods are effective as oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal compositions. Such compositions are prepared by methods well known in the pharmaceutical arts and contain at least one active compound. (See, e.g., Remington, 2020.)

[0200] The disclosed compositions are preferably formulated in unit dosage forms, each dosage containing a therapeutically effective amount of the active ingredient, for example, the dosages disclosed below. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for a subject to be treated, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in combination with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are often used for ease of administration and uniformity of dosage. A unit dosage form can contain a single or individual dose or unit, sub-dose, or an appropriate fraction thereof (e.g., 1 / 2 of a "full" dose for a "booster" dose as described below) of the pharmaceutical composition to be administered.

[0201] The unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampoules, and vials, and may contain compositions in a freeze-dried or lyophilized state. For example, a sterile liquid carrier can be added before administration or delivery in vivo. The unit dosage forms also include ampoules and vials into which liquid compositions are placed. The unit dosage forms also include compounds for transdermal administration, such as "patches" that contact the epidermis (including mucous membranes) of a subject for long or short periods of time.

[0202] In some embodiments, the disclosed compositions are formulated into pharmaceutically acceptable oral dosage forms. Oral dosage forms include oral liquid dosage forms (e.g., tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions) and oral solid dosage forms. The disclosed pharmaceutical compositions can also be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, including 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, the disclosed compositions are formulated as oral solid dosage forms. Oral solid dosage forms may include, but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combination thereof. Oral solid dosage forms may be formulated as immediate-release, controlled-release, sustained-release, extended-release, or modified-release formulations. Thus, in some embodiments, the disclosed oral solid dosage forms may be in the form of tablets (including suspension tablets, fast-dissolving tablets, bite-disintegrating tablets, fast-disintegrating tablets, effervescent tablets, or caplets), pills, powders (including sterile packaged powders, dispensable powders, or effervescent powders), capsules (including both soft and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled-release formulations, pulsed-release dosage forms, multiparticulate dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-dissolving tablet. Furthermore, the pharmaceutical formulation can be administered as a single capsule or in multiple capsule dosage forms. 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, dispersants, suspending agents, disintegrants, thickeners, film-forming agents, granulation aids, flavorings, sweeteners, coating agents, solubilizers, and combinations thereof. Oral solid dosage forms may also contain one or more pharmaceutically acceptable additives, such as compatible carriers, complexing agents, ionic dispersion modifiers, disintegrants, surfactants, lubricants, colorants, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, alone or in combination, as well as auxiliary active compound(s).

[0205] Supplementary active compounds include antimicrobial agents, including preservatives, antioxidants, and biocides and bacteriostatic agents, such as antibacterial, antiviral, and antifungal agents. Preservatives can be used to inhibit microbial growth or increase the stability of the active ingredient, thereby extending 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 compounds such as vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherol, other vitamins or provitamins, and alpha-lipoic acid.

[0206] In some embodiments, the disclosed compositions are formulated as oral liquid dosage forms. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, solutions, and the like. These oral liquid dosage forms can be formulated with any pharmaceutically acceptable excipient known to those skilled in the art for preparing liquid dosage forms, as well as solvents, diluents, carriers, excipients, and the like appropriately selected for the solubility and other properties of the active agent and other ingredients. Solvents can be, for example, water, glycerin, simple syrup, alcohol, medium-chain triglycerides (MCTs), and combinations thereof.

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

[0208] In some embodiments, a formulation is provided comprising the disclosed composition and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, which, when mixed with water, form a substantially uniform suspension. The aqueous dispersion may comprise amorphous and non-amorphous particles of multiple effective particle sizes, allowing the drug to be absorbed in a controlled manner over time.

[0209] The dosage form for oral administration may be an aqueous suspension selected from the group consisting of pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, for example, Singh et al., Encyclopedia of Pharm.Tech., 2nd Ed., 754-757 (2002). In addition to the disclosed compounds, the liquid dosage form may contain one or more additives such as (a) disintegrants, (b) dispersants, (c) wetting agents, (d) preservatives, (e) thickeners, (f) sweeteners, or (g) flavoring agents.

[0210] The disclosed compositions can also be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, including 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, the disclosed pharmaceutical compositions can be formulated into topical dosage forms. Topical dosage forms include transmucosal and transdermal formulations such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. In such formulations, penetrants and carriers can be included in the pharmaceutical composition. Penetrants are known in the art and include detergents, bile salts, and fusidic acid derivatives for transmucosal administration. For transdermal administration, carriers that can be used include Vaseline®, lanolin, PEG, alcohol, transdermal enhancers, and combinations thereof.

[0212] D. Pharmaceutical Combinations It should be readily understood that the disclosed compositions are not limited to combinations of a single compound, or (when formulated as a pharmaceutical composition) limited to only a single carrier, diluent, and / or excipient, but may also include combinations of multiple compounds (including additional active compounds) and / or multiple carriers, diluents, and excipients. Thus, pharmaceutical compositions of the present disclosure may include the disclosed compounds in combination with one or more other active agents (or derivatives and analogs thereof), together with one or more pharmaceutically acceptable carriers, diluents, and / or excipients, and further together with one or more other active compounds.

[0213] In some embodiments, the formulations of the present disclosure are prepared to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf life, decrease an undesirable effect or property, alter a property in a desired manner (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., the neurotransmitter system), or provide a synergistic effect.

[0214] "Therapeutic effects" that may be increased or added with embodiments of the present disclosure include, but are not limited to, antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anti-anxiety, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anti-cancer, antiemetic, appetite stimulant, antiulcer, antihistamine, antihypertensive, anticonvulsant, anti-epileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, and stimulant effects.

[0215] "Synergy" should be understood to include an increase in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect that is greater than the additive contribution of the components acting alone. Numerous methods known to those skilled in the art exist for determining whether there is a synergistic effect with respect to a particular effect, i.e., whether two or more components, when mixed together, have an effect greater than the sum of the effects of the individual components applied alone, thereby resulting in "1 + 1 > 2." Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol. 2019; 10: 1222) or the Loewe additivity equation (Loewe & Muischnek, Arch Exp Pathol Pharmacol. 1926; 114: 313-326). Synergistic effects can also 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 above-mentioned equations are the concentration-effect curve and the combination index curve, respectively. Each of the above-mentioned equations can be applied to experimental data to generate corresponding graphs that can aid in evaluating the effects of drug combinations.

[0216] In some embodiments, the disclosed pharmaceutical compositions comprise an additional active compound, which in some embodiments is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathic and anti-nociceptive agents, anti-migraine agents, anti-anxiety agents, antidepressants, antipsychotics, anti-PTSD agents, dissociative agents, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, appetite stimulants, anti-ulcer agents, antihistamines, antihypertensives, anticonvulsants, anti-epileptics, bronchodilators, neuroprotective agents, cognitive enhancers, empathogens, psychedelics, plasticity inducers (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, reduce undesirable effects, increase stability or shelf life, improve bioavailability, induce synergy, increase plasticity (e.g., neuroplasticity), or alter pharmacokinetics or pharmacodynamics. In some embodiments, the additional therapeutic effect is antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anti-cancer, antiemetic, appetite stimulant, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant.

[0217] In various embodiments, the additional active compound is tryptamine. As will be appreciated by those skilled in the art, tryptamine is a compound having the following general structure: N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 is as defined herein and commonly understood in the art. [ka]

[0218] In some embodiments, R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 are 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. N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 Any two of can be taken together with the intervening atoms to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, or an optionally substituted heterocyclyl. In various embodiments, tryptamine is R N1 and R N2 An additional R is attached to the nitrogen N3 is a quaternary salt to which R N3 is 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 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-α-methyltryptamine (α,O-DMS), N,N-dimethyl-tryptamine (DMT), 2,α-dimethyltryptamine (2,α-DMT), α,N-dimethyltryptamine (α,N -DMT), N,N-dipropyltryptamine (DPT), N-ethyl-N-isopropyltryptamine (EiPT), α-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-hydroxytryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl-4-hydroxytryptamine N,N-Dimethyltryptamine (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, bufotenin), 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-methylenedioxytryptamine (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-methoxytryptamine N-isopropyl-5-methoxytryptamine (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-M eO-NMT), 5-methoxy-N,N-tetramethylenetryptamine-tetra- (5-MeO-pyr-T), 6-methoxy-1-methyl-1,2,3,4 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), α-methyltryptamine (α-MT), N-ethyltryptamine (NET), N-methyl A tryptamine selected from the group consisting of tryptamine (NMT), 6-propylnorlysergamide (PRO-LAD), N,N-tetra-methylenetryptamine (pyr-T), tryptamine (T), 7-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (THH), or α,N-dimethyl-5-methoxytryptamine (α,N,O-TMS), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.

[0220] In some embodiments, the additional tryptamine is a "conjugated tryptamine" or other indoleamine, examples of which include iboga alkaloids such as ivocaine, and their analogs, metabolites, and derivatives, as well as beta-carbolines.

[0221] In some embodiments, the additional active compound is a phenylalkylamine. In some embodiments, as will be appreciated by those skilled in the art, the phenylalkylamine can be a phenylalkylamine having the structure of formula (A), where R N1 , R N2 , R α , R β , and R 2 ~R 6 each as defined herein and as commonly understood in the art.

[0222] In some embodiments, the additional active compound is alpha-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-4-methylthioamphetamine (ALEPH-8), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-9), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-10), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-11), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-12), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-13), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-14), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-15), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-16), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-17), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-18), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-19 ... Amphetamine (ALEPH-7), 2,5-dimethoxy-α-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,β-trimethoxyphenethylamine (BOB), 2,5,β-trimethoxy-4-methylphenethylamine (BOD), β-methylamphetamine 2,5-Dimethoxy-β-hydroxy-4-methylphenethylamine (BOHD), 3,4,5,β-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-dimethoxy-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-GN), 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 Netethylamine (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-propyl Thiophenethylamine (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-dimethoxyphenethylamine (2C-T-15), 4-(s)-butylthio-2,5-dimethoxyphenethylamine (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine ) phenethylamine (2C-T-21), 3,5-dimethoxy-4-trideuteromethyl-phenethylamine (4-D), β,β-dideutero-3,4,5-trimethoxyphenethylamine (β-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-β-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-ethylamino-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-aminopropyl)benzonorbornane (G-5), 2,5-dimethoxy-3,4-dimethyl-amphetamine (GANESHA), 1,4-Dimethoxy-naphthyl-2-isopropylamine (GN), 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-isopropoxyphenyl Phenethylamine (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-methylenedioxyamphetamine (MDBZ), N-cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM), N,N-dimethyl-3,4-methylenedioxyamphetamine (MDDM), N-ethyl-3,4-methylenedioxyamphetamine (MDE), N-(2-hydroxyethyl)-3,4-methylene Dioxyamphetamine (MDHOET), N-isopropyl-3,4-methylenedioxyamphetamine (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-α,α,N-trimethylphenethylamine (MDMP), N-hydroxy-3,4-Methylenedioxyamphetamine (MDOH), 3,4-methylenedioxyphenethylamine (MDPEA), α,α-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 (M EE), 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-dimethoxy-N-methylamphetamine (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methylamphetamine (METHYL-DOB), 2-methylamino-1-(3,4-methylenedioxyphenyl)butane (METHYL-DMA) -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-methyl- Toxoxy-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-T, ASB), 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-trimethoxyamphetamine (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-ethylthiophenethylamine (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-methylenethiooxyamphetamine (4T-MMDA-2), 2,4,5-trimethoxyphenethylamine (TMPEA), 4-ethyl-5-methoxy-2-methylthioamphetamine (2-TOET), 4-ethyl-2-methoxy-5-methylthioamphetamine (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,A phenylalkylamine selected from the group consisting of 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 ergoline. In various embodiments, the additional active compound is an ergot alkaloid. In various embodiments, the additional active compound is lysergamide. As will be appreciated by those skilled in the art, lysergamide is a compound having the following general structure: N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 is as defined herein and as commonly understood in the art. [ka]

