Deuterated and fluorinated empathogens

Abstract

Provided are deuterated and / or fluorinated empathogen compounds, including analogs of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxymethcathinone (methylone), and similar compounds. In some aspects, useful features of disclosed compounds include neuromodulatory properties affecting, for example, monoaminergic neurotransmission. Also provided are methods of making the compounds and pharmaceutical compositions thereof, and methods of using disclosed compounds and compositions for treating medical conditions, such as mental, behavioral, and neurodevelopmental disorders.

Description

[0001] 2024-03-01 DEUTERATED AND FLUORINATED EMPATHOGENS INVENTORS: Nicholas V. Cozzi, Paul F. Daley CROSS-REFERENCE

[0001] Priority is claimed under PCT Art.8(1) and Rule 4.10 to U.S. Prov. App. Nos.63 / 449,252, filed March 1, 2023, and 63 / 465,860, filed May 11, 2023, both fully incorporated by reference for all purposes. TECHNICAL FIELD

[0002] This disclosure relates in some aspects to deuterated and / or fluorinated empathogen compounds, including analogs of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxymethcathinone (bk-MDMA, methylone), and similar compounds. The disclosure also relates to methods of making such compounds, pharmaceutical compositions thereof, and methods of using the same. BACKGROUND OF THE INVENTION

[0003] The enormous public health burden of mental health disorders, combined with the shortcomings of currently available treatments, reveal the necessity of developing novel alternative treatments, especially those which minimize side effects and optimize efficacy.

[0004] One alternative treatment being developed for mental health disorders is MDMA, which showed promise in two phase 3 trials and received Priority Review for its NDA submission to the U.S. FDA for approval to treat post-traumatic stress disorder (PTSD), administered in combination with psychotherapy. Another treatment is methylone, a cathinone related to MDMA that was first made (and given its name) by the chemists Peyton Jacob III and Alexander (Sasha) Shulgin in 1995 for potential use as an antidepressant ( see PCT Pub. No. WO1996 / 039133A1), and is currently also being investigated as a treatment for PTSD.

[0005] However, MDMA, methylone, and other known empathogens have numerous drawbacks relating to their pharmacology as well as to other aspects of their potential therapeutic and commercial use.

[0006] Disclosed herein are various novel therapeutic empathogens including those which will have enhanced metabolic stability, reduced toxicity, and other improvements on known compounds, and which will meet the needs for additional alternative treatments. INCORPORATION BY REFERENCE

[0007] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated by reference individually, and as if each is fully set forth herein. However, no such citation should be construed as an admission that a cited reference comes from an area that is analogous or directly applicable to the invention, nor should any citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or is part of the common general knowledge in the art. 2024-03-01 BRIEF SUMMARY OF THE INVENTION

[0008] The following is a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. This summary is not an extensive overview of the invention. It is not intended to identify key or critical elements of the invention or to delineate the scope of the invention. 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 that follows.

[0009] In a first aspect, provided is a compound of Formula (I): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: R1is H, methyl, or ethyl; R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; Raand Rbare both H, or together represent =O; and R' and R'' are each independently H, D, or F.

[0010] In some embodiments, the compound has the structure of Formula (II): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: Raand Rbtogether represent =O, or are both H; R1is methyl, ethyl, or H; R2is either: C1-C3deuteroalkyl or C1-C3fluoroalkyl, when Raand Rbare both H; or H, C1-C3alkyl, C1-C3deuteroalkyl or C1-C3fluoroalkyl, when Raand Rbtogether represent =O; and R3is H, C1-C3alkyl, C1-C3deuteroalkyl or C1-C3fluoroalkyl.

[0011] In some embodiments, the compound has the structure of Formula (II-6): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0012] In some embodiments, the compound has the structure of Formula (II-4): 2024-03-01 or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0013] In some embodiments, Raand Rbtogether represent =O. In embodiments, Raand Rbare both H.

[0014] In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In embodiments, R1is H.

[0015] In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is —CH3. In some embodiments, R2is —CH2CH3. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is —CD3. In some embodiments, R2is —CD2CD3. In some embodiments, R2is C1-C3fluoroalkyl. In some embodiments, R2is —CF3. In some embodiments, R2is —CF2CF3.

[0016] In some embodiments, R3is H. In some embodiments, R3is methyl. In embodiments, R3is ethyl.

[0017] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0018] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0019] In some embodiments, the compound has the structure of: 2024-03-01 or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0020] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0021] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0022] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0023] In embodiments, the compound is the R -isomer. In embodiments, the compound is the S -isomer.

[0024] Also provided is a pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of the disclosed embodiments, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof. In some embodiments, the composition comprises the compound as a pure or substantially pure individual enantiomer, or an enantiomerically enriched mixture having an optical purity of between 0-25%, between 25-50%, between 50-75%, between 75-90%, between 90-95%, or at least 95% enantiomeric excess. In embodiments, the pure or substantially pure individual enantiomer is the R -isomer. In embodiments, the pure or substantially pure individual enantiomer is the S -isomer. 2024-03-01

[0025] In some embodiments, the pharmaceutical composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

[0026] In some embodiments, the composition is provided in unit dosage form. In some embodiments, pharmaceutical composition comprises the compound in a total amount of between about 1 and 1000 mg. In some embodiments, the pharmaceutical composition comprises the compound in a total amount of between about 50 and 500 mg. In some embodiments, the unit dosage form is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

[0027] In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof. In some embodiments, the additional active compound is selected from the group consisting of analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents, monoamine oxidase inhibitors, tryptamines, terpenes, phenylalkylamines, sedatives, stimulants, serotonergic agents, NMDA modulators, NMDA antagonists, and vitamins. In some embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, or alter pharmacokinetics or pharmacodynamics.In some embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

[0028] Also provided is a method for modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of the compound or composition of any of the disclosed embodiments. In some embodiments, modulating neurotransmission comprises activating a monoamine neurotransmitter receptor and / or modulating the uptake activity of a monoamine transporter. In some embodiments, the monoamine neurotransmitter receptor is any of a serotonin receptor (HTR), a dopamine receptor, and a norepinephrine receptor. In some embodiments, the monoamine transporter is any of a serotonin transporter (SERT), a dopamine transporter (DAT), or a norepinephrine transporter (NET). In some embodiments, the HTR is any of HTR1A, HTR1B, HTR2A, HTR2B, and HTR6. In some embodiments, modulating neurotransmission comprises agonizing HTR2A.

[0029] Also provided is a method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or composition of any of the disclosed embodiments. In some embodiments, the medical condition is a disorder 2024-03-01 linked to dysregulation or inadequate functioning of neurotransmission. In some embodiments, the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission. In some embodiments, the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of serotonergic, dopaminergic, or noradrenergic neurotransmission.

[0030] In some embodiments, the medical condition is a mental health disorder. In some embodiments, the mental health disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, alcohol or drug abuse or dependence disorders, a substance use disorder, substance-induced mood disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, and dissociative disorders.

[0031] In some embodiments, the disorder is PTSD. In embodiments, the PTSD is treatment-resistant.

[0032] In some embodiments, the subject is suicidal.

[0033] In some embodiments, the disorder is depression. In some embodiments, depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

[0034] In some embodiments, the compound or composition is used in combination with an additional therapy for the mental health disorder. In some embodiments, the additional therapy is psychotherapy. In some embodiments, the additional therapy comprises administering one or more additional psychoactive agents to the subject. In some embodiments, the additional psychoactive agents are selected from the group consisting of selective-serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin-norepinephrine- dopamine reuptake inhibitors (SDNRIs), and anxiolytic agents. In some embodiments, the additional psychoactive agent is a selective-serotonin reuptake inhibitor (SSRI). In some embodiments, the subject is taking or is continuing to take the SSRI concurrently with the compound or composition.

[0035] Also provided is the compound or composition of any of the disclosed embodiments, for use in the treatment of a mental health disorder.

[0036] Also provided is the use of the compound or composition of any of the disclosed embodiments for the manufacture of a medicament for the treatment of a mental health disorder patient according to the method of any of the following claims.

[0037] The foregoing has outlined broadly and in summary certain pertinent features of the disclosure so that the detailed description of the invention that follows may be better understood, and so that the present contribution to the art can be more fully appreciated. Hence, this summary is to be considered as a brief and general synopsis of only some of the objects and embodiments disclosed herein, is provided solely for the 2024-03-01 benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are lawfully entitled. Additional features of the invention are described hereinafter. It should be appreciated by those in the art that all disclosed specific compositions and methods are only exemplary, and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods will be appreciated to be also within the scope and spirit of the invention as set forth in the claims. It also will be appreciated that headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner. DETAILED DESCRIPTION OF THE INVENTION

[0038] While various aspects and features of certain embodiments are summarized above, the following detailed description illustrates several exemplary embodiments in further detail to enable one of skill in the art to practice such embodiments, and to make and use the full scope of the invention claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications. It will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention illustrated herein can be made by those in the art without departing from the spirit of the invention, or the scope of the invention as described in the claims. The headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner.

[0039] The scope of the invention includes all embodiments and formulations thereof, not only those expressly described below, and it will be understood that many modifications, substitutions, changes, and variations in the described embodiments, applications, and details of the invention illustrated herein can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as set forth in the appended claims.

[0040] Provided are deuterated and / or fluorinated empathogens, such as deuterated and / or fluorinated analogs and derivatives of MDMA and beta-keto (bk) MDMA (methylone) analogs. Also provided are methods of making the disclosed compounds, such as by chemical synthesis. Additionally provided are compositions, such as pharmaceutical compositions, comprising the disclosed compounds. Further provided are kits containing such compositions together with instructions for use. In other aspects, provided are methods of using the disclosed compounds and compositions thereof.

[0041] In some embodiments, the methods comprise modulating neurotransmission, such as in a subject. In some embodiments (equivalently, and simply as shorthand, “in embodiments”), disclosed compounds and compositions are used to treat a condition, such as a disease or a disorder. In some embodiments, any of the disclosed compounds or compositions may be used for treating a disease, preventing a disease, treating a condition, preventing a condition, and / or causing an effect. In embodiments, the methods of use are for treatment of a mental health disorder, or for the improvement of mental health and functioning. 2024-03-01

[0042] Results have been published for certain deuterium-substituted MDMA having deuterium substitution of hydrogen at the methylenedioxy ring moiety (e.g., Berquist et al., Drug Alcohol Dependence, 2020; 208, 107850; Fukuto et al., J Med Chem., 1991, 34(9), 2871-2876 [d2-MDMA]), and certain deuterated MDMA and methylone compounds are available as analytical reference materials for use as an internal standard for quantification (e.g., Cayman Chemical, Ann Arbor, Mich., d3-MDMA HCl [Item No.15822] and d5-MDMA HCl [Item Nos.18573 (RM), 20743 (CRM)]) and (CRM)]; d3-Methylone HCl [Item No.18732]). Substituted amphetamine derivatives, including certain deuterated amphetamine and cathinone compounds, are also disclosed in WO 2023 / 081403, WO 2023 / 081897, and WO 2023 / 081899. Certain fluorinated MDMA analogs have also been disclosed, such as 3,4-methylenedioxy-N-(2,2,2-trifluoroethyl)amphetamine (MDTFEA), and the fluorinated MDMA analogs e.g., Fig.6B, compounds 90-98 of Trachsel, Drug Test. Analysis 2012, 4, 577–590. However, Applicant is unaware of the specific compounds and compositions disclosed herein having been synthesized, formulated, and / or used in the compositions and methods of the disclosure.

[0043] In some embodiments, Applicant’s disclosed deuterated and / or fluorinated compounds are particularly advantageous. For example, by reducing the rate of metabolism (and particularly the rate of enzymatic oxidation of the methylenedioxy methylene moiety, and / or the rate of N-dealkylation), disclosed deuterated and / or fluorinated compounds may produce fewer species or lower concentrations of metabolites responsible for adverse effects, resulting in improved side-effect profiles, and may provide other advantages compared to corresponding non-substituted compounds. A. General Definitions and Terms

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

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

[0046] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the disclosure are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of 2024-03-01 measure. The term “substantially,” where it is applied to modify a feature or limitation herein, will be read in the context of the disclosure and in light of the knowledge in the art to provide the appropriate certainty, e.g., by using a standard that is recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the art.

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

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

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

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

[0051] “Alkyl” will be understood to include straight or branched radicals having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” can also be used. Preferably, an alkyl group comprises from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, and most preferably from 1 to 3 carbon atoms. For any alkyl, the alkyl may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, 2024-03-01 heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, —OP(O)(OH)2, —OC(O)H, —OSO2OH, —OC(O)NH2, and —SONH2.

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

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

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

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

[0056] “Cycloalkyl” refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 2024-03-01 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Monocyclic cycloalkyl rings include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decahydronaphthalene and adamantane. When cycloalkyl is a monocyclic C3-8cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a monocyclic 6cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0057] “Cycloalkenyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring. However, if there is more than one double bond, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. Cycloalkenyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Representative Cycloalkenyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. A cycloalkenyl group may be unsubstituted or substituted.

[0058] “Halogen” refers to fluorine, chlorine, bromine, and iodine.

[0059] “Heterocycloalkyl” and “heterocyclyl” both refer to a cycloalkyl as defined above, having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Heterocycloalkyl and heterocyclyl include bicyclic compounds which include a heteroatom. Bicyclic compounds includes spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds The heteroatoms can also be oxidized, such as, but not limited to, —S(O)— and —S(O)2—. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 2024-03-01 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C1-6 alkyl or oxo (═O), among many others.

[0060] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0061] “Alkoxy” refers to the formula —OR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0062] “Acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, connected via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0063] Deuterium (2H or D), also called “heavy hydrogen,” is a stable isotope of hydrogen (1H) with a natural abundance in the Earth’s oceans of approximately one atom per 6,500 of hydrogen (˜154 ppm). Deuterium thus accounts for approximately 0.0154% (alternately, on a mass basis, 0.0308%) of all naturally occurring hydrogen in the oceans. “Non-substituted,” “non-deuterated,” and “undeuterated” may refer to compounds having no greater than the amount of deuterium expected as a percentage of naturally occurring hydrogen in a compound.

[0064] “Deuteroalkyl” will be understood to include any alkyl group as defined above, wherein one or more 2024-03-01 hydrogen atoms are replaced by a deuterium (i.e.,2H, or D). Where an alkyl radical is substituted by more than one deuterium, it may be referred to using a prefix corresponding to the number of deuterium substitutions. For example, trideuteroalkyl refers to an alkyl in which three hydrogens have been replaced by deuteriums. A deuteroalkyl can be fully deuterated (i.e., all of the hydrogens have been replaced by deuteriums) or partially deuterated (i.e., only some of the hydrogens have been replaced by deuteriums). For example, a deuteromethyl deuteroalkyl) group refers to —CH2D, —CHD2, or —CD3. A deuteroethyl (i.e., a C2deuteroalkyl) group refers to —CH2CH2D, —CHDCH2D, —CD2CH2D, —CH2CHD2, —CHDCHD2, —CD2CHD2, —CH2CD3, —CHDCD3, or —CD2CD3. A deuteropropyl group (i.e., a C3deuteroalkyl) refers to any partially or fully substituted n -propyl or isopropyl group.

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

[0066] “Hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxy- propyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

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

[0068] “Sulfenyl” refers to an —SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A sulfenyl may be substituted or unsubstituted.

[0069] “Sulfinyl” refers to an —S(═O)—R group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0070] “Sulfonyl” refers to an —SO2R group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0071] “O-carboxy” refers to a —RC(═O)O— group in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carboxy may be substituted or unsubstituted.

[0072] “Ester” and “C-carboxy” refer to a —C(═O)OR group in which R can be the same as defined with respect to O-carboxy. Ester and C-carboxy groups may be substituted or unsubstituted.

[0073] “Thiocarbonyl” refers to a —C(═S)R group in which R can be the same as defined with respect to 2024-03-01 O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0074] “Trihalomethanesulfonyl” refers to an X3CSO2— group wherein each X is a halogen.

[0075] “Trihalomethanesulfonamido” refers to an X3CS(O)2N(RA)— group wherein each X is a halogen, and RAis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0076] “S-sulfonamido” refers to a —SO2N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An S-sulfonamido may be substituted or unsubstituted.

[0077] “N-sulfonamido” refers to a RSO2N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-sulfonamido may be substituted or unsubstituted.

[0078] “Oxo” refers to =O.

[0079] “O-carbamyl” refers to a —OC(═O)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carbamyl may be substituted or unsubstituted.

[0080] “N-carbamyl” refers to an ROC(═O)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-carbamyl may be substituted or unsubstituted.

[0081] “O-thiocarbamyl” refers to a —OC(═S)—N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-thiocarbamyl may be substituted or unsubstituted.

[0082] “N-thiocarbamyl” refers to an ROC(═S)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-thiocarbamyl may be substituted or unsubstituted.

[0083] “C-amido” group refers to a —C(═O)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A C-amido may be substituted or unsubstituted.

[0084] “N-amido” refers to a RC(═O)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-amido may be substituted or unsubstituted.

[0085] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group 2024-03-01 has three substituents. In another embodiment, an optionally substituted group has four substituents. If no substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, oxo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group. B. Compounds

[0086] In a first aspect, provided is a compound of Formula (I): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: R1is H, methyl, or ethyl; R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; Raand Rbare both H, or together represent =O; and R' and R'' are each independently H, D, or F.

[0087] In some embodiments of Formula (I), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0088] In some embodiments of Formula (I), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl (e.g., methyl, ethyl, n -propyl, or isopropyl). In some embodiments, R2is C1-C3deuteroalkyl (e.g., methyl, ethyl, n -propyl, or isopropyl, wherein at least one of the hydrogens on the methyl, ethyl, n -propyl, or isopropyl has been replaced by a deuterium). In some embodiments, R2is C1-C3fluoroalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, and the like).

[0089] In some embodiments of Formula (I), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl (e.g., methyl, ethyl, n -propyl, or isopropyl). In some embodiments, R3is C1-C3deuteroalkyl (e.g., methyl, ethyl, n -propyl, or isopropyl, wherein at least one of the hydrogens on the methyl, ethyl, n -propyl, or isopropyl has been replaced by a deuterium). In some embodiments, R3is C1-C3fluoroalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, and the like).

[0090] In some embodiments of Formula (I), Raand Rbare both H, or together represent =O. In some 2024-03-01 embodiments, Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O.

[0091] In some embodiments of Formula (I), R' and R'' are each independently H, D, or F; provided that at least one of R' and R'' is not H; and when Raand Rbare both H, and R' and R'' are both D, R2is C1-C3fluoroalkyl; and when Raand Rbare both H, and R' and R'' are both F, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In some embodiments, R' is H and R'' is D. In some embodiments, R' is H and R'' is F. In some embodiments, R' and R'' are both D. In some such embodiments, wherein R' and R'' are both D and Raand Rbare both H, R2is C1-C3fluoroalkyl. In some embodiments, R' and R'' are both F. In some such embodiments, wherein R' and R'' are both F and Raand Rbare both H, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In some embodiments, wherein R' and R'' are both F and Raand Rbare both H, R2is C1-C3deuteroalkyl. wherein R' and R'' are both F and Raand Rbare both H, R2is C1-C3fluoroalkyl. In some embodiments, R' is D and R'' is F.

[0092] In some embodiments of Formula (I), wherein R' and R'' are both D and Raand Rbare both H, R2is not alkyl. In embodiments, wherein R' and R'' are both D and Raand Rbare both H, R2is not deuteroalkyl.

[0093] In some embodiments, the compound has the structure of Formula (I-1): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: R1is H, methyl, or ethyl; R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; Raand Rbare both H, or together represent =O; and R' and R'' are each independently H, D, or F.

[0094] In some embodiments of Formula (I-1), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0095] In some embodiments of Formula (I-1), R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0096] In some embodiments of Formula (I-1), Raand Rbare both H, or together represent =O. In some embodiments, Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O.

[0097] In some embodiments of Formula (I-1), R' and R'' are each independently H, D, or F; provided that at least one of R' and R'' is not H; and when Raand Rbare both H, and R' and R'' are both D, R2is C1-C3fluoroalkyl; and when Raand Rbare both H, and R' and R'' are both F, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In some embodiments, R' is H and R'' is D. In some embodiments, R' is H and R'' is F. In some embodiments, R' and R'' are both D. In some such embodiments, wherein R' and R'' are both D and Raand Rbare both H, R2is C1-C3fluoroalkyl. In some embodiments, R' and R'' are both F. In some such 2024-03-01 embodiments, wherein R' and R'' are both F and Raand Rbare both H, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In some embodiments, wherein R' and R'' are both F and Raand Rbare both H, R2is C1-C3deuteroalkyl. wherein R' and R'' are both F and Raand Rbare both H, R2is C1-C3fluoroalkyl. In some embodiments, R' is D and R'' is F.

[0098] In some embodiments of Formula (I-1), wherein R' and R'' are both D and Raand Rbare both H, R2is not alkyl. In embodiments, wherein R' and R'' are both D and Raand Rbare both H, R2is not deuteroalkyl.

[0099] In some embodiments, the compound of Formula (I) has the structure of Formula (I-2): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0100] In some embodiments of Formula (I-2), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0101] In some embodiments of Formula (I-2), R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0102] In some embodiments of Formula (I-2), R' and R'' are each independently H, D, or F; provided that at least one of R' and R'' is not H; and when R' and R'' are both D, R2is C1-C3fluoroalkyl; and when R' and R'' are both F, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In some embodiments, R' is H and R'' is D. In some embodiments, R' is H and R'' is F. In some embodiments, R' and R'' are both D. In some such embodiments, wherein R' and R'' are both D, R2is C1-C3fluoroalkyl. In some embodiments, R' and R'' are both F. In some such embodiments, wherein R' and R'' are both F, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In some embodiments, wherein R' and R'' are both F, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In some embodiments, R' is D and R'' is F.

[0103] In some embodiments of Formula (I-2), wherein R' and R'' are both D, R2is not alkyl. In some embodiments, wherein R' and R'' are both D, R2is not deuteroalkyl.

[0104] In some embodiments of Formula (I-2), wherein R' and R'' are both F, R2is not alkyl.

[0105] In some embodiments, the compound of Formula (I) has the structure of Formula (I-3): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0106] In some embodiments of Formula (I-3), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0107] In some embodiments of Formula (I-3), R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In 2024-03-01 some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0108] In some embodiments of Formula (I-3), R' and R'' are each independently H, D, or F; provided that at least one of R' and R'' is not H. In some embodiments, R' is H and R'' is D. In some embodiments, R' is H and R'' is F. In some embodiments, R' and R'' are both D. In some embodiments, R' and R'' are both F.

[0109] In some embodiments, the compound has the structure of Formula (II): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: Raand Rbare both H, or together represent =O; R1is methyl, ethyl, or H; and R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; and R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl.

[0110] In some embodiments of Formula (II), Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O.

[0111] In some embodiments of Formula (II), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0112] In some embodiments of Formula (II), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0113] In some embodiments of Formula (II), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0114] In some embodiments of Formula (II), Raand Rbare both H, or together represent =O. In some embodiments, Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O. In some embodiments, when Raand Rbare both H, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In embodiments, when Raand Rbtogether represent =O, R2is C1-C3alkyl, C1-C3deuteroalkyl or C1-C3fluoroalkyl.

[0115] In some embodiments, the compound of Formula (II) has the structure of Formula (II-1): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof. 2024-03-01

[0116] In some embodiments of Formula (II-1), Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O.

[0117] In some embodiments of Formula (II-1), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0118] In some embodiments of Formula (II-1), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0119] In some embodiments of Formula (II-1), Raand Rbare both H, or together represent =O. In some embodiments, Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O. In some embodiments, when Raand Rbare both H, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In embodiments, when Raand Rbtogether represent =O, R2is C1-C3alkyl, C1-C3deuteroalkyl or C1-C3fluoroalkyl.

