Alpha-substituted asymmetric phenylalkylamines

Abstract

Provided herein are substituted phenylalkylamines, such as 2,5-dialkoxyphenethylamines that are asymmetrically substituted (e.g., having different 2-alkoxy and 5-alkoxy substituents), and have alpha-alkyl substitutions, such as DOx (alpha-methyl) compounds and 4C-x (alpha-ethyl) compounds, including those of Formula (1). Also provided are methods of making such compounds, pharmaceutical compositions thereof, and methods of their use, such as to treat mental health disorders and other medical conditions.

Description

[0001] 2025-11-28 ALPHA-SUBSTITUTED ASYMMETRIC PHENYLALKYLAMINES INVENTORS: Thomas Szabo, Mark J. Martini, Nicholas V. Cozzi, Paul F. Daley

[0002] CROSS-REFERENCE

[0003]

[0001] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U. S. Provisional Application No.

[0004] 63 / 726,316, filed November 28, 2024, and fully incorporated by reference for all purposes.

[0005] TECHNICAL FIELD

[0006]

[0002] This disclosure relates in some aspects to substituted phenylalkylamines, such as asymmetrically substituted phenylalkylamines, including those with alpha-alkyl substitutions. The disclosure also relates to methods of making such compounds, pharmaceutical compositions thereof, and methods of using the same.

[0007] BACKGROUND OF THE INVENTION

[0008]

[0001] Psychedelics have gained attention as therapeutic tools for various mental health conditions, such as depression, anxiety, PTSD, and addiction. Aside from remarkable subjective effects on consciousness, there is increasing interest in their physiological effects and their potential application in the treatment of physical and neurological disorders. While much progress has been made towards understanding the structure-activity relationships underlying the effects of classical psychedelics, many open questions remain concerning the efficacy of these compounds for the treatment of complex diseases that may lack effective treatments, such as depression and attention-deficit / hyperactivity disorder (ADHD). As such, there is an ongoing unmet need for novel alternative treatments, especially those which minimize side effects, increase access, and optimize efficacy. Provided herein are phenylalkylamine compounds to meet these needs and others, and that have such advantages and improvements as will become readily apparent through the disclosure below.

[0009] INCORPORATION BY REFERENCE

[0010]

[0002] 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 is from an area that is analogous or directly applicable to the invention, nor should any citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or part of the common general knowledge in the art.

[0011] BRIEF SUMMARY OF THE INVENTION

[0012]

[0003] A simplified summary of some embodiments follows to provide a basic understanding of the invention.

[0013]

[0004] In some aspects are provided the compounds of Formula (1):

[0014]

[0015] 2025-11-28 or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein:

[0016] Rais CrC6alkyl;

[0017] Rβis H, OH, or C1-C6alkoxy;

[0018] X is Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, CrC6haloalkoxy, C^Cg haloalkylthio, C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; and

[0019] RNis H, CrC6alkyl, or C^Cg alkylene-C6-C12aryl; wherein:

[0020] one of R2and R5is methyl, and the other is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, C^Cg haloalkyl, CrC6alkylene— 3- to 6-membered cycloalkyl, C^Cg alkylene— 4- to 6-membered heterocycloalkyl, or C^Cg alkylene— aryl, or C^Cg alkylene— heteroaryl; and R3and R6are both H; or

[0021] R2and R3together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl;

[0022] R5is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, CrC6haloalkyl, CrC6alkylene— 3- to 6-membered cycloalkyl, CrC6alkylene— 4- to 6-membered heterocycloalkyl, or CrC6alkylene— aryl, or CrC6alkylene— heteroaryl; and

[0023] R6is H; or

[0024] R5and R6together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl;

[0025] R2is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, C^Cg haloalkyl, C^Cg alkylene— 3- to 6-membered cycloalkyl, C^Cg alkylene— 4- to 6-membered heterocycloalkyl, or C^Cg alkylene— aryl, or C^Cg alkylene— heteroaryl; and

[0026] R3is H.

[0027]

[0005] In some embodiments, the compound of Formula (1) has the structure of Formula (I). In some embodiments of Formula (I), Rais methyl. In some embodiments of Formula (I), Rais ethyl.

[0028]

[0006] In some embodiments, the compound of Formula (1) has the structure of Formula (II). In some embodiments of Formula (II), Rais methyl. In some embodiments of Formula (II), Rais ethyl.

[0029]

[0007] In some embodiments, the compound of Formula (1) has the structure of Formula (III). In some

[0030]

[0031]

[0032] 2025-11-28

[0008] In some embodiments of Formula (1), Rais methyl. In some embodiments of Formula (1), Rais ethyl.

[0033]

[0009] In some embodiments, the compound of Formula (1) has the structure of Formula (IV) or (V). In some embodiments, the compound of Formula (1) has the structure of Formula (IV). In some embodiments, the compound of Formula (1) has the structure of Formula (V). In some embodiments, the compound of Formula (1) has the structure of Formula (VI) or (VII). In some embodiments, the compound of Formula (1) has the structure of Formula (VI). In some embodiments, the compound of Formula (1) has the structure of Formula (VII). In some embodiments, the compound of Formula (1) has the structure of Formula (VIII) or (IX). In some embodiments, the compound of Formula (1) has the structure of Formula (VIII). In some embodiments, the compound of Formula (1) has the structure of Formula (IX). In some embodiments, the compound of Formula (I) has the structure of Formula (X) or (XI). In some embodiments, the compound of Formula (1) has the structure of Formula (X). In some embodiments, the compound of Formula (1) has the structure of Formula (XI). In some embodiments, the compound of Formula (1) has the structure of Formula (XII) or (XIII). In some embodiments, the compound of Formula (1) has the structure of Formula (XII). In some embodiments, the compound of Formula (1) has the structure of Formula (XIII). Formulas (IV)— (XI 11) are as disclosed herein.

[0034]

[0010] In some embodiments of any disclosed Formula, R2, if present, is methyl. In some embodiments of any Formula, R5, if present, is C3-C6alkyl. In some embodiments of any Formula, R5is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or n-pentyl. In some embodiments of any Formula, R5, if present, is C3-C6alkenyl. In some embodiments of any Formula, R5is allyl. In some embodiments of any Formula, X is F, Cl, Br, or I. In embodiments of any Formula, X is C^Cg alkyl. In some embodiments of any Formula, X is methyl. In some embodiments of any Formula, X is ethyl. In some embodiments of any Formula, X is C^Cg alkylthio or C^Cg haloalkylthio. In some embodiments of any Formula, X is methylthio, ethylthio, or 2-fluoroethylthio. In some embodiments of any Formula, X is C^Cg haloalkyl. In some embodiments of any Formula, X is trifluoromethyl. In some embodiments of any Formula, Rais methyl. In some embodiments of any Formula, Rais ethyl.

[0035] [II] In some embodiments, the compound is selected from TABLE 1 disclosed herein.

[0036]

[0012] In some embodiments, the compound is selected from TABLE 2 disclosed herein.

[0037]

[0013] Also provided is a pharmaceutical composition comprising the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0038]

[0014] In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration. In some embodiments, the composition is provided in unit dosage form. In some embodiments, the unit dosage form is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

[0039]

[0015] In some embodiments, the pharmaceutical composition comprises the compound in a total amount of between 1 and 200 mg, or between 5 and 100 mg. In some embodiments, the pharmaceutical composition comprises the compound in a total amount of between 10 and 75 mg, or between 20 and 50 mg. 2025-11-28

[0016] In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof. 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, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins. In 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 PK or PD. In 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.

[0040]

[0017] Also provided are methods of modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of the compound or composition of any of the disclosed embodiments. In some embodiments, modulating neurotransmission comprises activating a monoamine neurotransmitter receptor and / or modulating the uptake activity of a monoamine transporter. In some embodiments, the monoamine neurotransmitter receptor is any of a serotonin receptor, a dopamine receptor, and a norepinephrine receptor. In some embodiments, the serotonin receptor is the 5-HT2Areceptor. In some embodiments, the monoamine transporter is a serotonin transporter (SERT).

[0041]

[0018] Also provided are methods of treating a medical condition in a subject in need thereof, the method comprising administering to the subject the compound or composition of any of the disclosed embodiments.

[0042]

[0019] In some embodiments, the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission. In some embodiments, the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission. In some embodiments, the disorder linked to dysregulation or inadequate functioning of monoaminergic neurotransmission is that of serotonergic, dopaminergic, or noradrenergic neurotransmission.

[0043]

[0020] 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 2025-11-28 disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, and dissociative disorders. In some embodiments, the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD). In some embodiments, the anxiety is generalized anxiety disorder (GAD). In some embodiments, the mental health disorder is PTSD. In some embodiments, the substance use disorder is alcohol use disorder (AUD), nicotine dependence or tobacco use disorder, opioid use disorder (OUD), stimulant use disorder, or sedative, hypnotic, or anxiolytic use disorder.

[0044]

[0021] In some embodiments, the medical condition is a neurodegenerative disorder, pain or a pain disorder, or inflammation or an inflammatory disorder. In some embodiments, the medical condition is an ischemic injury. In some embodiments, the ischemic injury is a stroke or an ischemia-reperfusion injury.

[0045]

[0022] In some embodiments, the compound or composition is administered together with one or more sessions of psychotherapy or psychological support.

[0046]

[0023] Also provided is the use of the compound or composition of any of the disclosed embodiments for the treatment of a medical condition or the manufacture of a medicament for the treatment of a medical condition.

[0047]

[0024] Also provided are such further compounds, compositions, kits, methods and uses as disclosed herein, such as comprising or characterized by any one or more aspects or embodiments disclosed herein.

[0048]

[0025] The foregoing outlines broadly and in summary certain features of the disclosure so the detailed description may be better understood, and the contribution to the art more fully appreciated. This summary is a brief and general synopsis of only some of the disclosed aspects and embodiments, and is solely for the benefit and convenience of the reader. It is not intended to limit in any manner the scope or range of equivalents to which the claims are entitled. Additional features of the invention are described hereinafter. It should be appreciated by those in the art that all disclosed aspects and embodiments are only exemplary, and may be readily utilized as a basis for modifying or designing other aspects and embodiments for carrying out the same purposes. Any such equivalents are also within the scope and spirit of the invention.

[0049]

[0026] The headings are only to facilitate review by a reader and do not limit the invention in any manner.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051]

[0027] The phenylalkylamine or phenethylamine pharmacophore is one of the most well-known chemical scaffolds found in bioactive molecules, including as neurotransmitters (e.g., dopamine) and psychoactive drugs (e.g., the empathogen 3,4-methylenedioxymethamphetamine, MDMA). Among the phenylalkylamines, the class of “2C” or “2C-x” compounds are ring-substituted phenylalkylamines with 2,5-dimethoxy substitution on the core phenyl ring, and commonly an additional substituent at the 4 position. Some 2C compounds have effects similar to those of empathogens (e.g., MDMA); others have effects similar to those of classic psychedelics (e.g., LSD, psilocybin). Although some 2C compounds are generally well-tolerated within certain dose ranges, adverse effects have been reported, and many 2C compounds are known to be associated with heavy “body load” and gastrointestinal effects (see, e.g., Dean et al., J Med Toxicol, 2013; 9(2), 172-178). 2025-11-28

[0028] Besides the 2C-x compounds, which are unsubstituted at the alpha position of the ethylamine side chain, other compounds having an alpha-methyl substituent (sometimes, “DOx” compounds), and having an alpha-ethyl substituent (sometimes, “4C-x” compounds) also have been of interest, although less explored.

[0052]

[0029] While there has been a resurgence of interest in the therapeutic application of psychedelics in treating a variety of medical diseases and disorders, there is also a need for novel compounds that have limited or no hallucinogenic or psychedelic effects. For example, certain individuals may be contraindicated for traditional psychedelics due to a personal or family history of psychotic disorders (Reiff et al. Am. J. Psychiatry 2020, 177(5), 391-410). These conditions are characterized by alterations in perception, thinking, and cognition, and the hallucinogenic effects of psychedelics could potentially exacerbate or trigger these symptoms. Developing compounds with therapeutic properties but without hallucinogenic effects (or with reduced hallucinogenic effects) is crucial for providing safe and effective treatment options for individuals who may be vulnerable to adverse psychiatric reactions. Moreover, chronic or daily administration of psychedelics for conditions such as depression may not be feasible or practical due to the potential for tolerance and the extended duration of psychedelic experiences. Daily dosing with compounds that produce strong hallucinogenic effects could be disruptive to daily functioning and could pose challenges for individuals seeking to integrate treatment into their daily lives. For these and other reasons, non- and less-hallucinogenic alternatives could provide a more sustainable approach for long-term treatment, enhancing adherence and optimizing therapeutic outcomes.

[0053]

[0030] Provided herein are asymmetrically substituted phenylalkylamines, including alpha-alkyl substituted phenylalkylamines, to meet these needs and others. Also provided are methods of making the compounds, pharmaceutical compositions and kits comprising the compounds, and methods of using the compounds and compositions, such as in the treatment of mental health disorders and other medical conditions.

[0054] A. General Definitions and Terms

[0055]

[0031] As used in the specification and the claims, the singular forms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Reference to “an” active agent thus may mean two or more active agents, and “an” excipient may mean 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.

[0056]

[0032] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). The term “including” thus means, and is used interchangeably with, the phrase “including but not limited to,” and “include” means “include, for example.” The term “or” means, and is interchangeable with, the term “and / or,” unless context clearly indicates otherwise.