[0224] In some embodiments, R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14are 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. N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 Any two of can be taken together with the intervening atoms to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, or an optionally substituted heterocyclyl. In various embodiments, the lysergamide can be R 6 An additional R is attached to the nitrogen 6A is a quaternary salt to which R 6A is 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 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-propyl-6-nor-lysergic acid diethylamide (IP-LAD), 6-cyclopropyl-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 (i.e., ALD-52 ... Lysergic acid diethylamide (1P-LSD), 1-butyryl-lysergic acid diethylamide (1B-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 (1D-LSD), 1-propionyl-6-allyl-6-nor-lysergic acid diethylamide (1P-AL-LAD) ), 1-(cyclopropylmethanoyl)-6-allyl-6-nor-lysergic acid diethylamide (1cP-AL-LAD), 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), lysergic acid 2,4-dimethylazetidide (i.e., LA-SS-Az, LSZ), lysergic acid piperidide (LSD-Pip), and lysergic acid methylisopropylamide (MIPLA).

[0226] Other tryptamines, phenylalkylamines, and lysergamides useful as additional active compounds for purposes of the present disclosure, and therefore contemplated for inclusion therein, are 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).

[0227] E. Dosage and Administration 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. Administering a "therapeutically effective amount" or "effective amount" of a pharmaceutical composition to a subject means administering an amount of the composition sufficient to achieve a desired effect. Where "effective amount" means an amount effective to treat a stated disorder or condition in a subject, a "therapeutic effect" will be understood to mean a response in the subject following treatment that is deemed desirable and beneficial. Thus, depending on the mental health disorder being treated, or the improvement in mental health or functioning sought, and on the specific components in the disclosed compositions under consideration, the response will vary, but will be readily understood by one of ordinary skill in the art through an understanding of the disclosure herein and the general knowledge of one of ordinary skill in 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, when a pharmaceutical composition comprises a disclosed compound, it can be administered in a single dose (in milligram doses calculated based on the patient's kilogram weight), for example, at or below 0.25 mg / kg (including doses of at or below 0.10 mg / kg, at or below 0.05 mg / kg, at or below 0.01 mg / kg, and at or below 0.005 mg / kg), 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, when a pharmaceutical composition comprises a disclosed compound, it may be present in an amount such that a single dose (in milligram doses calculated based on the patient's kilogram weight) is between about 0.01 mg / kg and about 0.1 mg / kg, e.g., 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, and ranges between these values. In some embodiments, the single dose is between about 0.1 mg / kg and 1.0 mg / kg, e.g., 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 0.8 mg / kg, about 0.9 mg / kg, and about 1.0 mg / kg, and ranges between these values.

[0230] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it may be present in a single dose (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including doses 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 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, at least 180 mg, at least 190 mg, at least 210 mg, at least 220 mg, at least 230 mg, at least 240 mg, at least 250 mg, at least 260 mg, at least 270 mg, at least 280 mg, at least 290 mg, at least 300 mg, at least 310 mg, at least 320 mg, at least 330 mg, at least 340 mg, at least 350 mg, at least 360 mg, at least 370 mg, at least 380 mg, at least 390 mg, at least 400 mg, at least 410 mg, at least 420 mg, at least 430 mg, at least 440 mg, at least 450 mg, at least 450 mg, at least 460 mg, at least 470 mg, at least 480 mg, at least 49 The amount may be present in an amount such as 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, when a pharmaceutical composition comprises a disclosed compound, it may be present in an amount such that a single dose (whether or not such a dose is present in a unit dosage form) is between about 0.1 mg and 1.0 mg, for example, 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, and ranges therebetween. In various embodiments, a single dose is between about 1 mg and about 10 mg, for example, 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, and ranges therebetween. In some embodiments, a single dose is between about 10 mg and about 100 mg.

[0232] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it can be administered in a single dose (in microgram doses calculated based on the patient's kilogram weight), for example, at or below 0.25 μg / kg (including doses of at or below 0.10 μg / kg, at or below 0.05 μg / kg, and at or below 0.01 μg / kg), at least 0.50 μg / kg, at least 0.55 μg / kg, at least 0.60 μg / kg, at least 0.65 μg / kg, at least 0.70 μg / kg, at least 0.75 μg / kg, at least 0.80 μg / kg, at least 0.85 μg / kg, at least 0.90 μg / kg, at least 0.95 μg / kg, at least 1.0 μg / kg, at least or at least 1.1 μg / kg, at least 1.2 μg / kg, at least 1.3 μg / kg, at least 1.4 μg / kg, at least 1.5 μg / kg, at least 1.6 μg / kg, at least 1.7 μg / kg, at least 1.8 μg / kg, at least 1.9 μg / kg, at least 2.0 μg / kg, at least 2.1 μg / kg, at least 2.2 μg / kg, at least 2.3 μg / kg, at least 2.4 μg / kg, at least 2.5 μg / kg, at least 2.6 μg / kg, at least 2.7 μg / kg, at least 2.8 μg / kg, at least 2.9 μg / kg, or at least 3.0 μg / kg, as well as amounts within these ranges.

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

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

[0235] In some embodiments, when the pharmaceutical composition includes an additional active compound, for example, when the additional active compound is a phenylalkylamine or tryptamine, it may be administered in a single dose (in milligrams calculated based on the patient's kilogram weight) of, for example, 0.25 mg / kg or less (including doses 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, g / 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, when the pharmaceutical composition includes an additional active compound, for example, when the additional active compound is a phenylalkylamine or tryptamine, it may be administered in a single dose (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including doses 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 g, 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, the dose of the disclosed compounds ranges from about 1 mg to about 100 mg. For example, the dose can 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 about 100 mg. In some embodiments, the dose of the disclosed compounds is 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, the dose of the disclosed compounds is about 1 mg, about 10 mg, or about 25 mg. In some embodiments, the dose of the disclosed compounds ranges from about 0.001 mg to about 1 g. In some embodiments, the dose of the disclosed compounds ranges from about 100 mg to about 250 mg. In some embodiments, the dose of the disclosed compound is about 25 mg.

[0238] In some embodiments, the disclosed compounds are administered daily. In embodiments, the disclosed compounds are administered twice daily. In embodiments, the disclosed compounds are administered three times daily. In embodiments, the disclosed compounds are administered every other day. In embodiments, the disclosed compounds are administered every three days. In embodiments, the disclosed compounds are administered every four days. In embodiments, the disclosed compounds are administered every five days. In embodiments, the disclosed compounds are administered weekly. In embodiments, the disclosed compounds are administered every other week. In embodiments, the disclosed compounds are administered every three weeks. In embodiments, the disclosed compounds are administered monthly.

[0239] In some embodiments, about 50 mg of the disclosed compounds are administered daily. In some embodiments, about 50 mg of the disclosed compounds are administered twice daily. In some embodiments, about 50 mg of the disclosed compounds are administered three times daily. In some embodiments, about 50 mg of the disclosed compounds are administered every other day. In some embodiments, about 50 mg of the disclosed compounds are administered every three days. In some embodiments, about 50 mg of the disclosed compounds are administered every four days. In some embodiments, about 50 mg of the disclosed compounds are administered every five days. In some embodiments, about 50 mg of the disclosed compounds are administered weekly. In some embodiments, about 50 mg of the disclosed compounds are administered every other week. In some embodiments, about 50 mg of the disclosed compounds are administered every three weeks. In some embodiments, about 50 mg of the disclosed compounds are administered monthly.

[0240] In some embodiments, about 100 mg of the disclosed compounds are administered daily. In some embodiments, about 100 mg of the disclosed compounds are administered twice daily. In some embodiments, about 100 mg of the disclosed compounds are administered three times daily. In some embodiments, about 100 mg of the disclosed compounds are administered every other day. In some embodiments, about 100 mg of the disclosed compounds are administered every three days. In some embodiments, about 100 mg of the disclosed compounds are administered every four days. In some embodiments, about 100 mg of the disclosed compounds are administered every five days. In some embodiments, about 100 mg of the disclosed compounds are administered weekly. In some embodiments, about 100 mg of the disclosed compounds are administered every other week. In some embodiments, about 100 mg of the disclosed compounds are administered every three weeks. In some embodiments, about 100 mg of the disclosed compounds are administered monthly.

[0241] In some embodiments, about 150 mg of the disclosed compounds are administered daily. In some embodiments, about 150 mg of the disclosed compounds are administered twice daily. In some embodiments, about 150 mg of the disclosed compounds are administered three times daily. In some embodiments, about 150 mg of the disclosed compounds are administered every other day. In some embodiments, about 150 mg of the disclosed compounds are administered every three days. In some embodiments, about 150 mg of the disclosed compounds are administered every four days. In some embodiments, about 150 mg of the disclosed compounds are administered every five days. In some embodiments, about 150 mg of the disclosed compounds are administered weekly. In some embodiments, about 150 mg of the disclosed compounds are administered every other week. In some embodiments, about 150 mg of the disclosed compounds are administered every three weeks. In some embodiments, about 150 mg of the disclosed compounds are administered monthly.

[0242] In some embodiments, about 200 mg of the disclosed compounds are administered daily. In some embodiments, about 200 mg of the disclosed compounds are administered twice daily. In some embodiments, about 200 mg of the disclosed compounds are administered three times daily. In some embodiments, about 200 mg of the disclosed compounds are administered every other day. In some embodiments, about 200 mg of the disclosed compounds are administered every three days. In some embodiments, about 200 mg of the disclosed compounds are administered every four days. In some embodiments, about 200 mg of the disclosed compounds are administered every five days. In some embodiments, about 200 mg of the disclosed compounds are administered weekly. In some embodiments, about 200 mg of the disclosed compounds are administered every other week. In some embodiments, about 200 mg of the disclosed compounds are administered every three weeks. In some embodiments, about 200 mg of the disclosed compounds are administered monthly.