[0120] In some embodiments, the compound of Formula (II) has the structure of Formula (II-2): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0121] In some embodiments of Formula (II-2), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0122] In some embodiments of Formula (II-2), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0123] In some embodiments of Formula (II-2), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0124] In some embodiments, the compound of Formula (II) has the structure of Formula (II-3): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0125] In some embodiments of Formula (II-3), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0126] In some embodiments of Formula (II-3), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. 2024-03-01 In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0127] In some embodiments of Formula (II-3), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0128] In some embodiments, the compound of Formula (II) has the structure of Formula (II-4): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0129] In some embodiments of Formula (II-4), is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0130] In some embodiments of Formula (II-4), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0131] In some embodiments, the compound of Formula (II) has the structure of Formula (II-5): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0132] In some embodiments of Formula (II-5), R1is H, methyl, or ethyl. In some embodiments, R1is H. Insome embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0133] In some embodiments of Formula (II-5), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0134] In some embodiments, the compound of Formula (II) has the structure of Formula (II-6): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0135] In some embodiments of Formula (II-6), R1is H, methyl, or ethyl. In some embodiments, R1is H. In 2024-03-01 some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0136] In some embodiments of Formula (II-6), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0137] In some embodiments of Formula (II-6), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0138] In some embodiments, the compound of Formula (II) has the structure of Formula (II-7): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0139] In some embodiments of Formula (II-7), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0140] In some embodiments of Formula (II-7), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0141] In some embodiments, the compound of Formula (II) has the structure of Formula (II-8): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0142] In some embodiments of Formula (II-8), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0143] In some embodiments of Formula (II-8), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0144] In some embodiments of Formula (II-7), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0145] In some embodiments, the compound of Formula (II) has the structure of Formula (II-9): 2024-03-01 or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0146] In some embodiments of Formula (II-9), is H, methyl, or ethyl. In some embodiments, is H. In some embodiments, is methyl. In some embodiments, is ethyl.

[0147] In some embodiments of Formula (II-9), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0148] In some embodiments, the compound has the structure as shown in TABLES 1-4 , or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof. TABLE 1. Exemplary Compounds 2024-03-01 2024-03-01 2024-03-01 TABLE 2. Exemplary Compounds 2024-03-01 2024-03-01 2024-03-01 2024-03-01 TABLE 3. Exemplary Compounds 2024-03-01 2024-03-01 2024-03-01 TABLE 4. Exemplary Compounds 2024-03-01 2024-03-01 2024-03-01

[0149] I n some embodiments, the compound has the structure of Formula (III): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: Raand Rbare both H, or together represent =O; R1is methyl, ethyl, or H; and R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; and R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl.

[0150] In some embodiments of Formula (III), Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O.

[0151] In some embodiments of Formula (III), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. 2024-03-01

[0152] In some embodiments of Formula (III), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0153] In some embodiments of Formula (III), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0154] In some embodiments, the compound of Formula (III) has the structure of Formula (III-1): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: Raand Rbare both H, or together represent =O; R1is methyl, ethyl, or H; and R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl.

[0155] In some embodiments of Formula (III-1), Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O.

[0156] In some embodiments of Formula (III-1), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0157] In some embodiments of Formula (III-1), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0158] In some embodiments of Formula (III-1), Raand Rbare both H, or together represent =O. In some embodiments, Raand Rbare both H. In some embodiments, Raand Rbtogether represent =O. In some embodiments, when Raand Rbare both H, R2is C1-C3deuteroalkyl or C1-C3fluoroalkyl. In embodiments, when Raand Rbtogether represent =O, R2is C1-C3alkyl, C1-C3deuteroalkyl or C1-C3fluoroalkyl.

[0159] In some embodiments, the compound of Formula (III) has the structure of Formula (III-2): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0160] In some embodiments of Formula (III-2), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. 2024-03-01

[0161] In some embodiments of Formula (III-2), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0162] In some embodiments of Formula (III-2), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0163] In some embodiments, the compound of Formula (III) has the structure of Formula (III-3): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0164] In some embodiments of Formula (III-3), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0165] In some embodiments of Formula (III-3), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0166] In some embodiments of Formula (III-3), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0167] In some embodiments, the compound of Formula (III) has the structure of Formula (III-4): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0168] In some embodiments of Formula (III-4), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0169] In some embodiments of Formula (III-4), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0170] In some embodiments, the compound of Formula (III) has the structure of Formula (III-5): 2024-03-01 or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0171] In some embodiments of Formula (III-5), is H, methyl, or ethyl. In some embodiments, is H. In some embodiments, is methyl. In some embodiments, is ethyl.

[0172] In some embodiments of Formula (III-5), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0173] In some embodiments, the compound of Formula (III) has the structure of Formula (III-6): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0174] In some embodiments of Formula (III-6), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0175] In some embodiments of Formula (III-6), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0176] In some embodiments of Formula (III-6), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0177] In some embodiments, the compound of Formula (III) has the structure of Formula (III-7): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0178] In some embodiments of Formula (III-7), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0179] In some embodiments of Formula (III-7), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some 2024-03-01 embodiments, R2is C1-C3fluoroalkyl.

[0180] In some embodiments, the compound of Formula (III) has the structure of Formula (III-8): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0181] In some embodiments of Formula (III-8), is H, methyl, or ethyl. In some embodiments, is H. In some embodiments, is methyl. In some embodiments, is ethyl.

[0182] In some embodiments of Formula (III-8), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0183] In some embodiments of Formula (III-8), R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is C1-C3deuteroalkyl. In some embodiments, R3is C1-C3fluoroalkyl.

[0184] In some embodiments, the compound of Formula (III) has the structure of Formula (III-9): or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0185] In some embodiments of Formula (III-9), R1is H, methyl, or ethyl. In some embodiments, R1is H. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0186] In some embodiments of Formula (III-9), R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, R2is H. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is C1-C3deuteroalkyl. In some embodiments, R2is C1-C3fluoroalkyl.

[0187] In some embodiments, the compound has the structure as shown in TABLES 5-8 , or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof. 2024-03-01 TABLE 5. Exemplary Compounds 2024-03-01 2024-03-01 2024-03-01 TABLE 6. Exemplary Compounds 2024-03-01 2024-03-01 2024-03-01 TABLE 7. Exemplary Compounds 2024-03-01 2024-03-01 2024-03-01 2024-03-01 TABLE 8. Exemplary Compounds 2024-03-01 2024-03-01 2024-03-01

[0188] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0189] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0190] In some embodiments, the compound has the structure of: , , , 2024-03-01 or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0191] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0192] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0193] In some embodiments, the compound has the structure of: or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof. In some the has the structure of: 2024-03-01 or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

[0195] In some embodiments, the compound is not any of:

[0197] In some embodiments, the compound is not any of: 2024-03-01

[0199] In some embodiments, the is not of: ,

[0200] Herein, “a single compound of” will mean the specified compound (e.g., by description or structural formula) is the only disclosed compound in the described or claimed embodiment, i.e., that a compound, composition, or method consists of, consists essentially of, or comprises no further disclosed compound(s) (i.e., compound(s) having a different structural formula or description). It does not mean the embodiment has only a single molecule or single instance of the specified compound. For instance, embodiments “consisting of a single compound of Formula (I)” will include embodiments of “a compound of Formula (I),” or the use of “a compound of Formula (I),” and such embodiments, as well as embodiments of a composition “consisting essentially of a single compound of Formula (I),” each may comprise, e.g., 10 mg, 50 mg, 100 mg, 125 mg, 150 mg, and other disclosed or known mass amounts or molar amounts of the compound of Formula (I).

[0201] Accordingly, and for example, in some embodiments one or more compounds may be excluded from a claim to a group of compounds, such as a Markush group of compounds, such as “a compound of Formula (I).” In some embodiments, one or more compounds also may be excluded from a claim to a composition consisting essentially of a group of compounds. In some embodiments, one or more compounds also may be excluded from a claim to a composition comprising a group of compounds. In some embodiments, one or more compounds also may be excluded from a claim to a use of a group of compounds. In some embodiments, one or more compounds also may be excluded from a claim to a use of a composition consisting essentially of a group of compounds. In some embodiments, one or more compounds also may be excluded from a claim to a use of a composition comprising a group of compounds. In some embodiments, one or more compounds may be excluded from all claims to a group of compounds.

[0202] In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, but are not excluded from a claim to a use of a group of compounds or compositions thereof. In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition comprising a group of compounds, but are not excluded from a claim to a use of a group of compounds or compositions thereof.

[0203] In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, but are not excluded from a composition comprising the one or more compounds together with 2024-03-01 one or more additional disclosed compounds and / or additional active compounds. In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, and also may be excluded from a claim to a use of a group of compounds or compositions consisting essentially thereof, but are not excluded from a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds, or a use of a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds. In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, and also may be excluded from a claim to a use of a group of compounds or compositions consisting essentially thereof, and further may be excluded from a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds, but are not excluded from a claim to a use of a composition comprising the one or more compounds together with one or more additional disclosed compounds and / or additional active compounds.

[0204] T he individual compounds of the disclosed compositions will be understood to also encompass pharmaceutically acceptable salts of such compounds. The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, and which may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, 2024-03-01 methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polyalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc and the like. (Berge et al. (1977) “Pharmaceutical Salts,” J. Pharm. Sci. 66:1-19.) In embodiments, the pharmaceutically acceptable salts are those employing a hydrochloride anion.

[0205] Prodrugs of the disclosed compounds also will be appreciated to be within the scope of the disclosure. “Prodrug” refers to a precursor of a biologically active pharmaceutical agent, which may undergo a chemical or a metabolic conversion to become the biologically active agent. A prodrug can be converted ex vivo to the biologically active pharmaceutical agent by chemical transformative processes. In vivo, a prodrug is converted to the biologically active pharmaceutical agent by the action of a metabolic process, an enzymatic process or a degradative process that removes the prodrug moiety, such as a glycoside or acetyl group, to form the biologically active pharmaceutical agent. Other examples include addition of hydroxyl groups (Tsujikawa et al.2011. Xenobiotica, 41(7), 578-584; Yamamoto et al.1984. Xenobiotica, 14(11), 867-875), acyloxyalkoxycarbonyl derivatives, amino acids, vitamins, or peptides (Vig et al.2013. Advanced Drug Delivery Reviews, 65(10), 1370-1385), which are generally added to the amine, and can be removed within the body by chemical reactions or enzymes, but other prodrugs and precursors, at the amine and other sites, should be understood to be within the scope of the disclosure (Simplício, Clancy, & Gilmer.2008. Molecules, 13(3), 519-547; Shah et al. (Eds.).2020. Recent Advancement in Prodrugs. CRC Press).

[0206] Types of prodrugs contemplated to be within the scope of the disclosure include compounds that are transformed in various organs or locations in the body (e.g., liver, kidney, G.I., lung, tissue) to release the active compound. For example, liver prodrugs include active compounds conjugated with a polymer or chemical moiety that is not released until acted upon by liver cytochrome enzymes; CYP metabolism includes dealkylation, dehydrogenation, reduction, hydrolysis, oxidation, and the breakdown of aromatic rings. Kidney prodrugs include active compounds conjugated to L-gamma-glutamyl or N-acetyl-L-gamma glutamic moieties so that they are metabolized by gamma-glutamyl transpeptidase before they are bioactive; alternatively, they may be conjugated to alkylglucoside moieties to create glycosylation-based prodrugs. Digestive or G.I. prodrugs include those where an active compound is, e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or conjugated with a linear polysaccharide such as pectin that will delay activation until the combination reaches the bacteria in the colon. Besides these exemplary prodrug forms, many others will be known to one of skill.

[0207] Typical examples of prodrugs also include compounds with biologically labile or cleavable 2024-03-01 (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Pat. Nos.6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce a disclosed compound. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0208] In some embodiments, a prodrug comprising a disclosed compound is an amino acid prodrug. Amino acid refers to molecules comprising an amine group, a carboxylic acid group and a side-chain that varies among different amino acids. In some embodiments, one or more amino acids are directly conjugated to a disclosed compound to prepare a prodrug thereof. In some embodiments, a linker is used to conjugate a disclosed compound to the one or more amino acids to prepare a prodrug thereof. In some embodiments, amino acid prodrugs improve poor solubility, poor permeability, sustained release, intravenous delivery, drug targeting, and metabolic stability of the parent drug. See, e.g., Vig et al., Advanced Drug Delivery Reviews, 2013;65(10):1370-1385; Vale, et al., Molecules, 2018;23(9);2318.

[0209] In some embodiments, a disclosed compound is attached to a single amino acid which is either a naturally occurring amino acid or a synthetic amino acid. In some embodiments, a disclosed compound is attached to a dipeptide or tripeptide, which could be any combination of naturally occurring amino acids and / or synthetic amino acids. In some embodiments, the amino acids are selected from L-amino acids for digestion by proteases. In some embodiments a carrier peptide is attached to a disclosed compound through the carrier peptide’s N-terminus, C-terminus, or side chain of an amino acid which may be either a single amino acid or part of a longer chain sequence (i.e., a dipeptide, tripeptide, oligopeptide, or polypeptide). The carrier peptide may also be (i) a homopolymer of a naturally occurring amino acid, (ii) a heteropolymer of two or more naturally occurring amino acids, (iii) a homopolymer of a synthetic amino acid, (iv) a heteropolymer of two or more synthetic amino acids, or (v) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids. For example, carrier peptides may be homopolymers or heteropolymers of glutamic acid, aspartic acid, serine, lysine, cysteine, threonine, asparagine, arginine, tyrosine, and glutamine. Examples of peptides include, Lys, Ser, Phe, Gly-Gly-Gly, Leu-Ser, Leu-Glu, homopolymers of Glu and Leu, and heteropolymers of (Glu)n-Leu-Ser.

[0210] In some embodiments, amino acid prodrugs of disclosed compounds are synthesized according to the following general reaction scheme, involving amide coupling of a disclosed compound with an amino acid. In some embodiments, the amino acid is an N-protected amino acid (e.g., N-Boc, N-Fmoc), and the protecting group is removed after the amide coupling step: 2024-03-01 wherein R is an amino acid side chain, such as hydrogen (in the case of glycine), methyl (in the case of alanine), or any other side chain known to those of skill in the art to correspond to a natural or unnatural amino acid. In some embodiments, the amino acid is a natural amino acid. In other embodiments, the amino acid is an unnatural amino acid. In some embodiments, the amino acid is an L-amino acid. In some embodiments, the amino acid is a D-amino acid. In some embodiments, the amino acid is alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In some embodiments, the amino acid is alanine. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is asparagine. In some embodiments, the amino acid is aspartic acid. In some embodiments, the amino acid is cysteine. In some embodiments, the amino acid is glutamine. In some embodiments, the amino acid is glutamic acid. In some embodiments, the amino acid is glycine. In some embodiments, the amino acid is histidine. In some embodiments, the amino acid is isoleucine. In some embodiments, the amino acid is leucine. In some embodiments, the amino acid is lysine. In some embodiments, the amino acid is methionine. In some embodiments, the amino acid is phenylalanine. In some embodiments, the amino acid is proline. In some embodiments, the amino acid is serine. In some embodiments, the amino acid is threonine. In some embodiments, the amino acid is tryptophan. In some embodiments, the amino acid is tyrosine. In some embodiments, the amino acid is valine.

[0211] Also provided are amino acid prodrugs of other deuterated empathogens, such as those disclosed in Applicant’s International Application No. PCT / US2022 / 041279 (Pub. No. WO2023 / 028091A1), fully incorporated herein by reference, and which discloses deuterated compounds of the following formula: , wherein: R1is hydrogen or C1-C6alkyl; and R2and R2 ’are each independently a deuterated C1-C6alkyl; or R2is H and R2 ’is a deuterated C1-C6alkyl; or R2and R2 ’are taken together to form a deuterated 4- to 8-membered heterocyclyl; Raand Rbare each independently hydrogen, —OH, or C1-C6alkoxy; or 2024-03-01 Raand Rbtogether represent =O; and Rxand Ryare taken together as —OCH=CH—, —CH=CHO—, —OCH2O—, —SCH=CH—, —CH=CHS—, —SCH2S—, —SCH2O—, —OCH2S—, —NHCH=CH—, —CH=CHNH—, —NHCH2NH—, —NHCH2O—, —OCH2NH—, —NHCH2S—, or —SCH2NH—; or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof; provided that the compound is not (MDMA-d3).

[0212] Also provided are amino acid prodrugs of other fluorinated empathogens, such as those disclosed in Applicant’s International Application No. PCT / US2022 / 041283 (Pub. No. WO2023 / 028092A1), fully incorporated herein by reference, and which discloses fluorinated compounds of the following formula: , wherein: R1is hydrogen or C1-C6alkyl; and R2and R2 ’are each independently a fluorinated C1-C6alkyl; or R2is H and R2 ’is a fluorinated C1-C6alkyl; or R2and R2 ’are taken together to form a fluorinated 4- to 8-membered heterocyclyl; Raand Rbare each independently hydrogen, —OH, or C1-C6alkoxy; or Raand Rbtogether represent =O; and Rxand Ryare taken together as —OCH=CH—, —CH=CHO—, —OCH2O—, —SCH=CH—, —CH=CHS—, —SCH2S—, —SCH2O—, —OCH2S—, —NHCH=CH—, —CH=CHNH—, —NHCH2NH—, —NHCH2O—, —OCH2NH—, —NHCH2S—, or —SCH2NH—; or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof; provided that the compound is not

[0213] In some aspects, the present disclosure relates to amino acid prodrugs of the compounds disclosed in PCT / US2022 / 041279 and PCT / US2022 / 041283, wherein the amino acid is a natural amino acid or an unnatural amino acid. In some embodiments, the amino acid is an L-amino acid. In some embodiments, the amino acid is a D-amino acid. In some embodiments, the amino acid is alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In embodiments, the amino acid is alanine. In embodiments, the amino acid is arginine. In embodiments, the amino acid is asparagine. In 2024-03-01 embodiments, the amino acid is aspartic acid. In embodiments, the amino acid is cysteine. In embodiments, the amino acid is glutamine. In embodiments, the amino acid is glutamic acid. In embodiments, the amino acid is glycine. In embodiments, the amino acid is histidine. In embodiments, the amino acid is isoleucine. In embodiments, the amino acid is leucine. In embodiments, the amino acid is lysine. In embodiments, the amino acid is methionine. In embodiments, the amino acid is phenylalanine. In embodiments, the amino acid is proline. In embodiments, the amino acid is serine. In embodiments, the amino acid is threonine. In embodiments, the amino acid is tryptophan. In embodiments, the amino acid is tyrosine. In embodiments, the amino acid is valine. In embodiments, a disclosed compound is attached to a dipeptide or tripeptide, which could be any combination of naturally occurring amino acids and / or synthetic amino acids.

[0214] Generally, the individual compounds of the disclosure shall be administered as part of a pharmaceutical composition or formulation, and will be prepared for inclusion in such composition or formulations as isolated or purified compounds. The terms “isolated,” “purified,” or “substantially pure,” used herein, refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced. An “isolated,” “purified,” or “substantially pure” preparation of a compound is accordingly defined as a preparation having a chromatographic purity (of the desired compound) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method.

[0215] Preferably, a substantially pure compound is substantially free of any other active compounds which are not intended to be administered to a subject. In this context “substantially free” can mean that no active compound(s) other than the active compound intended to be administered to a subject are detectable by HPLC or other detection method, or are below a desired threshold of detection such as defined above.

[0216] It should be understood that any reference to a disclosed compound or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, will include all amorphous and polymorphic forms. In the case of solid compositions, in particular, it is understood that the compounds used in the disclosed compositions and methods may exist in different forms. For example, the compounds may exist in stable and metastable crystalline forms, isotropic and amorphous forms, milled forms and nano-particulate forms, all of which are intended to be within the scope of the disclosure. In addition, disclosed compounds may include crystalline forms, known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0217] The disclosed compounds now generally described will be more readily understood by reference to 2024-03-01 the following description and examples, which are included for the purposes of illustration of certain aspects of the embodiments of the present disclosure. The following is not intended to limit the disclosure, as one of skill in the art would recognize from the teachings and examples herein that other techniques and methods can satisfy the claims and be employed without departing from the scope of the disclosure. Indeed, while this disclosure has been particularly shown and described with reference to certain exemplary embodiments, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope or spirit of the disclosure encompassed by the appended claims. a. Isotopic Purity

[0218] In some embodiments, a disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, has a deuterium isotopic purity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%. In some embodiments, the compound has an isotopic purity of at least 50%. In an embodiment, the compound has an isotopic purity of at least 55%. In another embodiment, the compound has an isotopic purity of at least 60%. In yet another embodiment, the compound has an isotopic purity of at least 65%. In another embodiment, the compound has an isotopic purity of at least 70%. In another embodiment, the compound has an isotopic purity of at least 75%. In another embodiment, the compound has an isotopic purity of at least 80%. In another embodiment, the compound has an isotopic purity of at least 85%. In another embodiment, the compound has an isotopic purity of at least 90%. In another embodiment, the compound has an isotopic purity of at least 91%. In another embodiment, the compound has an isotopic purity of at least 92%. In another embodiment, the compound has an isotopic purity of at least 93%. In another embodiment, the compound has an isotopic purity of at least 94%. In another embodiment, the compound has an isotopic purity of at least 95%. In another embodiment, the compound has an isotopic purity of at least 96%. In another embodiment, the compound has an isotopic purity of at least 97%. In another embodiment, the compound has an isotopic purity of at least 98%. In another embodiment, the compound has an isotopic purity of at least 99%. In another embodiment, the compound has an isotopic purity of at least 99.5%. In another embodiment, the compound has an isotopic purity of at least 99.6%. In another embodiment, the compound has an isotopic purity of at least 99.7%. In another embodiment, the compound has an isotopic purity of at least 99.8%. In another embodiment, the compound has an isotopic purity of at least 99.9%. For such isotopically-labeled molecules, isotopic enrichment may be described as a percentage indicating the percent of isotopic atoms at a particular site on the molecule. The percentage can be referred to as the “isotopic purity” of the isotopically-labeled compound.

[0219] In some embodiments, a disclosed deuterated and / or fluorinated compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, will be a mixture of the deuterated and / or fluorinated compound and a corresponding non-substituted compound (i.e., the corresponding compound wherein none of the hydrogens are substituted by a deuterium or fluorine, e.g., at no position of the compound will the 2024-03-01 presence of deuterium be higher than the natural abundance of deuterium isotope), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. 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- and / or fluorine-substituted compounds (wherein the other compounds in such mixtures are the corresponding non-substituted compounds). In an embodiment, at least 1% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 2% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 3% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 4% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 5% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 10% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 20% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 30% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 40% of the compounds are deuterium- and / or fluorine- substituted. In an embodiment, at least 50% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 60% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 70% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 80% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 90% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 95% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 96% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 97% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 98% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 99% of the compounds are deuterium- and / or fluorine- substituted. In an embodiment, at least 99.5% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 99.8% of the compounds are deuterium- and / or fluorine-substituted. In an embodiment, at least 99.9% of the compounds are deuterium- and / or fluorine-substituted. b. Mixtures of Deuterated and Undeuterated Compounds

[0220] In some embodiments, a disclosed composition is a mixture of one or more deuterium-substituted compounds and corresponding non-substituted compounds in a fixed ratio, and will contain a ratio of deuterium-substituted to non-substituted compounds (as mole ratio or mass ratio), including a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, of 1:1, at least 1:1, at least 1.1:1, at least 1.2:1, at least 1.3:1, at least 1.4:1, at least 1.5:1, at least 1.6:1, at least 1.7:1, at least 1.8:1, at least 1.9:1, at least 2.0:1, at least 2.5:1, at least 3.0:1, at least 4.0:1, at least 5.0:1, at least 6.0:1, at least 7.0:1, at least 8.0:1, at least 9.0:1, and at least 10:1, at least 11:1, at least 12:1, at least 13:1, at least 14:1, at least 15:1, at least 16:1, at least 17:1, at least 18:1, at least 19:1, at least 20:1, at least 25:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, and at least 100:1, including the 2024-03-01 exact above-listed ratios themselves.