[0057]

[0033] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about,” even where not so stated explicitly. In alternative embodiments, such numbers will be understood as not being modified by the 2025-11-28 term “about.” In some embodiments (equivalently, and simply as shorthand, “in 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 embodiments, “about” may refer to plus or minus five percent (±5%) of the recited unit of measure. In other embodiments, “about” may refer to plus or minus ten percent (±10%) of the recited unit of measure. Where “about” is used to modify one number in a series or range, it is understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range; thus, the term “about 1, 2, or 3” is understood to mean “about 1, about 2, or about 3” and the term “about 1 to 10” means “about 1 to about 10.”

[0058]

[0034] The term “substantially,” where it is applied to modify a feature or limitation herein, will be read in the context of the invention and in light of the knowledge in the art to provide the appropriate certainty, e.g., by using a standard that is recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the art.

[0059]

[0035] In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0060]

[0036] A comprehensive list of the abbreviations utilized by organic chemists of skill 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 filing date is incorporated by reference as if fully set forth herein.

[0061]

[0037] 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.” Unless otherwise specified, the nomenclature and procedures herein are those known in fields relating to one or more aspects hereof, e.g., biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or medicinal chemistry, as may be known and employed in such fields. Where not otherwise disclosed, standard techniques and procedures may be used, such as those generally performed according to conventional methods in the art, and known to those of ordinary skill.

[0062]

[0038] Further definitions that may assist a reader in understanding the disclosed embodiments follow; however, it will be appreciated that such definitions are not intended to limit the scope of the invention, which shall be properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill) in view of the language used in the claims. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0063]

[0039] “Alkyl” will be understood to include straight-chain 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 2025-11-28 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” also can be used. In some embodiments, an alkyl group comprises from 1-10 carbons, from 1-6 carbons, from 1-4 carbons, or from 1-3 carbons (all inclusive). For any alkyl, the alkyl may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, or-SONH2.

[0064]

[0040] “Alkanyl” refers to saturated straight-chain, branched, or cyclic alkyl radicals derived by the removal of one 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.

[0065]

[0041] “Alkenyl” refers to an unsaturated straight-chain, branched, 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.

[0066]

[0042] “Alkynyl” refers to an unsaturated straight-chain, branched, or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom (i.e., “H”) 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.

[0067]

[0043] “Aryl” refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen (H) atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include those 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. In some embodiments, an aryl group comprises from 6-20 carbons, or from 6-12 carbons.

[0068]

[0044] “Amino” refers to — NR2, wherein each R is independently H, OH, or CrC6alkyl, wherein the CrC6alkyl is optionally substituted. An amino group can be a primary amino group (— NH2) a secondary amino group (— NHR), a tertiary amino group (— NR2), or a quaternary amino group (— NR3+), wherein R is independently H or C^Ce alkyl, wherein the C^Ce alkyl is optionally substituted.

[0069]

[0045] “Cycloalkyl” refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring 2025-11-28 assembly containing from 3-12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3-6 carbons, 4-6 carbons, 5-6 carbons, 3-8 carbons, 4-8 carbons, 5-8 carbons, 6-8 carbons, 7-8 carbons, 3-9 carbons, 4-9 carbons, 5-9 carbons, 6-9 carbons, 7-9 carbons, 8-9 carbons, 3-10 carbons, 4-10 carbons, 5-10 carbons, 6-10 carbons, 7-10 carbons, 8-10 carbons, 9-10 carbons, 3-11 carbons, 4-11 carbons, 5-11 carbons, 6-11 carbons, 7-11 carbons, 8-11 carbons, 9-11 carbons, 10-11 carbons, 3-12 carbons, 4-12 carbons, 5-12 carbons, 6-12 carbons, 7-12 carbons, 8-12 carbons, 9-12 carbons, 10-12 carbons, and 11-12 carbons (all inclusive). Monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyl rings include norbornane, bicyclooctane, decahydronaphthalene and adamantane. When cycloalkyl is a monocyclic C^8cycloalkyl, groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a monocyclic C3.6cycloalkyl, groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0070]

[0046] “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 3-6 carbons, 4-6 carbons, 5-6 carbons, 3-8 carbons, 4-8 carbons, 5-8 carbons, 6-8 carbons, 7-8 carbons, 3-9 carbons, 4-9 carbons, 5-9 carbons, 6-9 carbons, 7-9 carbons, 8-9 carbons, 3-10 carbons, 4-10 carbons, 5-10 carbons, 6-10 carbons, 7-10 carbons, 8-10 carbons, 9-10 carbons, 3-11 carbons, 4-11 carbons, 5-11 carbons, 6-11 carbons, 7-11 carbons, 8-11 carbons, 9-11 carbons, 10-11 carbons, 3-12 carbons, 4-12 carbons, 5-12 carbons, 6-12 carbons, 7-12 carbons, 8-12 carbons, 9-12 carbons, 10-12 carbons, and 11-12 carbons (all inclusive). Representative cycloalkenyl groups include 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.

[0071]

[0047] “Halogen” refers to fluorine, chlorine, bromine, and iodine.

[0072]

[0048] “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 include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds The heteroatoms also can be oxidized, including to — S(O)— and — S(O)2—. Heterocycloalkyl groups can include any number of ring atoms, such as from 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members (all inclusive). Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3 to 4 (all inclusive). The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 2025-11-28 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 alkyl or oxo (=0), among many others.

[0073]

[0049] “Heterocycloalkenyl” refers to cycloalkenyl as defined above, having from 3-12 ring members and from 1-4 heteroatoms of N, 0 and S. The heteroatoms can also be oxidized, such as, but not limited to, — S(0)— and — S(0)2—. Heterocycloalkenyl groups can include any number of ring atoms, such as from 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members (all inclusive). Any suitable number of heteroatoms can be included in the heterocycloalkenyl groups, such as 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4 (all inclusive). Exemplary heterocycloalkenyl groups include dihydrofuran, dihydropyran, dihydropyridine, tetrahydropyridine, dihydrothiazole, and dihydrothiophene.

[0074]

[0050] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5-16 ring atoms, where from 1-5 of the ring atoms are a heteroatom such as N, 0 or S. Heteroaryl groups can include any number of ring atoms, such as from 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members (all inclusive). Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5 (all inclusive). Heteroaryl groups can have from 5-8 ring members and from 1-4 heteroatoms, or from 5-8 ring members and from 1-3 heteroatoms, or from 5-6 ring members and from 1-4 heteroatoms, or from 5-6 ring members and from 1-3 heteroatoms (all inclusive). 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.

[0075]

[0051] “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.

[0076]

[0052] “Acyl” refers to a H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, connected via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0077]

[0053] Deuterium (2H or D) 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), thus accounting for approximately 0.0154% (alternately, on a mass basis, 0.0308%) of all naturally occurring hydrogen in the oceans. A 2025-11-28 “non-substituted,” “non-deuterated,” or “undeuterated” compound may refer to a compound having no greater than the amount of deuterium expected as a percentage of naturally occurring hydrogen in the compound.

[0078]

[0054] “Deuteroalkyl” includes any alkyl group as defined above, wherein one or more H atoms are replaced by a deuterium. Where an alkyl radical is substituted by more than one deuterium, it may be referred to using a prefix corresponding to the number of deuterium substitutions. For example, trideuteroalkyl refers to an alkyl in which three hydrogens have been replaced by deuteriums. A deuteroalkyl can be fully deuterated (i.e., all of the hydrogens have been replaced by deuteriums) or partially deuterated (i.e., only some of the hydrogens have been replaced by deuteriums). For example, a deuteromethyl (i.e., a C1deuteroalkyl) 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.

[0079]

[0055] “Haloalkyl” includes any alkyl group as defined above, wherein one or more H atoms are replaced by a halogen (e.g., F, Cl, Br, or I). 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).

[0080]

[0056] “Hydroxyalkyl” refers to an alkyl group in which one or more H atoms are replaced by a hydroxy. Hydroxyalkyl groups include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl.

[0081]

[0057] “Haloalkoxy” refers to an O-alkyl group in which one or more H atoms are replaced by a halogen (e.g., mono-, di-, or tri-haloalkoxy). Halogens may be the same or different in each instance. Groups include chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy.

[0082]

[0058] “Alkylthio” refers to the formula —SR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein. A non-limiting list of alkylthio are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio.

[0083]

[0059] “Sulfenyl” refers to an —SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0084]

[0060] “Sulfinyl” refers to an — S(=O)— R group, where R is the same as defined for sulfenyl.

[0085]

[0061] “Sulfonyl” refers to an — SO2R group, where R is the same as defined for sulfenyl.

[0086]

[0062] “O-carboxy” refers to a — RC(=0)0— group in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0087]

[0063] “Ester” and “C-carboxy” refer to a — C(=0)0R group, where R is the same as defined for O-carboxy.

[0088]

[0064] “Thiocarbonyl” refers to a — C(=S)R group, where R is the same as defined for O-carboxy.

[0089]

[0065] “Trihalomethanesulfonyl” refers to an X3CSO2— group wherein each X is a halogen. 2025-11-28

[0066] “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.

[0090]

[0067] “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.

[0091]

[0068] “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.

[0092]

[0069] “Oxo” refers to =0.

[0093]

[0070] “O-carbamyl” refers to a — 0C(=0)N(RARB) group in which RAand RBcan be independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0094]

[0071] “N-carbamyl” refers to an R0C(=0)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0095]

[0072] “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.

[0096]

[0073] “N-thiocarbamyl” refers to an R0C(=S)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0097]

[0074] “C-amido” group refers to a — C(=0)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0098]

[0075] “N-amido” refers to a RC(=0)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0099]

[0076] Any of the above substituents which permits substitution may, in some embodiments, be substituted. In some embodiments, the substituent is substituted. In some embodiments, the substituent is unsubstituted. In some embodiments, the substituent is optionally substituted.

[0100]

[0077] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. If no substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, oxo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, 2025-11-28 haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group.

[0101] B. Compounds

[0102]

[0078] In some aspects, provided is a compound of Formula (1):

[0103]

[0104] OR5

[0105] or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein:

[0106] Rais H or CrC6alkyl;

[0107] Rpis H, OH, or CrC6alkoxy;

[0108] X is Br, F, Cl, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, CrC6haloalkoxy, CrC6haloalkylthio, C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; and

[0109] RNis H, CrC6alkyl, or CrC6alkylene-C6-C12aryl;

[0110] wherein each CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, CrC6alkoxy, CrC6alkylthio, CrC6haloalkyl, C^Cs haloalkoxy, C^Cs haloalkylthio, C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, or-OC(O)NH2; and

[0111] one of R2and R5is methyl, and the other is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, C^Cs haloalkyl, C^Cs alkylene— 3- to 6-membered cycloalkyl, C^Cs alkylene— 4- to 6-membered hetero- cycloalkyl, or C^Cs alkylene— aryl, or C^Cs alkylene— heteroaryl; and R3and R6are both H; or

[0112] R2and R3together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl; R5is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, CrC6haloalkyl, CrC6alkylene— 3- to 6-membered cycloalkyl, CrC6alkylene— 4- to 6-membered heterocycloalkyl, or CrC6alkylene— aryl, or CrC6alkylene— heteroaryl; and R6is H; or R5and R6together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl; R2is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, CrC6haloalkyl, CrC6alkylene— 3- to 6-membered cycloalkyl, CrC6alkylene— 4- to 6-membered heterocycloalkyl, or C^Cs alkylene— aryl, or C^Cs alkylene— heteroaryl; and R3is H.

[0113]

[0079] In some embodiments of Formula (1), Rais H or C^Cs alkyl. In some embodiments, Rais H. In some 2025-11-28 embodiments, Rais C^Cg alkyl. In some embodiments, Rais methyl. In some embodiments, Rais ethyl.

[0114]

[0080] In some embodiments of Formula (1), Rpis H, OH, or C^Cg alkoxy. In some embodiments, Rpis H. In some embodiments, Rpis OH. In some embodiments, Rpis C^Cg alkoxy. In embodiments, Rpis methoxy.

[0115]

[0081] In some embodiments of Formula (1), X is H, Br, F, Cl, I, C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, CrCg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, or— OC(O)NH2.

[0116]

[0082] In some embodiments of Formula (1), X is H. In some embodiments, X is halogen (i.e., F, Cl, Br, I). In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is Br. In some embodiments, X is I. In some embodiments, X is CrCg alkyl. In some embodiments, X is methyl (— CH3). In some embodiments, X is ethyl (— CH2CH3). In some embodiments, X is C2-C8alkenyl. In some embodiments, X is C2-C8alkynyl. In some embodiments, X is CrCg alkoxy. In some embodiments, X is methoxy. In some embodiments, X is ethoxy. In some embodiments, X is propoxy. In some embodiments, X is isopropoxy. In some embodiments, X is C^Cg alkylthio. In some embodiments, X is — SCH3. In some embodiments, X is — SCH2CH3. In some embodiments, X is — SCH2CH2CH3. In some embodiments, X is C^Cg haloalkyl. In some embodiments, X is C^Cg haloalkoxy. In some embodiments, X is 3- to 6-membered cycloalkyl. In some embodiments, X is 4- to 6-membered heterocycloalkyl. In some embodiments, X is cyano. In some embodiments, X is nitro. In embodiments, X is amino (i.e., -NR2, wherein each R is independently H, OH, or CrCg alkyl, wherein the C^Cg alkyl is optionally substituted according to embodiments described below).

[0117]

[0083] In some embodiments of Formula (1), wherein X is C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each C^Cg alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cg alkoxy, C^Cg alkylthio, C^Cg haloalkyl, C^Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, or— OC(O)NH2.