[0243] In some embodiments, about 250 mg of the disclosed compounds are administered daily. In some embodiments, about 250 mg of the disclosed compounds are administered twice daily. In some embodiments, about 250 mg of the disclosed compounds are administered three times daily. In some embodiments, about 250 mg of the disclosed compounds are administered every other day. In some embodiments, about 250 mg of the disclosed compounds are administered every three days. In some embodiments, about 250 mg of the disclosed compounds are administered every four days. In some embodiments, about 250 mg of the disclosed compounds are administered every five days. In some embodiments, about 250 mg of the disclosed compounds are administered daily. In some embodiments, about 250 mg of the disclosed compounds are administered weekly. In some embodiments, about 250 mg of the disclosed compounds are administered every other week. In some embodiments, about 250 mg of the disclosed compounds are administered every three weeks. In some embodiments, about 250 mg of the disclosed compounds are administered monthly.

[0244] In some embodiments, an initial dose of a disclosed compound is administered, followed by a boost 30 minutes to 4 hours later with a second dose of a disclosed compound. In some embodiments, the boost dose is administered about 30 minutes after the initial dose. In some embodiments, the boost dose is administered about 60 minutes after the initial dose. In some embodiments, the boost dose is administered about 90 minutes after the initial dose. In some embodiments, the boost dose is administered about 120 minutes after the initial dose. In some embodiments, the boost dose is administered about 150 minutes after the initial dose. In some embodiments, the boost dose is administered about 180 minutes after the initial dose. In some embodiments, the boost dose is administered about 210 minutes after the initial dose. In some embodiments, the boost dose is administered about 240 minutes after the initial dose.

[0245] In some embodiments, the boost dose is about 10% to about 100% of the amount of the initial dose. In some embodiments, the boost dose is the same amount as the initial dose. In some embodiments, the boost dose is about half the amount of the initial dose. In some embodiments, the dosing schedule is daily. In some embodiments, the dosing schedule is twice daily. In some embodiments, the dosing schedule is three times daily. In some embodiments, the dosing schedule is every other day. In some embodiments, the dosing schedule is every three days. In some embodiments, the dosing schedule is every four days. In some embodiments, the dosing schedule is every five days. In some embodiments, the dosing schedule is weekly. In some embodiments, the dosing schedule is every other week. In some embodiments, the dosing schedule is every three weeks. In some embodiments, the dosing schedule is monthly.

[0246] In some embodiments, the dose of the disclosed compounds can range from about 1 mg / kg to about 100 mg / kg. For example, the dose can 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 the disclosed compounds is 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 the disclosed compounds is about 1 mg / kg, about 10 mg / kg, or about 25 mg / kg. In some embodiments, the dose of the disclosed compounds is in the range of about 0.001 mg / kg to about 1 g / kg. In some embodiments, the dose of the disclosed compounds is in the range of about 100 mg / kg to about 250 mg / kg. In some embodiments, the dose of the disclosed compounds is about 25 mg / kg.

[0247] In some embodiments, the disclosed compounds are administered, for example, as a single dose, or one or more times per week (up to twice daily, or even three times daily). In some embodiments, the disclosed compounds are administered according to the dosing schedules provided herein. In some embodiments, the disclosed compounds are administered as extended or sustained release formulations, for example, to achieve the dosing regimens disclosed herein and release 50 mg to 1 g to patients on a set schedule according to the indication being treated in those patients.

[0248] It will be readily understood that the dosage may vary depending on whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability or susceptibility of the condition to which the treatment is directed, the desired clinical endpoint, previous, concurrent or subsequent treatment, the general health, age, sex and race of the subject, bioavailability, the possibility of systemic, local or regional adverse side effects, the presence of other disorders or diseases in the subject, and other factors understood by those of skill in the art (e.g., medical history or family history).

[0249] The amount, frequency, or duration of the dose may be increased or decreased as indicated by the desired clinical result, the state of the disease state or symptom, any adverse side effects of the treatment or therapy, or concomitant medications. One of ordinary skill in the art with the teachings of this disclosure at hand will understand the factors that can affect the amount, frequency, and timing of administration necessary to provide an amount sufficient or effective to provide 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] In some embodiments, the actual dose administered will be determined by a physician in light of the relevant circumstances, including the disorder being treated, the selected route of administration, the actual composition or formulation being administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore it will be understood that any dosage ranges disclosed herein are not intended to limit the scope of the present disclosure. In some cases, dosage levels below the lower limit of the disclosed range may be more than sufficient, while in other cases, doses above the range may be used without causing adverse side effects, for example, when such a larger dose can also be divided into several smaller doses for administration, taken either together or separately.

[0251] In embodiments, the recommended dosage may be known by reference to the format of the formulation itself, particularly when the formulation is prepared in a single unit dosage form such as a capsule, tablet, or lozenge. In embodiments in which the formulation is prepared in multiple dosage forms, e.g., a liquid suspension and a topical formulation, the recommended dosage may be known by reference to the means for administration, or by reference to the packaging and labeling, insert, marketing materials, training materials, or other information and knowledge available to those skilled in the art or the public.

[0252] Therefore, another aspect of the present disclosure provides a pharmaceutical kit containing the pharmaceutical composition or formulation of the present disclosure, the corresponding recommended administration guidelines or prescribing information, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. The pharmaceutical formulation can also be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

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

[0254] The kit generally includes suitable packaging. The kit may include one or more containers containing any of the compounds described herein. Each component (if there are two or more components) can be packaged in a separate container, or several components can be combined in one container where cross-reactivity and shelf life are acceptable. The kit may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or sub-unit doses. For example, a kit may be provided containing sufficient dosages of the compounds disclosed herein and / or additional pharmaceutically active compounds useful for the diseases detailed herein to provide effective treatment of an individual over an extended period of time (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer). The kit may also include multiple unit doses of the compound and instructions for use, packaged in an amount sufficient for storage and use in a pharmacy (e.g., hospital pharmacy and compounding pharmacy).

[0255] Preferably, dosing and proper administration information (if necessary) is printed directly on the multi-dose kit (e.g., on the blister pack or other internal packaging holding the disclosed compositions or formulations). However, the kits of the present disclosure may further contain package inserts and other printed instructions (e.g., on the external packaging) for administering the disclosed compositions and for their proper therapeutic use.

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

[0257] As used herein, the terms "subject," "user," "patient," and "individual" are used interchangeably and refer to any mammal, including mice, monkeys, livestock mammals, sport animals, and pet mammals such as dogs and cats, but preferably humans. Such terms are understood to include anyone with an indication for which the compounds, compositions, or methods described herein may be effective or who may otherwise benefit from the invention. Generally, it is understood that all of the compounds, compositions, and disclosed methods will work for all individuals, although individual variability is anticipated and understood. The disclosed treatment methods can also be modified to treat multiple patients at once, including couples or families. Thus, these terms are also understood to refer to two or more individuals.

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

[0259] a. Regulation of neurotransmission and neuroplasticity In some embodiments, administration of a disclosed compound modulates neurotransmission in a subject, e.g., after administration of a pharmacologically effective amount to said subject. In some embodiments, modulating neurotransmission includes, e.g., modulating monoamine levels in the CNS and peripheral tissues. In some embodiments, modulating neurotransmission includes, e.g., increasing monoamine levels in the CNS and peripheral tissues of a subject to which a disclosed compound has been administered. In some embodiments, modulating neurotransmission includes, e.g., decreasing monoamine levels in the CNS and peripheral tissues of a subject to which 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 the disclosed compounds or compositions thereof results in inhibition of reuptake of one or more neurotransmitters, hi some embodiments, administration of the disclosed compounds or compositions thereof increases 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 regulate neurotransmission, such as neurotransmission, in a subject. Thus, in some methods herein, the disclosed compositions, when administered in a pharmacologically effective amount, affect monoaminergic neurotransmission, including serotonergic, dopaminergic, and noradrenergic neurotransmission. Thus, in some embodiments, the disclosed compositions, when administered in a pharmacologically effective amount, are used to treat medical conditions associated with dysregulated or insufficient function of neurotransmission, and in certain embodiments, are used to treat medical conditions associated with monoaminergic neurotransmission.

[0262] In various embodiments, administration of the disclosed compounds or compositions thereof results in modulation of one or more monoamine receptors, such as serotonin receptors, dopamine receptors, or norepinephrine receptors, hi various embodiments, administration of the disclosed compounds or compositions thereof results in agonism or partial agonism of monoamine receptors, including any one or more of serotonin receptors, dopamine receptors, and norepinephrine receptors.

[0263] In some embodiments, administration of the disclosed compounds or compositions thereof results in activation of serotonin receptors. In some embodiments, administration of the disclosed compounds or compositions thereof results in agonism and / or antagonism of serotonin receptors (HTR). In some embodiments, administration of the disclosed compounds or compositions thereof results in activation of HTR (HTR 1A and HTR 1B HTR1, HTR etc. 2A , HTR 2B and HTR 2C and HTR2, such as any one or more of HTR6.

[0264] In some embodiments, the disclosed compounds contain a drug at an HTR of less than 10 μM, less than 5 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. 1A , HTR 1B , HTR2A HTR 2B and HTR6 in vitro EC 50 In various embodiments, the disclosed compounds have an HTR of less than 1 μM, less than 0.5 μM, less than 0.1 μM, less than 0.05 μM, less than 0.01 μM, less than 0.005 μM, or less than 0.001 μM. 2A In vitro EC 50 (agonist mode).

[0265] In some embodiments, administration of the disclosed compounds or compositions thereof may enhance HTR activity compared to other HTRs. 2A In some embodiments, administration of the disclosed compounds or compositions thereof results in increased agonism of HTR1 (e.g., HTR 1A and HTR 1B ), another HTR2 (e.g., HTR 2B and HTR 2C ), HTR5 (e.g., HTR 5A ), HTR6, and HTR7 (e.g., HTR 7D ) compared to one or more of HTR 2A resulting in increased agonism of

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

[0267] Determine agonism and antagonism, EC 50 and IC 50 Each of these measurements can be determined according to methods available to those skilled in the art. In one example, measuring Gq-mediated calcium flux is related to HTR, a widely recognized target of psychedelic compounds. 2A This is a known method for assessing modulation, e.g., activation, of a protein. See, for example, 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 (Berl). 2019; 236(2): 799-808. As will be appreciated by those skilled in the art, partial agonists may be more potent than full agonists (E MAX = 100%) compared to maximum efficacy (E MAX ) reduction, for example, serotonin in the example of HTR.

[0268] In some embodiments, the 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 the serotonin membrane transporter (SERT), dopamine membrane transporter (DAT), norepinephrine membrane transporter (NET), and vesicular monoamine transporter. In some embodiments, the drug contained in the disclosed compounds blocks the uptake activity of a monoamine transporter. In some embodiments, the drug contained in the disclosed compounds blocks the uptake activity of one or more of the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).