[0221] In some embodiments, a composition of the disclosure will be a mixture of one or more deuterium-substituted compounds and corresponding non-substituted compounds in a fixed ratio, and will contain a ratio of non-substituted to deuterium-substituted compounds (as mole ratio or mass ratio), including a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, of 1:1, at least 1:1, at least 1.1:1, at least 1.2:1, at least 1.3:1, at least 1.4:1, at least 1.5:1, at least 1.6:1, at least 1.7:1, at least 1.8:1, at least 1.9:1, at least 2.0:1, at least 2.5:1, at least 3.0:1, at least 4.0:1, at least 5.0:1, at least 6.0:1, at least 7.0:1, at least 8.0:1, at least 9.0:1, and at least 10:1, at least 11:1, at least 12:1, at least 13:1, at least 14:1, at least 15:1, at least 16:1, at least 17:1, at least 18:1, at least 19:1, at least 20:1, at least 25:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, and at least 100:1, including the exact above-listed ratios themselves. c. Mixtures of Fluorine-Substituted and Non-Fluorinated Compounds

[0222] In some embodiments, a disclosed composition is a mixture of one or more fluorine-substituted disclosed compounds and corresponding non-substituted compounds in a fixed ratio, and will contain a ratio of fluorine-substituted to non-substituted compounds (as mole ratio or mass ratio), including a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, of 1:1, at least 1:1, at least 1.1:1, at least 1.2:1, at least 1.3:1, at least 1.4:1, at least 1.5:1, at least 1.6:1, at least 1.7:1, at least 1.8:1, at least 1.9:1, at least 2.0:1, at least 2.5:1, at least 3.0:1, at least 4.0:1, at least 5.0:1, at least 6.0:1, at least 7.0:1, at least 8.0:1, at least 9.0:1, and at least 10:1, at least 11:1, at least 12:1, at least 13:1, at least 14:1, at least 15:1, at least 16:1, at least 17:1, at least 18:1, at least 19:1, at least 20:1, at least 25:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, and at least 100:1, including the exact above-listed ratios themselves.

[0223] In some embodiments, a disclosed composition will be a mixture of one or more fluorine-substituted disclosed compounds and corresponding non-substituted compounds in a fixed ratio, and will contain a ratio of non-substituted to fluorine-substituted compounds (as mole ratio or mass ratio), including a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, of 1:1, at least 1:1, at least 1.1:1, at least 1.2:1, at least 1.3:1, at least 1.4:1, at least 1.5:1, at least 1.6:1, at least 1.7:1, at least 1.8:1, at least 1.9:1, at least 2.0:1, at least 2.5:1, at least 3.0:1, at least 4.0:1, at least 5.0:1, at least 6.0:1, at least 7.0:1, at least 8.0:1, at least 9.0:1, and at least 10:1, at least 11:1, at least 12:1, at least 13:1, at least 14:1, at least 15:1, at least 16:1, at least 17:1, at least 18:1, at least 19:1, at least 20:1, at least 25:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, and at least 100:1, including the exact above-listed ratios themselves. d. Stereoisomers and Enantiomeric Mixtures

[0224] The disclosed compounds may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of 2024-03-01 absolute stereochemistry, as (R)– or (S)–. The disclosure is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms.

[0225] Optically active (R)– and (S)–, (–)– and (+)–, or (D)– and (L)–isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard tests described herein and other similar tests known in the art. Examples of methods that can be used to obtain optical isomers of the compounds according to the disclosure include the following: i) physical separation of crystals whereby macroscopic crystals of the individual enantiomers are manually separated. This technique may particularly be used if crystals of the separate enantiomers exist (i.e., the material is a conglomerate), and the crystals are visually distinct; ii) simultaneous crystallization whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis, a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually, in principle, all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomers; viii) kinetic resolutions comprising partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile 2024-03-01 phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; and xiii) transport across chiral membranes whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0226] In some embodiments, a disclosed compound may be provided in a composition that is not enantiomerically enriched (i.e., a composition comprising the disclosed compound(s) as a racemic mixture). In other embodiments, a disclosed compound may be provided in a composition that is enantiomerically enriched, such as a mixture of enantiomers in which one enantiomer is present in excess, in particular to the extent of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%, and up to (and including) 100%.

[0227] In embodiments, a compound is provided in a composition that is enantiomerically enriched with the R-isomer, comprising the R-isomer in enantiomeric excess of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0228] In embodiments, a compound is provided in a composition that is enantiomerically enriched with the S-isomer, comprising the S-isomer in enantiomeric excess of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0229] In some embodiments, a disclosed compound is provided in a composition comprising the R-isomer and the S-isomer in a R:S ratio of about 20:1 to about 1:20. In some embodiments, the R:S ratio is greater than about 20:1, or about 20:1, 15:1, 12:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1. In some embodiments, a disclosed compound is provided as the R-isomer in an enantiomerically pure composition. In some embodiments, the R:S ratio is about 1:1, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, or greater than about 1:20. In some embodiments, a disclosed compound is provided as the S-isomer in an enantiomerically pure composition.

[0230] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, tautomeric forms are included. e. Exemplary Features of Disclosed Compounds

[0231] In some aspects, features of disclosed compounds provide various advantages. Such advantages may be related to modulation of neurotransmission, pharmacokinetics, such as properties related to 2024-03-01 absorption, distribution, metabolism, and excretion of a disclosed compound, and subjective effects, such as upon administration to a subject. In some embodiments, such advantages are determined relative to a comparator. In some embodiments, the comparator is a corresponding undeuterated and / or non-fluorinated compound. In some embodiments, the comparator is an empathogen (or “entactogen”). In some embodiments, the comparator is an amphetamine. In some embodiments, the comparator is MDMA. In some embodiments, the comparator is MDA. In some embodiments, the comparator is a cathinone. In some embodiments, the comparator is methylone. In some embodiments, the comparator is ethylone. In some embodiments, the comparator is diethylone.

[0232] The use of an alternate isotope may change the kinetics of a chemical reaction, such as a reaction involved in the metabolism of an empathogen. This phenomenon is known as the kinetic isotope effect (“KIE”). For example, substituting a deuterium for a hydrogen may affect the reaction rate; this phenomenon is known as the “deuterium kinetic isotope effect” (DKIE). The DKIE can range from about 1 (no effect) to 50 or more, meaning that a reaction can be fifty or more times slower when deuterium is substituted for hydrogen (see, e.g., Foster et al., Adv. Drug Res., 14:1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol.77:79-88 (1999)). In some embodiments, the experimental or computed DKIE is at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.5, at least 3.0, at least 3.5, at least 4.0, at least 4.5, at least 5.0, at least 5.5, at least 6.0, at least 6.5, at least 7.0, at least 7.5, at least 8.0, at least 8.5, at least 9.0, at least 9.5, at least 10.0, at least 11.0, at least 12.0, at least 13.0, at least 14.0, at least 15.0, at least 20.0, at least 25.0, at least 30.0, at least 40.0, at least 45.0, or at least 50.

[0233] In some embodiments, incorporating deuterium or fluorine in place of hydrogen will improve the pharmacodynamic and pharmacokinetic profiles of the disclosed compounds by modifying the metabolic fate while retaining the pharmacologic activity and selectivity of the compounds.

[0234] In some embodiments, a disclosed compound has reduced clearance relative to a comparator. In embodiments, clearance is reduced 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%. In embodiments, clearance refers to intrinsic clearance. In embodiments, intrinsic clearance is determined using a metabolic stability study comprising liver microsomes (e.g., human liver microsomes, rat liver microsomes).

[0235] In some embodiments, a disclosed compound has an increased half-life relative to a comparator. In embodiments, the half-life of a compound is increased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200%.

[0236] In some embodiments, a disclosed compound positively impacts safety, efficacy, and / or tolerability, compared to undeuterated and / or non-fluorinated comparator.

[0237] In some embodiments, a composition comprising a disclosed deuterated and / or fluorinated compound will reduce or eliminate the need for “re-dosing” compared to the non-deuterated and / or 2024-03-01 non-fluorinated compound or composition, i.e., wherein a second or further additional “booster” dose is used or is necessary to prolong the effects of a composition to achieve a desired or therapeutic effect. In conventional empathogen-assisted psychotherapy, for example, a booster dose may be taken at about 90 to about 120 minutes after administration of the initial dose, in an amount of about half the initial dose. In some embodiments, the improved pharmacokinetics of the disclosed compounds when used in a composition will reduce or eliminate the need for such re-dosing. In some embodiments, reducing or eliminating re-dosing will reduce or eliminate one or more adverse events or unwanted side effects. In some embodiments, reducing or eliminating re-dosing will provide benefits relating to ease of administration and patient compliance. In some embodiments, a composition comprising a mixture of disclosed deuterated and / or fluorinated compounds, and their non-deuterated and / or non-fluorinated counterparts, will have an improved pharmacokinetic profile compared to the substituted compound or composition, such as earlier onset, shorter time to peak effect, or longer peak effects. In some embodiments, a composition comprising a mixture of disclosed deuterated and / or fluorinated compounds, and their non-deuterated and / or non-fluorinated counterparts, will have an improved pharmacokinetic profile compared to the non-substituted compound or composition, such as earlier onset, shorter time to peak effect, or longer peak effects. In some embodiments, a disclosed compound or composition reduces or eliminates the need for re-dosing because of an improved in vivo pharmacokinetic profile, which may include a longer half-life.

[0238] In some embodiments, a disclosed compound or composition has a reduced rate of metabolism by N-demethylation or N-dealkylation relative to a comparator, in an amount of 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.

[0239] In some embodiments, a disclosed compound or composition has a reduced rate of metabolism by oxidation of the methylenedioxy moiety relative to a comparator, in an amount of 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.

[0240] In some embodiments, a disclosed compound has increased clearance relative to a comparator. In some embodiments, clearance of a disclosed compound is increased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200%.

[0241] In some embodiments, a disclosed compound has a reduced half-life relative to a comparator. In some embodiments, the half-life of a disclosed compound is reduced 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%.

[0242] In some embodiments, a disclosed compound has reduced adverse events relative to a comparator, in an amount for at least one adverse event of at least a 5% reduction, at least a 10% reduction, at least a 2024-03-01 15% reduction, at least a 25% reduction, at least a 50% reduction, at least a 75% reduction, at least a 90% reduction, at least a 95% reduction, at least a 99% reduction, or a reduction beyond the threshold of measurement, whether determined within-patient or across patients or patient groups, or in a rodent or other suitable animal model, or determined in vitro, in silico, or otherwise measured using a standard such as one known to those of skill for the determination or quantification of the adverse event(s) in question, such as relating to anxiety, cardiovascular effects such as blood pressure and heart rate, hyperthermia, hyper- hidrosis, jaw tightness and bruxism, muscle tightness, psychostimulation, appetite, nausea, concentration, and balance, as well as markers for or correlated with potential neurotoxicity, and including such exemplary tests and procedures that are in silico (e.g., computer analysis or simulation, including by AI, machine learning, or deep learning), in vitro (e.g., biochemical assays, tissue culture), and in vivo (e.g., behavioral assessment; functional observational batteries; tests of motor activity, schedule-controlled operant behavior, neurological function, neurophysiological function, nerve-conduction, evoked-potential; neurochemical, neuroendocrine, or neuropathological measures; EEG; imaging), as well as the use of physiological biomarkers (body temperature; heart rate; respiratory rate; blood oxygenation; systolic blood pressure (SBP); diastolic blood pressure (DBP); mean arterial pressure (MAP); pulse pressure (PP); Continuous Beat-by-Beat Blood Pressure (CNIBP); heart rate variability (HRV); hemodynamic response (HR); glucose; cortisol; serotonin; dopamine; and brain derived neurotrophic factor (BDNF)), and patient assessments.

[0243] In some embodiments, a disclosed compound or composition thereof does not cause a neurotoxic effect, such as in an in vitro assay or upon administration to a subject. In some embodiments, a disclosed compound or composition thereof causes a reduced neurotoxic effect, such as in an in vitro assay or upon administration to a subject. In some embodiments, the reduction of a neurotoxic effect is at least a 5% reduction, at least a 10% reduction, at least a 15% reduction, at least a 25% reduction, at least a 50% reduction, at least a 75% reduction, at least a 90% reduction, or at least a 95% reduction, or at least a 99% reduction, relative to a comparator.

[0244] In some embodiments, the neurotoxic effect is determined by measuring one or more of: a) at least one toxic metabolite; b) oxidative stress and dopamine-based quinones; c) mitochondrial dysfunction; and d) activation of glial cells.

[0245] In some embodiments, neurotoxicity or a reduction thereof is determined by measuring the generation of potentially neurotoxic metabolites (e.g., MDA, in embodiments wherein a disclosed compound has the structure of a deuterated and / or fluorinated MDMA), such as from evaluating levels in blood, brain, or cerebrospinal fluid (CSF) samples. In some embodiments, neurotoxicity or a reduction thereof is determined by evaluating oxidative stress and dopamine-based quinones. In some embodiments, neurotoxicity or a reduction thereof is determined by evaluating activity and gene expression of antioxidant enzymes and / or pathways. In some embodiments, neurotoxicity or a reduction thereof is determined by measuring reactive oxygen species (ROS) production. See, e.g., Costa et al.’s assessment of superoxide 2024-03-01 dismutase and ubiquitin-proteasome system expression and activity in mouse neurons (Costa et al., Front Pharmacol.2021;12:713486). In humans, oxidative stress associated with administration of MDMA has been shown using blood samples. Specifically, Zhou et al., determined higher levels of erythrocyte lipoperoxide, superoxide dismutase, and catalase, and lower levels of plasma vitamin C, vitamin E, and carotene, in MDMA abusers (Zhou et al., Free Radic Res.2003;37(5):491-7).

[0246] In some embodiments, neurotoxicity or a reduction thereof is determined by evaluating mitochondrial dysfunction. Mitochondrial dysfunction may be evaluated by measuring one or more of mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the mitochondrial cytochrome c release, and ADP / ATP ratio. See, e.g., Taghizadeh et al.’s assessment of MDMA toxicity in mice, which showed markers of mitochondrial dysfunction following administration of MDMA, including significant increase in ROS formation, collapse of MMP, mitochondrial swelling, outer membrane damage, cytochrome c release from the mitochondria, and increased ADP / ATP ratio (Taghizadeh et al., Free Radic. Biol. Med.2016;99: 11–19).

[0247] In some embodiments, neurotoxicity or a reduction thereof is determined by assessing the activation of glial cells. Activation of quiescent glial cells by MDMA, MDA, and thioether metabolites of MDA derived from α-methyldopamine has been described, e.g., by Herndon et al., Toxicological Sciences, 2014;138(1):130–138. Reactive astrogliosis can be measured with glial fibrillary acidic protein (GFAP) staining, and microglia reactivity can be visualized by immunostaining complement type 3 receptor (CD11b). See, e.g., Frau et al., J Neurochem.2013;124(1):69-78 and Frau et al., Neurotoxicology.2016;56:127-138. In embodiments, neurotoxicity or a reduction thereof is determined in vitro. In embodiments, neurotoxicity or a reduction thereof is determined in vivo. C. Methods of Synthesis

[0248] In some aspects, provided herein are methods of preparing the disclosed compounds. In some embodiments, certain disclosed compounds are synthesized according to the reaction sequence below, in which a suitable benzaldehyde precursor (in which R' and R'' are as defined according to any of the disclosed embodiments, and Raand Rbare both H) is converted to a nitroalkene intermediate, which is then reduced with a suitable reducing agent (e.g., LiAlH4or NaBH4 / CuCl2). This produces a compound wherein R2and R3are both H. Other compounds can be synthesized by alkylation of the primary amine, which can be accomplished with a variety of known techniques. One of the simplest techniques is alkylation using an alkyl halide (or, in some embodiments, a fluoroalkyl halide such as trifluoroiodomethane; or a deuteroalkyl halide, such as trideuteromethyl iodide). 2024-03-01

[0249] In some embodiments, disclosed compounds may be synthesized by Leuckart reaction (A), reductive amination (B), or amination of an a suitable alkyl halide precursor (C), as depicted in the reaction schemes below:

[0250] In some embodiments, the ketone precursor used in the reductive amination (A) or Leuckart reaction (B) schemes above can be generated by reduction of a nitroalkene intermediate with iron, hydrochloric acid, and water in the presence of a ferric chloride catalyst:

[0251] In some embodiments, the reduction of the nitroalkene intermediate can be conducted as described in, e.g., Hass, et al., J Org Chem . 1950, 15(1), 8-14 and Pearl, I., J Am Chem. Soc.1952, 74(17), 4260-4262.

[0252] In some embodiments, certain disclosed compounds are synthesized according to the reaction sequence below, by amination of a suitable alkyl halide precursor (in which R' and R'' are as defined according to any of the disclosed embodiments, and Raand Rbtogether represent =O): 2024-03-01

[0253] In embodiments, certain disclosed compounds wherein R2is deuteroalkyl can be synthesized by any of the disclosed synthetic routes, using a suitable deuterated amine precursor (e.g., a deuterated alkyl- amine, such as d3-methylamine, d2-methylamine, or d1-methylamine). In embodiments, these compounds can be synthesized from an undeuterated amine precursor according to the following general scheme:

[0254] In some embodiments, these compounds are synthesized in an analogous manner, but using -d2 or -d1 formaldehyde instead of undeuterated formaldehyde.

[0255] Compounds having a fully or partially fluorinated N-fluoroalkyl substituent can be synthesized from a fluorinated alkylamine precursor (e.g., H2NCH2F, H2NCHF2, etc.), which may be commercially available or synthesized from by fluorination of a suitable precursor according to methods known in the art.

[0256] Specific examples of the synthesis of certain compounds are provided in Examples 1-3.

[0257] Additional methods for synthesis of the compounds described herein and any necessary starting materials are either described in the art or will be readily apparent to the skilled artisan in view of general references well-known in the art ( see, e.g., Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed.1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols.1-8 (John Wiley and Sons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute Organic Chem., 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,” Vols.1-45, Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Intersci., 1991; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995) and may be used to synthesize the disclosed compounds.

[0258] In general, the approaches used for similar compounds (Shulgin & Shulgin.1992. PiHKAL. A chemical love story, Transform Press, Berkeley CA; Glennon et al.1986. J Med Chem., 29(2), 194-199; Nichols et al.1991. J Med Chem., 34(1), 276-281; Kedrowski et al.2007. Organic Letters, 9(17), 3205-3207; Heravi & Zadsirjan.2016. Current Organic Synthesis, 13(6), 780-833; Keri et al.2017. European J Med Chem., 138, 1002-1033; Pérez-Silanes et al.2001. J Heterocyclic Chem, 38(5), 1025-1030; Trachsel et al. Chem Biodivers. 2006;3:326-336); and references therein), such adaptation being that known and understood to those of ordinary skill. 2024-03-01 C. Pharmaceutical Compositions

[0259] In some aspects, provided herein are compositions, such as pharmaceutical compositions, comprising a disclosed compound, such as a compound of any disclosed Formulae or subformula thereof. “Pharmaceutical compositions” are compositions comprising disclosed compound(s) together in an amount (for example, in a unit dosage form) with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments will not have a single carrier, diluent, or excipient alone, but will include multiple carriers, diluents, and / or excipients. Compositions can be prepared by standard pharmaceutical formulation techniques as disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th ed., Academic Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, N.J.; Pharm. Principles of Solid Dosage Forms (1993), Technomic Pub. Co., Inc., Lancaster, Pa.; and Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; & Poznansky et al. Drug Delivery Systems (1980), R.L. Juliano, ed., Oxford, N.Y., pp.253-315).

[0260] “Pharmaceutically acceptable” used in connection with an excipient, carrier, diluent, or other ingredient means the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with cells of humans and animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk / benefit ratio.

[0261] In some embodiments, pharmaceutical compositions comprising a disclosed compound can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal. In some embodiments, the compounds employed in the methods of this disclosure are effective as oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. (See, e.g., Remington, 2020.)

[0262] The disclosed compositions are preferably formulated in a unit dosage form, each dosage containing a therapeutically effective amount of the active ingredients, for example in the dosage amounts disclosed below. The term “unit dosage form” refers to a physically discrete unit suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect(s), in association with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are often used for ease of administration and uniformity of dosage. Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof (e.g., one half a “full” dose for a “booster” dose as described below), of the pharmaceutical composition administered.

[0263] Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Unit dosage forms also include ampules and vials with liquid compositions disposed therein. Unit dosage forms further include compounds for transdermal administration, 2024-03-01 such as “patches” that contact the epidermis (including the mucosa) of a subject for an extended or brief period of time.

[0264] In some embodiments, the disclosed compositions are formulated in a pharmaceutically acceptable oral dosage form. Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like) and oral solid dosage forms. The disclosed pharmaceutical compositions also may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0265] In some embodiments, a disclosed composition is formulated as an oral solid dosage form. Oral solid dosage forms may include but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combinations thereof. Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations. Accordingly, in some embodiments, the disclosed oral solid dosage forms may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-melt tablet. Additionally, pharmaceutical formulations may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.

[0266] Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof. Oral solid dosage forms also can comprise one or more pharmaceutically acceptable additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).

[0267] Supplementary active compounds include preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents. Preservatives can be used to inhibit microbial growth or increase stability of the active ingredient thereby prolonging the shelf life of the 2024-03-01 formulation. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate. Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as alpha lipoic acid.

[0268] In some embodiments, a disclosed composition is formulated as an oral liquid dosage form. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients. Solvents may be, for example, water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.

[0269] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. Liquid formulations also may be prepared as single dose or multi-dose beverages. Suspensions may include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include carrier oils such as MCT and long chain triglyceride (LCT) oils. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations may include alcohols, (such as ethanol, isopropyl alcohol, hexadecyl alcohol), glycerol, and propylene glycol. Ethers, such as poly(ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations. Suspension can thus include an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion, or a water-in-oil emulsion.

[0270] In some embodiments, formulations are provided comprising the disclosed compositions and at least one dispersing agent or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained. The aqueous dispersion can comprise amorphous and non-amorphous particles consisting of multiple effective particle sizes such that a drug is absorbed in a controlled manner over time.

[0271] Dosage forms for oral administration can be aqueous suspensions selected from the group including pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, e.g., Singh et al., Encyclopedia of Pharm. Tech., 2nd Ed., 754-757 (2002). In addition to the disclosed compounds, the liquid dosage forms may comprise additives, such as one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, or (g) flavoring agents.

[0272] Disclosed compositions also may be prepared as formulations suitable for intramuscular, 2024-03-01 subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0273] In other embodiments, disclosed pharmaceutical compositions may be formulated into a topical dosage form. Topical dosage forms include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. For such formulations, penetrants and carriers can be included in the pharmaceutical composition. Penetrants are known in the art, and include, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. For transdermal administration, carriers which may be used include Vaseline®, lanolin, PEG, alcohols, transdermal enhancers, and combinations thereof. D. Pharmaceutical Combinations

[0274] It should be readily appreciated that the disclosed compositions are not limited to combinations of a single compound, or (when formulated as a pharmaceutical composition) limited to a single carrier, diluent, and / or excipient alone, but may also include combinations of multiple compounds (including additional active compounds), and / or multiple carriers, diluents, and excipients. Pharmaceutical compositions of this disclosure thus may comprise a disclosed compound together with one or more other active agents (or their derivatives and analogs) in combination, together with one or more pharmaceutically-acceptable carriers, diluents, and / or excipients, and additionally with one or more other active compounds.

[0275] In some embodiments, a formulation of the disclosure will be prepared so as to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects.

[0276] “Therapeutic effects” that may be increased or added in embodiments of the disclosure include, but are not limited to, antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, and stimulant effects.