[0118]

[0084] In some embodiments of Formula (1), X is unsubstituted CrCg alkyl, unsubstituted C2-C8alkenyl, unsubstituted C2-C8alkynyl, unsubstituted CrCg alkoxy, unsubstituted CrCg alkylthio, unsubstituted CrCg haloalkyl, unsubstituted CrCg haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH2).

[0119]

[0085] In some embodiments of Formula (1), X is substituted C^Cg alkyl, substituted C2-C8alkenyl, 2025-11-28 substituted C2-C8alkynyl, substituted CrC6alkoxy, substituted CrC6alkylthio, substituted CrC6haloalkyl, substituted CrC6haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR2, wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, or— OC(O)NH2).

[0120]

[0086] In some embodiments of Formula (1), one of R2and R5is methyl, and the other is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, C^Cs haloalkyl, C^Cs alkylene— 3- to 6-membered cycloalkyl, C^Cs alkylene— 4- to 6-membered heterocycloalkyl, or C^Cs alkylene— aryl, or C^Cs alkylene— heteroaryl; and R3and R6are both H. In some embodiments, R2is methyl; R5is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, C^Cs haloalkyl, C^Cs alkylene- 3- to 6-membered cycloalkyl, CrC6alkylene— 4- to 6-membered heterocycloalkyl, or CrC6alkylene— aryl, or CrC6alkylene— heteroaryl; and R3and R6are both H.

[0121]

[0087] In some embodiments of Formula (1), R5is methyl; R2is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, CrC6haloalkyl, CrC6alkylene— 3- to 6-membered cycloalkyl, CrC6alkylene— 4- to 6-membered heterocycloalkyl, or CrC6alkylene— aryl, or CrC6alkylene— heteroaryl; and R3and R6are both H.

[0122]

[0088] In some embodiments of Formula (1), R2and R3together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl; R5is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, CrC6haloalkyl, C^Cs alkylene— 3- to 6-membered cycloalkyl, C^Cs alkylene— 4- to 6-membered heterocycloalkyl, or C^Cs alkylene— aryl, or C^Cs alkylene— heteroaryl; and R6is H.

[0123]

[0089] In some embodiments of Formula (1), R2and R3together with the intervening atoms form a dihydrofuranyl. In some embodiments, R2and R3together with the intervening atoms form a furanyl.

[0124]

[0090] In some embodiments of Formula (1), R5and R6together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl; R2is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, CrC6haloalkyl, C^Cs alkylene— 3- to 6-membered cycloalkyl, C^Cs alkylene— 4- to 6-membered heterocycloalkyl, or C^Cs alkylene— aryl, or C^Cs alkylene— heteroaryl; and R3is H.

[0125]

[0091] In some embodiments of Formula (1), R5and R6together with the intervening atoms form a dihydrofuranyl. In some embodiments, R5and R6together with the intervening atoms form a furanyl.

[0126]

[0127] (Formula (I)), or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein: X is F, Cl, Br, I, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, CrC6haloalkyl, CrC6alkylthio, CrC6haloalkylthio, CrC6alkoxy, cyano, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; Rais H or CrC6alkyl; RNis H, CrC6alkyl, or 2025-11-28 CrCg alkylene-C6-C12aryl; and one of R2and R5is methyl, and the other is C3-C6alkyl or C3-C6alkenyl.

[0128]

[0093] In some embodiments of Formula (I), X is F, Cl, Br, I, C^Cg alkyl, C2-C6alkenyl, C2-C6alkynyl, C^Cg haloalkyl, C^Cg alkylthio, C^Cg haloalkylthio, C^Cg alkoxy, cyano, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl. In embodiments, X is F, Cl, Br, or I. In embodiments, X is F. In embodiments, X is Cl. In embodiments, X is Br. In embodiments, X is I. In embodiments, X is C^Cg alkyl. For example, in some embodiments, X is methyl. In embodiments, X is ethyl.

[0129]

[0094] In some embodiments of Formula (I), X is C2-C6alkenyl. In embodiments, X is C2-C6alkynyl. In embodiments, X is C^Cg haloalkyl. For example, in some embodiments, X is CF3. In embodiments, X is C^Cg alkylthio. For example, in some embodiments, X is — S— CH3. In embodiments, X is C^Cg haloalkylthio. In embodiments, X is C^Cg alkoxy. In embodiments, X is cyano. In embodiments, X is C3-C6cycloalkyl. In embodiments, X is 4- to 6-membered heterocycloalkyl.

[0130]

[0095] In some embodiments of Formula (I), Rais H or CrCg alkyl. In embodiments, Rais H. In embodiments, Rais CrCg alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl. In embodiments, Rais propyl.

[0131]

[0096] In embodiments of Formula (I), RNis H, CrCg alkyl, or CrCg alkylene-C6-C12aryl. In embodiments, RNis H. In embodiments, RNis CrCg alkyl. In embodiments, RNis CrCg alkylene-C6-C12aryl. In embodiments, RNis CrCg alkylene— phenyl. In embodiments, RNis — CH2-C6-C12aryl. In embodiments, RNis — CH2-phenyl.

[0132]

[0097] In some embodiments of Formula (I), one of R2and R5is methyl, and the other is C3-C6alkyl or C3-C6alkenyl. In embodiments, one of R2and R5is methyl, and the other is C3-C6alkyl. In embodiments, R2is methyl and R5is C3-C6alkyl. In embodiments, R2is methyl and R5is propyl, butyl, pentyl, or hexyl. In embodiments, R2is methyl and R5is propyl. In embodiments, R2is methyl and R5is butyl. In embodiments, R2is methyl and R5is pentyl. In embodiments, R2is methyl and R5is hexyl. In embodiments, R2is methyl and R5is n-propyl, isopropyl (1 -methylethyl), n-butyl, sec-butyl (butan-2-yl), isobutyl (2-methylpropyl), tert-butyl, n-pentyl, tertpentyl (2-methylbutan-2-yl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), sec-pentyl (pentan-2-yl), pentan-3-yl, sec-isopentyl (3-methylbutan-2-yl), or 2-methylbutyl. In embodiments, R2is methyl and R5is n-propyl. In embodiments, R2is methyl and R5is isopropyl (1 -methylethyl). In embodiments, R2is methyl and R5is n-butyl. In embodiments, R2is methyl and R5is sec-butyl (butan-2-yl). In embodiments, R2is methyl and R5is isobutyl (2-methylpropyl). In embodiments, R2is methyl and R5is tert-butyl. In embodiments, R2is methyl and R5is n-pentyl. In embodiments, R2is methyl and R5is tert-pentyl (2-methylbutan-2-yl). In embodiments, R2is methyl and R5is neopentyl (2,2-dimethylpropyl). In embodiments, R2is methyl and R5is isopentyl (3-methylbutyl). In embodiments, R2is methyl and R5is sec-pentyl (pentan-2-yl). In embodiments, R2is methyl and R5is pentan-3-yl. In embodiments, R2is methyl and R5is sec-isopentyl (3-methylbutan-2-yl). In embodiments, R2is methyl and R5is 2-methylbutyl. In embodiments, R2is methyl and R5is hexyl (including n-hexyl and all other hexyl isomers). In embodiments, R2is methyl and R5is n-propyl, n-butyl, n-pentyl, or n-hexyl.

[0133]

[0098] In some embodiments of Formula (I), R2is methyl and R5is C3-C6alkenyl. In embodiments, R2is methyl and R5is ethenyl (i.e., vinyl), propenyl (e.g., allyl), buteneyl, pentenyl, or hexenyl. In embodiments, R2 2025-11-28 is methyl and R5is vinyl. In embodiments, R2is methyl and R5is allyl.

[0134]

[0099] In some embodiments of Formula (I), R5is methyl and R2is C3-C6alkyl. In embodiments, R5is methyl and R2is propyl, butyl, pentyl, or hexyl. In embodiments, R5is methyl and R2is propyl. In embodiments, R5is methyl and R2is butyl. In embodiments, R5is methyl and R2is pentyl. In embodiments, R5is methyl and R2is hexyl. In embodiments, R5is methyl and R2is n-propyl, isopropyl (1 -methylethyl), n-butyl, sec-butyl (butan-2-yl), isobutyl (2-methylpropyl), tert-butyl, n-pentyl, tert-pentyl (2-methylbutan-2-yl), neopentyl (2,2-dimethyl-propyl), isopentyl (3-methylbutyl), sec-pentyl (pentan-2-yl), pentan-3-yl, sec-isopentyl (3-methylbutan-2-yl), or 2-methylbutyl. In embodiments, R5is methyl and R2is n-propyl. In embodiments, R5is methyl and R2is isopropyl (1 -methylethyl). In embodiments, R5is methyl and R2is n-butyl. In embodiments, R5is methyl and R2is sec-butyl (butan-2-yl). In embodiments, R5is methyl and R2is isobutyl (2-methylpropyl). In embodiments, R5is methyl and R2is tert-butyl. In embodiments, R5is methyl and R2is n-pentyl. In embodiments, R5is methyl and R2is tert-pentyl (2-methylbutan-2-yl). In embodiments, R5is methyl and R2is neopentyl (2,2-dimethylpropyl). In embodiments, R5is methyl and R2is isopentyl (3-methylbutyl). In embodiments, R5is methyl and R2is sec-pentyl (pentan-2-yl). In embodiments, R5is methyl and R2is pentan-3-yl. In embodiments, R5is methyl and R2is sec-isopentyl (3-methylbutan-2-yl). In embodiments, R5is methyl and R2is 2-methylbutyl. In embodiments, R5is methyl and R2is hexyl (including n-hexyl and all other hexyl isomers).

[0135]

[0100] In some embodiments of Formula (I), R5is methyl and R2is C3-C6alkenyl. In embodiments, R5is methyl and R2is ethenyl (i.e., vinyl), propenyl (e.g., allyl), buteneyl, pentenyl, or hexenyl. In embodiments, R5is methyl and R2is vinyl. In embodiments, R5is methyl and R2is allyl.

[0136]

[0101] In some embodiments, the compound has the structure:

[0137]

[0138] (Formula (II)), or a pharma, acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein: X is F, Cl, Br, I, C^Cg alkyl, C2-C6alkenyl, C2-C6alkynyl, C^Cg haloalkyl, C^Cg alkylthio, C^Cg haloalkylthio, C^Cg alkoxy, cyano, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; Rais H or C^Cg alkyl; and R5is C3-C6alkyl or C3-C6alkenyl.

[0139]

[0102] In some embodiments of Formula (II), X is F, Cl, Br, I, CrCg alkyl, C2-C6alkenyl, C2-C6alkynyl, CrCg haloalkyl, CrCg alkylthio, CrCg haloalkylthio, CrCg alkoxy, cyano, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl. In embodiments, X is F, Cl, Br, or I. In embodiments, X is F. In embodiments, X is Cl. In embodiments, X is Br. In embodiments, X is I. In embodiments, X is CrCg alkyl. For example, in some embodiments, X is methyl. In embodiments, X is ethyl. In embodiments, X is C2-C6alkenyl. In embodiments, X is C2-C6alkynyl. In embodiments, X is CrCg haloalkyl. For example, in some embodiments, X is CF3. In embodiments, X is CrCg alkylthio. For example, in some embodiments, X is — S— CH3. In embodiments, X is C^Cg haloalkylthio. In embodiments, X is C^Cg alkoxy. In embodiments, X is cyano. In embodiments, X is 2025-11-28 C3-C6cycloalkyl. In embodiments, X is 4- to 6-membered heterocycloalkyl.

[0140]

[0103] In some embodiments of Formula (II), Rais H or C^Cg alkyl. In embodiments, Rais H. In embodiments, Rais C^Cg alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl. In embodiments, Rais propyl.

[0141]

[0104] In embodiments of Formula (II), R5is C3-C6alkyl or C3-C6alkenyl. In embodiments, R5is n-propyl, n-butyl, n-pentyl, n-hexyl, or C3-C6alkenyl. In embodiments, R5is n-propyl, isopropyl (1 -methylethyl), n-butyl, sec-butyl (butan-2-yl), isobutyl (2-methylpropyl), tert-butyl, n-pentyl, tert-pentyl (2-methylbutan-2-yl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), sec-pentyl (pentan-2-yl), pentan-3-yl, sec-isopentyl (3-methyl-butan-2-yl), or 2-methylbutyl. In embodiments, R5is n-propyl. In embodiments, R5is isopropyl (1 -methylethyl). In embodiments, R5is n-butyl. In embodiments, R5is sec-butyl (butan-2-yl). In embodiments, R5is isobutyl (2-methylpropyl). In embodiments, R5is tert-butyl. In embodiments, R5is n-pentyl. In embodiments, R5is tert-pentyl (2-methylbutan-2-yl). In embodiments, R5is neopentyl (2,2-dimethylpropyl). In embodiments, R5is isopentyl (3-methylbutyl). In embodiments, R5is sec-pentyl (pentan-2-yl). In embodiments, R5is pentan-3-yl. In embodiments, R5is sec-isopentyl (3-methylbutan-2-yl). In embodiments, R5is 2-methylbutyl. In embodiments, R5is hexyl (including n-hexyl and all other hexyl isomers). In embodiments, R5is ethenyl (i.e., vinyl), propenyl (e.g., allyl), buteneyl, pentenyl, or hexenyl. In embodiments, R5is vinyl. In embodiments, R5is allyl.

[0142] X0

[0143] O.