[0269] In some embodiments, the disclosed compounds comprise a drug that inhibits the uptake activity of any one or more of SERT, DAT, and NET. In some embodiments, the disclosed compounds comprise a drug that inhibits the uptake activity of SERT, DAT, and NET. In various embodiments, the disclosed compounds comprise a drug that has an in vitro IC of less than 10 μM for any one or more of SERT, DAT, and NET. 50 In various embodiments, the drug contained in the disclosed compounds does not inhibit the uptake activity of SERT. In various embodiments, the drug contained in the disclosed compounds has an in vitro IC for SERT of less than 10 μM. 50 In various embodiments, the disclosed compounds comprise a drug that selectively inhibits the uptake activity of SERT. In various embodiments, the disclosed compounds comprise a drug that exhibits greater potency for inhibiting the uptake activity of SERT compared to DAT and NET.

[0270] Determining whether the disclosed compounds inhibit the uptake activity of monoamine transporters, or whether they lack such activity, can be determined according to available methods, which may include live cell fluorescence assays or radioactive assays. In some examples, inhibition of monoamine uptake can be determined in rat synaptosomes or human platelets. See, for example, 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 can be compared to uptake inhibitors with low nM potency, such as the DAT inhibitor GBR 12909, the NET inhibitor desipramine, and the SERT inhibitor clomipramine.

[0271] In some embodiments, administration of the disclosed compounds or compositions according to the methods herein results in an improved pharmacological profile, such as a relative increase in agonism of serotonin receptors relative to dopamine receptors 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, including amounts therebetween. Measurement of receptor agonism will be understood by those skilled in the art or by reference to general knowledge in the art.

[0272] In some embodiments, the improved pharmacological profile of the disclosed compounds or compositions is a relative increase in the extracellular concentration of serotonin relative to dopamine and / or norepinephrine compared to the corresponding unsubstituted composition, which can be an increase of 5% or more, 10% or more, 25% or more, or 50% or more, including amounts therebetween. Measuring the extracellular concentration of neurotransmitters will be understood by one skilled in the art or by reference to general knowledge in the art.

[0273] Detection of changes in monoamine levels in a subject, such as an increase or decrease, can be achieved according to methods known to those skilled in the art, such as cerebral 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, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) (see, e.g., Wong & Gjedde, Encyclopedia Neurosci, 2009; 939-952 and Takano, Front Psychiatry. 2018; 9: 228).

[0274] In some embodiments, the disclosed compounds are used to enhance neuroplasticity. Neuroplasticity, also known as neural plasticity or brain plasticity, refers to the brain's ability to change and adapt in response to experience, 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, increased neuroplasticity contributes to the therapeutic effects of the disclosed compounds 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, spine formation, and synaptogenesis in neurons. Neuritogenesis refers to the way neurons generate and extend their neurites (i.e., form axons and dendrites). Neuritogenesis is a key process in neurogenesis and the formation of neural circuits. Spine formation refers to the formation of dendritic spines, which are small projections on the dendrites of neurons. Dendritic spines are important for synaptic connections and play a key role in synaptic transmission and plasticity. Synaptogenesis refers to the formation of synapses, which is important 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 neurite formation. Neurite formation can be measured in terms of total neurite length, maximum neurite length, number of neurite nodes, and / or number of neurite terminals. 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 terminals.

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

[0278] b. Treatment In some embodiments, the disclosed compounds are used to treat a medical condition, such as a disease or disorder. In various embodiments, the disclosed compounds are used in the manufacture of a medicament for treating a condition, such as a disease or disorder. Methods are also provided for administering the disclosed compounds to a subject having a condition, such as a disease or disorder, thereby treating the condition.

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

[0280] In some embodiments, methods for treating and / or preventing a condition in a subject are provided, comprising administering a therapeutically effective amount of a disclosed compound or pharmaceutical composition to a mammal. In some embodiments, "treating" or "treatment" refers to treating a disease or disorder in a subject, and preferably 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 the disorder; (b) inhibiting the disorder, i.e., halting its development; (c) alleviating the disorder, i.e., causing its regression; (d) protecting against or alleviating symptoms or conditions caused by or associated with the disorder; (e) reducing, diminishing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency, or probability of one or more symptoms or conditions associated with the disorder; and (f) preventing or inhibiting the worsening or progression of symptoms or conditions associated with or coexisting with the disorder. In various 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 apparent to those of skill in the art in view of the teachings herein and the knowledge of those skilled in the art.

[0281] In various embodiments, the disclosed compounds are used to treat central nervous system (CNS) disorders. Generally, CNS disorders include diseases of the nervous system (e.g., movement disorders, neurodegenerative disorders), as well as psychiatric, behavioral, and neurodevelopmental disorders, such as those in DSM-5, the Merck Manual, ICD-11, or other such diagnostic resources known to those skilled in the art.

[0282] i. Mental, behavioral, or neurodevelopmental disorders In some embodiments, the disclosed compounds are used to treat psychiatric, behavioral, or neurodevelopmental disorders. In some embodiments, the disclosed compounds are administered, e.g., in a therapeutically effective amount, to a subject with a psychiatric, behavioral, or neurodevelopmental disorder, thereby treating the psychiatric, behavioral, or neurodevelopmental disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide a beneficial therapeutic effect in treating a psychiatric, behavioral, or neurodevelopmental disorder.

[0283] The ICD-11, which is incorporated herein by reference in its entirety, defines a "mental, behavioral, or neurodevelopmental disorder" as a syndrome characterized by clinically significant impairments in an individual's cognition, emotional regulation, or behavior that reflect dysfunction in the psychological, biological, or developmental processes underlying 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 related to stress, dissociative disorders, nutritional (or eating) disorders, elimination disorders, bodily pain disorders or somatic experience disorders, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or antisocial disorders, personality disorders (and related traits), paraphilic disorders, confabulation disorders, neurocognitive disorders, mental or behavioral disorders related to pregnancy, childbirth, or the postpartum period, sleep-wake disorders, sexual dysfunction, and gender nonconformity.

[0284] Mental, behavioral, or neurodevelopmental disorders not otherwise defined are understood to refer to disorders as defined in ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or "mental health disorder") generally refers to a disease state involving negative changes in emotions, moods, thoughts, and / or behaviors. Generally, mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotions, behavior, or a combination thereof, that result in impaired functioning, distress, or increased risk of morbidity. The terms "mental disorder" and "mental health disorder," as well as terms defining specific diseases and disorders, generally refer to patients with ICD-11 criteria, or a diagnosis based thereon, although it will be understood that the disclosed methods are equally applicable to patients with comparable underlying disorders, regardless of whether the disorder is diagnosed based on ICD-11, ICD-10, DSM-5, or DSM-IV criteria (each of which is incorporated herein by reference in its entirety), whether the diagnosis is based on other clinically accepted criteria, or whether the patient has not yet received a formal clinical diagnosis.

[0285] In some embodiments, the disclosed compounds are used to treat mental health disorders. In some embodiments, the disclosed compounds are administered, for example, in a therapeutically effective amount, to a subject with a mental health disorder, thereby treating the mental health disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide a beneficial therapeutic effect in treating a mental health disorder. In some embodiments, the disclosed compounds or compositions are used to reduce the symptoms of a mental health disorder. The symptoms of a mental health disorder to be treated can be determined by one of ordinary skill in the art by reference to the general understanding in the art of the disorder.

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

[0287] In some embodiments, the disclosed compounds are used to treat neurodevelopmental disorders. In some embodiments, a "neurodevelopmental disorder" is a neurological and / or cognitive disorder that occurs during development involving significant difficulties in the acquisition and performance of a particular neurological function (e.g., intellectual, motor, language, or social function). In some embodiments, the neurodevelopmental disorder is intellectual developmental disorder, developmental speech or language disorder, autism spectrum disorder, developmental learning disorder, developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.

[0288] In some embodiments, the disclosed compounds are used to treat schizophrenia or another primary psychotic disorder. Generally, these disorders are characterized by significant disturbances in reality and behavioral changes, manifested by positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking and speech, and markedly disorganized behavior, and negative symptoms such as blunted or flat affect and experiences such as aversion and psychomotor disorders. In some embodiments, the disclosed compounds are used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or substance-induced psychotic disorder.

[0289] In some embodiments, the disclosed compounds are 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, catatonia is associated with another psychiatric disorder. In some embodiments, catatonia is substance- or drug-induced.

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

[0291] In some embodiments, the disclosed compounds are used to treat anxiety or fear-related disorders. "Anxiety disorders" refers to a class of mental disorders that induce excessive or abnormal fear, terror, or apprehension. 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 substance-induced anxiety disorder.

[0292] In some embodiments, the disclosed compounds are used to treat obsessive-compulsive disorder or related disorders. Generally, 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 desire to accumulate possessions and distress associated with discarding them (i.e., hoarding disorder). In some embodiments, the disorder is body-focused and may be characterized by recurrent and addictive behaviors (hair plucking, skin picking). In some embodiments, the disorder is obsessive-compulsive disorder, body dysmorphic disorder, olfactory-related disorder, hypochondriasis, hoarding disorder, body-focused repetitive behavior disorder, or substance-induced obsessive-compulsive disorder.

[0293] In some embodiments, the disclosed compounds are used to treat stress-related disorders. In some embodiments, stress-related disorders have an identifiable stressor as a causative factor, such as exposure to a stressful or traumatic event or a series of such events or adverse experiences. The stressor may be within the realm of normal life experiences (e.g., separation, socioeconomic problems) or may be from a threatening or traumatic experience. Generally, the nature and duration of symptoms occurring in response to a stressor can distinguish the disorder from everyday stress. In various embodiments, the disclosed compounds are 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, the disclosed compounds are used to treat dissociative disorders. Dissociative disorders can be characterized by an involuntary disruption or discontinuity in one or more of the following normal integrations: identity, sensation, perception, emotion, thought, memory, motor control, or behavior. In some subjects, the symptoms of dissociative disorders can be severe and can result in impairments in personal, social, educational, occupational, or other areas of functioning. In some embodiments, the disclosed compounds are used to treat dissociative neurological symptom disorders, dissociative amnesia (including amnesia with and without dissociative fugue), trance disorder, possession-trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization-derealization disorder.

[0295] In some embodiments, the disclosed compounds are used to treat feeding or eating disorders. Feeding or eating disorders generally involve abnormal eating or feeding behaviors that are not explained by another health condition, developmentally inappropriate, or culturally sanctioned. These disorders may involve a preoccupation with food and concerns about weight and body shape. In various embodiments, the disclosed compounds are used to treat anorexia nervosa (including significantly underweight anorexia, dangerously underweight anorexia, or normal weight recovered anorexia), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination reflux disorder.

[0296] In some embodiments, the disclosed compounds are used to treat elimination disorders, including, for example, recurrent leakage of urine into clothing or bedding and recurrent defecation in inappropriate places in individuals who have reached the developmental age for normal continence. In various embodiments, the disclosed compounds are used to treat enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or fecal incontinence (including fecal incontinence with constipation or overflow incontinence, and fecal incontinence without constipation or overflow incontinence).