[0277] “Synergistic effects” should be understood to include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect, that are greater than the additive contributions of the components acting alone. Numerous methods known to those of skill in the art exist to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby producing “1+1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol., 2019; 10:1222), or the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch Exp Pathol Pharmacol. 2024-03-01 114: 313-326). A synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin Pharmacokinet.6: 429-453) and the median-effect equation (Chou & Talalay, 1984, Adv Enzyme Regul.22:27-55). The corresponding graphs associated with the equations referred to above are the concentration-effect curve and combination index curve, respectively. Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.

[0278] In some embodiments, a disclosed pharmaceutical composition comprises an additional active compound. In some embodiments, the additional active compound is selected from the group consisting of: amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents (e.g., psychoplastogens), monoamine oxidase inhibitors, tryptamines, terpenes, phenylalkylamines, sedatives, stimulants, serotonergic agents, and vitamins. In some embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, increase plasticity (e.g., neural plasticity), or alter pharmacokinetics or pharmacodynamics. In some embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

[0279] In embodiments, an additional active compound is a tryptamine. As will be understood by those in the art, tryptamines are compounds having the general structure below, wherein RN1, RN2, Rɑ, Rβ, R2, R4, R5, R6, and R7are as defined herein and as generally understood in the art:

[0280] In some embodiments, RN1, RN2, Rɑ, Rβ, R2, R4, R5, R6, and R7are each independently hydrogen, deuterium, halogen (F, Cl, Br, or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Additionally, any two of RN1, RN2, Rɑ, Rβ, R2, R4, R5, R6, and R7and the intervening atoms can be taken together to form an 2024-03-01 optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In embodiments, the tryptamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0281] In some embodiments, the additional active compound is a tryptamine selected from the group consisting of O-Phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 6-allyl-N,N-diethyl- norlysergamide (AL-LAD), N,N-dibutyltryptamine (DBT), N,N-diethyltryptamine (DET), N,N-diisopropyl- tryptamine (DiPT), 5-methoxy-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-hydroxy-tryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl-4-hydroxytryptamine (4-HO-DiPT), 4-hydroxy-N,N,N-trimethyltryptamine (4-HO-TMT), N,N-dimethyl-4-hydroxytryptamine (4-HO-DMT), N,N-dimethyl-5-hydroxytryptamine (5-HO-DMT, bufotenine), N,N-dipropyl-4-hydroxytryptamine (4-HO-DPT), N-ethyl-4-hydroxy- N-methyltryptamine (4-HO-MET), 4-hydroxy-N-isopropyl-N-methyltryptamine (4-HO-MiPT), 4-hydroxy-N-methyl-N-propyl-tryptamine (4-HO-MPT), 4-hydroxy-N,N-tetramethylene- tryptamine (4-HO-pyr-T), 12-methoxyibogamine (Ibogaine), N-butyl-N-methyltryptamine (MBT), N,N-diisopropyl-4,5-methylenedioxytryptamine (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylenedioxytryptamine (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxy- tryptamine (4,5-MDO-DMT), N,N-dimethyl-5,6-methylenedioxytryptamine (5,6-MDO-DMT), N-isopropyl- N-methyl-5,6-methylenedioxytryptamine (5,6-MDO-MiPT), N,N-diethyl-2-methyltryptamine (2-Me-DET), 2,N,N-trimethyltryptamine (2-Me-DMT), N-acetyl-5-methoxytryptamine (melatonin), N,N-diethyl- 5-methoxytryptamine (5-MeO-DET), N,N-diisopropyl-5-methoxy-tryptamine (5-MeO-DiPT), N,N,diallyl- 5-methoxytryptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-isopropyl- 4-methoxy-N-methyltryptamine (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyltryptamine (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyltryptamine (5,6-MeO-MiPT), 5-methoxy-N-methyl-tryptamine (5-MeO-NMT), 5-methoxy-N,N-tetramethylenetryptamine (5-MeO-pyr-T), 6-methoxy-1-methyl-1,2,3,4-tetra- hydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl-tryptamine (5-MeO-TMT), N,N-dimethyl- 5-methylthiotryptamine (5-MeS-DMT), N-isopropyl-N-methyltryptamine (MiPT), α-methyltryptamine (α-MT), N-ethyltryptamine (NET), N-methyltryptamine (NMT), 6-propylnorlysergamide (PRO-LAD), N,N-tetra- methylenetryptamine (pyr-T), tryptamine (T), 7-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (THH), or 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. 2024-03-01

[0282] In some embodiments, an additional tryptamine will be a “complex tryptamine” or other indolamine and including such examples as iboga alkaloids such as ibogaine, and their analogs, metabolites, and derivatives, and beta-carbolines.

[0283] In some embodiments, the additional active compound is a phenylalkylamine. In some embodiments, and as will be understood by those in the art, a phenylalkylamine may be a phenylalkylamine having the structure of Formula (A), wherein RN1, RN2, Rɑ, Rβ, and each of R2-R6are as defined herein and as generally understood in the art.

[0284] In some embodiments, the additional active compound is a phenylalkylamine selected from the group consisting of α-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- 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,ß-trimethoxyphenethylamine (BOB), 2,5,ß-trimethoxy-4- methylphenethylamine (BOD), ß-methoxy-3,4-methylenedioxyphenethylamine (BOH), 2,5-dimethoxy-ß- hydroxy-4-methylphenethylamine (BOHD), 3,4,5,ß-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-G-N), 2,5-dimethoxyphenethylamine (2C-H), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), 2,5-dimethoxy-4-nitro-phenethylamine (2C-N), 2,5-dimethoxy-4-isopropoxyphenethylamine (2C-O-4), 2,5-dimethoxy-4-propylphenethylamine (2C-P), 4-cyclopropylmethoxy- 3,5-dimethoxyphenethylamine (CPM), 2,5-dimethoxy-4-methylselenophenethylamine (2C-SE), 2,5-dimethoxy-4-methylthiophenethylamine (2C-T), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,6-dimethoxy-4- isopropylthiophenethylamine (psi-2C-T-4), 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), 4-cyclopropylmethylthio-2,5-dimethoxyphenethylamine (2C-T-8), 4-(t)-butylthio-2,5-dimethoxy- phenethylamine (2C-T-9), 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine (2C-T-13), 4-cyclopropylthio-2,5-dimethoxyphenethylamine (2C-T-15), 4-(s)-butylthio-2,5- dimethoxyphenethylamine (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine (2C-T-21), 3,5-dimethoxy-4-trideuteromethyl- 2024-03-01 phenethylamine (4-D), ß,ß-dideutero-3,4,5-trimethoxyphenethylamine (ß-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-ß-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-amino- propyl)benzonorbornane (G-5), 2,5-dimethoxy-3,4-dimethyl-amphetamine (GANESHA), 1,4-dimethoxy- naphthyl-2-isopropylamine (G-N), 2,5-dimethoxy-4- ethylthio-N-hydroxyphenethylamine (HOT-2), 2,5-dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine (HOT-7), 4-(s)-butylthio-2,5-dimethoxy-N-hydroxy- phenethylamine (HOT-17), 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA), 2,3,4-trimethoxy- phenethylamine (IM), 3,5-dimethoxy-4-isopropoxyphenethylamine (IP), 5-ethoxy-2-methoxy-4-methyl- amphetamine (IRIS), 2-amino-1-(3,4-methylenedioxyphenyl)butane (J, BDB), 3-methoxy-4,5-methylene- dioxyphenethylamine (LOPHOPHINE), 3,4,5-trimethoxyphenethylamine (M), 4-methoxyamphetamine (4-MA, PMA), 2,N-dimethyl-4,5-methylenedioxyamphetamine (MADAM-6), 3,5-dimethoxy-4-methallyloxy- phenethylamine (MAL), 3,4-methylenedioxyamphetamine (MDA), N-allyl-3,4-methylenedioxyamphetamine (MDAL), N-butyl-3,4-methylenedioxyamphetamine (MDBU), N-benzyl-3,4-methylenedioxy-amphetamine (MDBZ), N-cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM), N,N-dimethyl-3,4-methylene- dioxyamphetamine (MDDM), N-ethyl-3,4-methylenedioxy-amphetamine (MDE), N-(2-hydroxyethyl)-3,4-methylenedioxyamphetamine (MDHOET), N-isopropyl-3,4-methylenedioxy- amphetamine (MDIP), N-methyl-3,4-methylenedioxyamphetamine (MDMA), 3,4-ethylenedioxy-N-methyl- amphetamine (MDMC), N-methoxy-3,4-methylenedioxyamphetamine (MDMEO), N-(2-methoxyethyl)-3,4- methylenedioxyamphetamine (MDMEOET), 3,4-methylenedioxy-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 2024-03-01 (MDPL), 3,4-methylenedioxy-N-propyl-amphetamine (MDPR), 3,4-dimethoxy- 5-ethoxyphenethylamine (ME), 4,5-ethylenedioxy-3-methoxyamphetamine (MEDA), 4,5-diethoxy-2-methoxyamphetamine (MEE), 2,5-dimethoxy-4-ethoxyamphetamine (MEM), 4-ethoxy-3-methoxyphenethylamine (MEPEA), 5-bromo-2,4-dimethoxyamphetamine (META-DOB), 2,4-dimethoxy-5-methylthioamphetamine (META-DOT), 2,5-dimethoxy- N-methylamphetamine (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methylamphetamine (METHYL-DOB), 2-methylamino-1-(3,4-methylenedioxyphenyl)butane (METHYL-J, MBDB), 2-methylamino-1-(3,4-methylenedioxyphenyl)pentane (METHYL-K), 4-methoxy-N-methyl- amphetamine (METHYL-MA, PMMA), 2-methoxy-N-methyl-4,5-methylenedioxyamphetamine (METHYL-MMDA-2), 3-methoxy-4,5-methylenedioxyamphetamine (MMDA), 2-methoxy- 4,5-methylenedioxyamphetamine (MMDA-2), 2-methoxy-3,4-methylenedioxyamphetamine (MMDA-3a), 4-methoxy-2,3-methylenedioxy- amphetamine (MMDA-3b), 2,4-dimethoxy-5-ethoxyamphetamine (MME), 3,4-dimethoxy-5-(n)- propoxyphenethylamine (MP), 2,5-dimethoxy-4-(n)-propoxyamphetamine (MPM), 4,5-dimethoxy-2- methylthioamphetamine (ORTHO-DOT), 3,5-dimethoxy-4-propoxyphenethylamine (P), 3,5-dimethoxy-4- phenethyloxyphenethylamine (PE), phenethylamine (PEA), 3,5-dimethoxy-4-(2-propynyloxy) phenethylamine (PROPYNYL), 3,5-diethoxy-4-methoxyphenethylamine (SB), 2,3,4,5-tetra- methoxyamphetamine (TA), 4-ethoxy-3-ethylthio-5-methoxyphenethylamine (3-TASB), 3-ethoxy-4-ethylthio-5-methoxyphenethylamine (4-TASB), 3,4-diethoxy-5-methylthio- phenethylamine (5-TASB), 4-(n)-butylthio-3,5-dimethoxyphenethylamine (TB), 4-ethoxy-5-methoxy-3-methylthio- phenethylamine (3-TE), 3,5-dimethoxy-4-ethylthiophenethylamine (TE, 4-TE), 3,4-dimethoxy-2- methylthiophenethylamine (2-TIM), 2,4-dimethoxy-3-methylthio- phenethylamine (3-TIM), 2,3-dimethoxy-4-methylthiophenethylamine (4-TIM), 3,4-dimethoxy- 5-methylthiophenethylamine (3-TM), 3,5-dimethoxy-4-methylthiophenethylamine (4-TM), 3,4,5-trimethoxyamphetamine (TMA), 2,4,5-trimethoxy- amphetamine (TMA-2), 2,3,4-trimethoxyamphetamine (TMA-3), 2,3,5-trimethoxyamphetamine (TMA-4), 2,3,6-trimethoxyamphetamine (TMA-5), 2,4,6-trimethoxyamphetamine (TMA-6), 4,5-dimethoxy-3-ethylthio- phenethylamine (3-TME), 3-ethoxy-5-methoxy-4-methylthiophenethylamine (4-TME), 3-ethoxy-4-methoxy- 5-methylthiophenethylamine (5-TME), 3,4-methylenedioxy-2-methylthioamphetamine (2T-MMDA-3a), 2-methoxy-4,5-methylene- thiooxyamphetamine (4T-MMDA-2), 2,4,5-trimethoxyphenethylamine (TMPEA), 4-ethyl-5-methoxy-2-methylthioamphetamine (2-TOET), 4-ethyl-2-methoxy-5-methylthio- amphetamine (5-TOET), 5-methoxy-4-methyl-2-methylthioamphetamine (2-TOM), 2-methoxy-4-methyl-5-methylthio- amphetamine (5-TOM), 2-methoxy-4-methyl-5-methylsulfinylamphetamine (TOMSO), 3,5-dimethoxy-4- propylthiophenethylamine (TP), 3,4,5-triethoxyphenethylamine (TRIS), 3-ethoxy-5-ethylthio-4-methoxy- phenethylamine (3-TSB), 3,5-diethoxy-4-methylthiophenethylamine (4-TSB), 3,4-diethoxy-5-ethylthio- phenethylamine (3-T-TRIS), 3,5-diethoxy-4-ethylthiophenethylamine (4-T-TRIS), (R)-2,5-dimethoxy-4-iodo- amphetamine (R-DOI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof. 2024-03-01

[0285] In some embodiments, the additional active compound is an ergoline. In embodiments, the additional active compound is an ergot alkaloid. In embodiments, the additional active compound is a lysergamide. As will be understood by those in the art, lysergamides are compounds having the general structure below, wherein RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are as defined herein and as generally understood in the art:

[0286] In some embodiments, RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are each independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Additionally, any two of RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14and the intervening atoms can be taken together to form an optionally substituted optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In embodiments, the lysergamide is a quaternary salt, in which an additional R6Ais connected to the nitrogen to which R6is bound; wherein R6Ais optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0287] In some embodiments, the additional active compound is a lysergamide selected from the group consisting of lysergic acid diethylamide (i.e., LSD, LSD-25, LAD, Delysid), 6-ethyl-6- nor -lysergic acid diethylamide (ETH-LAD), 6-propynyl-6- nor -lysergic acid diethylamide (PARGY-LAD), 6-allyl-6- nor -lysergic acid diethylamide (AL-LAD), 6-propyl-6- nor -lysergic acid diethylamide (PRO-LAD), 6-isopropyl-6- nor -lysergic acid diethylamide (IP-LAD), 6-cylopropyl-6- nor -lysergic acid diethylamide (CIP-LAD), 6-butyl-6- nor -lysergic acid diethylamide (BU-LAD), 6-(2-fluoroethyl)-6- nor -lysergic acid diethylamide (FLUOROETH-LAD), 1-acetyl-lysergic acid diethylamide (i.e., ALD, ALD-52, N-acetyl-LSD), 1-propionyl-lysergic acid diethylamide (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 2024-03-01 (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 methylisopropyl amide (MIPLA).

[0288] Other tryptamines, phenylalkylamines, and lysergamides useful as additional active compounds for purposes of the disclosure and thus contemplated for inclusion therein will be as generally known in the art (see, e.g., Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997); Grob & Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi & Liechti, Arch Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacological Reviews, 2016; 68(2), 264-355; Glennon, Pharmacol Biochem and Behavior, 1999; 64, 251-256; each of which is incorporated by reference as if fully set forth herein). E. Dose and Dosage

[0289] In some embodiments, pharmaceutical compositions comprise a therapeutically effective amount or an effective amount of a disclosed compound, such as for administration to a subject. Administration of pharmaceutical compositions in a “therapeutically effective amount,” or an “effective amount” to a subject means administration of an amount of composition sufficient to achieve the desired effect. When an “effective amount” means an amount effective in treating the stated disorder or symptoms in a subject, “therapeutic effect” would be understood to mean the responses(s) in a mammal after treatment that are judged to be desirable and beneficial. Hence, depending on the mental health disorder to be treated, or improvement in mental health or functioning sought, and depending on the particular constituent(s) in the disclosed compositions under consideration, those responses shall differ, but would be readily understood by those of ordinary skill, through an understanding of the disclosure herein and the general knowledge of the art (e.g., by reference to the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for the stated disorder).

[0290] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, as well as amounts within these ranges.

[0291] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the 2024-03-01 kilogram weight of the patient) between about 0.01 mg / kg and 0.1 mg / kg, such as about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg about 0.08 mg / kg about 0.09 mg / kg, and about 0.1 mg / kg, as well as ranges between these values. In some embodiments, a single dose is between about 0.1 mg / kg and 1.0 mg / kg, such as about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg about 0.8 mg / kg about 0.9 mg / kg, and about 1.0 mg / kg, as well as ranges between these values.

[0292] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, as well as amounts within these ranges.

[0293] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) between about 0.1 mg and 1.0 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, and about 1.0 mg, as well as ranges between these values. In embodiments, a single dose is between about 1 mg and 10 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg, as well as ranges between these values. In some embodiments, a single dose is between about 10 mg and 100 mg.

[0294] In some embodiments, where a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenylalkylamine or tryptamine, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, as well as amounts within these ranges. 2024-03-01

[0295] In some embodiments, where a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenylalkylamine or a tryptamine, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, as well as amounts within these ranges.

[0296] In some embodiments, a dose of a disclosed compound is in the range of about 1 mg to about 100 mg. For example, the dose may be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some embodiments, a dose of a disclosed compound is between about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 30 mg. In some embodiments, a dose of a disclosed compound is about 1 mg, about 10 mg, or about 25 mg. In some embodiments, a dose of a disclosed compound is in the range of about 0.001 mg to about 1 g. In some embodiments, a dose of a disclosed compound is in the range of about 100 mg to about 250 mg. In some embodiments, a dose of a disclosed compound is about 25 mg.

[0297] In some embodiments, a disclosed compound is administered daily. In embodiments, a disclosed compound is administered twice a day. In embodiments, a disclosed compound is administered three times a day. In embodiments, a disclosed compound is administered every other day. In embodiments, a disclosed compound is administered every third day. In embodiments, a disclosed compound is administered every fourth day. In embodiments, a disclosed compound is administered every fifth day. In embodiments, a disclosed compound is administered weekly. In embodiments, a disclosed compound is administered every other week. In embodiments, a disclosed compound is administered every third week. In embodiments, a disclosed compound is administered monthly.

[0298] In some embodiments, about 50 mg of a disclosed compound is administered daily. In some embodiments, about 50 mg of a disclosed compound is administered twice a day. In some embodiments, about 50 mg of a disclosed compound is administered three times a day. In some embodiments, about 50 mg of a disclosed compound is administered every other day. In some embodiments, about 50 mg of a disclosed compound is administered every third day. In some embodiments, about 50 mg of a disclosed compound is administered every fourth day. In some embodiments, about 50 mg of a disclosed compound is 2024-03-01 administered every fifth day. In some embodiments, about 50 mg of a disclosed compound is administered weekly. In some embodiments, about 50 mg of a disclosed compound is administered every other week. In some embodiments, about 50 mg of a disclosed compound is administered every third week. In some embodiments, about 50 mg of a disclosed compound is administered monthly.

[0299] In some embodiments, about 100 mg of a disclosed compound is administered daily. In some embodiments, about 100 mg of a disclosed compound is administered twice a day. In some embodiments, about 100 mg of a disclosed compound is administered three times a day. In some embodiments, about 100 mg of a disclosed compound is administered every other day. In some embodiments, about 100 mg of a disclosed compound is administered every third day. In some embodiments, about 100 mg of a disclosed compound is administered every fourth day. In some embodiments, about 100 mg of a disclosed compound is administered every fifth day. In some embodiments, about 100 mg of a disclosed compound is administered weekly. In some embodiments, about 100 mg of a disclosed compound is administered every other week. In some embodiments, about 100 mg of a disclosed compound is administered every third week. In some embodiments, about 100 mg of a disclosed compound is administered monthly.

[0300] In some embodiments, about 150 mg of a disclosed compound is administered daily. In some embodiments, about 150 mg of a disclosed compound is administered twice a day. In some embodiments, about 150 mg of a disclosed compound is administered three times a day. In some embodiments, about 150 mg of a disclosed compound is administered every other day. In some embodiments, about 150 mg of a disclosed compound is administered every third day. In some embodiments, about 150 mg of a disclosed compound is administered every fourth day. In some embodiments, about 150 mg of a disclosed compound is administered every fifth day. In some embodiments, about 150 mg of a disclosed compound is administered weekly. In some embodiments, about 150 mg of a disclosed compound is administered every other week. In some embodiments, about 150 mg of a disclosed compound is administered every third week. In some embodiments, about 150 mg of a disclosed compound is administered monthly.

[0301] In some embodiments, about 200 mg of a disclosed compound is administered daily. In some embodiments, about 200 mg of a disclosed compound is administered twice a day. In some embodiments, about 200 mg of a disclosed compound is administered three times a day. In some embodiments, about 200 mg of a disclosed compound is administered every other day. In some embodiments, about 200 mg of a disclosed compound is administered every third day. In some embodiments, about 200 mg of a disclosed compound is administered every fourth day. In some embodiments, about 200 mg of a disclosed compound is administered every fifth day. In some embodiments, about 200 mg of a disclosed compound is administered weekly. In some embodiments, about 200 mg of a disclosed compound is administered every other week. In some embodiments, about 200 mg of a disclosed compound is administered every third week. In some embodiments, about 200 mg of a disclosed compound is administered monthly.

[0302] In some embodiments, about 250 mg of a disclosed compound is administered daily. In some 2024-03-01 embodiments, about 250 mg of a disclosed compound is administered twice a day. In some embodiments, about 250 mg of a disclosed compound is administered three times a day. In some embodiments, about 250 mg of a disclosed compound is administered every other day. In some embodiments, about 250 mg of a disclosed compound is administered every third day. In some embodiments, about 250 mg of a disclosed compound is administered every fourth day. In some embodiments, about 250 mg of a disclosed compound is administered every fifth day. In some embodiments, about 250 mg of a disclosed compound is administered daily. In some embodiments, about 250 mg of a disclosed compound is administered weekly. In some embodiments, about 250 mg of a disclosed compound is administered every other week. In some embodiments, about 250 mg of a disclosed compound is administered every third week. In some embodiments, about 250 mg of a disclosed compound is administered monthly.

[0303] In some embodiments, an initial dose of a disclosed compound is administered, which is then boosted 30 minutes-4 hours later by administering a second dose of the disclosed compound. In some embodiments, the boosted dose is administered about 30 min after the initial dose. In some embodiments, the boosted dose is administered about 60 min after the initial dose. In some embodiments, the boosted dose is administered about 90 min after the initial dose. In some embodiments, the boosted dose is administered about 120 min after the initial dose. In some embodiments, the boosted dose is administered about 150 min after the initial dose. In some embodiments, the boosted dose is administered about 180 min after the initial dose. In some embodiments, the boosted dose is administered about 210 min after the initial dose. In some embodiments, the boosted dose is administered about 240 min after the initial dose.

[0304] In some embodiments, the boosted dose is from about 10% to 100% of the amount of the initial dose. In some embodiments, the boosted dose is the same amount as the initial dose. In some embodiments, the boosted dose is about half of the amount of the initial dose. In some embodiments, this dosing schedule is performed daily. In some embodiments, this dosing schedule is performed twice a day. In some embodiments, this dosing schedule is performed three times a day. In some embodiments, this dosing schedule is performed every other day. In some embodiments, this dosing schedule is performed every third day. In some embodiments, this dosing schedule is performed every fourth day. In some embodiments this dosing schedule is performed every fifth day. In some embodiments, this dosing schedule is performed weekly. In some embodiments, this dosing schedule is performed every other week. In some embodiments, this dosing schedule is performed every third week. In some embodiments, this dosing schedule is performed monthly.

[0305] In some embodiments, a dose of a disclosed compound may be in the range of about 1 mg / kg to about 100 mg / kg. For example, the dose may be about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, the 2024-03-01 dose of a disclosed compound is between about 0.1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, or about 5 mg / kg to about 30 mg / kg. In some embodiments, the dose of a disclosed compound is about 1 mg / kg, about 10 mg / kg, or about 25 mg / kg. In some embodiments, the dose of a disclosed compound is in the range of about 0.001 mg / kg to about 1 g / kg. In some embodiments, the dose of a disclosed compound is in the range of about 100 mg / kg to about 250 mg / kg. In some embodiments, the dose of a disclosed compound is about 25 mg / kg.