[0144]

[0105] In some embodiments, the compound has the structure:

[0145]

[0146] \ (Formula (III)), or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein: X is F, Cl, Br, I, CrCg alkyl, C2-C6alkenyl, C2-C6alkynyl, C^Cg haloalkyl, C^Cg alkylthio, C^Cg haloalkylthio, C^Cg alkoxy, cyano, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; and Rais H or C^Cg alkyl.

[0147]

[0106] In some embodiments of Formula (III), X is F, Cl, Br, I, C^Cg alkyl, C2-C6alkenyl, C2-C6alkynyl, C^Cg haloalkyl, C^Cg alkylthio, C^Cg haloalkylthio, C^Cg alkoxy, cyano, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl. In embodiments, X is F, Cl, Br, or I. In embodiments, X is F. In embodiments, X is Cl. In embodiments, X is Br. In embodiments, X is I. In embodiments, X is C^Cg alkyl. For example, in some embodiments, X is methyl. In embodiments, X is ethyl. In embodiments, X is C2-C6alkenyl. In embodiments, X is C2-C6alkynyl. In embodiments, X is C^Cg haloalkyl. For example, in some embodiments, X is CF3. In embodiments, X is CrCg alkylthio. For example, in some embodiments, X is — S— CH3. In embodiments, X is CrCg haloalkylthio. In embodiments, X is CrCg alkoxy. In embodiments, X is cyano. In embodiments, X is C3-C6cycloalkyl. In embodiments, X is 4- to 6-membered heterocycloalkyl.

[0148]

[0107] In embodiments of Formula (III), Rais H or CrCg alkyl. In embodiments, Rais H. In embodiments, Rais CrCg alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl. In embodiments, Rais propyl. 2025-11-28

[0108] In some embodiments, the compound has the structure of any of Formulas (IV)-(XII I), wherein Ra, Rp, RN, X, R2, R3, R5, and R6, if present, are as defined for Formula (1):

[0149] OR2RP,, OR2Rp

[0150] „ j H

[0151] R;JL JL N R3JL JL N

[0152] K^ Y^R6X^^y ^R6

[0153] Formula (IV) OR5Formula (V) OR2

[0154] ?R2H / bcA

[0155] X^T X'^’Y

[0156] OR5Formula (VI) OR0Formula (VII) OR2OR2

[0157] X'^Y

[0158] OR5Formula (VIII) OR5Formula (IX)vo ^0

[0159] x'^Y

[0160] OR5Formula (X) OR5Formula (XI) ^0X0

[0161] x^T X^ Y^

[0162] 0

[0163] °\

[0164] \ Formula (XII) \ Formula (XIII)

[0165]

[0166]

[0109] In embodiments, the compound has the structure:

[0167]

[0168] OR5(Formula (XIV)), or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein Ra, X, R2, and R5are as defined for Formula (1), and Ar is C6-C12aryl. 2025-11-28

[0110] In some embodiments of Formula (XIV), the compound has the structure of any of Formulas (XlV-a),

[0169]

[0170] pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein Ra, X, and R5are as defined for Formula (1); Y is CH, 0, N, or S; and represents a single or double bond.

[0171]

[0112] In some embodiments of Formula (XV), Rais H. In some embodiments of Formula (XV), Rais methyl. In some embodiments of Formula (XV), Rais ethyl.

[0172]

[0113] In embodiments, the compound has the structure:

[0173]

[0174] (Formula (XVI)), or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein Ra, X, and R5are as defined for Formula (1); Y is CH, 0, N, or S; and

[0175]

[0176] represents a single or double bond.

[0177]

[0114] In some embodiments of Formula (XVI), the compound has the structure of any of the Formulas

[0178]

[0179] 2025-11-28

[0180]

[0115] In some embodiments, the compound has the structure

[0181]

[0182] OR5, with R2, R5, Ra, and X as provided in TABLE 1, i.e., the compound is selected from any of Compound Nos. 1-462 of TABLE 1. TABLE 1. Exemplary compounds

[0183] No. R2 R5 Ra X

[0184] 1 -CH3 -CH2CH2CH3 -CH3 -Br 2 -CH3 — CH2(CH3)2 -CH3 -Br 3 -CH3 — CH2CH2=CH2 -CH3 -Br 4 -CH3 — (CH2)3CH3 -CH3 -Br 5 -CH3 — CH(CH3)CH2CH3 -CH3 -Br 6 -CH3 — CH2CH(CH3)2 -CH3 -Br 7 -CH3 — C(CH3)3 -CH3 -Br 8 -CH3 — CH2(CH2)4CH3 -CH3 -Br 9 -CH3 — CH2C(CH3)3 -CH3 -Br 10 -CH3 -CH2CH2CH3 -CH3 — F

[0185] 11 -CH3 — CH2(CH3)2 -CH3 — F

[0186] 12 -CH3 — CH2CH2=CH2 -CH3 — F

[0187] 13 -CH3 — (CH2)3CH3 -CH3 — F

[0188] 14 -CH3 — CH(CH3)CH2CH3 -CH3 — F

[0189] 15 -CH3 — CH2CH(CH3)2 -CH3 — F

[0190] 16 -CH3 — C(CH3)3 -CH3 — F

[0191] 17 -CH3 — CH2(CH2)4CH3 -CH3 — F

[0192] 18 -CH3 — CH2C(CH3)3 -CH3 — F

[0193] 19 -CH3 -CH2CH2CH3 -CH3 -Cl 20 -CH3 — CH2(CH3)2 -CH3 -Cl 21 -CH3 — CH2CH2=CH2 -CH3 -Cl 22 -CH3 — (CH2)3CH3 -CH3 -Cl 23 -CH3 — CH(CH3)CH2CH3 -CH3 -Cl 24 -CH3 — CH2CH(CH3)2 -CH3 -Cl 25 -CH3 — C(CH3)3 -CH3 -Cl 26 -CH3 — CH2(CH2)4CH3 -CH3 -Cl 27 -CH3 — CH2C(CH3)3 -CH3 -Cl 28 -CH3 -CH2CH2CH3 -CH3 -I

[0194] 29 -CH3 — CH2(CH3)2 -CH3 -I

[0195] 30 -CH3 — CH2CH2=CH2 -CH3 -I

[0196]

[0197] 2025-11-28 No. R2 R5 Ra X 31 — CH3 — (CH2)3CH3 — CH3 -I 32 — CH3 — CH(CH3)CH2CH3 — CH3 -I 33 — CH3 — CH2CH(CH3)2 — CH3 -I 34 — CH3 — C(CH3)3 — CH3 -I 35 — CH3 — CH2(CH2)4CH3 — CH3 -I 36 — CH3 — CH2C(CH3)3 — CH3 -I 37 — CH3 — CH2CH2CH3 — CH3 — CF3 38 — CH3 — CH2(CH3)2 — CH3 -CF3 39 — CH3 — CH2CH2=CH2 — CH3 -CF3 40 — CH3 — (CH2)3CH3 — CH3 -CF3 41 — CH3 — CH(CH3)CH2CH3 — CH3 -CF3 42 — CH3 — CH2CH(CH3)2 — CH3 -CF3 43 — CH3 — C(CH3)3 — CH3 -CF3 44 — CH3 — CH2(CH2)4CH3 — CH3 -CF3 45 — CH3 — CH2C(CH3)3 — CH3 -CF3 46 — CH3 — CH2CH2CH3 — CH3 — CH3 47 — CH3 — CH2(CH3)2 — CH3 — CH3 48 — CH3 — CH2CH2=CH2 — CH3 — CH3 49 — CH3 — (CH2)3CH3 — CH3 — CH3 50 — CH3 — CH(CH3)CH2CH3 — CH3 — CH3 51 — CH3 — CH2CH(CH3)2 — CH3 — CH3 52 — CH3 — C(CH3)3 — CH3 — CH3 53 — CH3 — CH2(CH2)4CH3 — CH3 — CH3 54 — CH3 — CH2C(CH3)3 — CH3 — CH3 55 — CH3 — CH2CH2CH3 — CH3 -SCH3 56 — CH3 — CH2(CH3)2 — CH3 -SCH3 57 — CH3 — CH2CH2=CH2 — CH3 -SCH3 58 — CH3 — (CH2)3CH3 — CH3 -SCH3 59 — CH3 — CH(CH3)CH2CH3 — CH3 -SCH3 60 — CH3 — CH2CH(CH3)2 — CH3 -SCH3 61 — CH3 — C(CH3)3 — CH3 -SCH3 62 — CH3 — CH2(CH2)4CH3 — CH3 -SCH3 63 — CH3 — CH2C(CH3)3 — CH3 -SCH3 64 — CH3 — CH2CH2CH3 — CH3 — SCH2CH3 65 — CH3 — CH2(CH3)2 — CH3 — SCH2CH3

[0198]

[0199] 66 — CH3 — CH2CH2=CH2 — CH3 — SCH2CH3 2025-11-28 No. R2 R5 Ra X 67 — CH3 — (CH2)3CH3 — CH3 — SCH2CH3 68 — CH3 — CH(CH3)CH2CH3 — CH3 — SCH2CH3 69 — CH3 — CH2CH(CH3)2 — CH3 — SCH2CH3 70 — CH3 — C(CH3)3 — CH3 — SCH2CH3 71 — CH3 — CH2(CH2)4CH3 — CH3 — SCH2CH3 72 — CH3 — CH2C(CH3)3 — CH3 — SCH2CH3 73 — CH3 — CH2CH2CH3 — CH3 — S(CH2)2CH3 74 — CH3 — CH2(CH3)2 — CH3 — S(CH2)2CH3 75 — CH3 — CH2CH2=CH2 — CH3 — S(CH2)2CH3 76 — CH3 — (CH2)3CH3 — CH3 — S(CH2)2CH3 77 — CH3 — CH(CH3)CH2CH3 — CH3 — S(CH2)2CH3 78 — CH3 — CH2CH(CH3)2 — CH3 — S(CH2)2CH3 79 — CH3 — C(CH3)3 — CH3 — S(CH2)2CH3 80 — CH3 — CH2(CH2)4CH3 — CH3 — S(CH2)2CH3 81 — CH3 — CH2C(CH3)3 — CH3 — S(CH2)2CH3 82 — CH3 — CH2CH2CH3 — CH3 — SCH(CH3)2 83 — CH3 — CH2(CH3)2 — CH3 — SCH(CH3)2 84 — CH3 — CH2CH2=CH2 — CH3 — SCH(CH3)2 85 — CH3 — (CH2)3CH3 — CH3 — SCH(CH3)2 86 — CH3 — CH(CH3)CH2CH3 — CH3 — SCH(CH3)2 87 — CH3 — CH2CH(CH3)2 — CH3 — SCH(CH3)2 88 — CH3 — C(CH3)3 — CH3 — SCH(CH3)2 89 — CH3 — CH2(CH2)4CH3 — CH3 — SCH(CH3)2 90 — CH3 — CH2C(CH3)3 — CH3 — SCH(CH3)2 91 — CH3 — CH2CH2CH3 — CH3 -CH2CH3 92 — CH3 — CH2(CH3)2 — CH3 -CH2CH3 93 — CH3 — CH2CH2=CH2 — CH3 -CH2CH3 94 — CH3 — (CH2)3CH3 — CH3 -CH2CH3 95 — CH3 — CH(CH3)CH2CH3 — CH3 -CH2CH3 96 — CH3 — CH2CH(CH3)2 — CH3 -CH2CH3 97 — CH3 — C(CH3)3 — CH3 -CH2CH3 98 — CH3 — CH2(CH2)4CH3 — CH3 -CH2CH3 99 — CH3 — CH2C(CH3)3 — CH3 -CH2CH3 100 — CH3 — CH(CH3)(CH2)2CH3 — CH3 -CH2CH3 101 — CH3 — CH2CH2(CH3)2 — CH3 -CH2CH3

[0200]

[0201] 102 — CH3 — CH2C(CH3) — CH3 -CH2CH3 2025-11-28 No. R2 R5 Ra X 103 — CH3 — CH2CH2CH3 -CH2CH3 — Br 104 — CH3 — CH2(CH3)2 -CH2CH3 — Br 105 — CH3 — CH2CH2=CH2 -CH2CH3 -Br 106 — CH3 — (CH2)3CH3 -CH2CH3 -Br 107 — CH3 — CH(CH3)CH2CH3 -CH2CH3 -Br 108 — CH3 — CH2CH(CH3)2 -CH2CH3 -Br 109 — CH3 — C(CH3)3 -CH2CH3 -Br 110 — CH3 — CH2(CH2)4CH3 -CH2CH3 -Br 111 — CH3 — CH2C(CH3)3 -CH2CH3 -Br 112 — CH3 — CH2CH2CH3 -CH2CH3 — F 113 — CH3 — CH2(CH3)2 -CH2CH3 — F 114 — CH3 — CH2CH2=CH2 -CH2CH3 — F 115 — CH3 — (CH2)3CH3 -CH2CH3 — F 116 — CH3 — CH(CH3)CH2CH3 -CH2CH3 — F 117 — CH3 — CH2CH(CH3)2 -CH2CH3 — F 118 — CH3 — C(CH3)3 -CH2CH3 — F 119 — CH3 — CH2(CH2)4CH3 -CH2CH3 — F 120 — CH3 — CH2C(CH3)3 -CH2CH3 — F 121 — CH3 — CH2CH2CH3 -CH2CH3 -Cl 122 — CH3 — CH2(CH3)2 -CH2CH3 -Cl 123 — CH3 — CH2CH2=CH2 -CH2CH3 -Cl 124 — CH3 — (CH2)3CH3 -CH2CH3 -Cl 125 — CH3 — CH(CH3)CH2CH3 -CH2CH3 -Cl 126 — CH3 — CH2CH(CH3)2 -CH2CH3 -Cl 127 — CH3 — C(CH3)3 -CH2CH3 -Cl 128 — CH3 — CH2(CH2)4CH3 -CH2CH3 -Cl 129 — CH3 — CH2C(CH3)3 -CH2CH3 -Cl 130 — CH3 — CH2CH2CH3 -CH2CH3 -I 131 — CH3 — CH2(CH3)2 -CH2CH3 -I 132 — CH3 — CH2CH2=CH2 -CH2CH3 -I 133 — CH3 — (CH2)3CH3 -CH2CH3 -I 134 — CH3 — CH(CH3)CH2CH3 -CH2CH3 -I 135 — CH3 — CH2CH(CH3)2 -CH2CH3 -I 136 — CH3 — C(CH3)3 -CH2CH3 -I 137 — CH3 — CH2(CH2)4CH3 -CH2CH3 -I