[0297] In some embodiments, the disclosed compounds are used to treat somatic pain disorders or somatic experience disorders. Somatic stress disorders typically involve physical symptoms that cause the subject distress and to which the subject pays excessive attention. Body integrity dysphoria typically involves a disturbance in a person's experience of the body, manifested by persistent discomfort in the body structure or intense feelings. In some embodiments, the disclosed compounds are used to treat somatic pain disorders (including mild, moderate, and severe somatic pain disorders) or body integrity dysphoria.

[0298] In some embodiments, the disclosed compounds are used to treat substance use or addictive behavior disorders. Substance use or addictive behavior disorders are mental and / or behavioral disorders that primarily result from the use of psychoactive substances (including drugs and illicit or illegal substances), or specific repetitive reward and reinforcement behaviors. In some embodiments, the disclosed compounds are used to treat substance use disorders (i.e., substance use disorders, or SUDs). In some embodiments, the substance use disorder is associated with alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics, or anxiolytics, cocaine, stimulants (e.g., amphetamine, methamphetamine, methanthinone, synthetic cathinones, caffeine), hallucinogens, nicotine, volatile inhalants, dissociative drugs such as MDMA or MDA, ketamine, and phencyclidine, or another substance (including drugs 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, inhalant use disorder, opioid use disorder, sedative use disorder, hypnotic use disorder, anxiolytic use disorder, stimulant 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 some embodiments, the substance use disorder is inhalant use disorder. In some embodiments, the substance use disorder is opioid use disorder. In some embodiments, the substance use disorder is sedative use disorder. In some embodiments, the substance use disorder is hypnotic use disorder. In some embodiments, the substance use disorder is anxiolytic use disorder. In some embodiments, the substance use disorder is stimulant use disorder. In some embodiments, the substance use disorder is tobacco use disorder. In some embodiments, the substance use disorder is an alcohol use disorder, and the alcohol use disorder is selected from alcohol abuse, alcoholism, and alcoholism, hi some embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorder, gaming disorder).In some embodiments, substance use disorders can be screened using 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), Opioid Risk Tool-OUD (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).

[0299] In some embodiments, the disclosed compounds are used to treat impulse control disorders. Generally, impulse control disorders are characterized by a repeated inability to resist urges, motivations, or urges to perform actions that benefit the subject, despite negative long-term consequences, such as harm to the subject or significant impairment in important areas of the subject's functioning. In some embodiments, impulse control behaviors include firefighting, theft, inappropriate sexual behavior, and explosive emotional outbursts. In some embodiments, the disclosed compounds are used to treat pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.

[0300] In some embodiments, the disclosed compounds are used to treat disruptive behavior disorders or antisocial disorders. Such disorders can be broadly characterized by persistent behavioral problems ranging from persistently defiant, disobedient, aggressive, or malicious behavior to behaviors that violate the rights of others or norms, rules, or laws. In some embodiments, the disclosed compounds are used to treat oppositional defiant disorder (including oppositional defiant disorder with chronic irritable anger and oppositional defiant disorder without chronic irritable anger) or conduct antisocial disorder (including childhood-onset conduct antisocial disorder and adolescent-onset conduct antisocial disorder).

[0301] In some embodiments, the disclosed compounds are used to treat personality disorders. Personality disorders can generally be characterized by problems perceiving one's identity, self-worth, the accuracy of one's self-view, and self-discipline, which manifest in patterns of cognition, emotional experience, emotional expression, and maladaptive behavior. In some embodiments, the disclosed compounds are used to treat mild, moderate, or severe personality disorders. In some embodiments, the disclosed compounds are used to treat prominent personality traits or patterns (e.g., negative emotionality, detachment, antisociality, disinhibition, obsessive-compulsive, borderline personality patterns). 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, the disclosed compounds are used to treat paraphilic disorders. Paraphilic disorders can be characterized by a pattern of persistent and intense atypical sexual arousal, the focus of which involves others who are unwilling or unable to consent due to age or status. In some embodiments, the disclosed compounds are used to treat exhibitionism disorder, voyeurism disorder, pedophilic disorder, compulsive sexual sadism disorder, excoriation disorder, other paraphilic disorders involving non-consenting individuals, or paraphilic disorders involving solitary behavior or consenting individuals.

[0303] In some embodiments, the disclosed compounds are used to treat confabulation disorders. Generally, confabulation disorders can be characterized by intentionally disguising, falsifying, inducing, or exacerbating medical, psychological, or behavioral signs and symptoms or harm to oneself or another. A subject with a confabulation disorder can seek treatment or otherwise present themselves or another person as ill, injured, or disabled. In various embodiments, the disclosed compounds are used to treat self-imposed confabulation disorders or other-imposed confabulation disorders.

[0304] In some embodiments, the disclosed compounds are used to treat neurocognitive disorders. Neurocognitive disorders can be characterized by a primary clinical deficit in acquired (as opposed to developmental) cognitive function, such that the subject experiences a decline from a previously achieved level of functioning. In some embodiments, the disclosed compounds are used to treat delirium. In some embodiments, the delirium is associated with another disease or disorder. In some embodiments, the delirium is associated with psychoactive substances (including drugs and illicit or illegal substances). In some embodiments, the disclosed compounds are used to treat mild neurocognitive disorders. In some embodiments, the disclosed compounds are used to treat amnesic disorders. In some embodiments, the amnesic disorder is associated with another disease or disorder. In some embodiments, the delirium is associated with psychoactive substances (including drugs and illicit or illegal substances). In some embodiments, the disclosed compounds are used to treat dementia. In some embodiments, the dementia is associated with Alzheimer's disease, Parkinson's disease, cerebrovascular disease, Lewy body disease, or psychoactive substances (including drugs and illicit or illegal substances). In some embodiments, the disclosed compounds are used to treat behavioral or psychological disorders associated with dementia. In some embodiments, dementia is assessed using the Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), and Neuropsychiatric Inventory Questionnaire (NPI-Q).

[0305] In some embodiments, the disclosed compounds are used to treat mental or behavioral disorders associated with pregnancy, childbirth, or the postpartum period. In some embodiments, the pregnancy or postpartum period-related syndrome includes significant mental and behavioral features, including depressive symptoms. In some embodiments, the disorder includes psychotic symptoms. In some embodiments, the disclosed compounds are used to treat mental or behavioral disorders associated with pregnancy, childbirth, or the postpartum period that involve psychotic symptoms. In various embodiments, the disclosed compounds are used to treat mental or behavioral disorders associated with pregnancy, childbirth, or the postpartum period that do not involve psychotic symptoms.

[0306] In various embodiments, the disclosed compounds are used to treat sleep-wake disorders. Generally, sleep-wake disorders are associated with difficulty initiating or maintaining sleep (e.g., insomnia), excessive sleepiness (e.g., hypersomnia disorder), breathing disorders during sleep (e.g., sleep-related breathing disorders (SRBD), such as obstructive sleep apnea (OSA), central sleep apnea (CSA), sleep-related hypoventilation disorder, sleep-related hypoxemia disorder, snoring, catatonia, Cheyne-Stokes respiration, and sleep-disordered breathing disorders), disturbances in sleep-wake schedules (e.g., circadian rhythm sleep-wake disorders), abnormal movements during sleep, or problematic behavioral or psychological events occurring during sleep onset, during sleep, or awakening from sleep (e.g., parasomnia). In various embodiments, the disclosed compounds are used to treat insomnia disorder, hypersomnia disorder, sleep-related breathing disorder, circadian rhythm sleep-wake disorder, or parasomnia disorder.

[0307] In some embodiments, the disclosed compounds are used to treat sexual dysfunction. Sexual dysfunction can be defined as a syndrome in which a subject may have difficulty experiencing personally satisfying, non-compulsive sexual activity. In some embodiments, the disclosed compounds are used to treat sexual dysfunction associated with hypoactive sexual desire, sexual arousal, orgasmic dysfunction, ejaculatory dysfunction, or pelvic organ prolapse.

[0308] In some embodiments, the disclosed compounds or compositions are used in conjunction with psychotherapy, such as 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; J Consul Clin Psychol. 2005;73(2):354-59; or 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 approaches used by MAPS to treat patients with PTSD (e.g., Mithoefer, M(2017).Manual for MDMA-Assisted Psychotherapy in the Treatment of PTSD).

[0309] In some embodiments, the disclosed compounds or compositions can be administered in combination with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is not necessary or desirable, or no particular type of psychotherapy is necessary or desirable, but any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in a particular therapy and to choose between any such therapy (or decide to discontinue any particular therapy) while still receiving clinically significant therapeutic benefits is one advantage of the present invention. Furthermore, it should be understood that patients can participate in numerous other therapeutically beneficial activities, including breathing exercises, meditation and concentration exercises, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or interacting with pets or animals, and such participation may follow or be associated with administration of the compositions, and may occur with or without the participation or guidance of a therapist.

[0310] In some embodiments, the "psychotherapy" specifically refers to "psychedelic-assisted psychotherapy." Psychedelic-assisted psychotherapy broadly includes a variety of related approaches that involve at least one session in which a patient takes a psychedelic and, while under the influence of the psychedelic, is monitored, supported, or otherwise involved by one or more trained mental health professionals (see, e.g., Schenberg 2018). Protocols have been developed to standardize procedures that emphasize a high level of care (see, e.g., Johnson 2008), such as the treatment approach used by MAPS to treat patients with PTSD using MDMA (described, e.g., in Mithoefer 2017).

[0311] In some embodiments, psychotherapy using the disclosed compounds is conducted in widely spaced sessions. These sessions can be as frequent as once a week, but are often approximately monthly or less frequent. In most cases, a small number of sessions, on the order of one to three, are necessary 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 involves multiple sessions, some of which involve the administration of the disclosed compounds ("medication-assisted psychotherapy"). In other cases, patients participate in psychosocial or behavioral therapy without the co-administration of medications or without the administration of the disclosed compounds.

[0312] In some embodiments, the disclosed compounds or compositions are administered in conjunction with standardized psychological treatment or support. This refers to any recognized modality of standard psychotherapy or counseling sessions, whether administered once a week, twice a week, or on an as-needed basis; whether in-person or virtually (e.g., via telehealth or a web program or mobile app); and whether the therapist is a human or a virtual or AI "therapist." As used herein, "therapist" refers to a person who treats a patient using the disclosed compositions and methods, regardless of 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 are appropriate for certain aspects of medication-assisted therapy (e.g., prescribing, dispensing, or administering medications, providing psychotherapeutic support). In some embodiments, "person" can also include AI.

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

[0314] Preferably, when the disclosed pharmaceutical compositions are administered, such administration is done without or with a reduced risk of side effects that require medical supervision, thus allowing for treatment at home or otherwise outside of a clinic, without the need for such supervision and / or without the need for further adjunctive psychological therapy (although this may be provided in certain embodiments herein).