[0306] In some embodiments, a disclosed compound is administered, e.g., as a single dose or one or more times per week (up to twice daily or even three times a days). In some embodiments, a disclosed compound is administered according to a dosing schedule provided herein. In some embodiments, a disclosed compound is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.

[0307] It will be readily appreciated that dosages may vary depending upon whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by the skilled artisan (e.g., medical or familial history).

[0308] Dose amount, frequency or duration may be increased or reduced, as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications. The skilled artisan with the teaching of this disclosure in hand will appreciate the factors that may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0309] It will be understood that, in some embodiments, the dose actually administered will be determined by a physician, in light of the relevant circumstances, including the disorder to be treated, the chosen route of administration, the actual composition or formulation administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms, and therefore any dosage ranges disclosed herein are not intended to limit the scope of the disclosure. In some instances, dosage levels below the lower limit of a disclosed range may be more than adequate, while in other cases doses above a range may be employed without causing any harmful side effects, provided for instance that such larger doses also may be divided into several smaller doses for administration, either taken together or separately.

[0310] In embodiments, especially where a formulation is prepared in single unit dosage form, such as a capsule, tablet, or lozenge, suggested dosage amounts may be known by reference to the format of the preparation itself. In embodiments, where a formulation is prepared in multiple dosage form, for instance 2024-03-01 liquid suspensions and topical preparations, suggested dosage amounts may be known by reference to the means of administration or by reference to the packaging and labeling, package insert(s), marketing materials, training materials, or other information and knowledge available to one of skill or the public.

[0311] Accordingly, another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration. F. Kits

[0312] Another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0313] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub- unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and / or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0314] Preferably, information pertaining to dosing and proper administration (if needed) will be printed onto a multi-dose kit directly (e.g., on a blister pack or other interior packaging holding the compositions or formulations of the disclosure); however, kits of the disclosure can further contain package inserts and other printed instructions (e.g., on exterior packaging) for administering the disclosed compositions and for their appropriate therapeutic use. G. Methods of Use

[0315] Empathogens like MDMA and methylone have shown promise in rapidly and effectively treating mental health disorders when taken in combination with psychotherapy. For example, findings from a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial demonstrated that, compared to therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD 2024-03-01 and treatment is safe and well-tolerated, even in those with comorbidities (Mitchell et al., Nat Med., 2021; 27, 1025-1033). Studies have demonstrated potential for MDMA to address other difficult-to-treat mental health conditions, including substance abuse, post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), phobias, eating disorders, depression, end-of-life anxiety, and social anxiety. Methylone has likewise shown promise for treating mental health conditions, such as PTSD and depression (Kelmendi et al. Clin Case Rep.2006;7:2209).

[0316] Although MDMA generally produces no long-lasting or serious adverse events, it is known to cause transient adverse events that are mild to moderate in severity, including increased anxiety, cardiovascular effects such as increased blood pressure and heart rate, hyperthermia, hyperhidrosis, jaw tightness and bruxism, muscle tightness, unpleasant stimulation, reduced appetite, nausea, poor concentration, and impaired balance (see, e.g., Harris et al., Psychopharmacol (Berl), 2002; 162(4), 396-405; Lietchti 2001, Oehen et al., J Psychopharmacol, 2013; 40-52; Mas et al., J Pharmacol Exp. Ther., 1999; 290(1): 136-45, Mithoefer, et al., J of Psychopharmacol, 2010; 25(4): 439-452; Rogers et al., Health Technol Assess, 2009; 13(6): iii-iv, ix-xii, 1-315). Fatal intoxications from methylone have been reported, in some cases connected with metabolic acidosis (Pearson et al. J Anal Toxicol.2012;36(6):444–451).

[0317] Accordingly, compounds that can harness the therapeutic benefits of known empathogens while reducing their negative side effects have been highly sought after. Mitigating one or more of these side effects and improving the safety profile would both increase the value of an empathogen for therapeutic use, and broaden the population of patients who could benefit.

[0318] In some aspects, provided are methods of using the disclosed compounds. In some embodiments, disclosed compounds are used to modulate neurotransmission. In embodiments, disclosed compounds are used to treat a condition, such as a disease or a disorder. In embodiments, disclosed compounds are used in the manufacture of a medicament for the therapeutic and / or the prophylactic treatment of a condition, such as a disease or a disorder. In embodiments, disclosed compounds are administered as part of therapy. In embodiments, disclosed compounds are administered along with psychotherapy, psychological support, or patient monitoring. In embodiments, disclosed compounds are administered in a therapeutically effective amount to a subject having a condition, such as a disease or a disorder. In embodiments, the condition is a mental health disorder. In embodiments, the condition is a neurodegenerative disorder. In embodiments, the condition is an inflammatory disorder. In embodiments, the condition is pain and / or inflammation. In embodiments, disclosed compounds are administered to a subject that is healthy.

[0319] As used herein, the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to any mammal, including murines, simians, mammalian farm animals, mammalian sport animals, and mammalian pets, such as canines and felines, although preferably humans. Such terms will be understood to include one who has an indication for which a compound, composition, or method described herein may be efficacious, or who otherwise may benefit by the disclosure. In general, all of the compounds, 2024-03-01 compositions, and disclosed methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood. The disclosed methods of treatment also can be modified to treat multiple patients at once, including couples or families. Hence, these terms will be understood to also mean two or more individuals.

[0320] In some embodiments, disclosed compounds or compositions thereof are orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation or transdermally administered to a subject. In embodiments, when administered through one or more such routes, the disclosed compounds and the disclosed compositions and formulations comprising them are useful in methods for treating a patient in need of such treatment. a. Modulating Neurotransmission and Neuroplasticity

[0321] In some embodiments, the disclosed compounds modulate neurotransmission in a subject, such as following administration of a pharmacologically effective amount to said subject. In some embodiments, modulating neurotransmission comprises regulating levels of monoamines in, for example, the CNS and peripheral tissues. In some embodiments, modulating neurotransmission comprises increasing levels of monoamines in, for example, the CNS and peripheral tissues of a subject to whom a disclosed compound has been administered. In some embodiments, modulating neurotransmission comprises decreasing levels of monoamines in, for example, the CNS and peripheral tissues of a subject to whom a disclosed compound has been administered. In some embodiments, modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0322] In some embodiments, disclosed compounds or compositions thereof, when administered in a pharmacologically effective amount, inhibit the reuptake of one or more neurotransmitters. In some embodiments, the disclosed compositions, when administered in a pharmacologically effective amount, increase the extracellular concentration of one or more neurotransmitters, including the amount of extracellular serotonin, dopamine, or norepinephrine.

[0323] In some embodiments, the disclosed compounds are used to modulate neurotransmission, such as neurotransmission in a subject. In some methods herein, the disclosed compositions, when administered in a pharmacologically effective amount, thus affect monoaminergic neurotransmission, including serotonergic, dopaminergic, and noradrenergic neurotransmission. Accordingly, in some embodiments, the disclosed compositions, when administered in a pharmacologically effective amount, are used to treat a medical condition linked to dysregulation or inadequate functioning of neurotransmission, and in specific embodiments, are used to treat a medical condition linked to monoaminergic neurotransmission.

[0324] In embodiments, disclosed compounds or compositions, when administered in a pharmacologically effective amount, act on or modulate one or more monoamine receptors, such as a serotonin receptor, a dopamine receptor, or a norepinephrine receptor. In embodiments, the compositions are agonists or partial agonists of a monoamine receptor, including any one or more of a serotonin receptor, a dopamine receptor, 2024-03-01 and a norepinephrine receptor.

[0325] In some embodiments, disclosed compounds activate serotonin receptors. In some embodiments, disclosed compounds agonize and / or antagonize serotonin receptors (HTRs). In some embodiments, disclosed compounds agonize or partially agonize HTRs, such as any one or more of an HTR1receptor, such as HTR1Aand HTR1B, an HTR2receptor, such as HTR2Aand HTR2B, and HTR6.

[0326] In some embodiments, disclosed compounds have an in vitro EC50(agonist mode) for any one or more of HTR1A, HTR1B, HTR2AHTR2B, and HTR6that is less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, or less than 0.1 µM. In embodiments, disclosed compounds have an in vitro EC50(agonist mode) for HTR2Athat is 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.

[0327] In some embodiments, disclosed compounds show greater potency at HTR2Arelative to other HTRs. In some embodiments, disclosed compounds show greater potency at HTR2Arelative to any one or more of an HTR1, such as HTR1Aand HTR1B, another HTR2, such as HTR2Band HTR2C, an HTR5, e.g., HTR5A, HTR6, and an HTR7, e.g., HTR7D.

[0328] In some embodiments, disclosed compounds show greater potency at HTR2Arelative to HTR1A. In some embodiments, disclosed compounds show at least a 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold greater potency at HTR2Arelative to HTR1A. In some embodiments, disclosed compounds have an in vitro EC50of greater than 10 µM at HTR1A. In some embodiments, disclosed compounds show greater potency at HTR2Arelative to HTR2B. In some embodiments, disclosed compounds show at least a 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold greater potency at HTR2Arelative to HTR2B. In some embodiments, disclosed compounds show greater potency at HTR2Arelative to HTR2C. In some embodiments, disclosed compounds show at least a 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold greater potency at HTR2Arelative to HTR2C. In some embodiments, disclosed compounds show greater potency at HTR2Brelative to HTR2A. In some embodiments, disclosed compounds show at least a 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold greater potency at HTR2Brelative to HTR2A.

[0329] In some embodiments disclosed compounds modulate the activity of a dopamine receptor (DR), such as any one or more of DRD1, DRD2, DRD3, DRD4, and DRD5. In some embodiments, disclosed compounds agonize or partially agonize a dopamine receptor. In some embodiments, disclosed compounds agonize or partially agonize DRD2. In some embodiments, disclosed compounds agonize or partially agonize the DRD2 short isoform (DRD2S). In embodiments, disclosed compounds have 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.

[0330] Determining agonism and antagonism, and measuring EC50and IC50, respectively, may be determined according to methods available to one of skill in the art. In one example, measuring Gq-mediated calcium flux is a known method for assessing modulation, e.g., activation, of HTR2A, a widely recognized target of psychedelic compounds. See, e.g., Klein et al., ACS Pharmacol Transl Sci.202014;4(2):533-542; 2024-03-01 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 would be recognized by one of skill, a partial agonist is one that shows reduced maximum efficacy (EMAX) relative to a full agonist (EMAX= 100%), e.g., serotonin in the example of an HTR.

[0331] In some embodiments, disclosed compounds or compositions thereof, when administered in a pharmacologically effective amount, act on or modulate one or more membrane monoamine transporters, including any one or more of a serotonin membrane transporter (SERT), a dopamine membrane transporter (DAT), a norepinephrine membrane transporter (NET), and a vesicular monoamine transporter. In some embodiments, disclosed compounds block the uptake activity of monoamine transporters. In some embodiments, disclosed compounds block the uptake activity of one or more of a serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).

[0332] In some embodiments, disclosed compounds do not inhibit the uptake activity of any one or more of SERT, DAT, and NET. In some embodiments, disclosed compounds do not inhibit the uptake activity of DAT and / or NET. In some embodiments, disclosed compounds do not inhibit the uptake activity of SERT, DAT, and NET. In embodiments, disclosed compounds do not inhibit the uptake activity of DAT and NET. In some embodiments, disclosed compounds do not inhibit the uptake activity of DAT. In embodiments, disclosed compounds have an in vitro IC50of greater than 10 µM for any one or more of SERT, DAT, and NET.

[0333] In some embodiments, disclosed compounds inhibit the uptake activity of any one or more of SERT, DAT, and NET. In some embodiments, disclosed compounds inhibit the uptake activity of SERT, DAT, and NET. In embodiments, disclosed compounds have an in vitro IC50of less than 10 µM for any one or more of SERT, DAT, and NET. In embodiments, disclosed compounds do not inhibit the uptake activity of SERT. In embodiments, disclosed compounds have an in vitro IC50of less than 10 µM for SERT. In embodiments, disclosed compounds selectively inhibit the uptake activity of SERT. In embodiments, disclosed compounds show greater potency for inhibiting the uptake activity of SERT relative to DAT and NET.

[0334] Determining whether a disclosed compound inhibits the uptake activity of a monoamine transporter, or whether such activity is lacking, may be determined according to available methods, which may include live-cell fluorescent assays or radioactive assays. In some examples, inhibition of monoamine uptake may be determined in rat synaptosomes or human platelets. See, e.g., Segonzac et al., J Neurochem. 1985;44(2):349-56; Cozzi et al., J Neural Transm (Vienna).2009;116(12):1591-9. In some examples, inhibitory activity may be compared to uptake inhibitors having low nM potency, e.g., DAT inhibitor GBR 12909, NET inhibitor desipramine, and SERT inhibitor clomipramine.

[0335] In some embodiments, administration of a composition of the disclosure according to the methods herein will have an improved pharmacological profile, such as a relative increase in agonism of serotonin receptors compared to dopamine and / or norepinephrine receptors, compared to a corresponding non-substituted composition, which may be an increase of 5% or more, 10% or more, 25% or more, or 50% 2024-03-01 or more, and including amounts in between. Measurements of agonism of a receptor will be as understood by those in the art or by reference to the general knowledge in the art.

[0336] In some embodiments, an improved pharmacological profile of a composition of the disclosure will be a relative increase in extracellular concentration of serotonin compared to dopamine and / or norepinephrine, compared to a corresponding non-substituted composition, which may be an increase of 5% or more, 10% or more, 25% or more, or 50% or more, and including amounts in between. Measurements of extracellular concentration of a neurotransmitter will be as understood by those in the art or by reference to the general knowledge in the art.

[0337] Detecting a change in monoamine levels in a subject, such as an increase or a decrease, can be achieved according to methods known to one of skill, for example, brain microdialysis (Chefer et al., Curr Protoc Neurosci.2009; Chapter: Unit 7.1; Darvesh et al., Expert Opin Drug Discov.2011; 6(2): 109–127) and brain imaging, for example, positron emission tomography (PET) and single photon emission computed tomography (SPECT) (see e.g., Wong & Gjedde, Encyclopedia of Neuroscience, 2009; 939-952 and Takano, Front Psychiatry., 2018; 9:228).

[0338] In some embodiments, disclosed compounds are not substrates for monoamine oxidase enzymes. In some embodiments, disclosed compounds do not inhibit the activity of monoamine oxidase enzymes. In some embodiments, disclosed compounds are not substrates for monoamine oxidase A (MAO-A). In some embodiments, disclosed compounds do not inhibit the activity of MAO-A. In some embodiments, the in vitro IC50of disclosed compounds at MAO-A is greater than 10 µM. In some embodiments, disclosed compounds are orally bioavailable. In some embodiments, the disclosed compositions, when administered in a pharmacologically effective amount, inhibit a monoamine oxidase enzyme, including MAO-A and MAO-B.

[0339] In some embodiments, administration of a disclosed fluorine-substituted composition according to the methods herein will affect a decreased inhibition of, and / or metabolism by, at least one cytochrome P450 enzyme or monoamine oxidase isoform (e.g., MAO-A or MAO-B) in a subject during treatment, as compared to a corresponding non-substituted composition, which may be a decrease of 5% or more, 10% or more, 25% or more, or 50% or more, and including amounts in between. Measurements of inhibition and metabolism will be as understood by those in the art or by reference to the general knowledge in the art (see, e.g., Ko et al., Br J Clin Pharmacol, 2000; 49(4), 343–351; Uebelhack, Franke & Schewe, Pharmacopsych, 1998; 31(5), 187–192; Weyler & Salach, J Biol Chem, 1985; 260(24), 13199–13207).

[0340] In some embodiments, a disclosed compound is used to increase neuroplasticity. Neuroplasticity, also known as neural plasticity or brain plasticity, refers to the brain's ability to change and adapt in response to experiences, learning, and environmental factors. Neuroplasticity occurs through several mechanisms, including synaptic plasticity, which involves the strengthening or weakening of connections (synapses) between neurons. Synaptic plasticity is often associated with learning and memory processes. Another form of plasticity is called structural plasticity, which involves changes in the physical structure of neurons, such 2024-03-01 as the growth of new dendritic branches or the formation of new synapses. In some embodiments, increasing neuroplasticity contributes to the therapeutic effects of a disclosed compound in a subject. In some embodiments, increasing neuroplasticity by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0341] Neuroplasticity can be defined in terms of neuritogenesis, spinogenesis, and synaptogenesis in neurons. Neuritogenesis refers to the process by which neurons generate and extend their neurites (i.e., to form axons and dendrites). Neuritogenesis is a critical step in neural development and the formation of neuronal circuits. Spinogenesis refers to the formation of dendritic spines, which are small protrusions on the dendrites of neurons. Dendritic spines are crucial for synaptic connections and play a vital role in synaptic transmission and plasticity. Synaptogenesis refers to the formation of synapses, which is crucial for the establishment and refinement of neural circuits, and is a fundamental process underlying learning, memory, and information processing in the brain.

[0342] In some embodiments, a disclosed compound increases neuritogenesis. Neuritogenesis can be measured in terms of total neurite length, maximum neurite length, number of neurite nodes, and / or number of neurite extremities. In some embodiments, a disclosed compound increases total neurite length. In some embodiments, a disclosed compound increases maximum neurite length. In some embodiments, a disclosed compound increases the number of neurite nodes. In some embodiments, a disclosed compound increases the number of neurite extremities.

[0343] In some embodiments, administration of a disclosed compound to a subject results in an increase in the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., number of synapses per neuron), or total dendritic length. These factors can be measured using a Sholl analysis and other techniques known to those of skill in the art (Ly et al. ACS Pharmacol Transl Sci .2020;4(2):452-460). b. Treatment

[0344] In some embodiments, disclosed compounds are used to treat a medical condition, such as a disease or disorder. In embodiments, disclosed compounds are used in the manufacture of a medicament to treat a condition, such as a disease or disorder. Also provided are methods of administering disclosed compounds to a subject having a condition, such as a disease or disorder, thereby treating said condition.

[0345] In some embodiments, disclosed compounds or pharmaceutical compositions comprising the disclosed compounds are administered to a subject by one or more routes of administration, including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes. When administered through one or more of such routes, the compound(s) of the disclosure and the disclosed compositions and formulations comprising them are useful in methods for treating a patient in need of such treatment.

[0346] In some embodiments are provided methods of treating and / or preventing a condition in a mammal, 2024-03-01 the method comprising administering to the mammal a therapeutically effective amount of a disclosed compound or pharmaceutical composition. In some embodiments, “treating” or “treatment” refers to treating a disease or disorder in a mammal, and preferably in a human, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e. arresting its development; (c) relieving a disorder, i.e., causing regression thereof; (d) protecting from or relieving a symptom or pathology caused by or related to a disorder; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a disorder; and (f) preventing or inhibiting of a worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder. In embodiments, treatment includes prevention. In other embodiments, treatment does not include prevention. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood to one of skill in view of the teachings herein and the knowledge in the art.

[0347] In embodiments, disclosed compounds are used to treat a central nervous system (CNS) disorder. Broadly, CNS disorders include diseases of the nervous system (e.g., movement disorders, neuro- degenerative disorders) as well as mental, behavioral, and neurodevelopmental disorders, such as those characterized by the DSM-5, Merck Manual, ICD-11, or other diagnostic resources known to those of skill. i. Mental, Behavioral, and Neurodevelopmental Disorders

[0348] In some embodiments, disclosed compounds are used to treat a mental, behavioral, or neurodevelopmental disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental, behavioral, or neurodevelopmental disorder, thereby treating said mental, behavioral, or neurodevelopmental disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental, behavioral, or neurodevelopmental disorder.

[0349] The ICD-11, which is incorporated by reference herein in its entirety, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant disturbance in an individual's cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning. Such disorders include, but are not limited to, neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual 2024-03-01 dysfunctions, and gender incongruence.

[0350] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or “mental health disorder”) generally refers to a disease condition that involves negative changes in emotion, mood, thinking, and / or behavior. In general, mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotion, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of suffering. Although the terms “mental disorder” and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11, or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11, ICD-10, DSM-5, or DSM-IV (each of which is incorporated by reference herein in its entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.

[0351] In some embodiments, disclosed compounds are used to treat a mental health disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating said mental health disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental health disorder. In some embodiments, the compounds and compositions of the disclosure are used to reduce the symptoms of a mental health disorder. The symptoms of the mental health disorder to be treated shall be able to be determined by one of skill in the art, by reference to the general understanding of the art regarding that disorder.

[0352] In some embodiments, measures of therapeutic efficacy include reports by a subject or an observer. In some embodiments, measures of therapeutic efficacy include responses to a questionnaire. Non-limiting representative examples of applicable measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject- or observer-reported measures.

[0353] In some embodiments, a disclosed compound is used to treat a neurodevelopmental disorder. In some embodiments, a “neurodevelopmental disorder” is a neurological and / or cognitive disorder that arises during the developmental period that involves significant difficulties in the acquisition and execution of specific neurological functions (e.g., intellectual, motor, language, or social functions). In some 2024-03-01 embodiments, the neurodevelopmental disorder is a disorder of intellectual development, a developmental speech or language disorder, autism spectrum disorder, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.

[0354] In some embodiments, a disclosed compound is used to treat schizophrenia or another primary psychotic disorder. In general, these disorders are characterized by significant impairments in reality and alterations in behavior manifest in positive symptoms like persistent delusions, persistent hallucinations, disorganized thinking and speech, grossly disorganized behavior, as well as experience of negative symptoms such as blunted or flat affect and avolition and psychomotor disturbances. In some embodiments, a disclosed compound is used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder.

[0355] In some embodiments, a disclosed compound is used to treat catatonia. In some embodiments, “catatonia” refers to a category of syndromes characterized by the co-occurrence of several symptoms of decreased, increased, or abnormal psychomotor activity. In some embodiments, the catatonia is associated with another mental disorder. In some embodiments, the catatonia is induced by substances or medications.

[0356] In some embodiments, a disclosed compound is used to treat a mood disorder. As defined in the ICD-11, mood disorders are categorized according to the specific type(s) of mood episodes, and their pattern over time. The primary types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. In some embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder), a depressive disorder, or a substance-induced mood disorder. In some embodiments, the mood disorder is a depressive disorder. In embodiments, the depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder (formally known as dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, seasonal affective disorder, mixed depressive and anxiety disorder, or an unspecified depressive disorder. In embodiments, the depressive disorder is major depressive disorder (MDD) or treatment-resistant depression (TRD).

[0357] In embodiments, depression is assessed through the Patient Health Questionnaire-9 (PHQ-9) screening tool, Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale, Beck Depression Inventory (BDI-II), Zung Self-Rating Depression Scales (SDS), Major Depression Inventory (MDI), Center for Epidemiologic Studies Depression Scale (CED-D), Rome Depression Inventory (RDI), Hamilton Rating Scale for Depression (HRSD), and Carroll Rating Scale (CRS).

[0358] In some embodiments, a disclosed compound is used to treat an anxiety or fear-related disorder. An “anxiety disorder” refers to a class of mental disorders that induce excessive or abnormal fear, dread, or worry. In some embodiments, the anxiety disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety 2024-03-01 disorder, selective mutism, or a substance-induced anxiety disorder.

[0359] In some embodiments, a disclosed compound is used to treat an obsessive-compulsive or related disorder. In general, these disorders are characterized by repetitive thoughts and behaviors, such as cognitive phenomena (obsessions, intrusive thoughts and preoccupations). In some embodiments, the disorder is characterized by a compulsive need to accumulate possessions and distress related to discarding them (i.e., hoarding disorder). In some embodiments, the disorder is body-focused and can be characterized by recurrent and habitual actions (hair-pulling, skin-picking). In some embodiments, the disorder is obsessive-compulsive disorder, body dysmorphic disorder, olfactory reference disorder, hypochondriasis, hoarding disorder, a body-focused repetitive behavior disorder, or a substance-induced obsessive-compulsive disorder.