[0202]

[0203] 138 — CH3 — CH2C(CH3)3 -CH2CH3 -I 2025-11-28 No. R2 R5 Ra X 139 — CH3 — CH2CH2CH3 -CH2CH3 — CF3 140 — CH3 — CH2(CH3)2 -CH2CH3 -CF3 141 — CH3 — CH2CH2=CH2 -CH2CH3 -CF3 142 — CH3 — (CH2)3CH3 -CH2CH3 -CF3 143 — CH3 — CH(CH3)CH2CH3 -CH2CH3 -CF3 144 — CH3 — CH2CH(CH3)2 -CH2CH3 -CF3 145 — CH3 — C(CH3)3 -CH2CH3 -CF3 146 — CH3 — CH2(CH2)4CH3 -CH2CH3 -CF3 147 — CH3 — CH2C(CH3)3 -CH2CH3 -CF3 148 — CH3 — CH2CH2CH3 -CH2CH3 — CH3 149 — CH3 — CH2(CH3)2 -CH2CH3 — CH3 150 — CH3 — CH2CH2=CH2 -CH2CH3 — CH3 151 — CH3 — (CH2)3CH3 -CH2CH3 — CH3 152 — CH3 — CH(CH3)CH2CH3 -CH2CH3 — CH3 153 — CH3 — CH2CH(CH3)2 -CH2CH3 — CH3 154 — CH3 — C(CH3)3 -CH2CH3 — CH3 155 — CH3 — CH2(CH2)4CH3 -CH2CH3 — CH3 156 — CH3 — CH2C(CH3)3 -CH2CH3 — CH3 157 — CH3 — CH2CH2CH3 -CH2CH3 -SCH3 158 — CH3 — CH2(CH3)2 -CH2CH3 -SCH3 159 — CH3 — CH2CH2=CH2 -CH2CH3 -SCH3 160 — CH3 — (CH2)3CH3 -CH2CH3 -SCH3 161 — CH3 — CH(CH3)CH2CH3 -CH2CH3 -SCH3 162 — CH3 — CH2CH(CH3)2 -CH2CH3 -SCH3 163 — CH3 — C(CH3)3 -CH2CH3 -SCH3 164 — CH3 — CH2(CH2)4CH3 -CH2CH3 -SCH3 165 — CH3 — CH2C(CH3)3 -CH2CH3 -SCH3 166 — CH3 — CH2CH2CH3 -CH2CH3 — SCH2CH3 167 — CH3 — CH2(CH3)2 -CH2CH3 — SCH2CH3 168 — CH3 — CH2CH2=CH2 -CH2CH3 — SCH2CH3 169 — CH3 — (CH2)3CH3 -CH2CH3 — SCH2CH3 170 — CH3 — CH(CH3)CH2CH3 -CH2CH3 — SCH2CH3 171 — CH3 — CH2CH(CH3)2 -CH2CH3 — SCH2CH3 172 — CH3 — C(CH3)3 -CH2CH3 — SCH2CH3 173 — CH3 — CH2(CH2)4CH3 -CH2CH3 — SCH2CH3

[0204]

[0205] 174 — CH3 — CH2C(CH3)3 -CH2CH3 — SCH2CH3 2025-11-28 No. R2 R5 Ra X 175 — CH3 — CH2CH2CH3 -CH2CH3 — S(CH2)2CH3 176 — CH3 — CH2(CH3)2 -CH2CH3 — S(CH2)2CH3 177 — CH3 — CH2CH2=CH2 -CH2CH3 — S(CH2)2CH3 178 — CH3 — (CH2)3CH3 -CH2CH3 — S(CH2)2CH3 179 — CH3 — CH(CH3)CH2CH3 -CH2CH3 — S(CH2)2CH3 180 — CH3 — CH2CH(CH3)2 -CH2CH3 — S(CH2)2CH3 181 — CH3 — C(CH3)3 -CH2CH3 — S(CH2)2CH3 182 — CH3 — CH2(CH2)4CH3 -CH2CH3 — S(CH2)2CH3 183 — CH3 — CH2C(CH3)3 -CH2CH3 — S(CH2)2CH3 184 — CH3 — CH2CH2CH3 -CH2CH3 — SCH(CH3)2 185 — CH3 — CH2(CH3)2 -CH2CH3 — SCH(CH3)2 186 — CH3 — CH2CH2=CH2 -CH2CH3 — SCH(CH3)2 187 — CH3 — (CH2)3CH3 -CH2CH3 — SCH(CH3)2 188 — CH3 — CH(CH3)CH2CH3 -CH2CH3 — SCH(CH3)2 189 — CH3 — CH2CH(CH3)2 -CH2CH3 — SCH(CH3)2 190 — CH3 — C(CH3)3 -CH2CH3 — SCH(CH3)2 191 — CH3 — CH2(CH2)4CH3 -CH2CH3 — SCH(CH3)2 192 — CH3 — CH2C(CH3)3 -CH2CH3 — SCH(CH3)2 193 — CH3 — CH2CH2CH3 -CH2CH3 -CH2CH3 194 — CH3 — CH2(CH3)2 -CH2CH3 -CH2CH3 195 — CH3 — CH2CH2=CH2 -CH2CH3 -CH2CH3 196 — CH3 — (CH2)3CH3 -CH2CH3 -CH2CH3 197 — CH3 — CH(CH3)CH2CH3 -CH2CH3 -CH2CH3 198 — CH3 — CH2CH(CH3)2 -CH2CH3 -CH2CH3 199 — CH3 — C(CH3)3 -CH2CH3 -CH2CH3 200 — CH3 — CH2(CH2)4CH3 -CH2CH3 -CH2CH3 201 — CH3 — CH2C(CH3)3 -CH2CH3 -CH2CH3 202 — CH3 — CH(CH3)(CH2)2CH3 -CH2CH3 -CH2CH3 203 — CH3 — CH2CH2(CH3)2 -CH2CH3 -CH2CH3 204 — CH3 — CH2C(CH3) -CH2CH3 -CH2CH3 205 — CH2CH2CH3 — CH3 — CH3 — Br 206 — CH2(CH3)2 — CH3 — CH3 — Br 207 — CH2CH2=CH2 — CH3 — CH3 -Br 208 — (CH2)3CH3 — CH3 — CH3 -Br 209 — CH(CH3)CH2CH3 — CH3 — CH3 -Br

[0206]

[0207] 210 — CH2CH(CH3)2 — CH3 — CH3 -Br 2025-11-28 No. R2 R5 Ra X 211 — C(CH3)3 — CH3 — CH3 — Br 212 — CH2(CH2)4CH3 — CH3 — CH3 — Br 213 — CH2C(CH3)3 — CH3 — CH3 -Br 214 — CH2CH2CH3 — CH3 — CH3 — F 215 — CH2(CH3)2 — CH3 — CH3 — F 216 — CH2CH2=CH2 — CH3 — CH3 — F 217 — (CH2)3CH3 — CH3 — CH3 — F 218 — CH(CH3)CH2CH3 — CH3 — CH3 — F 219 — CH2CH(CH3)2 — CH3 — CH3 — F 220 — C(CH3)3 — CH3 — CH3 — F 221 — CH2(CH2)4CH3 — CH3 — CH3 — F 222 — CH2C(CH3)3 — CH3 — CH3 — F 223 — CH2CH2CH3 — CH3 — CH3 -Cl 224 — CH2(CH3)2 — CH3 — CH3 -Cl 225 — CH2CH2=CH2 — CH3 — CH3 -Cl 226 — (CH2)3CH3 — CH3 — CH3 -Cl 227 — CH(CH3)CH2CH3 — CH3 — CH3 -Cl 228 — CH2CH(CH3)2 — CH3 — CH3 -Cl 229 — C(CH3)3 — CH3 — CH3 -Cl 230 — CH2(CH2)4CH3 — CH3 — CH3 -Cl 231 — CH2C(CH3)3 — CH3 — CH3 -Cl 232 — CH2CH2CH3 — CH3 — CH3 -I 233 — CH2(CH3)2 — CH3 — CH3 -I 234 — CH2CH2=CH2 — CH3 — CH3 -I 235 — (CH2)3CH3 — CH3 — CH3 -I 236 — CH(CH3)CH2CH3 — CH3 — CH3 -I 237 — CH2CH(CH3)2 — CH3 — CH3 -I 238 — C(CH3)3 — CH3 — CH3 -I 239 — CH2(CH2)4CH3 — CH3 — CH3 -I 240 — CH2C(CH3)3 — CH3 — CH3 -I 241 — CH2CH2CH3 — CH3 — CH3 -CF3 242 — CH2(CH3)2 — CH3 — CH3 -CF3 243 — CH2CH2=CH2 — CH3 — CH3 -CF3 244 — (CH2)3CH3 — CH3 — CH3 -CF3 245 — CH(CH3)CH2CH3 — CH3 — CH3 -CF3

[0208]

[0209] 246 — CH2CH(CH3)2 — CH3 — CH3 -CF3 2025-11-28 No. R2 R5 Ra X 247 — C(CH3)3 — CH3 — CH3 — CF3 248 — CH2(CH2)4CH3 — CH3 — CH3 -CF3 249 — CH2C(CH3)3 — CH3 — CH3 -CF3 250 — CH2CH2CH3 — CH3 — CH3 — CH3 251 — CH2(CH3)2 — CH3 — CH3 — CH3 252 — CH2CH2=CH2 — CH3 — CH3 — CH3 253 — (CH2)3CH3 — CH3 — CH3 — CH3 254 — CH(CH3)CH2CH3 — CH3 — CH3 — CH3 255 — CH2CH(CH3)2 — CH3 — CH3 — CH3 256 — C(CH3)3 — CH3 — CH3 — CH3 257 — CH2(CH2)4CH3 — CH3 — CH3 — CH3 258 — CH2C(CH3)3 — CH3 — CH3 — CH3 259 — CH2CH2CH3 — CH3 — CH3 -SCH3 260 — CH2(CH3)2 — CH3 — CH3 -SCH3 261 — CH2CH2=CH2 — CH3 — CH3 -SCH3 262 — (CH2)3CH3 — CH3 — CH3 -SCH3 263 — CH(CH3)CH2CH3 — CH3 — CH3 -SCH3 264 — CH2CH(CH3)2 — CH3 — CH3 -SCH3 265 — C(CH3)3 — CH3 — CH3 -SCH3 266 — CH2(CH2)4CH3 — CH3 — CH3 -SCH3 267 — CH2C(CH3)3 — CH3 — CH3 -SCH3 268 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 269 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 270 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 271 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 272 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 273 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 274 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 275 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 276 — CH2C(CH3)3 — CH3 — CH3 — SCH2CH3 277 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3 278 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3 279 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3 280 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3 281 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3

[0210]

[0211] 282 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3 2025-11-28 No. R2 R5 Ra X 283 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3 284 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3 285 — CH2C(CH3)3 — CH3 — CH3 — S(CH2)2CH3 286 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 287 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 288 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 289 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 290 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 291 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 292 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 293 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 294 — CH2C(CH3)3 — CH3 — CH3 — SCH(CH3)2 295 — CH2CH2CH3 — CH3 — CH3 -CH2CH3 296 — CH2(CH3)2 — CH3 — CH3 -CH2CH3 297 — CH2CH2=CH2 — CH3 — CH3 -CH2CH3 298 — (CH2)3CH3 — CH3 — CH3 -CH2CH3 299 — CH(CH3)CH2CH3 — CH3 — CH3 -CH2CH3 300 — CH2CH(CH3)2 — CH3 — CH3 -CH2CH3 301 — C(CH3)3 — CH3 — CH3 -CH2CH3 302 — CH2(CH2)4CH3 — CH3 — CH3 -CH2CH3 303 — CH2C(CH3)3 — CH3 — CH3 -CH2CH3 304 — CH(CH3)(CH2)2CH3 — CH3 — CH3 -CH2CH3 305 — CH2CH2(CH3)2 — CH3 — CH3 -CH2CH3 306 — CH2C(CH3) — CH3 — CH3 -CH2CH3 307 — CH2CH2CH3 — CH3 -CH2CH3 — Br 308 — CH2(CH3)2 — CH3 -CH2CH3 — Br 309 — CH2CH2=CH2 — CH3 -CH2CH3 -Br 310 — (CH2)3CH3 — CH3 -CH2CH3 -Br 311 — CH(CH3)CH2CH3 — CH3 -CH2CH3 -Br 312 — CH2CH(CH3)2 — CH3 -CH2CH3 -Br 313 — C(CH3)3 — CH3 -CH2CH3 -Br 314 — CH2(CH2)4CH3 — CH3 -CH2CH3 -Br 315 — CH2C(CH3)3 — CH3 -CH2CH3 -Br 316 — CH2CH2CH3 — CH3 -CH2CH3 — F 317 — CH2(CH3)2 — CH3 -CH2CH3 — F