[0315] In some embodiments, the disclosed compounds or compositions can be administered in combination with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is not necessary or desirable, or no particular type of psychotherapy is necessary or desirable, but any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in a particular therapy and to choose between any such therapy (or decide to discontinue any particular therapy) while still receiving clinically significant therapeutic benefits is one advantage of the present invention. Furthermore, it should be understood that patients can participate in numerous other therapeutically beneficial activities, including breathing exercises, meditation and concentration exercises, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or interacting with pets or animals, and such participation may follow or be associated with administration of the compositions, and may occur with or without the participation or guidance of a therapist.

[0316] In some cases, specific individualized 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 variations. The term "genetic variation" refers to a change in a gene sequence relative to a reference sequence (e.g., a commonly found sequence and / or a wild-type sequence). Genetic variations can be recombination events or mutations, e.g., substitution / deletion / insertion events such as point mutations 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 affect drug metabolism, including metabolism of the disclosed compositions, including CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP3A5. Other examples of CYP enzymes include CYP1A1, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, C These include YP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0317] In some embodiments, the disclosed compounds or compositions are taken together with compounds that are metabolized by the same CYP enzymes as the disclosed compounds, to allow for lower dosages, increase the effective bioavailability of one or both, or otherwise affect drug metabolism or pharmacokinetics. In some embodiments, the dose of the disclosed compositions is adjusted, such as lowered when administered to subjects known to be poor metabolizers of the active compounds in the composition (e.g., with genetic variations in CYP2D6 and / or CYP3A4), or increased when administered to subjects known to be rapid metabolizers. In some embodiments, patients are tested using routine means known to those of skill in the art to determine whether they are poor or rapid metabolizers 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 is involved 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 higher levels of FKBP51 protein compared to individuals lacking such SNPs. The FKBP5 gene is involved in responses to stress and trauma, and such SNPs are correlated with susceptibility to certain depression, PTSD, and anxiety disorders. In some embodiments, the genetic variation is an inclusion criterion for administration of the disclosed compounds. In some embodiments, the genetic variation is an exclusion criterion for administration of the disclosed compounds.

[0319] In some embodiments, the treated mammal has altered epigenetic regulation of genes, 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.

[0320] ii. Neurodegenerative disorders In some embodiments, the disclosed compounds are used to treat neurodegenerative disorders. In some embodiments, the disclosed compounds are administered to a subject with a neurodegenerative disorder, for example, in a therapeutically effective amount. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects in the treatment of neurodegenerative disorders.

[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 nerve cells, resulting in a decline in cognitive, motor, and / or sensory abilities.

[0322] Neurodegenerative disorders can be classified according to major clinical features, such as dementia, parkinsonism, or motor neuron disease; anatomical distribution of neurodegeneration, such as frontotemporal degeneration, extrapyramidal disorders, or spinocerebellar degeneration; or primary molecular abnormalities (Dugger B, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology. 2017:9(7); a028035). These disorders can involve a variety of etiologies, including, but not limited to, the 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, dementia including vascular dementia, Huntington's disease, Rickobodig's disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson's disease or parkinsonism, prion disease, progressive supranuclear palsy, and traumatic brain injury.

[0324] i. Pain and inflammation In some embodiments, the disclosed compounds are used to treat pain and / or inflammation, e.g., pain disorders and / or inflammatory disorders. In some embodiments, the disclosed compounds are administered, e.g., in a pharmacologically effective amount, to a subject suffering from pain and / or inflammation, thereby treating the pain and / or inflammation. In some methods, the disclosed compositions, when administered in a pharmacologically effective amount, provide beneficial therapeutic effects in the treatment of pain and / or inflammation.

[0325] In some embodiments, the disclosed compounds are used to treat a pain disorder, which may be any of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatodysplasia, hypoesthesia, hyperalgesia, neuralgia, neuritis, neuropathic pain, phantom limb pain, analgesia, analgesic pain syndrome, caustic pain, sciatica disorders, degenerative joint disorders, fibromyalgia, visceral diseases, chronic pain disorders, headache disorders, migraine, chronic cluster headache, concussive headache, short-lasting unilateral neuralgic headache attacks, chronic fatigue syndrome, complex regional pain syndrome, neurological dystrophy, plantar fasciitis, or pain associated with cancer.

[0326] In some embodiments, the disclosed compounds are used to treat inflammatory disorders. In some embodiments, the inflammatory disorder is characterized by inflammation of an organ or tissue. In various embodiments, the inflammatory disorder includes 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, stomach inflammation, intestinal inflammation, neuroinflammation, and brain inflammation. In various embodiments, the inflammatory disorder is a disorder that causes acute inflammation or exhibits chronic inflammation as a symptom. In some embodiments, the inflammatory disorder includes chronic inflammation.

[0327] In some embodiments, the disclosed compounds are used to reduce inflammation. In some embodiments, the disclosed compounds are used in the manufacture of a medicament for reducing inflammation. In some embodiments, for example, a therapeutically effective amount of a disclosed compound is administered to a subject to reduce inflammation.

[0328] The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with or described in relation to actual or potential tissue damage." While the mechanism by which serotonin modulators, such as 5-HT2A agonists and 5-HT2A antagonists, improve pain remains unclear, the synaptic plasticity associated with such compounds may alter the pathological changes in neural connections seen in chronic pain states, potentially resulting in a reduction in pain intensity and duration (Castellanos et al., Reg Anesth Pain Med. 2020;45(7):486-494). Furthermore, 5-HT2AR activation has been shown to promote anti-inflammatory effects, such as reducing TNF-α-induced inflammation. For example, 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 See Psychiatry.2018;30(4):363-375, Okamoto et al., Neurosci.2005;130(2):465-74.

[0329] Pain, such as chronic pain, and its improvement, such as symptom reduction, can be measured according to known methods, for example, by subject report, pain diary, pain scale, applicable questionnaire (assessing chronic pain and its impact on physical, emotional, and social functioning), ecological momentary assessment, and its computerized version.See, for example, 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, Migraine-Screen Questionnaire (MS-Q), and Fibromyalgia Survey Questionnaire (FSQ).

[0330] Reduction of inflammation, such as chronic systemic inflammation, can be measured according to various methods available to those skilled in the art. Inflammatory biomarkers can be detected in biological specimens, such as a subject's blood, e.g., plasma or serum, or saliva. In one example, inflammation can be detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell count from a blood test. CRP can also be detected in saliva samples. Salivary CRP is not synthesized locally in the oral cavity and may reflect a more systemic level of inflammation compared to other inflammatory biomarkers, such as cytokines (Szabo & Slavish, Psychoneuroendocrinology. 202;124:105069). Furthermore, clinical pathology data, such as hematology data regarding red blood cell parameters, platelet count, total white blood cell count, and white blood cell differentiation and morphology, coagulation data regarding clotting time and fibrinogen, and clinical chemistry data regarding total protein, albumin and globulin, liver enzymes, kidney parameters, electrolytes, and bilirubin, can provide an early indication of the presence and potential location of inflammation, even in the absence of specific data regarding immune tissue. See, for example, Germolec et al., Methods Mol Biol. 2018;1803:57-79 and Luo et al., Clin Lab. 2019 1;65(3).

[0331] H. Example The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0332] Example 1: Synthesis of 4-(((4-bromo-2,5-dimethoxyphenethyl)amino)methyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol HCl (Compound 1A-1) [ka] 0.492 g (1.54 mmol) of 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine acetate and 0.313 g (1.54 mmol) of pyridoxal HCl were added to an Erlenmeyer flask containing 20 mL of methanol and 0.5 g of 4 Å 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, 0.464 g of NaBH4 (12.3 mmol) was added in four portions over 10 minutes, allowing the effervescence to subside before adding the next portion. Upon addition of NaBH4 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 of dichloromethane and shaken with 20 mL of saturated NaHCO in a separatory funnel. The organic layer was removed, and the aqueous layer was washed once with 20 mL of dichloromethane. The organic fractions were combined, dried over NaSO, and then filtered. The solvent was removed in vacuo to give a viscous yellow oil.

[0333] Flash chromatography was performed on the oil. 5 mL of the oil was dissolved in a 1:1 solution of methanol:water. 2 mL of this solution was chromatographed on a Revelis X2 equipped 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 with an Rf = 0.33 (3:2:2; n-butanol:acetic acid:water) as determined by thin-layer chromatography (TLC). Removal of the solvent from the product-containing fractions resulted in 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, a methanol:water solution containing an oil began to precipitate a whitish-yellow solid. This solid was dissolved in 20 mL of 33:67 methanol:water and filtered. The off-yellow precipitate was dried overnight in a vacuum oven at 50°C to yield 0.185 g of a yellow solid. The yellow solid was dissolved in 2 mL of methanol and chromatographed on a Revelis X2 equipped with a 40 g C18 column using an EtOH and water solvent system, gradient eluting as described above, starting with 0% EtOH and increasing to 100% EtOH over 20 minutes. The desired product eluted at 11.8 minutes with an Rf = 0.33 (3:2:2; n-butanol:acetic acid:water), as determined by TLC. Removal of the solvent from the product-containing fractions precipitated a white solid. The solid was filtered and dried overnight under vacuum at 50°C.

[0335] The combined white solids were dissolved in 2 mL of methanol, followed by the addition of 1 mL of 1 M HCl in diethyl ether. This was then diluted with an additional 10 mL of ether, resulting in the formation of a fine white solid. The solid was collected by filtration and dried overnight under vacuum at 50° C. to give 0.180 g of 4-(((4-bromo-2,5-dimethoxyphenethyl)amino)methyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol HCl (Compound 1A-1).

[0336] HRMS calculated value C 18 H 26 NO4Br 2+ (M+2H + )=412.0986; Actual value=412.1038.

[0337] Example 2: In vitro metabolic stability the purpose: Determining the metabolic stability of the disclosed compounds relative to their corresponding component drugs. The metabolic stability assay measures the intrinsic clearance (CL) of a compound. int ) and other important pharmacokinetic parameters such as bioavailability and half-life (t 1 / 2 ) provides the key data needed to calculate

[0338] method: A high-throughput assay is used to determine the metabolic stability of the disclosed compounds and any of their comparators in human liver microsomes. LC / MS analysis is used to quantify the percentage of compound remaining after incubation. Half-life (t 1 / 2 ) is estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) versus time, assuming first-order kinetics.

[0339] Example 3: In vitro metabolic profiling the purpose: Determining whether the disclosed compounds are metabolized and identifying the metabolic products thereof.

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

[0341] Phase I and / or Phase II metabolites are identified using mass spectrometry (MS). The percent remaining compound and half-life of the disclosed compound (parent compound) are determined. MS data, such as extracted ion chromatograms, show the parent and major metabolites. The metabolic transformation of each observed metabolite is elucidated, and the metabolite mass, peak area, and retention time are determined. Metabolic profiling may be performed 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 and Significance:Compounds that undergo metabolism in vivo may produce pharmacologically active or chemically reactive metabolites that result in unexpected effects or potential toxicity. The FDA Guidance for Industry on Safety Testing of Drug Metabolites emphasizes the relevance of in vitro metabolite profiling early in drug development, as metabolites that are unique to or disproportionate in humans may require additional toxicological studies.