[0360] In some embodiments, a disclosed compound is used to treat a disorder associated with stress. In some embodiments, the disorder associated with stress has an identifiable stressor that is a causal factor, like exposure to a stressful or traumatic event, or a series of such events or adverse experiences. Stressors may be within the normal range of life experiences (e.g., divorce, socioeconomic problems), or from a threatening or traumatizing experience. In general, the nature and duration of the symptoms that arise in response to the stressor can distinguish the disorder from everyday stress. In embodiments, a disclosed compound is used to treat post-traumatic stress disorder, complex post-traumatic stress disorder, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder.

[0361] In some embodiments, a disclosed compound is used to treat a dissociative disorder. Dissociative disorders can be characterized by involuntary disruption or discontinuity in the normal integration of one or more of the following: identity, sensations, perceptions, affects, thoughts, memories, control over body movements, or behavior. In some subjects, dissociative disorder symptoms can be severe, and may result in impairment in personal, social, educational, occupational or other areas of functioning. In some embodiments, a disclosed compound is used to treat dissociative neurological symptom disorder, dissociative amnesia (including amnesia with dissociative fugue and without dissociative fugue), trance disorder, possession trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization- derealization disorder.

[0362] In some embodiments, a disclosed compound is used to treat a feeding or eating disorder. Feeding or eating disorders generally involve abnormal eating or feeding behaviors that are not explained by another health condition, and are not developmentally appropriate or culturally sanctioned. These disorders can involve preoccupation with food as well as body weight and shape concerns. In embodiments, a disclosed compound is used to treat anorexia nervosa (including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.

[0363] In some embodiments, a disclosed compound is used to treat an elimination disorder. Elimination 2024-03-01 disorders include, for example, the repeated voiding of urine into clothes or bed, and the repeated passage of feces in inappropriate places once the individual has reached a developmental age when continence is ordinarily expected. In embodiments, a disclosed compound is used to treat enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or encopresis (including both with encopresis constipation or overflow incontinence, and encopresis without constipation or overflow incontinence).

[0364] In some embodiments, a disclosed compound is used to treat a disorder of bodily distress or bodily experience. Disorders of bodily stress typically involve bodily symptoms that the subject finds distressing and to which the subject devotes excessive attention. Bodily integrity dysphoria typically involves a disturbance in the person’s experience of the body manifested by persistent discomfort or intense feelings of body configuration. In some embodiments, a disclosed compound is used to treat a bodily distress disorder (including mild, moderate, and severe bodily distress disorder) or body integrity dysphoria.

[0365] In some embodiments, a disclosed compound is used to treat a disorder due to substance use or addictive behaviors. Disorders due to substance use or addictive behaviors are mental and / or behavioral disorders that develop predominantly as a result of the use of psychoactive substances (including medications and illegal or illicit substances), or specific repetitive rewarding and reinforcing behaviors. In some embodiments, a disclosed compound is used to treat disorders due to substance use (i.e., a substance use disorder, or SUD). In some embodiments, the substance use disorder is associated with alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics or anxiolytics, cocaine, stimulants (e.g., amphetamines, methamphetamines, methcathinone, synthetic cathinones, caffeine), hallucinogens, nicotine, volatile inhalants, MDMA or MDA, dissociative drugs like ketamine and phencyclidine, or another substance (including medications and non-psychoactive substances). In some embodiments, the substance use disorder is selected from alcohol use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalants use disorder, opioids use disorder, sedatives use disorder, hypnotics use disorder, anxiolytics use disorder, stimulants use disorder, and tobacco use disorder. In some embodiments, the substance use disorder is alcohol use disorder. In some embodiments, the substance use disorder is cannabis use disorder. In some embodiments, the substance use disorder is caffeine use disorder. In some embodiments, the substance use disorder is phencyclidine use disorder. In some embodiments, the substance use disorder is inhalant use disorder. In some embodiments, the substance use disorder is opioids use disorder. In some embodiments, the substance use disorder is sedatives use disorder. In some embodiments, the substance use disorder is hypnotics use disorder. In some embodiments, the substance use disorder is anxiolytics use disorder. In some embodiments, the substance use disorder is stimulants use disorder. In some embodiments, the substance use disorder is tobacco use disorder. In some embodiments, the substance use disorder is alcohol use disorder, wherein said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism. In some embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder). In 2024-03-01 some embodiments, a substance use disorder can be screened using a Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), the Opioid Risk Tool - OUD (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).

[0366] In some embodiments, a disclosed compound is used to treat an impulse control disorder. In general, impulse control disorders are characterized by the repeated failure to resist an impulse, drive, or urge to perform an act that is rewarding to the subject despite negative long-term consequences, such as harm to the subject or a significant impairment in important areas of the subject’s functioning. In some embodiments, impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts. In some embodiments, a disclosed compound is used to treat pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.

[0367] In some embodiments, a disclosed compound is used to treat a disruptive behavior disorder or a dissocial disorder. Such disorders may be broadly characterized by persistent behavior problems that range from persistently defiant, disobedient, provocative or spiteful behaviors to behaviors that violate the rights of others or norms, rules, or laws. In some embodiments, a disclosed compound is used to treat oppositional defiant disorder (including oppositional defiant disorder with chronic irritability-anger and oppositional defiant disorder without chronic irritability-anger) or conduct-dissocial disorder (including childhood-onset conduct-dissocial disorder and adolescent-onset conduct-dissocial disorder).

[0368] In some embodiments, a disclosed compound is used to treat a personality disorder. Personality disorders may be generally characterized by problems in perceiving one’s identity, self-worth, accuracy of self-view, and self-discretion that is manifest in patterns of cognition, emotional experience, emotional expression, and maladaptive behavior. In some embodiments, a disclosed compound is used to treat a mild, moderate, or severe personality disorders. In some embodiments, a disclosed compound is used to treat a prominent personality trait or patterns (e.g., negative affectivity, detachment, dissociality, disinhibition, anankastia, borderline pattern). In some embodiments, the personality disorder is antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, masochistic or sadistic behavior, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, psychopathy, sociopathy, schizoid personality disorder, or schizotypal personality disorder.

[0369] In some embodiments, a disclosed compound is used to treat a paraphilic disorder. Paraphilic disorders can be characterized by persistent and intense patterns of atypical sexual arousal, the focus of which involves others whose age or status renders them unwilling or unable to consent. In some embodiments, a disclosed compound is used to treat exhibitionistic disorder, voyeuristic disorder, pedophilic disorder, coercive sexual sadism disorder, frotteuristic disorder, other paraphilic disorders involving 2024-03-01 non-consenting individuals, or paraphilic disorders involving solitary behavior or consenting individuals.

[0370] In some embodiments, a disclosed compound is used to treat a factitious disorder. In general, factitious disorders may be characterized by intentionally feigning, falsifying, inducing or aggravating medical, psychological, or behavior signs and symptoms or injury to oneself or another person. Subjects with factitious disorders may seek treatment or otherwise present themselves or another person as ill, injured, or impaired. In embodiments, a disclosed compound is used to treat factitious disorder imposed on self or a factitious disorder imposed on another.

[0371] In some embodiments, a disclosed compound is used to treat a neurocognitive disorder. Neurocognitive disorders may be characterized by primary clinical defects in cognitive functioning that are acquired (rather than developmental), and therefore the subject experiences a decline from a previously attained level of functioning. In some embodiments, a disclosed compound is used to treat delirium. In some embodiments, the delirium is associated with another disease or disorder. In some embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat mild neurocognitive disorder. In some embodiments, a disclosed compound is used to treat an amnestic disorder. In some embodiments, the amnestic disorder is associated with another disease or disorder. In some embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat dementia. In some embodiments, the dementia is associated with Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, Lewy body disease, a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat a behavioral or psychological disturbance associated with dementia. In some embodiments, dementia is assessed using a Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).

[0372] In some embodiments, a disclosed compound is used to treat a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. In some embodiments, the syndrome associated with pregnancy or the puerperium involves significant mental and behavioral features, including a depressive symptom. In some embodiments, the disorder includes psychotic symptoms. In some embodiments, a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, with psychotic symptoms. In embodiments, a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, without psychotic symptoms.

[0373] In some embodiments, a disclosed compound is used to treat a sleep-wake disorder. In general, sleep-wake disorders are associated with difficulty initiating or maintaining sleep (e.g., insomnia), excessive sleepiness (e.g., hypersomnolence disorders), respiratory disturbance during sleep (e.g., sleep-related breathing disorders (SRBDs), such as obstructive sleep apnea (OSA), central sleep apnea (CSA), 2024-03-01 sleep-related hypoventilation disorders, sleep-related hypoxemia disorder, snoring, catathrenia, Cheyne- Stokes breathing, and sleep-disordered breathing), disorders of the sleep-wake schedule (e.g., circadian rhythm sleep-wake disorders), abnormal movements during sleep, or problematic behavioral or psychological events that occur while falling asleep, during sleep, or upon arousal from sleep (e.g., parasomnia disorders). In some embodiments, a disclosed compound is used to treat an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder.

[0374] In some embodiments, a disclosed compound is used to treat sexual dysfunction. Sexual dysfunctions can be defined as syndromes wherein a subject may have difficulty experiencing personally satisfying, non-coercive sexual activities. In some embodiments, a disclosed compound is used to treat hypoactive sexual desire dysfunction, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse.

[0375] In some embodiments, a disclosed compound or composition is administered together with psychotherapy, such as psychosocial or behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174; in J Consul Clin Psychol 2005; 73(2): 354-59; or in Case Reports in Psychiatry, Vol.2012, Article ID 731638), motivational interviewing based therapy (e.g., as described in J Consul Clin Psychol 2001; 69(5): 858-62), meditation based therapy, such as transcendental meditation based therapy (e.g., as described in J Consul Clin Psychol 2000; 68(3): 515-52), or the therapeutic approach used by MAPS to treat patients with PTSD (e.g., as in Mithoefer, M (2017). Manual for MDMA-Assisted Psychotherapy in the Treatment of Post-traumatic Stress Disorder).

[0376] In some embodiments, disclosed compounds and compositions may be administered in conjunction with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is neither necessitated nor desired, or no specific type of psychotherapy is necessitated or desired, however any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in specific therapies, as well as to choose between any such therapies (or to decide to forgo any specific therapy), while still receiving clinically significant therapeutic effects, is among the advantages of the disclosure. Furthermore, a patient can participate in numerous other therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.

[0377] In some embodiments, “psychotherapy” is specifically “psychedelic-assisted psychotherapy.” 2024-03-01 Psychedelic-assisted psychotherapy, broadly, includes a range of related approaches that involve at least one session where the patient ingests a psychedelic and is monitored, supported, or otherwise engaged by one or more trained mental health professionals while under the effects of the psychedelic (see, e.g., Schenberg 2018). Protocols have been developed for the standardization of procedures which emphasize a high degree of care (see, e.g., Johnson 2008), such as the therapeutic approach used by MAPS to treat patients with PTSD using MDMA (e.g., as described in Mithoefer 2017).

[0378] In some embodiments, the psychotherapy conducted with a disclosed compound is conducted in widely spaced sessions. These sessions can be as frequently as weekly but are more often approximately monthly or less frequently. In most cases, a small number of sessions, on the order of one to three, is needed for a patient to experience significant clinical progress, as indicated, for example, by a reduction in the symptoms of the mental health disorder being treated. In some embodiments, psychotherapy comprises multiple sessions, during some of which a disclosed compound is administered (“drug-assisted psychotherapy”); in others, the patient participates in psychosocial or behavioral therapy without concomitant administration of a drug, or without administration of a disclosed compound.

[0379] In some embodiments, a disclosed compound or composition is administered together with standardized psychological treatment or support, which refers to any accepted modality of standard psychotherapy or counseling sessions, whether once a week, twice a week, or as needed; whether in person or virtual (e.g., over telemedicine or by means of a web program or mobile app); and whether with a human therapist or a virtual or AI “therapist.” As used herein, “therapist” refers to a person who treats a patient using the disclosed compositions and methods, whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, although it will be understood that certain requirements will be appropriate to certain aspects of the drug-assisted therapy (e.g., prescribing, dispensing, or administering a drug, offering psychotherapeutic support). In some embodiments, a “person” may also include an AI.

[0380] In some embodiments, a patient will participate in a treatment protocol or a disclosed method, or be administered a disclosed composition as part of such a method, if the patient meets certain specified inclusion criteria, does not meet certain specified exclusion criteria, does not meet any specified withdrawal criteria during the course of treatment, and otherwise satisfies any requirements of a disclosed embodiment.

[0381] In some embodiments, where a disclosed composition is administered, such administration occurs without or with reduced risk of side effects that would require physician supervision, and therefore allow for treatment at home or otherwise outside of a clinic and without the need for such supervision, and / or additionally without the requirement of adjunctive psychotherapy or psychological support.

[0382] In some embodiments, the disclosed compositions may be administered in conjunction with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is neither necessitated nor desired, or no specific type of psychotherapy is necessitated or desired, however any of the disclosed methods can be 2024-03-01 used in combination with one or more psychotherapy sessions. The flexibility to participate in specific therapies, as well as to choose between any such therapies (or to decide to forgo any specific therapy), while still receiving clinically significant therapeutic effects, is among the advantages of the disclosure. Furthermore, a patient can participate in numerous other therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.

[0383] In embodiments, personalized approaches (“personalized” or “precision” medicine) may be used, based on individual characteristics, including drug metabolism (e.g., CYP2D6 or CYP3A4) or individual genetic variation. The term “genetic variation” refers to a change in a gene sequence relative to a reference sequence (e.g., a commonly-found and / or wild-type sequence). Genetic variation may be recombination events or mutations such as substitution / deletion / insertion events like point and splice site mutations.

[0384] In some embodiments, the genetic variation is a genetic variation in one or more cytochrome P450 (CYP or CYP450) enzymes that affects drug metabolism, including metabolism of a disclosed composition, and including CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5. Other examples of CYP enzymes include CYP1A1, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0385] In some embodiments, a disclosed composition is taken together with a compound that is metabolized by the same CYP enzyme(s) as the disclosed composition, so as to permit a lower dose to be taken, increase the effective bioavailability of one or both, or otherwise affect drug metabolism or pharmacokinetics. In some embodiments, the dose of a disclosed composition is adjusted, such as reduced, when administered to a subject known to be a poor metabolizer of an active compound in the composition (e.g., having a genetic variation in CYP2D6 and / or CYP3A4), or increased when administered to a subject known to be a rapid metabolizer. In some embodiments, a patient is tested using ordinary means known to those of skill to determine if the patient is a poor or rapid metabolizer for one or more such CYP enzymes.

[0386] In some embodiments, the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which has been implicated in mood and anxiety symptoms in humans. In another embodiment, the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs. The FKBP5 gene has been implicated in responses to stress and trauma, and such SNPs are correlated with 2024-03-01 susceptibility to certain depression, PTSD, and anxiety disorders. In some embodiments, the genetic variation is a genetic variation such as a SNP in a membrane transporter, such as SERT, DAT, NET, or VMAT. In some embodiments, the mammal being treated has altered epigenetic regulation of a gene, the expression of which is associated with a mental health condition or susceptibility to a mental health treatment, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.

[0387] In some embodiments, a genetic variation or altered epigenetic regulation of a gene is an inclusion criteria for the administration of a disclosed compound. In some embodiments, a genetic variation or altered epigenetic regulation of a gene is an exclusion criteria for the administration of a disclosed compound. ii. Neurodegenerative Disorders

[0388] In some embodiments, disclosed compounds are used to treat a neurodegenerative disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a neurodegenerative disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a neurodegenerative disorder.

[0389] The term “neurodegenerative disorder” refers to a class of progressive, chronic, and debilitating conditions characterized by the gradual loss of structure and function of neurons within the central nervous system (CNS) or peripheral nervous system (PNS). These disorders involve the degeneration, impairment, or death of neuronal cells, leading to a decline in cognitive, motor, and / or sensory abilities.

[0390] Neurodegenerative disorders can be classified according to primary clinical features, e.g., dementia, parkinsonism, or motor neuron disease, anatomic distribution of neurodegeneration, e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations, or principal molecular abnormality (Dugger B, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology.2017:9(7);a028035). T hese disorders may involve various etiologies, including but not limited to, presence of pathogenic proteins, age, environmental stressors, and genetic predisposition (Armstrong R. Folia Neuropathologica.2020:58(2);93-112).

[0391] In some embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis or Charcot’s disease, chronic traumatic encephalopathy, corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease or Parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury. iii. Pain and Inflammation

[0392] In some embodiments, the disclosed compounds are used to treat pain and / or inflammation, such as a pain disorder and / or an inflammatory disorder. In some embodiments, disclosed compounds are administered, such as in a pharmacologically effective amount, to a subject having pain and / or inflammation, 2024-03-01 thereby treating said pain and / or inflammation. In some methods, the disclosed compositions, when administered in a pharmacologically effective amount, provide beneficial therapeutic effects for the treatment of pain and / or inflammation.

[0393] In some embodiments, disclosed compounds are used to treat a pain disorder. In embodiments, the pain disorder is any of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesia, hyperalgesia, neuralgia, neuritis, neurogenic pain, phantom limb pain, analgesia, anesthesia dolorosa, causalgia, sciatic nerve pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorders, headache disorders, migraine headaches, chronic cluster headaches, concussion headache, short-lasting unilateral neuralgiform headache attacks, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, or pain associated with cancer.

[0394] In some embodiments, disclosed compounds are used to treat an inflammatory disorder. In some embodiments, the inflammatory disorder is characterized by inflammation of an organ or tissue. In embodi- ments, the inflammatory disorder comprises any one or more of skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, bladder inflammation, gastric inflammation, intestinal inflammation, neuroinflammation, and brain inflammation. In embodiments, the inflammatory disorder is a disorder that causes acute inflammation, or that exhibits chronic inflammation as a symptom. In some embodiments, the inflammatory disorder comprises chronic inflammation.

[0395] 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 to reduce inflammation. In some embodiments, the disclosed compounds, e.g., in a therapeutically effective amount, are administered to a subject to reduce inflammation.

[0396] The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Although the mechanism for serotonin modulators, such as 5-HT2A agonists and 5-HT2A antagonists, to ameliorate pain remains unclear, the synaptic plasticity associated with such compounds may alter pathologic changes in neural connections seen in chronic pain states, potentially resulting in a reduced pain intensity and duration (Castellanos et al. Reg Anesth Pain Med.2020;45(7):486-494). Additionally, 5-HT2AR activation has been shown to promote anti-inflammatory effects, e.g., a reduction of TNF-α-induced inflammation. See, e.g., Pelletier & Siegel. Mol Interv.2009;9(6):299-301; Flanagan et al. Sci Rep.2019;9(1):13444; Nichols et al. Clin Pharmacol Ther.2017;101(2):209-219; Flanagan & Nichols. Int Rev Psychiatry.2018;30(4):363-375; Okamoto et al. Neurosci.2005;130(2):465-74.

[0397] Pain, such as chronic pain, and improvements thereof, such as a reduction of symptoms, may be measured according to known methods, e.g., by subject reporting, pain diaries, pain scales, applicable questionnaires (assessments of chronic pain and its impact on physical, emotional and social functions), 2024-03-01 ecological momentary assessments and computerized versions thereof. See, e.g., Salaffi et al., Best Practice & Research Clinical Rheumatology, 2015; 29(1):164-186 and Hawker et al., Arthritis Care Res (Hoboken).2011;63 Suppl 11:S240-52. Exemplary questionnaires include the Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP), Migraine Diagnosis Questionnaire, the Migraine-Screen Questionnaire (MS-Q), the Fibromyalgia Survey Questionnaire (FSQ).

[0398] A reduction in inflammation, such as chronic systemic inflammation, may be measured according to various methods available to one of skill. Inflammatory biomarkers may be detected from biological specimens, for example, a subject’s blood, such as plasma or serum, or saliva. In one example, inflammation may be detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell count from a blood test. CRP may also be detected in a saliva sample. Salivary CRP is not synthesized locally in the mouth and may reflect more systemic levels of inflammation compared to other inflammatory biomarkers, such as cytokines (Szabo & Slavish, Psychoneuroendocrinology.202;124:105069). Additionally clinical pathology data, e.g., hematology data on erythrocyte parameters, platelet count, total number of leukocytes, and leukocyte differentials and morphology, coagulation data on clotting times and fibrinogen, and clinical chemistry data on total protein, albumin and globulin, liver enzymes, renal parameters, electrolytes, and bilirubin can provide an initial indication of the presence and potentially the location of inflammation, in the absence of specific data on immune tissues. See, e.g., Germolec et al., Methods Mol Biol.2018;1803:57-79 and Luo et al., Clin Lab.20191;65(3). F. Examples

[0399] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure. Example 1: Synthesis of 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-2-(methylamino) propan-1-one (Compound 1-1) i: bromine, DCM; ii: methylamine in H2O:EtOH

[0400] Step 1: 2-bromo-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propan-1-one ( B )

[0401] A 25 mL Erlenmeyer flask was equipped with a magnetic stirrer, to which 0.097 g (0.45 mmol) of A and 5 mL of dichloromethane (DCM) were added. As the solution was stirred, 0.023 g of bromine was added slowly by micropipette. The reaction was stirred for 10 minutes, and the orange color of bromine disappeared. Analysis of the reaction by GC-MS showed 95% completion. The reaction was quenched with 2024-03-01 1 mL of saturated aqueous NaHCO3. The solution was transferred to a test tube and the Erlenmeyer flask was washed with 1 mL dichloromethane, which was added to the test tube. The organic layer was separated by Pasteur pipette and dried over Na2SO4. Air evaporation of the solvents yielded a yellow residue remaining in the test tube.

[0402] Step 2: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-(methylamino)propan-1-one ( 1-1 )

[0403] The product ( B ) was used from the previous step without further purification. Absolute ethanol (1 mL) and a magnetic stir bar were added to the test tube containing B . A solution of 40% methylamine in water (0.07 g) was added to 1 mL absolute ethanol and the resulting solution was slowly added to the test tube with stirring. The reaction was stirred for 2 hours then analyzed by GC-MS. At 2 hours, the complex mixture contained six major peaks and two minor peaks. The product peak ( 1-1 ) comprised 36.3% of the total area. GC-MS: m / z 185 (M+, 13.7%), 157 (6.5), 91 (11.4), 63 (19.6), 58 (100), 56 (30.7). Example 2: Synthesis of 2-(Diethylamino)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) propan-1-one (Compound 1-104) i: bromine, cat. AcOH, DCM; ii: diethylamine

[0404] Step 1: 2-bromo-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propan-1-one ( B )

[0405] Added 3.07 g (14.33 mmol) of A , followed by 25 mL of dichloromethane, to a 125 mL Erlenmeyer flask equipped with a magnetic stir bar. The solution was stirred and cooled to 0 °C with an ice bath and 5 drops of acetic acid were added. A solution of 20% bromine in dichloromethane (12.4 g) was prepared. This was added slowly in portions of 1 mL, allowing the orange bromine color to dissipate between additions. The first addition required 15 minutes to go colorless, with subsequent additions finished over 10 minutes. A total of 11 g of the bromine solution was used. Stirring continued an additional 15 minutes when GC-MS analysis showed 98.5% product. An additional 0.5 g of the 20% dichloromethane and bromine solution was added, and the reaction was stirred for 10 minutes with no change in the persisting orange color. The reaction was quenched with 50 mL saturated NaHCO3. An additional 25 mL of dichloromethane was added, and organics were separated with a separatory funnel. The organic layer was washed once more with 75 mL saturated NaHCO3, separated, and dried over Na2SO4. The dried solution was filtered then organics were removed in vacuo to yield a light yellow liquid. After 4 hours of drying under high vacuum, the final mass was 4.01 g. GC-MS: m / z 294 (M+, 1.6%), 292 (1.7), 185 (100), 157 (12.1), 119 (5.2), 91 (17.3), 63 (16.3).