[0212]

[0213] 318 — CH2CH2=CH2 — CH3 -CH2CH3 — F 2025-11-28 No. R2 R5 Ra X 319 — (CH2)3CH3 — CH3 -CH2CH3 — F 320 — CH(CH3)CH2CH3 — CH3 -CH2CH3 — F 321 — CH2CH(CH3)2 — CH3 -CH2CH3 — F 322 — C(CH3)3 — CH3 -CH2CH3 — F 323 — CH2(CH2)4CH3 — CH3 -CH2CH3 — F 324 — CH2C(CH3)3 — CH3 -CH2CH3 — F 325 — CH2CH2CH3 — CH3 -CH2CH3 -Cl 326 — CH2(CH3)2 — CH3 -CH2CH3 -Cl 327 — CH2CH2=CH2 — CH3 -CH2CH3 -Cl 328 — (CH2)3CH3 — CH3 -CH2CH3 -Cl 329 — CH(CH3)CH2CH3 — CH3 -CH2CH3 -Cl 330 — CH2CH(CH3)2 — CH3 -CH2CH3 -Cl 331 — C(CH3)3 — CH3 -CH2CH3 -Cl 332 — CH2(CH2)4CH3 — CH3 -CH2CH3 -Cl 333 — CH2C(CH3)3 — CH3 -CH2CH3 -Cl 334 — CH2CH2CH3 — CH3 -CH2CH3 -I 335 — CH2(CH3)2 — CH3 -CH2CH3 -I 336 — CH2CH2=CH2 — CH3 -CH2CH3 -I 337 — (CH2)3CH3 — CH3 -CH2CH3 -I 338 — CH(CH3)CH2CH3 — CH3 -CH2CH3 -I 339 — CH2CH(CH3)2 — CH3 -CH2CH3 -I 340 — C(CH3)3 — CH3 -CH2CH3 -I 341 — CH2(CH2)4CH3 — CH3 -CH2CH3 -I 342 — CH2C(CH3)3 — CH3 -CH2CH3 -I 343 — CH2CH2CH3 — CH3 -CH2CH3 -CF3 344 — CH2(CH3)2 — CH3 -CH2CH3 -CF3 345 — CH2CH2=CH2 — CH3 -CH2CH3 -CF3 346 — (CH2)3CH3 — CH3 -CH2CH3 -CF3 347 — CH(CH3)CH2CH3 — CH3 -CH2CH3 -CF3 348 — CH2CH(CH3)2 — CH3 -CH2CH3 -CF3 349 — C(CH3)3 — CH3 -CH2CH3 -CF3 350 — CH2(CH2)4CH3 — CH3 -CH2CH3 -CF3 351 — CH2C(CH3)3 — CH3 -CH2CH3 -CF3 352 — CH2CH2CH3 — CH3 -CH2CH3 -CH3 353 — CH2(CH3)2 — CH3 -CH2CH3 -CH3

[0214]

[0215] 354 — CH2CH2=CH2 — CH3 -CH2CH3 -CH3 2025-11-28 No. R2 R5 Ra X 355 — (CH2)3CH3 — CH3 -CH2CH3 — CH3 356 — CH(CH3)CH2CH3 — CH3 -CH2CH3 — CH3 357 — CH2CH(CH3)2 — CH3 -CH2CH3 — CH3 358 — C(CH3)3 — CH3 -CH2CH3 — CH3 359 — CH2(CH2)4CH3 — CH3 -CH2CH3 — CH3 360 — CH2C(CH3)3 — CH3 -CH2CH3 — CH3 361 — CH2CH2CH3 — CH3 -CH2CH3 -SCH3 362 — CH2(CH3)2 — CH3 -CH2CH3 -SCH3 363 — CH2CH2=CH2 — CH3 -CH2CH3 -SCH3 364 — (CH2)3CH3 — CH3 -CH2CH3 -SCH3 365 — CH(CH3)CH2CH3 — CH3 -CH2CH3 -SCH3 366 — CH2CH(CH3)2 — CH3 -CH2CH3 -SCH3 367 — C(CH3)3 — CH3 -CH2CH3 -SCH3 368 — CH2(CH2)4CH3 — CH3 -CH2CH3 -SCH3 369 — CH2C(CH3)3 — CH3 -CH2CH3 -SCH3 370 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 371 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 372 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 373 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 374 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 375 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 376 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 377 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 378 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH2CH3 379 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 380 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 381 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 382 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 383 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 384 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 385 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 386 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 387 — CH2C(CH3)3 — CH3 -CH2CH3 — S(CH2)2CH3 388 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2 389 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2

[0216]

[0217] 390 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2 2025-11-28 No. R2 R5 Ra X 391 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2 392 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2 393 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2 394 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2 395 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2 396 — CH2C(CH3)3 — CH3 -CH2CH3 — SCH(CH3)2 397 — CH2CH2CH3 — CH3 -CH2CH3 -CH2CH3 398 — CH2(CH3)2 — CH3 -CH2CH3 -CH2CH3 399 — CH2CH2=CH2 — CH3 -CH2CH3 -CH2CH3 400 — (CH2)3CH3 — CH3 -CH2CH3 -CH2CH3 401 — CH(CH3)CH2CH3 — CH3 -CH2CH3 -CH2CH3 402 — CH2CH(CH3)2 — CH3 -CH2CH3 -CH2CH3 403 — C(CH3)3 — CH3 -CH2CH3 -CH2CH3 404 — CH2(CH2)4CH3 — CH3 -CH2CH3 -CH2CH3 405 — CH2C(CH3)3 — CH3 -CH2CH3 -CH2CH3 406 — CH(CH3)(CH2)2CH3 — CH3 -CH2CH3 -CH2CH3 407 — CH2CH2(CH3)2 — CH3 -CH2CH3 -CH2CH3 408 — CH2C(CH3) — CH3 -CH2CH3 -CH2CH3 409 — CH3 — CH2CH2CH3 — H — SCH2CH3 410 — CH3 — CH2(CH3)2 — H — SCH2CH3 411 — CH3 — CH2CH2=CH2 — H — SCH2CH3 412 — CH3 — (CH2)3CH3 — H — SCH2CH3 413 — CH3 — CH(CH3)CH2CH3 — H — SCH2CH3 414 — CH3 — CH2CH(CH3)2 — H — SCH2CH3 415 — CH3 — C(CH3)3 — H — SCH2CH3 416 — CH3 — CH2(CH2)4CH3 — H — SCH2CH3 417 — CH3 — CH2C(CH3)3 — H — SCH2CH3 418 — CH3 — CH2CH2CH3 — H — S(CH2)2CH3 419 — CH3 — CH2(CH3)2 — H — S(CH2)2CH3 420 — CH3 — CH2CH2=CH2 — H — S(CH2)2CH3 421 — CH3 — (CH2)3CH3 — H — S(CH2)2CH3 422 — CH3 — CH(CH3)CH2CH3 — H — S(CH2)2CH3 423 — CH3 — CH2CH(CH3)2 — H — S(CH2)2CH3 424 — CH3 — C(CH3)3 — H — S(CH2)2CH3 425 — CH3 — CH2(CH2)4CH3 — H — S(CH2)2CH3

[0218]

[0219] 426 — CH3 — CH2C(CH3)3 — H — S(CH2)2CH3 2025-11-28 No. R2 R5 Ra X 427 — CH3 — CH2CH2CH3 — H — SCH(CH3)2 428 — CH3 — CH2(CH3)2 — H — SCH(CH3)2 429 — CH3 — CH2CH2=CH2 — H — SCH(CH3)2 430 — CH3 — (CH2)3CH3 — H — SCH(CH3)2 431 — CH3 — CH(CH3)CH2CH3 — H — SCH(CH3)2 432 — CH3 — CH2CH(CH3)2 — H — SCH(CH3)2 433 — CH3 — C(CH3)3 — H — SCH(CH3)2 434 — CH3 — CH2(CH2)4CH3 — H — SCH(CH3)2 435 — CH3 — CH2C(CH3)3 — H — SCH(CH3)2 436 — CH2CH2CH3 — CH3 — H — SCH2CH3 437 — CH2(CH3)2 — CH3 — H — SCH2CH3 438 — CH2CH2=CH2 — CH3 — H — SCH2CH3 439 — (CH2)3CH3 — CH3 — H — SCH2CH3 440 — CH(CH3)CH2CH3 — CH3 — H — SCH2CH3 441 — CH2CH(CH3)2 — CH3 — H — SCH2CH3 442 — C(CH3)3 — CH3 — H — SCH2CH3 443 — CH2(CH2)4CH3 — CH3 — H — SCH2CH3 444 — CH2C(CH3)3 — CH3 — H — SCH2CH3 445 — CH2CH2CH3 — CH3 — H — S(CH2)2CH3 446 — CH2(CH3)2 — CH3 — H — S(CH2)2CH3 447 — CH2CH2=CH2 — CH3 — H — S(CH2)2CH3 448 — (CH2)3CH3 — CH3 — H — S(CH2)2CH3 449 — CH(CH3)CH2CH3 — CH3 — H — S(CH2)2CH3 450 — CH2CH(CH3)2 — CH3 — H — S(CH2)2CH3 451 — C(CH3)3 — CH3 — H — S(CH2)2CH3 452 — CH2(CH2)4CH3 — CH3 — H — S(CH2)2CH3 453 — CH2C(CH3)3 — CH3 — H — S(CH2)2CH3 454 — CH2CH2CH3 — CH3 — H — SCH(CH3)2 455 — CH2(CH3)2 — CH3 — H — SCH(CH3)2 456 — CH2CH2=CH2 — CH3 — H — SCH(CH3)2 457 — (CH2)3CH3 — CH3 — H — SCH(CH3)2 458 — CH(CH3)CH2CH3 — CH3 — H — SCH(CH3)2 459 — CH2CH(CH3)2 — CH3 — H — SCH(CH3)2 460 — C(CH3)3 — CH3 — H — SCH(CH3)2 461 — CH2(CH2)4CH3 — CH3 — H — SCH(CH3)2

[0220]

[0221] 462 — CH2C(CH3)3 — CH3 — H — SCH(CH3)2 2025-11-28

[0222]

[0116] In some embodiments, the compound, or the pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, has the structure of any of the compounds of TABLE 2.

[0223]

[0224] 2025-11-28

[0117] In some embodiments, wherein R2is methyl and R5is isopropyl, X is not Br. In embodiments, wherein R2is methyl and R5is isopropyl, X is not I. In embodiments, wherein R2is methyl and R5is isopropyl, X is not ethyl. In embodiments, wherein R2is methyl and R5is isopropyl, X is F, Cl, I, or CF3. In embodiments, wherein R2is methyl and R5is isopropyl, X is F, Cl, or CF3. In embodiments, wherein R2is methyl and R5is isopropyl, X is F. In embodiments, wherein R2is methyl and R5is isopropyl, X is Cl. In embodiments, wherein R2is methyl and R5is isopropyl, X is CF3. In embodiments, R5is not isopropyl. In embodiments, wherein X is Br and R2is methyl, R5is not isopropyl. In embodiments, wherein X is I and R2is methyl, R5is not isopropyl. In embodiments, wherein X is Br and R2is methyl, R5is n-propyl. In embodiments, wherein X is I and R2is methyl, R5is n-propyl. In embodiments, wherein X is Br and R2is methyl, R5is butyl, pentyl, or hexyl (including n-butyl, n-pentyl, n-hexyl, and all other isomers). In embodiments, wherein X is I and R2is methyl, R5is butyl, pentyl, or hexyl (including n-butyl, n-pentyl, n-hexyl, and all other isomers). In embodiments, wherein R5is methyl and R2is isopropyl, X is not Br. In embodiments, wherein R5is methyl and R2is isopropyl, X is not I. In embodiments, wherein R5is methyl and R2is isopropyl, X is F, Cl, I, or CF3. In embodiments, wherein R5is methyl and R2is isopropyl, X is F, Cl, or CF3. In embodiments, wherein R5is methyl and R2is isopropyl, X is F. In embodiments, wherein R5is methyl and R2is isopropyl, X is Cl. In embodiments, wherein R5is methyl and R2is isopropyl, X is CF3. In embodiments, R2is not isopropyl. In embodiments, wherein X is Br and R5is methyl, R2is not isopropyl. In embodiments, wherein X is I and R5is methyl, R2is not isopropyl. In embodiments, wherein X is Br and R5is methyl, R2is n-propyl. In embodiments, wherein X is I and R5is methyl, R2is n-propyl. In embodiments, wherein X is Br and R5is methyl, R2is butyl, pentyl, or hexyl (including n-butyl, n-pentyl, n-hexyl, and all other isomers). In embodiments, wherein X is I and R5is methyl, R2is butyl, pentyl, or hexyl (including n-butyl, n-pentyl, n-hexyl, and all other isomers).

[0225]

[0118] In some embodiments, the compound is the (R)-enantiomer. In some embodiments, the compound is the (S)-enantiomer. In some embodiments, the compound is in enantiomerically enriched form, such as having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.