[0343] Example 4: In vitro CYP enzyme inhibition the purpose: Evaluating interactions between the disclosed compounds and cytochrome P450 (CYP450) enzymes. Such interactions provide insight into potential metabolism-mediated drug-drug interactions when compounds affect the pharmacokinetics, such as absorption, distribution, metabolism, and excretion, of co-administered drugs by altering the activity of drug-metabolizing enzymes and / or drug transporters.

[0344] method: In vitro studies are conducted to evaluate the inhibitory effects of the disclosed compounds on recombinant human CYP450 isoenzymes. Recombinant human CYP450 isoenzymes are used to metabolize profluorescent probe substrates into fluorescent products. Inhibition of human P450 isoforms is measured by the reduction in fluorescence after treatment with various concentrations of the disclosed compounds.

[0345] Briefly, the disclosed compounds are incubated at different concentrations in a mixture containing a buffer, an enzyme, and a substrate. Fluorescence is then measured using a plate reader, and the percentage of inhibition can be extrapolated from the readings. Alternatively, the inhibitory effect of the disclosed compounds on CYP enzymes can be assessed using high-performance liquid chromatography. Inhibition is assessed using the Michaelis-Menten method. CYP enzyme inhibition can be performed 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 and Significance: Metabolic enzymes in the liver, such as CYP450 enzymes, are responsible for the majority of drug metabolism in the body. Six CYP450 class enzymes metabolize 90 percent of drugs, with two of the most important metabolizers being 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).

[0347] Example 5: In vitro evaluation of membrane permeability and interaction with P-glycoprotein (P-gp) in MDCKII MDR1 cells the purpose: Evaluating the permeability and transportability of the disclosed compounds. Permeability is assessed using MDCK (Madin-Darby canine kidney) cells, and the effect of P-glycoprotein (P-gp) is assessed to determine drug transport.

[0348] method: Bidirectional permeability studies (apical to basolateral [AB] and basolateral to apical [BA]) are performed to assess the apparent permeability of the disclosed compounds. Additionally, compounds are evaluated to determine whether they act as P-gp substrates in MDCKII-MDR1 and mimic MDCKII cell lines.

[0349] Briefly, the disclosed compounds and reference compounds are evaluated in two directions, in the absence and presence of a P-gp inhibitor. MDCKII cells and MDCKII-MDR1 cells are incubated in transport buffer on both the apical [A] and basolateral [B] sides. The disclosed compounds are then added to both sides of the cells and incubated. The transport rate of the disclosed compounds is determined in the absence or presence of a P-gp inhibitor. After incubation, if the disclosed compounds permeate the cells in both the AB and BA directions, the cell permeability is measured using an LC MS / MS system. The efflux ratio of the disclosed compounds is calculated to determine whether they are P-gp substrates.

[0350] Results and Significance: This screening provides insight into the behavior of compounds in biological systems. Compounds are classified as follows (Cambridge MedChem Consulting, ADME, 2019): [Table 8]

[0351] Mass balance as a percentage (%) is calculated using % recovery = 100 x (CD(t) + CR(t)) / C0.

[0352] where CD(t) is the measured concentration in the donor well at time t (expressed as an IS ratio), CR(t) is the measured concentration in the receiver well at time t (expressed as an IS ratio), and C0 is the initial concentration in the donor solution (expressed as an IS ratio).

[0353] The percentage of cell integrity is calculated using the following equation: Integrity %=100x[1-RFU basolateral / RFU apical]

[0354] LY RFU values ​​are normalized by the background mean value. A test article is considered to be a P-gp substrate if the efflux ratio in the absence of an inhibitor is >2 and if the ratio is significantly reduced in the presence of a P-gp inhibitor.

[0355] Example 6: In vitro activity at trace amine associated receptor 1 (TAAR1) the purpose: Evaluating the activity of the 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] method: Radioligand binding assays are performed according to previously described methods, e.g., by Rickli et al., Neuropsychopharmacology, 2016;26(8), 1327-1337, using [H]RO5166017 as the radiolabel and RO5166017 as the competitor. Briefly, membrane preparations of human embryonic kidney (HEK) 293 cells overexpressing the TAAR1 receptor (Revel et al., PNAS, 2011;108:8485-8490), for example, of human origin, are incubated with K d The compound is incubated with a radiolabeled selective ligand at a concentration equal to 1000 kJ / well. Ligand displacement by the compound is then measured. Specific binding of the radioligand to the target receptor is defined as the difference between total binding and nonspecific binding, as determined in the presence of an excess of a selected competitor.

[0357] Results and Significance:TAAR1 activation has been shown to regulate monoaminergic neurotransmission. See, for example, Revel et al., PNAS. 2011; 108(20): 8485-8490. TAAR1 may be a promising target for the treatment of neuropsychiatric disorders. For example, the effect of TAAR1 activation on dopaminergic neurotransmission may provide therapeutic benefits for addictions such as substance use disorders (Liu & Li, Front Pharmacol. 2018; 9: 279).

[0358] Example 7: Prodrug Hydrolysis in Serum Pooled mixed human plasma (2 ml), mouse plasma, rat plasma, and dog plasma are equilibrated at 37°C. The disclosed compound is added to achieve a concentration of 1.0 μg / mL. Aliquots (50 μL) of the mixture are removed at timed intervals (0 h, 0.004 h, 0.5 h, 1 h, 2 h, and 4 h) and quenched with 200 μL of methanol / acetonitrile (1:1). Samples are vortexed and stored at -80°C until analysis. Assays are performed in triplicate. Control samples are run in phosphate-buffered saline (PBS, pH 7.4) and simulated gastric fluid (SGF, pH 2). Sample analysis is performed by HPLC-MS to determine the amount of prodrug and drug in each sample tested. The average concentration of prodrug remaining at different time points of the experiment is determined.

[0359] Example 8: Absorption and hydrolysis of prodrugs in an in vitro model of human intestinal mucosa the purpose:Caco-2 cells, derived from a human colon adenocarcinoma cell line, 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 semi-porous polycarbonate membranes, forming a continuous monolayer that closely mimics the morphology and function of human small intestinal epithelial cells, as well as bilateral compartments that mimic the intestinal lumen and blood flow. Due to their marker enzyme expression, uptake, transport, and permeability characteristics similar to those of small intestinal epithelial cells, Caco-2 cells provide a robust model for understanding drug absorption. Research suggests that in vitro cell experiments using Caco-2 cells can provide more accurate insight 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] method: The Caco-2 permeability assay is performed using the CacoReady™ model (Readycell, Barcelona, ​​Spain), which consists of Caco-2 cells seeded on polycarbonate filters (0.4 μm pore size, 6.5 mm diameter) in the apical chamber of a 24-well high-throughput screening plate (Corning Incorporated, NY, USA). Cells were seeded at 1 × 10 in appropriate medium and buffer. 5 Cells are seeded at a density of 1000 cells / mL. Cell culture is continued at 37 °C for 21 days, with the culture medium changed every 2 days 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 the experiment, the integrity of the monolayer was assessed by measuring the transepithelial electrical epithelial resistance (TEER) and the apparent permeability coefficient (P app ) is assessed by measuring the permeability of fluorescent paracellular markers. TEER values ​​>600 Ω cm -2 KatsP app <0.8 × 10 -6 cm s -1Only wells containing 100% ethanol are used for transport experiments.

[0362] The medium in the apical and basal chambers was removed and washed twice with preheated buffer (15 min at 37 °C in an incubator). 1.25 mL of preheated buffer was added to the basal chamber. The test compound was dissolved in DMSO and appropriately diluted with buffer to obtain a final DMSO concentration of 0.1% (v / v). 0.25 mL of the test compound solution was then added to the apical chamber of the transwell. 0.5 mL aliquots of the solution were collected from the basal chamber of the transwell at 0.5, 1, 2, and 4 hour intervals. The concentrations of the test compound and its hydrolyzed metabolites in these samples were determined by HPLC. To compensate for the reduction in total volume, an equal volume of buffer solution was added to the transwell after the samples were collected. The TEER values ​​of the monolayers were monitored throughout the experiment.

[0363] Results and Significance: The results may indicate that certain disclosed compounds having a drug attached to a vitamin B6 (e.g., pyridoxal) promoiety are likely to be absorbed and hydrolyzed by human intestinal mucosal cells. Absorption and hydrolysis rates are also assessed and compared between compounds. Results can be expressed as concentration (μg / mL) per incubation time. Differences in in vitro absorption and hydrolysis between the disclosed compounds and appropriate comparators are also determined according to the described methods.

[0364] Example 9: In vivo pharmacokinetics of the disclosed compounds in rats The disclosed compounds are administered to rats by injection (intravenous and subcutaneous) of a sterile solution (2 mg / ml) at a rate of 1.4-2 mg / kg. Blood samples are collected at 15, 30, 45, 60, 120, 240, and 360 minutes and analyzed by LC-MS for the disclosed compounds (i.e., prodrugs) and their corresponding component drugs. Pharmacokinetic (PK) profiles of the prodrug and active species are obtained, and relative bioavailability is determined for each route of administration. PK-PD type curves can be generated to demonstrate the activity of the disclosed compounds. PK parameters that can be determined according to this assay include C max , T max , t 1 / 2 , AUC and bioavailability.

[0365] Example 10: In vivo evaluation of the behavioral effects of the disclosed compounds using the head twitch response (HTR) assay the purpose: The mouse head twitch response (HTR) is a measure of 5-HT 2A HTR is a behavioral test that reflects receptor activation and can predict psychedelic effects in humans (Halberstadt et al., J Psychopharmacol. 2011;25(11):1548-1561). 2A Receptor agonists and non-psychedelic 5-HT 2A Due to its ability to reliably distinguish from receptor agonists, it is widely used as a behavioral surrogate for psychedelic effects in humans (Halberstadt & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3).

[0366] method:The HTR assay was performed as described by Klein et al., Neuropharmacol. 2018;142:231-239 to evaluate the effects of the disclosed compounds in mice. Male C57BL / 6 J mice (6-8 weeks old) were obtained and housed in a vivarium that met all requirements for the care and treatment of laboratory animals. Mice were housed up to four per cage in a climate-controlled room with a reverse light cycle (lights on at 19:00 h, lights off at 07:00 h) and allowed free access to food and water, except during behavioral testing. Testing was performed between 10:00 h and 18:00 h. All animal experiments were conducted in accordance with applicable guidelines and approved by the appropriate animal care committee.

[0367] HTR is assessed using a head-mounted magnet and magnetometer detection coil 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 skull using dental cement. After a 2-week recovery period, HTR experiments are performed in a well-lit room, with at least 7 days between sessions to avoid carryover effects.

[0368] Test compounds are dissolved in an appropriate solvent, such as water containing 5% Tween 80, and administered IP at a volume of 5 mL / kg body weight or 10 mL / kg body weight immediately before testing. Different doses are tested to generate dose-response curves. Mice are injected with drug or vehicle, and HTR activity is recorded for 30 minutes in a glass cylinder surrounded by a magnetometer coil. The coil voltage is low-pass filtered (2 x 10 kHz cutoff frequency), amplified, digitized (20 kHz sampling rate), and then filtered offline (40 x 200 Hz bandpass) using a Powerlab / 8SP with LabChart v 7.3.2 (ADInstruments, Colorado Springs, CO, USA).