[0406] Step 2: 2-(diethylamino)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propan-1-one ( 1-104 )

[0407] A 25 mL Erlenmeyer flask was equipped with a magnetic stirrer, then 0.30 g (1.02 mmol) of B and 10 mL of dichloromethane were added with stirring. Diethylamine (0.212 mL) was added slowly by 2024-03-01 micropipette and the reaction was covered and stirred overnight. After 18 hours, the solution was slightly yellow. GC-MS analysis showed 2 major peaks and one minor peak. The two major peaks corresponded to the product and starting material, comprising 46.9% and 48.5% of the total area, respectively. After 21 hours, the ratio had risen to 54.2% product and 43.8% starting material. After 6 days, the solution was orange and there were 3 major peaks: starting material, product ( 1-104 ), and an unknown, comprising 16.2%, 36.8% and 34.8% of the total peak area, respectively. The mixture was chromatographed through basic alumina using dichloromethane, resulting in the removal of orange color. GC-MS: m / z 185 (M+, 9.7%), 157 (6.9), 100 (100), 91 (12.6), 72 (9.5), 63 (14.3), 56 (8.9). Example 3: Synthesis of 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)propan-2-amine HCl (Compound 1-19) i: nitroethane / acetic acid / cyclohexylamine; ii: NaBH4 / CuCl2 / 2:1 isopropyl alcohol:H2O; iii: 1 M HCl in Et2O

[0408] Step 1: (E)-2,2-difluoro-5-(2-nitroprop-1-en-1-yl)benzo[d][1,3]dioxole ( D )

[0409] Added 2.5 g (13.43 mmol) of C and 10 mL of nitroethane to an Erlenmeyer flask fitted with a magnetic stirrer and an air-cooled Vigreaux column. Added 0.2 mL of cyclohexylamine and 0.2 mL of acetic acid by micropipette. The reaction was heated to reflux for 1.5 hours. The solvent was removed in vacuo and the residue suspended in 50 mL Et2O. The organic layer was washed twice with 0.1 N HCl and twice with 0.1 N NaOH. The organic layer was dried over Na2SO4, then filtered. The solvent was removed in vacuo to yield a yellow oil that solidified upon freezing at -20 °C. The yellow solid was recrystallized from 10 mL MeOH, suction filtered, and washed with cold MeOH to yield 1.85 g of D as a yellow crystalline solid. GC-MS: m / z 243 (M+,17%), 196 (31), 185 (12), 103 (100), 77 (60), 63 (27), 51 (30).

[0410] Step 2: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propan-2-amine hydrochloride ( 1-19 )

[0411] Dissolved 2.68 g of D in a solution of 40 mL isopropyl alcohol and 20 mL water in a 125 mL Erlenmeyer flask fitted with a magnetic stirrer and an air-cooled Vigreaux condenser. Added 3.13 g of NaBH4in portions, letting the effervescence subside between additions. Added 0.5 mL of a 2 M solution of CuCl2, which immediately formed black solids. The reaction was refluxed and monitored by gas chromatography. An additional 0.2 mL of the CuCl2solution was added and the mixture was stirred overnight. The next day the mixture was heated to reflux for 2 hours. Gas chromatography showed mostly product. The reaction was cooled and suction filtered. Added 20 mL of 32% w / w NaOH to the filtrate and the organic layer was separated. The organic layer was dried over Na2SO4, suction filtered, and the solvent was removed in vacuo to give a brown oil. The brown oil was taken up in 100 mL Et2O and filtered, removing a light yellow solid. The ether solution was treated with 3 mL of 1 M HCl in Et2O, causing a white precipitate to form. The 2024-03-01 precipitate was suction filtered and washed with ether, then suction dried to yield 0.441 g of 1-19. GC-MS: m / z 214 (M-1+, 4%), 200 (M+, 11%), 196 (9), 171 (45), 105 (28), 77 (85), 63 (28), 51 (100). LC-MS: 3.89 min, m / z 215.9313 (M+1, 100). Example 4: In Vitro Receptor and Transporter Interactions

[0412] Purpose: A comprehensive study is conducted to profile the interactions of disclosed compounds with various receptors, transporters, and ion channels. Comparisons may then be made regarding the pharmacological activity of a fluorinated and / or deuterated compound and its non-fluorinated and / or non-deuterated comparator, among other empathogens. Among other targets, activity is assessed at serotonin receptors HTR1A, HTR1B, HTR2A, HTR2B, HTR5AHTR6HTR7D, monoamine transporters DAT, NET, and SERT, and the nicotinic acetylcholine receptor nAChR (a4 / b2).

[0413] Methods - Arrestin: Activation of HTR5Aand HTR6, are determined using the PathHunter® β-Arrestin assay. The assay monitors restoration of β-galactosidase (β-Gal) as a marker of GPCR activation and recruitment of β-Arrestin to the receptor.

[0414] To determine agonistic activity, cells are expanded from freezer stocks, seeded into multi-well plates, and incubated at 37 °C prior to addition of a test compound.3.5 μL of concentrated sample is added to cells and incubated at 37°C or room temperature for 90 to 180 minutes. Vehicle concentration is 1%.

[0415] Assay signal is generated through a single addition of 50% v / v of PathHunter Detection reagent cocktail, followed by a one hour incubation at room temperature. Microplates are read following signal generation with a plate reader set to detect chemiluminescent signals. Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA).

[0416] Percentage activity can be calculated using the following formula:

[0417] % Activity =100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control).

[0418] Methods - cAMP: Activation of HTR7Dand GRM2 is determined using the Hit Hunter® cAMP assay. The assay monitors the activation of a GPCR via Gi and Gs secondary messenger signaling, using β-Gal as a functional reporter.

[0419] To determine agonistic activity at Gi / Gs, cells are expanded from freezer stocks, seeded into multi-well plates, and incubated at 37°C prior to addition of a test compound. To determine Gi / Gs agonism, media is aspirated from cells and replaced with 15 μL 2:1 HBSS / 10mM HEPES:cAMP XS+Ab reagent. Concentrated (4X) test compound in assay buffer is added to cells and incubated at 37°C or room temperature for 30 or 60 minutes. For Gi agonist activation, cells are incubated with EC80 forskolin in addition to a test compound. Vehicle concentration is 1%.

[0420] Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA). For Gs agonist mode assays, percentage activity can be calculated using the following formula:

[0421] % Activity =100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX 2024-03-01 control - mean RLU of vehicle control).

[0422] For Gi agonist mode assays, percentage activity can be calculated using the following formula:

[0423] % Activity = 100% x (1 - (mean RLU of test sample - mean RLU of MAX control) / (mean RLU of vehicle control - mean RLU of MAX control)).

[0424] Methods - Calcium Mobilization: GPCR activity of serotonin receptor 2 (e.g., HTR2A, HTR2B, HTR2C), among others, is measured using the Calcium No WashPLUS assay, which monitors calcium mobilization in cell lines expressing Gq-coupled GPCRs by loading a calcium-sensitive dye into cells. Administration of a compound may result in the release of calcium from intracellular stores and an increase in dye fluorescence that can be measured.

[0425] Cell lines are expanded from freezer stocks and seeded into multi-well microplates. Then, the plates are incubated at 37ºC for an appropriate amount of time and loaded with Dye Loading buffer. To determine compound agonist activity, cells are incubated with the sample to induce a response, and HBSS / 20 mM Hepes is added using a FLIPR Tetra (MDS). Activity is measured on a FLIPR Tetra. Calcium mobilization is monitored for 2 minutes.

[0426] To determine compound antagonist activity, cells are pre-incubated with the sample followed by an post-incubation administration of the compound with 3X EC80 agonist using FLIPR. Compound antagonist activity is measured on a FLIPR Tetra (MDS) and calcium mobilization is monitored for 2 minutes.

[0427] Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA). For agonist mode assays, percentage activity can be calculated using the following formula:

[0428] % Activity = 100% x (mean RFU of test sample - mean RFU of vehicle control) / (mean MAX RFU control ligand - mean RFU of vehicle control).

[0429] For antagonist mode assays, percentage inhibition can be calculated using the following formula:

[0430] % Inhibition = 100% x (1 - (mean RFU of test sample - mean RFU of vehicle control) / (mean RFU of EC80 control - mean RFU of vehicle control)).

[0431] Methods - Monoamine Transporter Assay: Neurotransmitter uptake via transporters is measured using the Neurotransmitter Transporter Uptake Assay Kit from Molecular Devices. Dopamine, norepinephrine or serotonin transporter activity in cells is detected using a homogeneous fluorescence based assay. Increased intracellular fluorescence intensity following uptake of biogenic amine neurotransmitters via transporters is measured and can be run in a kinetic or endpoint mode.

[0432] To determine percentage inhibition of neurotransmitter uptake via transporter, cell lines are expanded from freezer stocks, seeded into a multi-well microplate, and incubated at 37ºC. Then, the compound is administered and the mix is incubated again. Following compound incubation, dye is added to the wells and the plates are re-incubated. Microplates are then transferred to a PerkinElmer EnvisionTM instrument for fluorescence signal detection.

[0433] Compound activity is analyzed using CBIS data analysis (ChemInnovation, CA). For blocker mode 2024-03-01 assays, percentage inhibition can be calculated using the following formula:

[0434] % Inhibition = 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of positive control - mean RLU of vehicle control)).

[0435] Methods - Ion Channel Assay: Membrane potential changes are measured using the FLIPR® Membrane potential Assay Kit. A fluorescent indicator dye in combination with a quencher is used to reflect real-time membrane potential changes associated with ion channel activation and ion transporter proteins.

[0436] To determine agonist and antagonist activity, cell lines are expanded from freezer stocks, seeded into multi-well microplates, and incubated at 37 ºC. Cells are then loaded with dye and incubated again.

[0437] For agonist determination, cells are incubated with the sample a different dilutions to induce a response. For antagonist determination, cells are pre-incubated with the sample at different dilutions. Following dye administration, the sample is added to the cells in the presence of EC80 agonist and then re-incubated at room temperature in the dark.

[0438] Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA). For agonist mode assays, percentage activity can be calculated using the following formula:

[0439] % Activity = 100% x ( mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control).

[0440] For antagonist mode assays, percentage inhibition can be calculated using the following formula:

[0441] % Inhibition = 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of EC80 control - mean RLU of vehicle control)). Example 5: In Vitro Activity at Trace Amine-Associated Receptor 1 (TAAR1)

[0442] Purpose: To assess the activity of disclosed compounds at trace amine-associated receptor 1, a target of psychoactive substances. See, e.g., Rickli et al. Neuropsychopharmacology. 2016;26(8), 1327–1337, Simmler et al. Br J Pharmacol.2013;168(2):458–470, and Simmler et al. J Pharmacol Exp Ther. 2016;357(1):134-144.

[0443] Methods: A radioligand binding assay is performed according to previously described methods, for example, by Rickli et al., Neuropsychopharmacology, 2016;26(8), 1327–1337, using [3H] RO5166017 as a radiolabel and RO5166017 as a competitor. Briefly, membrane preparations of human embryonic kidney (HEK) 293 cells that overexpress TAAR1 receptors, for example, of human origin (Revel et al., PNAS, 2011;108:8485–8490) are incubated with the radiolabeled selective ligand at concentrations equal to Kd. Ligand displacement by the compounds is then measured. Specific binding of the radioligand to the target receptor is defined as the difference between the total binding and nonspecific binding that is determined in the presence of selected competitors in excess.

[0444] Results & Significance: Activation of TAAR1 has been shown to modulate monoaminergic neurotransmission. See, e.g., Revel et al., PNAS.2011;108(20):8485–8490. TAAR1 may be a promising target for the treatment of neuropsychiatric disorders. For example, the effects of TAAR1 activation on 2024-03-01 dopaminergic neurotransmission may provide therapeutic benefit for addiction, such as substance use disorders (Liu & Li, Front Pharmacol.2018;9:279). Example 6: In Vitro Metabolic Stability

[0445] Purpose: To determine the metabolic stability of a disclosed compound relative to its corresponding non-fluorinated analog. Metabolic stability assays measure the intrinsic clearance (CLint) of a compound, providing critical data needed to calculate other key pharmacokinetic parameters such as bioavailability and half-life (t1 / 2).

[0446] Methods: A high-throughput assay is used to determine metabolic stability of disclosed fluorinated and / or deuterated compound and its non-fluorinated and / or non-deuterated analogs thereof in human liver microsomes. LC / MS analysis is used to quantify the percent compound remaining after incubation. The half-life (t1 / 2) is estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) versus time, assuming first order kinetics.

[0447] Results & Significance: Disclosed compounds may exhibit comparable or substantially higher metabolic stability relative to a comparator lacking fluorination and / or deuteration. Example 7: In Vitro Metabolic Profiling

[0448] Purpose: To determine whether the disclosed compounds are metabolized and to identify metabolites thereof.

[0449] Methods: An in vitro study is conducted to evaluate metabolism and metabolites of disclosed compounds in human liver microsomes, such as S9 hepatocytes. Briefly, disclosed compounds are incubated with human liver microsomes and / or various recombinant enzymes to determine metabolism and formation of metabolites. Following incubation, the supernatant is analyzed directly by ultra-high performance liquid chromatography-mass spectrometry.

[0450] Phase I and / or Phase II metabolites are identified using mass spectrometry (MS). The % compound remaining and half-life of the disclosed compound (parent compound) are determined. MS data, such as extracted ion chromatograms, show parent and major metabolites. Metabolic transformation for each observed metabolite is elucidated, and metabolite masses, peak areas, and retention times are determined. Metabolic profiling may also be conducted according to the methods described in Muller & Rentsch, Anal Bioanal Chem.2012;402:2141–2151 and Pedersen et al. Drug Metab Dispos.2013;41:1247–1255.

[0451] Results & Significance: Compounds that undergo metabolism in vivo may produce pharmacologically active or chemically reactive metabolites that produce unexpected effects or potential toxicities. The FDA Guidance for Industry on Safety Testing of Drug Metabolites highlights the relevance of in vitro metabolite profiling early in drug development, as metabolites which are unique to or disproportionate in humans may require additional toxicological studies. Example 8: In Vitro CYP Enzyme Inhibition

[0452] Purpose: To assess the interactions between disclosed compounds and cytochrome P450 2024-03-01 (CYP450) enzymes. Such interactions will provide insight into metabolism-mediated drug-drug interactions, which can occur when a compound affects the pharmacokinetics, such as the absorption, distribution, metabolism, and excretion, of simultaneously administered drugs by altering the activities of drug metabolizing enzymes and / or drug transporters.

[0453] Methods: An in vitro study is conducted to assess the inhibitory effect of the disclosed compound on recombinant human CYP450 isoenzymes. Recombinant human CYP450 isoenzymes are used to metabolize pro-fluorescent probe substrates to fluorescent products. Inhibition of human P450 isoforms is measured by reduced fluorescence following treatment with the disclosed compound at various concentrations.

[0454] Briefly, the disclosed compound is incubated in different concentrations in a mix containing buffer, enzymes, and substrate. Then, fluorescence is measured using a plate reader and percentage inhibition may be extrapolated out from the readings. Alternatively, the inhibitory effects of the disclosed compound on CYP enzymes may be assessed using high-performance liquid chromatography. Inhibition is evaluated using the Michaelis-Menten method. CYP enzyme inhibition may be conducted according to the methods described in Lin et al., J Pharm Sci. 2007;96(9):2485-95 and Wójcikowski et al., Pharmacol Rep. 2020;72(3):612-621.

[0455] Results & Significance: Metabolizing enzymes in the liver, such as CYP450 enzymes, are responsible for the majority of drug metabolism that occurs in the body. Six CYP450 class enzymes metabolize 90 percent of drugs, and two of the most significant metabolizers are CYP3A4 and CYP2D6 (Lynch & Price, Am Fam Physician.2007;76(3):391-6). Compounds can interact with such enzymes by inhibiting their enzymatic activity (CYP inhibition) or by inducing their gene expression (CYP induction).

[0456] For context, MDMA has been shown to inhibit CYP2D6. See, e.g., Heydari et al., Drug Metab Dispos.2004;32(11):1213-7. CYP2D6 plays a role in both major and minor routes of MDMA metabolism, O-demethylation forming (6)-3,4-dihydroxymethamphetamine (HHMA) and N-demethylation resulting in (6)-3,4-methylenedioxyamphetamine (MDA), respectively. Example 9: In Vitro Evaluation of Membrane Permeability and Interactions with P-Glycoprotein (P-gp) in MDCKII MDR1 Cells

[0457] Purpose: To assess the permeability and transport liability of disclosed compounds. Permeability is assessed using MDCK (Madin-Darby canine kidney) cells, and the effects of P-glycoprotein (P-gp) are evaluated to determine drug transport.

[0458] Methods: A bidirectional permeability study (apical to basolateral [AB] and basolateral to apical [BA]) is conducted to evaluate the apparent permeability of the compound. Additionally, an evaluation to determine if the compound acts as a P-gp substrate in MDCKII-MDR1 and mock MDCKII cell lines is performed.

[0459] Briefly, the disclosed compound and reference compounds are evaluated in two directions in the absence and presence of a P-gp inhibitor. The MDCKII and MDCKII-MDR1 cells are incubated in a transport 2024-03-01 buffer on both apical [A] and basolateral [B] sides. Then, the disclosed compound is added to each side of the cells and incubated. The rate of transport of the disclosed compound is determined in the absence or presence of a P-gp inhibitor. Following incubation, where the disclosed compound will permeate the cells in both AB and BA directions, the permeability of the cells is measured using a LC MS / MS system. The efflux ratio of the disclosed compound is calculated to determine if it is a P-gp substrate.

[0460] Results & Significance: This screening provides insight into the movement of the compound in a biological system. Compounds are classified as follows (Cambridge MedChem Consulting, ADME, 2019):

[0461] Mass balance as a percentage (%) is calculated using the following equation: %Recovery = 100 x (CD(t) + CR(t)) / C0

[0462] Where CD(t) is the measured concentration in the donor well at time t (expressed as IS ratio), CR(t) is the measured concentration in the receiver well at time t (expressed as IS ratio), C0is the initial concentration in the donor solution (expressed as IS ratio).

[0463] The percentage of cell integrity is calculated using the following equation: %Integrity = 100 x [1-RFUbasolateral / RFUapical]

[0464] LY RFU values are normalized by background mean values. A test item is considered to be a P-gp substrate when the efflux ratio in the absence of the inhibitor is >2 and if the ratio is significantly reduced in the presence of a P-gp inhibitor. Example 10: Effects of Compounds on Fear Extinction Plasticity and Dendritic Architecture in Mice

[0465] In this study, the effects of disclosed compounds are assessed in a rodent in vivo model. Multiple conditions are tested: disclosed compounds, in both chronically exposed vs treatment naive groups (e.g., imipramine, or other antidepressant / anxiolytic agents); a positive control (e.g., another antidepressant / anxiolytic agent); and a vehicle control (saline). Disclosed compounds are assessed at multiple dosage levels. Plasticity-enhancing effects of administering a single dose of each compound on fear extinction behavior is also determined. Then, longitudinal effects of administering a single dose of each compound on the density and turnover of dendritic spines is determined using 2-photon imaging microscopy (Shao et al. Neuron.2021;109(16):2535-2544).

[0466] Fear Extinction Plasticity: Neural plasticity may promote alterations in emotional learning. Fear extinction is a behavior in which repeated exposure to an associated fear learning stimulus can reduce the intensity of the fear response, and which may be related to the mechanism of action of disclosed compounds 2024-03-01 in reducing anxiety or fear. In this study, the rate of fear extinction is determined after administration of either saline (control) or a disclosed compound in adult mice, with 10 mice tested per compound. Briefly, each mouse receives tone-shock pairing (day 1) then on a subsequent day they receive a single administration of either saline (control) or a disclosed compound, 30 minutes prior to re-exposure to the fear associated stimulus (day 2). On day 3, fear extinction learning is tested by re-exposing mice again to the associated tone in a fear conditioning apparatus. Fear extinction serves as a model for ameliorating anxiety- and fear-related behaviors in psychiatric disorders and may serve to identify separable behavioral effects from hallucinogenic effects. The circuit mechanisms of potential plasticity enhancement are subsequently addressed in two-photon imaging experiments.

[0467] Long-Term Effects on Dendritic Remodeling: In this study, dendritic spine turnover in medial frontal cortex is determined for either saline (control) or a disclosed compound in adult mice, with 5 mice tested per condition. Thyl-GFP-M transgenic mice are used, because a sparse subset of cortical pyramidal neurons expresses enhanced green fluorescent protein, allowing for visualization of their dendritic architecture. Each mouse receives a single administration of either saline (control) or a disclosed compound. Using a two-photon microscope, dendritic spines in the distal apical tuft branches are imaged and are tracked for 7 sessions at -3, -1, 1, 3, 5, 7, and ~30 days from the day of administration. Imaging the same sets of spines longitudinally allows the determination of the number density of dendritic spines, and also the turnover dynamics including the rates of spine formation and elimination, as well as the fraction of newly formed spines that remain persistent indicating the maturation of a new functional synapse. Results may demonstrate that disclosed compounds are suitable for treating certain neuropsychiatric illnesses. Example 11: Zebrafish Models of Neuropsychiatric Illnesses

[0468] Because of their physiological (neuroanatomical, neuroendocrine, neurochemical) and genetic homology to mammals, robust phenotypes, and value in high-throughput genetic and chemical genetic screens, zebrafish are ideal for developing valid experimental models of major depression, anxiety, and pain disorders to discover novel therapeutics. Behavioral testing approaches, such as approach-avoidance, cognitive, and social paradigms, are available in zebrafish and are useful for identifying depression-like indices in zebrafish in response to physiological, genetic, environmental, and / or psychopharmacological alterations. In addition, the high sensitivity of zebrafish to commonly prescribed psychoactive drugs support the use of this model as a tool for pharmacological research and drug screening. Possessing a fully characterized genome, both adult and larval zebrafish are currently widely used for in vivo screening of various psychoactive medicines.

[0469] Zebrafish Reserpine-induced Depression Model: As a specific inhibitor of monoamine transporters, reserpine is known to deplete monoamine neurotransmitters and cause decreased swimming distance and average velocity (hypoactivity), and reduced response to both visual and sound stimuli. Reserpine induces depression-like behavior both in adult zebrafish and in larvae; this is used herein as an assay for assessing 2024-03-01 the effects of disclosed compounds on these despair-like states. A camera algorithm, Histogram of Oriented Gradient (HOG), analyzes the depression and hypoactivity behavior of zebrafish shoaling to achieve accuracy that is not possible for the human observer.

[0470] Zebrafish Anxiety Disorder Models: Many behaviors including anxiety, fear, and stimuli dependent learning can be assessed as early as free-swimming larval stages, whereas social behavior like shoaling and directed aggression develop with age. Several anxiety tests are done, sequentially or in combination, including an elevated plus maze, novel tank, light-dark box, and open-field test. Known anxiolytic drugs such as benzodiazepines are used as positive controls to assess a disclosed compound’s effects on levels of diving and exploration behavior, thigmotaxis, hyperactive swimming, erratic swimming, freezing, or avoidance of bright area in adults (scototaxis) and dark area in larval fish. Example 12: Rodent Models of Neuropsychiatric Illnesses

[0471] This Example presents rodent models for several neurological and psychiatric conditions that are used to demonstrate the efficacy of disclosed compounds. Primate and rodent models have been traditionally used to study cellular mechanisms and neural circuits of psychoactive drug action.