[0226]

[0119] In embodiments, the compound is not

[0227]

[0228] In embodiments, the compound is

[0229]

[0230] 2025-11-28

[0231]

[0232] In some embodiments, it is not. In embodiments, it is not

[0233]

[0234]

[0120] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety may be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. It is also understood that all descriptions, variations, embodiments, or aspects of any formula herein, where applicable, apply equally to other formulas herein, and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulas. Hence, in some embodiments, a compound is any compound within, or from a formula that comprises all of the compounds in, Formulas (1) and (l)-(XII I), and in some embodiments also including Formulas (XIV)-(XVI).

[0235]

[0121] “A single compound of’ means that the specified compound (e.g., by structural formula or description) is the only disclosed compound in the 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 that the embodiment has only a single molecule or single instance of the specified compound. For instance, embodiments “consisting of a single compound of Formula (I)” will include embodiments of “a compound of Formula (I),” or the use of “a compound of Formula (I),” and such embodiments, as well as embodiments of a composition “consisting essentially of a single compound of Formula (I),” each may comprise for example 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, and other disclosed or known mass amounts or molar amounts of the compound of Formula (I).

[0236]

[0122] The individual compounds of disclosed compositions also encompass pharmaceutically acceptable salts of such compounds. “Pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, 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.

[0237]

[0123] 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, 2025-11-28 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, hydro-bromide / 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, methyl nitrate, 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, phosphateldi-phosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc and the like (e.g., Berge et al. (1977) “Pharmaceutical Salts,” J. Pharm. Sci. 66:1-19.)

[0238]

[0124] Prodrugs of the disclosed compounds are also provided in further aspects. “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.

[0239] 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 disclosure (Simplicio, Clancy, & Gilmer. 2008. Molecules, 13(3), 519-547; Shah, Chauhan, Chauhan, & Mishra (Eds.). 2020. Recent Advancement in Prodrugs. CRC Press).

[0240]

[0125] Prodrugs 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 will 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 will include active compounds conjugated to L-gamma-glutamyl or N-acetyl-L-gamma glutamic moieties so that they are 2025-11-28 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.l. prodrugs will 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 those of ordinary skill. For example, disclosed prodrugs also include compounds with biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include those 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. Patent Nos. 6,875,751, 7,585,851, and 7,964,580, all of which are incorporated herein by reference. Conventional procedures for the selection and preparation of suitable prodrugs are also described in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0241]

[0126] 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. In some embodiments, provided are amino acid prodrugs of disclosed compounds, having the following structure:

[0242]

[0243] 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 to correspond to a natural or unnatural amino acid.

[0244]

[0127] Amino acid prodrugs can be synthesized according to conventional methods known to those of skill. For example, a disclosed compound (bearing a primary amine group) can be contacted with an amino acid in the presence of a suitable peptide coupling reagent (and optionally a suitable base).

[0245]

[0128] In embodiments, the amino acid is a natural amino acid. In other embodiments, the amino acid is an unnatural amino acid. In embodiments, the amino acid is an L-amino acid. In embodiments, the amino acid is a D-amino acid. In embodiments, the amino acid is alanine, arginine, asparagine, aspartic acid, cysteine, 2025-11-28 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 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.

[0246]

[0129] 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 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 embodiments, the amino acids are selected from L-amino acids for digestion by proteases. In 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. Peptides include Lys, Ser, Phe, Gly-Gly-Gly, Leu-Ser, Leu-Glu, homopolymers of Glu and Leu, and heteropolymers of (Glu)n-Leu-Ser.

[0247]

[0130] In some aspects, also provided herein are prodrugs of disclosed compounds that incorporate a vitamin B6 moiety. Vitamin B6 has six chemically distinct forms, including pyridoxine, pyridoxal, pyridoxamine, and their respective phosphorylated derivatives:

[0248] pyridoxamine CH,

[0249] OPO3H2p

[0250]

[0251] yridoxine 5-phosphate pyridoxal S'-phosphate pyridoxamine 5’-phosphate 2025-11-28

[0131] Pyridoxal 5’-phosphate has the highest biological activity, but all of the other forms of vitamin B6 can be converted to pyridoxal 5’-phosphate in vivo (Bachmann, et al. Molecules 2018, 23(9), 2117). Humans cannot synthesize any forms of vitamin B6, and must obtain it by dietary means (Calderon-Ospina, et al. CNS Neurosci. Ther. 2020, 26(1), 5-13). Vitamin B6 plays an essential role in neurotransmitter production, and is transported into the CNS (id.). Transporters, such as SLC19A2 and SLC19A3, i.e., thiamine transporters (THTR) 1 and 2, are shown to transport pyridoxine (Yamashiro et al., J Biol Chem. 2020, 295(50), 16998-17008). Various vitamin B6 conjugates have been synthesized and evaluated for their ability to act as prodrugs by enabling the transport of a therapeutically active compound across cellular membranes (see, e.g., Araujo de Oliveira, et al. ACS Omega 2022, 7(14), 11678-11687; Day, et al. Mol Pharm. 2011, 8(1), 297-301; Wu, et al. FASEB J. 2011, 25(7), 2109-22; Zhang, et al. Proc. Natl. Acad. Sci. USA 1991, 88(23), 10407-10).

[0252]

[0132] In embodiments are vitamin B6 prodrugs, with the following structure, wherein X is H or PO3H2:

[0253]

[0254]

[0133] Vitamin B6 prodrugs are synthesized by first reacting a disclosed compound with a pyridoxal precursor, such as according to the methods disclosed in Applicant’s Int’l Application No PCT / US2024 / 18413, which is fully incorporated herein by reference. A condensation reaction between the primary amine (— NH2) of the compound and the pyridoxal aldehyde (— COH) reversibly forms the imine compound of Formula (A), along with water (H2O) as a reaction byproduct, as depicted in the exemplary scheme below:

[0255] OR2

[0256] Formt / fa (A)

[0257]

[0258] y / tamto pr&dmff

[0134] The imine compound of Formula (A) may be isolated from the reaction mixture. In embodiments, the compound of Formula (A) is isolated, purified, and used as a prodrug as described in various embodiments 2025-11-28 herein. Alternatively, the compound of Formula (A) is used as a synthetic intermediate (with or without being isolated from the reaction mixture) in the synthesis of vitamin B6 prodrugs. In embodiments, the compound of Formula (A) is reduced with a suitable reducing agent (e.g., NaBH4) to irreversibly form a vitamin B6 prodrug.

[0259]

[0135] In general, compounds are administered as part of a pharmaceutical composition and are prepared for inclusion in such compositions in isolated or purified form. The terms “isolated,” “purified,” and “substantially pure” refer herein to material that is substantially or essentially free of components that normally accompany the material when synthesized, manufactured, or otherwise produced. An isolated, purified, or substantially pure compound refers to a preparation having a chromatographic purity of greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9%, as determined by area normalization of an HPLC profile or a comparable analytical method. A substantially pure compound may be substantially free of other active compounds that are not intended to be administered to a subject, wherein “substantially free” can mean that no unintended active compounds are detectable by HPLC or a similar detection method, or are present only below a threshold such as those above.

[0260]

[0136] Unless the context indicates otherwise, reference to a disclosed compound, or to a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, or to a prodrug thereof, includes all amorphous and crystalline forms, including all polymorphs. In the case of solid compositions, such compounds may exist in multiple solid state forms, including stable and metastable crystalline forms, isotropic and amorphous forms, milled forms, and nanoparticulate forms, all of which are intended to be within the disclosure. Crystalline forms, i.e., polymorphs, may exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness values, crystal habits, optical and electrical properties, stabilities, and solubilities. Various factors, such as the choice of recrystallization solvent, the rate of crystallization, and storage temperature, may influence which particular crystal form predominates.

[0261] a. Isotopic Derivatives and / or Halogenated Derivatives

[0262]

[0137] In some aspects are provided isotopic derivatives of the disclosed compounds, such as having at least one desired isotopic substitution of an atom at an amount above the natural abundance of the isotope.

[0263]

[0138] Examples of isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine such as2H,3H,11C,13C,14C,15N,17O,18O, and36Cl respectively. In one non-limiting embodiment, isotopically labeled compounds can be used in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopic derivatives of the disclosed compounds can generally be prepared by carrying out the procedures disclosed or the schemes described or known, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0264]

[0139] By way of example and without limitation, isotopes of hydrogen including deuterium (2H) and tritium 2025-11-28 (3H) may be incorporated at any position in the disclosed structures that achieves one or more desired results. Alternatively or in addition, isotopes of carbon, e.g.,13C and14C, may be incorporated.

[0265]

[0140] Isotopic substitutions, such as deuterium substitutions, may be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is replaced with at least one deuterium atom. In some embodiments, the isotope is at least 60%, 70%, 80%, 90%, 95%, or 99% enriched in the desired isotope at any location of interest, and in some embodiments it is 90%, 95%, or 99% enriched at a specified location. Unless indicated otherwise, deuteration is at least 80% at the selected position. Deuteration may occur at any replaceable hydrogen atom that provides a desired result.

[0266]

[0141] In embodiments, isotopic derivatives are used as research tools, such as for scientific research. In embodiments, isotopic derivatives are used as analytical reagents. In embodiments, isotopic derivatives are used for spectroscopy, quality control, or forensic applications. In embodiments, isotopic derivatives are used for imaging, such as medical imaging. In embodiments, isotopic derivatives are used for tissue imaging.

[0267]

[0142] In embodiments, isotopic derivatives are used as a research tool in the determination of the structure and function of a receptor in vitro, in vivo, or in silico. In embodiments, isotopic derivatives are used in receptor, ion channel, enzyme, or transporter binding studies. In embodiments, isotopic derivatives are used in mapping, and functional studies. In embodiments, isotopic derivatives are used to identify binding sites.

[0268]

[0143] In embodiments, isotopic derivatives for any disclosed uses comprise an isotope of hydrogen and / or a radiohalogen. In embodiments, the isotope of hydrogen is protium, deuterium, or tritium. In embodiments, the radiohalogen is radioactive fluorine, chlorine, bromine, iodine, or astatine.

[0269]

[0144] In some embodiments, isotopic derivatives are used as research tools, such as receptor probes, for serotonin receptors, for example, HTR1, HTR2, and HTR6receptors, including subtypes thereof. In embodiments, isotopic derivatives are used as research tools for 5-HT2Areceptors. In embodiments, the research tool is a receptor probe, such as used for determining downstream events of receptor-ligand interaction, e.g., calcium regulation, kinase, phosphatase and phospholipase activation, and lipid trafficking. In embodiments, the receptor is a recombinant receptor. In embodiments, the receptor is a wild-type receptor. In embodiments, the receptors are of mammalian origin. In embodiments, the receptors are of human origin.

[0270]

[0145] In embodiments, a disclosed composition comprises a mixture of an isotopic derivative, for example a deuterium-substituted compound, and the corresponding non-substituted compound in a fixed ratio.

[0271]

[0146] In some aspects are provided halogenated derivatives of the disclosed compounds, such as compounds in which at least one hydrogen atom is replaced with a halogen atom. In some embodiments, the halogenated derivative is a fluorinated derivative, i.e., a compound in which at least one H is replaced with a F.

[0272]

[0147] In embodiments, a disclosed composition comprises a mixture of a halogenated derivative, for example a fluorine-substituted compound, and the corresponding non-substituted compound in a fixed ratio.

[0273]

[0148] Disclosed compounds also may be both isotopic derivatives and halogenated derivatives, i.e., in which one or more hydrogen atoms are replaced with one or more isotopes and one or more halogen atoms. 2025-11-28

[0149] In embodiments, a composition comprises substituted, e.g., deuterium- and / or fluorine-substituted, and non-substituted compounds in a mole ratio or a mass ratio of 1:1, or of 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 each ratio itself.

[0274]

[0150] In some embodiments, wherein a compound is a pharmaceutically acceptable salt, hydrate, or solvate thereof, and the ratio is a mass ratio, the mass includes the total mass of the salt, hydrate, or solvate, including any associated counterions or bound water or solvent molecules.

[0275] b. Stereoisomers and Enantiomeric Mixtures

[0276]

[0151] 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 absolute stereochemistry, as (R)- or (S)-. Disclosure of any compound herein, unless context indicates otherwise, is a disclosure of all such possible isomers, and mixtures thereof, as well as racemic and optically pure forms.

[0277]

[0152] 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, including by methods known in the art.

[0278]

[0153] Exemplary methods to obtain optical isomers of compounds include: i) physical separation of crystals whereby macroscopic crystals of the individual enantiomers are manually separated; ii) simultaneous crystallization whereby the individual enantiomers are separately crystallized from a solution of the racemate; iv) enzymatic asymmetric synthesis; v) chemical asymmetric synthesis; vi) diastereomer separation using an enantiomerically pure reagent (a chiral auxiliary); vii) first- and second-order asymmetric transformation; viii) kinetic resolution; ix) enantiospecific synthesis from non-racemic precursors; x) chiral liquid chromatography; xi) chiral gas chromatography; xii) extraction with chiral solvents; and xiii) transport across a chiral membrane.

[0279]

[0154] In some embodiments, a disclosed compound is provided as a racemic mixture. In other embodiments, a compound is 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%.

[0280]

[0155] In embodiments, a compound is provided in a composition that is enantiomerically enriched with the R-isomer, comprising the R-isomer in enantiomeric excess. In embodiments, a compound is provided in a composition that is enantiomerically enriched with the S-isomer, comprising the S-isomer in enantiomeric excess. In any such compositions, the isomer may be 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%. 2025-11-28

[0156] In some embodiments, a disclosed compound is provided, such as in a composition, as the R-isomer and the S-isomer in a R: S ratio of from about 20:1 to about 1:20. In 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 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.