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

[0370] Head twitch counts are analyzed using one-way analysis of variance (ANOVA). Post-hoc pairwise comparisons between selected groups are performed using Tukey's Student's Range method. The entire recording is examined for head twitches. Potency calculations can be confounded by long periods of inactivity, so in some cases shorter time blocks are analyzed to accommodate compounds with short durations of action. ED 50 Values ​​and 95% confidence limits are calculated using nonlinear regression. The relationship between HTR potency and binding affinity is assessed using linear regression and ordinary least squares regression. For all analyses, significance is demonstrated by exceeding an alpha level of 0.05.

[0371] Results and Significance:The results may indicate that certain disclosed compounds having a drug attached to a vitamin B6 (e.g., pyridoxal) promoiety are likely to produce psychedelic effects in humans. The magnitude of such effects will also be assessed and compared between compounds. Results may also be useful for evaluating ED. 50 The difference in mouse HTR between the disclosed compounds and appropriate comparators is 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 those skilled in the art that specific details are not required to practice the present invention. Accordingly, the foregoing description of specific embodiments of the present invention has been 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, etc. disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments have been chosen and described to best explain the principles of the invention and its practical application through the description of particular examples, and thereby enable those skilled in the art to best utilize the invention and its various embodiments with various modifications suited to the particular use envisioned, for applications beyond the scope of the specific examples disclosed. The scope of the present invention, therefore, is intended to be defined only by the following claims and their equivalents.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof; During the ceremony: X is H or PO ３ H ２ and R α is H or C １ ~C ６ is alkyl; R β is H, OH, or C １ ~C ６ is alkoxy; R ２ , R ３ , R ４ and R ５ are each independently H, Br, F, Cl, I, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Haloalkyl, C １ ~C ６ haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino are independently selected from 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, -OSO ２ OH, -OC(O)NH ２ or optionally substituted by -SONH; R ６ is H; or R ２ and R ３ , R ３ and R ４ , R ４ and R ５ , and R ５ and R ６ taken together form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, or a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and the remaining R ２ , R ３ , R ４ , R ５ , and R ６ is as defined above; However, R ２ , R ３ , R ４ , R ５ , and R ６ At least two of them are not H.

2. The compound of claim 1 having the structure of formula (IA): 【Chemistry 2】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof; In the formula, R ２Ａ and R ５Ａ However, each independently, C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, or C １ ~C ６ It is a deutero-deuteroalkyl.

3. R ４ 3. The compound of claim 2, wherein is Br, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

4. R ４ is C １ ~C ６ 3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R is alkyl.

5. R ４ Ga-CH ３ 5. The compound of claim 4, wherein:

6. R ４ is C １ ~C ６ 3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, which is alkylthio.

7. R ４ Ga-SCH ２ CH ２ CH ３ 7. The compound of claim 6, wherein:

8. R ２Ａ is C １ ~C ６ 3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R is alkyl.

9. R ２Ａ Ga-CH ３ 9. The compound of claim 8, wherein:

10. R ４Ａ is C １ ~C ６ 3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R is alkyl.

11. R ４Ａ Ga-CH ３ 11. The compound of claim 10, wherein:

12. R ４Ａ Ga-CH ２ CH ３ 11. The compound of claim 10, wherein:

13. R α 3. The compound of claim 2, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

14. R β 3. The compound of claim 2, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

16. X is PO ３ H ２ 3. The compound of claim 2, wherein:

17. The compound of claim 1 having the structure of formula (IB): 【Transformation 3】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein: R ３Ａ , R ４Ａ , and R ５Ａ However, each independently, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, or C １ ~C ６ haloalkyl, １ ~C ６ The alkyl is optionally substituted with a 3- to 6-membered cycloalkyl or a 6- to 10-membered aryl.

18. R ３Ａ is C １ ~C ６ 18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, which is alkyl.

19. R ３Ａ Ga-CH ３ 19. The compound of claim 18, which is: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

20. R ４Ａ is C １ ~C ６ 18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, which is alkyl.

21. R ４Ａ Ga-CH ３ 21. The compound of claim 20, wherein:

22. R ５Ａ is C １ ~C ６ 18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, which is alkyl.

23. R ５Ａ Ga-CH ３ 23. The compound of claim 22, which is: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

24. R α is C １ ~C ６ 18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, which is alkyl.

25. R α Ga-CH ３ 25. The compound of claim 24, which is: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

26. R α 18. The compound of claim 17, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

27. R β 18. The compound of claim 17, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

29. X is PO ３ H ２ 18. The compound of claim 17, which is: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

31. 31. The compound of claim 30 having the following structure: 【Chemistry 4】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 32】 【Chemistry 5】 32. The compound of claim 31 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 33】 【Transformation 6】 32. The compound of claim 31 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 34】 【Chemistry 7】 32. The compound of claim 31 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 35】 【Transformation 8】 32. The compound of claim 31 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 36】 【Chemistry 9】 31. The compound of claim 30 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 37】 【Chemistry 10】 31. The compound of claim 30 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 38】 【Chemistry 11】 31. The compound of claim 30 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 39】 【Chemistry 12】 31. The compound of claim 30 having the structure: or 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. 【Request Item 41】 【Chemistry 13】 41. The compound of claim 40 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. 【Request Item 42】 【Chemistry 14】 41. The compound of claim 40 having the structure: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

43. The compound according to claim 2, having the structure of formula (IA-1): 【Chemistry 15】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

44. The compound according to claim 2, having the structure of formula (IA-2): 【Chemistry 16】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

45. The compound according to claim 2, having the structure of formula (IA-3): 【Chemistry 17】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

46. The compound according to claim 2, having the structure of formula (IA-4): [Chemistry 18] or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

47. The compound according to claim 2, having the structure of formula (IA-5): 【Chemistry 19】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

48. The compound according to claim 2, having the structure of formula (IA-6): 【Chemistry 20】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

49. The compound according to claim 2, having the structure of formula (IA-7): 【Chemistry 21】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

50. R ４ 50. The compound of any one of claims 43 to 49, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein is Br.

51. R ４ is C １ ~C ６ 50. The compound of any one of claims 43 to 49, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, which is alkyl.

52. R ４ Ga-CH ３ 52. The compound of claim 51, which is: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

53. R ４ is C １ ~C ６ 50. The compound of any one of claims 43 to 49, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, which is alkylthio.

54. R ４ Ga-SCH ２ CH ２ CH ３ 54. The compound of claim 53, which is: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

55. The compound of claim 1 having the structure of formula (IC): 【Chemistry 22】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein n is independently 1 or 2 in each occurrence.

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

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

58. The compound of claim 1 having the structure of formula (ID): 【Chemistry 23】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

59. The compound of claim 1 having the structure of formula (IE): 【Chemistry 24】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof; wherein R′ and R″ are each independently H, F, or D.

60. 60. The compound of claim 59, wherein R' and R" are both H, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

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

63. R α 63. The compound of any one of claims 43 to 62, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

64. R α Ga-CH ３ 63. The compound according to any one of claims 43 to 62, wherein:

65. R β 65. The compound of any one of claims 43 to 64, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

67. X is PO ３ H ２ 66. The compound according to any one of claims 43 to 65, which is: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

68. A compound of formula (A), 【Chemistry 25】 or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein: X is H or PO ３ H ２ and R α is H or C １ ~C ６ is alkyl; R β is H, OH, or C １ ~C ６ is alkoxy; R ２ , R ３ , R ４ and R ５ are each independently H, Br, F, Cl, I, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Haloalkyl, C １ ~C ６ haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; each C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino are independently selected from 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, -OSO ２ OH, -OC(O)NH ２ or optionally substituted by -SONH; R ６ is H; or R ２ and R ３ , R ３ and R ４ , R ４ and R ５ , and R ５ and R ６ taken together form a 3- to 6-membered cycloalkyl, a 4- to 6-membered cycloalkenyl, or a 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkenyl, and the remaining R ２ , R ３ , R ４ , R ５ , and R ６ is as defined above.

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

70. 70. The pharmaceutical composition of claim 69, suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

71. 70. The pharmaceutical composition of claim 69 provided in unit dosage form.

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

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

74. 72. 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. 70. 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. 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, anti-neuropathic and anti-nociceptive agents, anti-migraine agents, anti-anxiety agents, antidepressants, antipsychotics, anti-PTSD agents, dissociative agents, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, appetite stimulants, anti-ulcer agents, antihistamines, antihypertensives, anticonvulsants, anti-epileptics, bronchodilators, neuroprotective agents, cognitive enhancers, empathogens, psychedelics, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins.

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

78. 77. The pharmaceutical composition of claim 76, wherein the additional therapeutic effect is an antioxidant effect, an anti-inflammatory effect, analgesic effect, anti-neuropathic effect, anti-nociceptive effect, anti-migraine effect, anxiolytic effect, antidepressant effect, antipsychotic effect, anti-PTSD effect, dissociative effect, immunostimulatory effect, anti-cancer effect, antiemetic effect, appetite stimulant effect, antiulcer effect, antihistamine effect, antihypertensive effect, anticonvulsant effect, antiepileptic effect, bronchodilator effect, neuroprotective effect, empathogenic effect, psychedelic effect, sedative effect, or stimulant effect.

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

80. 80. The method of claim 79, wherein the medical condition is a disorder associated with dysregulation or improper function of neurotransmission.

81. 81. The method of claim 80, wherein the disorder associated with dysregulation or inappropriate function of neurotransmission is a disorder of monoaminergic neurotransmission.

82. 82. The method of claim 81, wherein the disorder associated with dysregulation or inappropriate function of neurotransmission is a disorder of serotonergic, dopaminergic, or noradrenergic neurotransmission.

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

84. 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, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety disorder, phobic disorder, bulimia, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance use disorder, substance-induced mood disorder, mood disorder associated with another health condition, disruptive behavior disorder, eating disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, and dissociative disorder.

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

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

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

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

89. 80. 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. 80. The method of claim 79, wherein the compound is administered in conjunction with one or more sessions of psychotherapy or psychological support.

91. 50. A method of modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.

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

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

95. HTR is HTR １Ａ , H.T.R. １Ｂ , H.T.R. ２Ａ , H.T.R. ２Ｂ , H.T.R. ２Ｃ , and HTR ６ 94. The method of claim 93, wherein

96. Regulating neurotransmission is ２Ａ 96. The method of claim 95, comprising agonizing

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

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

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

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

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

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

103. 48. Use of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof, for the manufacture of a medicament for treating a patient suffering from a mental health disorder, by a method as claimed in any of the following claims.

104. 69. Use of a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, for the manufacture of a medicament for treating a patient suffering from a mental health disorder by a method as in any of the following claims.

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