[0472] Depression: Forced Swim Test (FST): The Forced Swim Test (FST) is a classic, and the most used preclinical behavioral assay to screen compounds with antidepressant-like activity and has high predictive and face validity (Porsolt et al. Nature. 1977;266:730-732; Borsini and Meli Psychopharmacol. 1988;94:147-160). The premise of the FST is that when rats are placed into a cylinder filled with water, they will initially try to escape, but over time will become immobile. This increased immobility reflects behavioral despair, modeling a depressive-like state. A broad range of antidepressant treatments has been shown to consistently reduce immobility time, with the observation that increases in swimming or climbing correlate with serotonergic or noradrenergic activity, respectively (Detke et al. Psychopharmacol.1995;121:66-72).

[0473] Anxiety: Open Field Test (Time Spent in the Center vs. Periphery): This behavioral assay, also widely used as an anxiety paradigm, capitalizes on a rodent’s innate fear of brightly lit open spaces, which are assumed to induce fear or anxiety. Rodents spend more time hugging the walls of the open field during the test, and these effects correlate to underlying brain regions and mechanisms.

[0474] Consecutive beam breaks and / or video-tracking of time spent in the center versus the periphery of the open field are measured. Also measured are parameters such as distance traveled and ambulatory activity (horizontal and vertical) for the duration of the test session.

[0475] Anxiolytics such as diazepam increase time spent (and / or distance traveled) in the center of the open field independent of changes in locomotion, used as positive control to assess a disclosed compound’s effect on these parameters.

[0476] Anxiety: Elevated Plus Maze: This behavioral assay, widely used as an anxiety paradigm, is based on unconditioned responses of rodents to a potentially dangerous environment: maze height, luminosity, and open space are assumed to induce fear or anxiety, and to correlate to underlying brain regions and 2024-03-01 mechanisms. Video-tracking of time spent in the open arms of the maze to the closed arms, for 5 min starting at the junction. Other ethological parameters include rears, dips, and stretched-attend postures. An anxiolytic (e.g., diazepam) that increases time spent in open arm activity (duration and / or entries) without decreasing locomotion is used as a positive control to assess a compound’s effect on these parameters.

[0477] Modified Geller Seifter Conflict Test: Rats are trained to lever-press for food under a multiple variable interval-fixed ratio (food; food + shock) schedule of reinforcement. This task generally exhibits good predictive validity for anxiolytic-like compounds, such as diazepam, which increase punished responding (i.e., antagonize response suppression in the punished period). It also exhibits selectivity for anxiolytics, with apparently no effects in other classes and can assess a disclosed compound’s anxiolytic effect with a positive control such as bupropion. Example 13: Clinical Assessment of Compounds for Treating Mental Health Disorders

[0478] This Example provides an illustrative clinical study design for assessing the safety, tolerability, and efficacy of a disclosed compound for treating certain mental health disorders, when administered by a medical practitioner in an outpatient therapy setting.

[0479] Study Design: Archival clinical data is obtained from patients with a primary diagnosis of a mental health disorder (e.g., depression, PTSD) who receive one or more administrations of a disclosed compound as part of specialty care in an outpatient psychiatric setting. No protected health information is disclosed and no consent is obtained from patients for the use of their archival data. Case narratives are systematically compiled from data collected as part of routine clinical work. Diagnoses are confirmed by an experienced clinician using semi-structured interviews. The study population comprises two groups:

[0480] Cohort 1: a healthy population providing information on safety and tolerability of a disclosed compound administered in a single dosing session.

[0481] Cohort 2: a population comprising subjects with a diagnosis of interest (e.g., PTSD, MDD). Cohort 2 is evaluated at baseline using the Clinical Global Impression-severity (CGI-S) assessment; and post-dosing using the Clinical Global Impression-Improvement (CGI-I), as described in more detail below, compared to baseline CGI-S established prior to first dosing. CGI-S scale is also evaluated in a subset of patients from Cohort 2 post-treatment. Cohort 2 is evaluated for any observed or reported safety events following a single dosing session.

[0482] Clinical Global Improvement Scale: The Clinical Global Impressions (CGI) scale includes 2 components: CGI-S (“severity”) and CGI- I (“improvement”).

[0483] CGI-S Guidelines:

[0484] 1 = Normal — not at all ill, symptoms of disorder not present past seven days

[0485] 2 = Borderline mentally ill — subtle or suspected pathology

[0486] 3 = Mildly ill — clearly established symptoms with minimal, if any, distress or difficulty in social and occupational function 2024-03-01

[0487] 4 = Moderately ill — overt symptoms causing noticeable, but modest, functional impairment or distress; symptom level may warrant medication

[0488] 5 = Markedly ill — intrusive symptoms that distinctly impair social / occupational function or cause intrusive levels of distress

[0489] 6 = Severely ill — disruptive pathology, behavior and function are frequently influenced by symptoms, may require assistance from others

[0490] 7 = Among the most extremely ill patients — pathology drastically interferes in many life functions; may be hospitalized

[0491] CGI-I Guidelines:

[0492] 1 = Very much improved — nearly all better; good level of functioning; minimal symptoms; represents a very substantial change

[0493] 2 = Much improved — notably better with significant reduction of symptoms; increase in the level of functioning but some symptoms remain

[0494] 3 = Minimally improved — slightly better with little or no clinically meaningful reduction of symptoms. Represents very little change in basic clinical status, level of care, or functional capacity

[0495] 4 = No change — symptoms remain essentially unchanged

[0496] 5 = Minimally worse — slightly worse but may not be clinically meaningful; may represent very little change in basic clinical status or functional capacity

[0497] 6 = Much worse — clinically significant increase in symptoms and diminished functioning

[0498] 7 = Very much worse — severe exacerbation of symptoms and loss of functioning

[0499] Dose and Regimen:

[0500] Cohort 1: Subjects in Cohort 1 are dosed in a group setting during a single session with a total dose of a disclosed compound of from about 790 mg to 870 mg, administered in a regimen of an initial dose of 280 mg, followed by three booster doses of about 190 mg to 220 mg, about 190 mg to 220 mg, and about 130 mg to 200 mg.

[0501] Cohort 2: The total dose of a disclosed compound at each session has a minimum range of about 100 mg to 690 mg and a maximum range of about 180 mg to 1020 mg. The initial dose ranges from about 100 to 270 mg, and the booster doses have a total cumulative dose that ranges from about 50 mg to 880 mg. Individual booster doses have a minimum range of about 50 mg to 240 mg and a maximum range of about 80 mg to 250 mg.

[0502] Safety: For all subjects in Cohorts 1 and 2, no serious adverse effects or after-effects are expected, although minor adverse effects may occur, such as lightheadedness, sleeplessness, loss of appetite, and minor disturbances to ordinary patterns of thought.

[0503] Results: Disclosed compounds are expected to produce acute and enduring improvements in both PTSD and depression symptoms, without any notable lasting adverse effects. All patients in Cohort 2 are 2024-03-01 expected to achieve at least minimal improvement (CGI-3 or better) following treatment with a disclosed compound. In some embodiments, CGI-I 1 or 2 is achieved in at least 80% of the subjects, corresponding to “much improved” or “very much improved” compared to baseline CGI-S. Additionally, in some embodiments, initial improvement is achieved with the first dosing session in about 90% or more of subjects. In some embodiments, subjects experience initial improvement following the 2nd and / or 3rd sessions, and in few cases, may require 10+ sessions for initial improvement. The durability of the improvements may last for at least one week, two weeks, three weeks, one month, two months, three months, or greater than three months. It is expected that some subjects may no longer qualify for clinical diagnosis of the disease (e.g., PTSD) following one, two, three, four, five, or more than five dosing sessions. Example 14: Assessment of Antidepressant Effects of Disclosed Compounds in a Forced Swim Test

[0504] In this Example, whether a disclosed compound can produce a fast-acting antidepressant-like effect in the rat forced swim test (FST) is investigated and the prototypical selective serotonin reuptake inhibitor (SSRI) fluoxetine is used as an antidepressant control. Methods :

[0505] Animals: Male Sprague Dawley rats (Charles River Laboratories) are used for this study. Rats are acclimated to their home cages for at least one week before testing, and are maintained in a controlled environment on a 12 h light / dark cycle with no more than 2 rats per cage. Animals receive ad libitum access to food and water and are assigned randomly to treatment groups. Animal use and procedures are in accordance with established protocols.

[0506] Forced Swim Test (FST): In the FST trial, rats are placed in a circular plexiglass container filled with water, with no means of escape. Water temperature is maintained at 22-25 °C and changed for every animal. After an acclimation period, rats are timed for inactivity (failure to struggle), activity, swim time and climbing time. Day 1 consists of a 15 min acclimation trial, and Day 2 (24 h later) consists of the 5 min test. A time sampling procedure is employed where animals are observed every 5 sec and scored for immobility, swimming, or climbing. Fluoxetine (10 mg / kg, IP, Sigma Aldrich) or 0.9% sterile saline vehicle are administered 23.5, 5, and 1 h before testing in the FST. A disclosed compound is administered (at multiple doses, e.g., 5, 15, or 30 mg / kg, IP) 30 min prior to FST testing. The control (0.9% saline vehicle) is also administered 30 min prior to FST testing. The experimenter is blinded to treatment.

[0507] Statistical Analysis: Data for each parameter of the test (immobility, swimming, or climbing) is expressed as the mean ± SEM. Differences between groups are determined by one-way ANOVA and post-hoc Tukey’s test with a p-value of less than 0.05 indicating statistically significant differences. Results and Conclusions:

[0508] A single dose of a disclosed compound is expected to produce a robust, dose-dependent and fast-acting antidepressant-like response in the rat FST. Notably, 2-3 injections of an SSRI antidepressant are 2024-03-01 generally required to elicit a behavioral response in the FST, which is expected to be demonstrated by the fluoxetine control group in the current study that receives 3 doses of fluoxetine prior to testing. However, rats treated with a single dose of a disclosed compound 30 minutes before testing in the FST are expected to show highly significant reductions in immobility. Mid and high doses of a disclosed compound are expected to significantly increase swimming. Climbing is expected to increase only at the lowest dose of a compound.

[0509] The magnitude of the effects of mid and high doses of disclosed compounds is expected to be greater than fluoxetine. Results may also show that disclosed compounds out-perform psychedelic drugs (e.g., ketamine, psilocybin). Example 15: Effects of Prior Selective Serotonin Reuptake Inhibitor (SSRI) Treatment on Efficacy of Disclosed Compounds in the Rat Forced Swim Test

[0510] As described in Example 14 , it is expected that disclosed compounds produce rapid, robust dose-dependent antidepressant-like effects in the FST. Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for a variety of central nervous system (CNS) disorders including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), anxiety disorders, obsessive compulsive disorder (OCD), and fibromyalgia. MDMA-assisted psychotherapy is in clinical trials for the treatment of PTSD, with the caveat that SSRIs inhibit the efficacy of the MDMA-assisted therapy (Feduccia et al. Psychopharmacol. 2021;238:581-588). If a patient requires MDMA-assisted therapy, they may need to stop taking their SSRI treatment. Since SSRIs require a tapered withdrawal period over many weeks, it could take a significant period of time off medication before a patient could begin MDMA treatment. This poses both logistical and safety risks for the most severely affected individuals with PTSD. Since SSRIs prevent the clinical efficacy of MDMA-assisted psychotherapy, this Example assesses whether prior administration of the prototypical SSRI fluoxetine affects the behavioral response to a disclosed compound in the FST. Methods

[0511] Animals: Male Sprague Dawley rats (Charles River Laboratories) are used for this study. Rats are acclimated to their home cages for at least one week before testing, and are maintained in a controlled environment on a 12 h light / dark cycle with no more than 2 rats per cage. Animals receive ad libitum access to food and water and are assigned randomly to treatment groups. Animal use and procedures are in accordance with established protocols.

[0512] Drug Treatment: Fluoxetine (10 mg / kg, IP, Sigma Aldrich) or 0.9% sterile saline vehicle are administered 23.5, 5, and 1 h before testing in the FST. A disclosed compound is administered (at multiple doses, e.g., 5, 15, or 30 mg / kg, IP) 30 min prior to FST testing. The control (0.9% saline vehicle) is also administered 30 min prior to FST testing. Control animals receive fluoxetine alone, the disclosed compound alone, or saline vehicle.

[0513] Forced Swim Test: In the FST trial, rats are placed in a circular plexiglass container filled with water, with no means of escape. Water temperature is maintained at 22-25 °C and changed for every animal. After 2024-03-01 an acclimation period, rats are timed for inactivity (failure to struggle), activity, swim time and climbing time. Day 1 consists of a 15 min acclimation trial, and Day 2 (24 h later) consists of the 5 min test. A time sampling procedure is employed where animals are observed every 5 sec and scored for immobility, swimming, or climbing.

[0514] Statistical Analysis: Data for each parameter of the test (immobility, swimming, or climbing) is expressed as the mean ± SEM. Differences between groups are determined by one-way ANOVA and post-hoc Tukey’s test with a p-value of less than 0.05 indicating statistically significant differences. Results and Conclusions:

[0515] Three prior doses of fluoxetine are expected to have no effect on the immobility in response to a single dose of a disclosed compound. Fluoxetine and the disclosed compound are both expected to reduce immobility, e.g., by at least 60% and 70%, respectively, compared to vehicle. Combined treatment with both fluoxetine and the disclosed compound is expected to reduce immobility even further (e.g., by about 95% or more) compared to vehicle.

[0516] The disclosed compound is also expected to significantly increase climbing behavior, and fluoxetine is expected to significantly increase swimming behavior, consistent with noradrenergic and serotonergic activity, respectively.

[0517] In summary, prior treatment with an SSRI (fluoxetine) is investigated and is not predicted to affect the behavioral response to a disclosed compound in the rat FST. These findings differentiate disclosed compounds from MDMA and suggest that, unlike with MDMA, an SSRI does not interfere with a disclosed compound’s behavioral efficacy. Since SSRIs are the first-line treatment for many CNS disorders, including PTSD, the results may suggest that patients could continue taking the SSRIs while taking a disclosed compound, potentially without concerns of reduced efficacy. Example 16: Effects of Disclosed Compounds in a Mouse Model of PTSD

[0518] Deficient fear extinction memory is a feature of PTSD in patients (Wicking et al. Neurobiology of Learning and Memory.2016;136:116). SSRI antidepressants, similar to the two approved for the treatment of PTSD (i.e., paroxetine and sertraline), prevent fear memory generalization and enhance extinction (Pedraza et al. Transl Psychiatry.2019;9:53). The enhancement of fear extinction might also underlie the beneficial effect of MDMA as a PTSD treatment (Feduccia & Mithoefer. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2018;84(A):221-228).

[0519] Effective PTSD treatments facilitate the disassociation between a traumatic memory and the patient’s fear response, making cues for the traumatic memory evoke less of a fear response. This is modeled in the mouse fear extinction paradigm which takes place over 3 days. On day 1 (fear conditioning), mice are trained to acquire a “traumatic memory,” namely associating the conditioned stimulus (CS, tone) to the unconditioned stimulus (US, foot shock). On day 2 (extinction training), they are trained to forget the traumatic memory association by presenting the CS 6 times (with no US) in a novel environment. On day 3 2024-03-01 (extinction recall), the mice are “asked” if that tone (CS) still elicits a fearful response, as measured by the time spent freezing when the tone is presented. Less time freezing means better extinction recall. Drugs that improve extinction recall reduce freezing time on day 3, and, therefore, show potential as a PTSD treatment.

[0520] Work with MDMA shows that after fear conditioning, administering MDMA (7.5 mg / kg) 30 minutes prior to extinction training enhances extinction recall measured as 35% reduced freezing compared to saline injected controls (Young et al. Transl Psychiatry.2015;5:e634).

[0521] Using a similar experimental design, the result may show that a disclosed compound significantly enhances fear extinction recall compared to saline controls. Example 17: Effects of Prior Selective Serotonin Reuptake Inhibitor (SSRI) Treatment on Efficacy of Disclosed Compounds in the Rat Open Field Test

[0522] The open field test (OFT) capitalizes on a rodent’s innate fear of open spaces to assess anxiety-like behavior. More time spent in the center of an open field reflects an anxiolytic (antianxiety) effect.

[0523] A single dose of a disclosed compound administered 30 minutes before testing is expected to significantly increase the time spent in the center of the open field compared to vehicle-treated controls. Locomotor activity is also measured in the OFT. Low doses of the compound are not expected to produce an effect compared to vehicle controls, but an increase in locomotor activity is expected with higher doses.

[0524] The foregoing description, for purposes of explanation, uses specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that specific details are not required in order to practice the invention. Thus, the foregoing description of specific embodiments of the invention is presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise compositions, formulations, methods, or the like disclosed; many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, through the elucidation of specific examples, and to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated, when such uses are beyond the specific examples disclosed. Accordingly, the scope of the invention shall be defined solely by the following claims and their equivalents.

Claims

2024-03-01 CLAIMS The invention claimed is:

1. A compound of Formula (II):or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: Raand Rbtogether represent =O, or are both H; R1is methyl, ethyl, or H; R2is either: C1-C3deuteroalkyl or C1-C3fluoroalkyl, when Raand Rbare both H; or H, C1-C3alkyl, C1-C3deuteroalkyl or C1-C3fluoroalkyl, when Raand Rbtogether represent =O; and R3is H, C1-C3alkyl, C1-C3deuteroalkyl or C1-C3fluoroalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein Raand Rbtogether represent =O.

3. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is methyl.

4. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is ethyl.

5. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is H.

6. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CH3.

8. The compound of claim 6, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CH2CH3.

9. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3deuteroalkyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or2024-03-01 solvate thereof, wherein R2is —CD3.

11. The compound of claim 9, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CD2CD3.

12. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3fluoroalkyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CF3.

14. The compound of claim 12, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CF2CF3.

15. The compound of claim 12, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is H.

16. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is methyl.

17. The compound of claim 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is ethyl.

18. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein Raand Rbare both H.

19. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is methyl.

20. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is ethyl.

21. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is H.

22. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3deuteroalkyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CD3.

24. The compound of claim 22, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or2024-03-01 solvate thereof, wherein R2is —CD2CD3.

25. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3fluoroalkyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CF3.

27. The compound of claim 25, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CF2CF3.

28. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is H.

29. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is methyl.

30. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is ethyl.

31. The compound of claim 1, having the structure of Formula (II-6):or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

32. The compound of claim 31, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is methyl.

33. The compound of claim 31, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is ethyl.

34. The compound of claim 31, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is H.

35. The compound of claim 31, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3alkyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CH3.2024-03-01 37. The compound of claim 35, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CH2CH3.

38. The compound of claim 31, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3deuteroalkyl.

39. The compound of claim 38, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CD3.

40. The compound of claim 38, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CD2CD3.

41. The compound of claim 31, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3fluoroalkyl.

42. The compound of claim 41, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CF3.

43. The compound of claim 41, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CF2CF3.

44. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is methyl.

45. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is ethyl.

46. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R3is H.

47. The compound of claim 1, having the structure of Formula (II-4):or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

48. The compound of claim 38, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3deuteroalkyl.

49. The compound of claim 39, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CD3.2024-03-01 50. The compound of claim 39, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CD2CD3.

51. The compound of claim 38, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is C1-C3fluoroalkyl.

52. The compound of claim 42, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CF3.

53. The compound of claim 42, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R2is —CF2CF3.

54. The compound of claim 38, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is methyl.

55. The compound of claim 38, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is ethyl.

56. The compound of claim 38, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein R1is H.

57. A compound having the structure of: ,, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

58. A compound having the structure of:,,,2024-03-01 , or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

59. A compound having the structure of:or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

60. A compound having the structure of:or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

61. A compound having the structure of:or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

62. A compound having the structure of:2024-03-01 , , , or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

63. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein the compound is the R -isomer.

64. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein the compound is the S -isomer.

65. A compound having the structure according to claims 1-64, or having the structure of Formula (I):or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, wherein: R1is H, methyl, or ethyl; R2is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; R3is H, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; Raand Rbare both H, or together represent =O; and R' and R'' are each independently H, D, or F.

66. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-62, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

67. The pharmaceutical composition of claim 66, wherein the compound, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, is a pure or substantially pure individual enantiomer, or an enantiomerically enriched mixture having an optical purity of between 0-25%, between 25-50%, between 50-75%, between 75-90%, between 90-95%, or at least 95% enantiomeric excess.

68. The pharmaceutical composition of 67, wherein the pure or substantially pure individual enantiomer is the R -isomer.2024-03-01 69. The pharmaceutical composition of 67, wherein the pure or substantially pure individual enantiomer is the S -isomer.

70. The pharmaceutical composition of claim 66, suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

71. The pharmaceutical composition of any one of claims 66, wherein the composition is provided in unit dosage form.

72. The pharmaceutical composition of claim 71, comprising the compound in a total amount of between about 1 and 1000 mg.

73. The pharmaceutical composition of claim 72, comprising the compound in a total amount of between about 50 and 500 mg.

74. The pharmaceutical composition of claim 72, wherein said unit dosage form is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

75. The pharmaceutical composition of claim 72, further comprising a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

76. The pharmaceutical composition of claim 75, wherein the additional active compound is selected from the group consisting of analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents, monoamine oxidase inhibitors, tryptamines, terpenes, phenylalkylamines, sedatives, stimulants, serotonergic agents, NMDA modulators, NMDA antagonists, and vitamins.

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

78. The pharmaceutical composition of claim 77, wherein the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic,2024-03-01 orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

79. A compound of any one of claims 1-62, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, for use in the treatment of a mental health disorder.

80. Use of the compound of any one of claims 1-62, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, for the manufacture of a medicament for the treatment of a mental health disorder patient according to the method of any of the following claims.

81. A method for modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-62, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

82. The method of claim 81, wherein modulating neurotransmission comprises activating a monoamine neurotransmitter receptor and / or modulating the uptake activity of a monoamine transporter.

83. The method of claim 82, wherein the monoamine neurotransmitter receptor is any of a serotonin receptor (HTR), a dopamine receptor, and a norepinephrine receptor.

84. The method of claim 82, wherein the monoamine transporter is any of a serotonin transporter (SERT), a dopamine transporter (DAT), or a norepinephrine transporter (NET).

85. The method of claim 82, wherein the HTR is any of HTR1A, HTR1B, HTR2A, HTR2B, and HTR6.

86. The method of claim 85, wherein modulating neurotransmission comprises agonizing HTR2A.

87. A method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-62, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

88. The method of claim 87, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission.

89. The method of claim 88, wherein the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission.

90. The method of claim 89, wherein the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of serotonergic, dopaminergic, or noradrenergic neurotransmission.

91. The method of claim 87, wherein the medical condition is a mental health disorder.2024-03-01 92. The method of claim 92, wherein the mental health disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, alcohol or drug abuse or dependence disorders, a substance use disorder, substance-induced mood disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, and dissociative disorders.

93. The method of claim 92, wherein the disorder is PTSD.

94. The method of claim 93, wherein the PTSD is treatment-resistant.

95. The method of claim 93, wherein the subject is suicidal.

96. The method of claim 82, wherein the disorder is depression.

97. The method of claim 96, wherein depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

98. The method of claim 91, wherein the compound is used in combination with an additional therapy for the mental health disorder.

99. The method of claim 98, wherein the additional therapy is psychotherapy.

100. The method of claim 98, wherein the additional therapy comprises administering one or more additional psychoactive agents to the subject.

101. The method of claim 100, wherein the additional psychoactive agents are selected from the group consisting of selective-serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin-norepinephrine-dopamine reuptake inhibitors (SDNRIs), and anxiolytic agents.

102. The method of claim 101, wherein the additional psychoactive agent is a selective-serotonin reuptake inhibitor (SSRI).

103. The method of claim 102, wherein the subject is taking or is continuing to take the SSRI concurrently with the compound.

104. A pharmaceutical composition comprising a therapeutically effective amount of the compound of2024-03-01 claim 65, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

105. A compound of claim 65, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, for use in the treatment of a mental health disorder.

106. Use of the compound of claim 65, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof, for the manufacture of a medicament for the treatment of a mental health disorder patient according to the method of any of the following claims.

107. A method for modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 65, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

108. A method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 65, or a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof.

Images