[0281]

[0157] In embodiments, a disclosed compound is provided as an enantiomerically pure R-isomer.

[0282]

[0158] In embodiments, a disclosed compound is provided as an enantiomerically pure S-isomer.

[0283]

[0159] Disclosure of compounds containing olefinic double bonds or other centers of geometric asymmetry, unless context indicates otherwise, includes E and Z geometric isomers. Tautomeric forms are also included.

[0284] c. Exemplary Features of Disclosed Compounds

[0285]

[0160] In some aspects, features of disclosed compounds provide various advantages.

[0286]

[0161] Advantages of a disclosed compound may be related to modulation of neurotransmission, pharmacokinetics, such as properties related to absorption, distribution, metabolism, and excretion of a disclosed compound, and subjective effects, such as upon administration to a subject.

[0287]

[0162] In some embodiments, advantages are determined relative to a comparator. In embodiments, the comparator is 2,5-dimethoxy-4-methyl-phenethylamine (2C-D), or another 2C-x compound. In embodiments, the comparator is 2,5-dimethoxy-4-methylamphetamine (DOM), or another alpha-methyl compound. In embodiments, the comparator is 2,5-dimethoxy-4-methyl-a-ethylphenethylamine (“Ariadne”), or another alpha-ethyl compound. In embodiments, the comparator is a 4-halo-substituted compound, such as 4-bromo-2,5-dimethoxyphenethylamine (2C-B), or an alpha-methyl or alpha-ethyl analog (e.g., DOB or 4C-B). In some embodiments, the comparator is an alpha-methyl substituted 2,5-dimethoxyphenethylamine. In some embodiments, the comparator is an alpha-ethyl substituted 2,5-dimethoxyphenethylamine.

[0288]

[0163] In embodiments, disclosed compounds selectively agonize the 5-HT2A receptor, and provide increased therapeutic efficacy, improved safety profiles, and / or reduced side effects. In embodiments, a compound has increased selectivity for the 5-HT2Areceptor over another 5-HT receptor (e.g., the 5-HT2Breceptor or 5-HT2Creceptor) relative to a comparator. In embodiments, the compound has increased selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor relative to a comparator. In embodiments, the compound has increased selectivity for the 5-HT2Areceptor over the 5-HT2Creceptor relative to a comparator. In embodiments, selectivity refers to the ratio of the half-maximal effective concentration (EC50) of the compound for the 5-HT2Areceptor compared to another receptor (e.g., a 5-HT receptor, the 5-HT2Breceptor, or the 5-HT2Creceptor).

[0289]

[0164] In embodiments, a disclosed compound has at least a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, or 200-fold selectivity for the 5-HT2Areceptor over another 5-HT receptor.

[0290]

[0165] In embodiments, a disclosed compound has at least a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, or 200-fold selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor.

[0291]

[0166] In some embodiments, a disclosed compound has reduced adverse events relative to a comparator. Examples of adverse events include those related to neurotoxicity, cardiotoxicity, renal toxicity, and the like. In 2025-11-28 some embodiments, the reduction of at least one adverse event is at least a 5% reduction, 10% reduction, 15% reduction, 25% reduction, 50% reduction, 75% reduction, 90% reduction, 95% reduction, at least a 99% reduction, or a reduction beyond the threshold of measurement, whether determined within a patient, 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 known to those of skill for determining or quantifying the adverse event(s) in question. Adverse events may relate to anxiety; cardiovascular effects such as blood pressure and heart rate; hyperthermia; hyperhidrosis; jaw tightness and bruxism; muscle tightness; psychostimulation; appetite; nausea; concentration; or balance. Adverse events also include markers of, or correlates with, potential toxicity, including neurotoxicity, assessed using in silico procedures (e.g., computer analysis or simulation), in vitro procedures (e.g., biochemical assays, tissue culture), or in vivo procedures (e.g., behavioral assessments; functional observational batteries; tests of motor activity; schedule-controlled operant behavior; neurological, neurophysiological, nerve-conduction, or evoked-potential assessments; neurochemical, neuroendocrine, or neuropathological measures; EEG; imaging). Additional assessments, such as to compare a compound to a comparator, include physiological measures or biomarkers such as 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), as well as patient assessments.

[0292]

[0167] In some embodiments, a disclosed compound does not cause a neurotoxic effect, whether assessed in an in vitro assay or upon administration to a subject. In other embodiments, a disclosed compound causes a reduced neurotoxic effect, whether measured in vitro or following administration to a subject. In some embodiments, the reduction of a neurotoxic effect is at least a 5% reduction, 10% reduction, 15% reduction, 25% reduction, 50% reduction, 75% reduction, 90% reduction, 95% reduction, or at least a 99% reduction relative to a comparator. In some embodiments, the neurotoxic effect is determined by measuring one or more of: (a) oxidative stress and dopamine-based quinones; (b) mitochondrial dysfunction; and (c) activation of glial cells. In some embodiments, neurotoxicity, or a reduction thereof, is determined by evaluating mitochondrial dysfunction. Mitochondrial dysfunction may be evaluated by measuring one or more of mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, mitochondrial cytochrome c release, and ADP / ATP ratio (e.g., Taghizadeh et al., Free Radic Biol Med. 2016;99:11-19), in which markers of mitochondrial dysfunction include increased ROS formation, collapse of MMP, mitochondrial swelling, outer membrane damage, cytochrome c release, and an increased ADP / ATP ratio.

[0293]

[0168] In some embodiments, neurotoxicity, or a reduction thereof, is determined by assessing the activation of glial cells, such as the activation of quiescent glial cells (e.g., Herndon et al., Tox Sci.2014; 138(1): 130-138). Reactive astrogliosis may be measured using glial fibrillary acidic protein (GFAP) staining, and microglial reactivity may be visualized by immunostaining complement type 3 receptor (CD11 b) (see, e.g., Frau et al., J. 2025-11-28 Neurochem. 2013; 124(1):69— 78; and Frau et al., Neurotoxicology 2016;56:127-138). In some embodiments, neurotoxicity, or a reduction thereof, is determined in vitro, and in some embodiments it is determined in vivo.

[0294]

[0169] In some embodiments, a subject administered a disclosed compound does not experience serotonin syndrome. In embodiments, a subject administered a disclosed compound experiences a reduced incidence or severity of serotonin syndrome relative to administration of a comparator. In some embodiments, subjects administered a disclosed compound do not experience, or experience a reduced incidence or severity of, autonomic dysfunction, neuromuscular excitation, and / or altered mental status (e.g., Boyer & Shannon, N Engl J Med. 2005;352(11 ): 1112-1120 and Wang et al., Cleve Clin J Med. 2016;83(11 ):810-817).

[0295]

[0170] In some embodiments, a subject administered a disclosed compound does not experience delirium. In embodiments, a subject administered a disclosed compound experiences a reduced incidence or severity of delirium relative to administration of a comparator. In some embodiments, subjects administered a disclosed compound do not experience, or experience a reduced incidence or severity of, disturbances of consciousness, attention, cognition, and / or perception. The severity of delirium may be assessed using tools such as the Memorial Delirium Assessment Scale (MDAS) subitems and the Karnofsky Performance Status scale (KPS) (e.g., Boettger et al., J Geriatr 2014:247042; Carter et al., Drug Saf. 1996;15(4):291— 301; Karlsson, Dement Geriatr Cogn Disord. 1999;10(5):412— 415).

[0296]

[0171] In some embodiments, disclosed compounds do not cause cardiotoxicity following administration to a subject. In some embodiments, reduced severity and / or incidence of cardiotoxicity is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator. In some embodiments, disclosed compounds do not cause irregular heartbeat, e.g., tachycardia. In some embodiments, disclosed compounds show reduced inhibition of a cardiac ion channel, such as by at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200% relative to a comparator. In some embodiments, disclosed compounds do not inhibit the function of, such as block, cardiac ion channels. In some embodiments, disclosed compounds do not block calcium channel CAV1.2. In some embodiments, disclosed compounds do not block potassium channel hERG. In some embodiments, disclosed compounds do not block sodium channel NAV1.5. In embodiments, a disclosed compound has an IC50of greater than 10 M for any one or more of CAV1.2, hERG, and NAV1.5. In some embodiments, CAV1.2, hERG, and NAV1.5 are of human origin.

[0297]

[0172] In some embodiments, disclosed compounds do not cause rhabdomyolysis following administration to a subject. In some embodiments, reduced severity and / or incidence of rhabdomyolysis is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator. In embodiments, disclosed compounds do not cause kidney injury, such as acute kidney injury, following administration to a subject. In embodiments, reduced severity and / or incidence of kidney injury is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator. In embodiments, disclosed compounds do not elevate serum levels of rhabdomyolysis markers and / or kidney injury markers, e.g., muscular enzymes and creatinine phosphokinase. In embodiments, administration of a 2025-11-28 disclosed compound results in reduced markers of rhabdomyolysis and / or kidney injury, such as reductions by at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200%, relative to a comparator. In embodiments, administration of disclosed compounds to a subject does not result in or results in a reduction of any one or more of renal vasoconstriction, intraluminal cast formation, and direct myoglobin toxicity.

[0298]

[0173] Signs of rhabdomyolysis and kidney injury may be determined according to known methods, including by measuring an elevation of muscular enzymes and creatinine phosphokinase, and by identifying renal vasoconstriction, intraluminal cast formation, and direct myoglobin toxicity. Measurements and comparisons of such toxicity can be made according to ordinary methods known to those in the art.

[0299]

[0174] In some embodiments, a disclosed compound has a reduced rate of metabolism, for example by O-demethylation or O-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.

[0300]

[0175] In some embodiments, a disclosed compound has an in vitro apparent permeability of 50-150 nm / s, wherein the range is inclusive (“medium permeability”). In some embodiments, a disclosed compound has an in vitro apparent permeability greater than 150 nm / s, wherein the range is inclusive (“high permeability”). Measures of permeability, such as in vitro methods, are known in the art and include the Madin-Darby canine kidney cell line (MDCK) permeability assay and the parallel artificial membrane permeation assay (PAMPA).

[0301]

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

[0302]

[0177] In embodiments, compounds selectively inhibit the update activity of the serotonin transporter (SERT). In embodiments, blocking the uptake activity of monoamine transporters by a compound, such as SERT, DAT, or NET, result in an increase of circulating monoamines and in neurotransmission modulated thereby.

[0303] C. Methods of Synthesis

[0304]

[0178] In some aspects, provided herein are methods of preparing the disclosed compounds.

[0305]

[0179] In embodiments, disclosed compounds are synthesized according to the general reaction sequence:

[0306]

[0307] 2025-11-28

[0180] Briefly, hydroquinone is monoalkylated to install R5, then oxidized to an aldehyde intermediate. The remaining phenol group is alkylated to install R2, then this dialkylated intermediate is converted to a nitrostyrene, which is reduced to a phenethylamine. Finally, X is installed. Each of these reactions can be performed according to methods known to one of skill, for example those disclosed in PCT Pub. No. W02023 / 049480, the entire disclosure of which is incorporated by reference as if fully set forth herein. For example, the method of Example 1 therein (Synthesis of 2-(4-bromo-5-propoxy-2-methoxyphenyl)ethan-1 -amine) may be modified to use nitroethane or nitropropane to provide the corresponding a-methyl or a-ethyl compounds. As will be appreciated, use of nitropropane may yield a mixture of products because more than one reactive position can participate in the condensation. In some embodiments, the method therefore further comprises a purification or enrichment step following the reaction to isolate the desired compound. In other embodiments, the synthetic route is selected to provide the desired asymmetrically substituted compound without necessitating a purification or enrichment step following the reaction.

[0308]

[0181] In embodiments, rather than for example condensing a precursor of a disclosed compound (in one such example, methylenedioxybenzaldehyde) with nitropropane, to give a mixture of two products as below:

[0309]

[0310] one may follow the methods of Nichols et al. 1986, avoiding the creation of the nitropropene (i.e., above right) (see also, e.g., the methods described in PiHKAL for #94 (“J”) and for #128 (“Methyl- J”)).

[0311]

[0182] As generally appreciated by those of skill, the synthesis of higher nitroalkanes may create one or more stereocenters. Methods therefore may be adapted to employ stereospecific or stereoselective steps and / or to include a resolution procedure following racemic synthesis to isolate the desired enantiomers, whether according to disclosed methods or methods known in the art.

[0312]

[0183] Compounds wherein R2and R3together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl can be synthesized according to the same general reaction sequence, starting with a heterocycloalkyl or heteroaryl precursor as follows:

[0313]

[0314] 2025-11-28

[0315]

[0316]

[0184] Compounds wherein RNis — C^Cg alkylene-C6-C12aryl can be synthesized by reductive amination of a disclosed compound wherein RNis H, as follows:

[0317]

[0318]

[0185] Other methods for synthesis of disclosed compounds, and any necessary starting materials, are either described in the art or will be readily apparent to one of skill in view of this disclosure and general references well known in the art (see, e.g., Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed. 1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1-17, Wiley Interscience; Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991; “Theilheimer’s Synthetic Methods of Organic Chemistry,” Volumes 1-45, Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Interscience, 1991; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995). In general, the approaches used for similar compounds may be used to synthesize the disclosed compounds, with such adaptation as will be appreciated by those of ordinary skill (e.g., Shulgin & Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991) (“PiHKAL”); Nichols et al. J Med Chem. 1986;29(10):2009-2015 (“Nichols et al. 1986”); Glennon et al. J Med Chem. 1986;29(2): 194-199; Nichols et al. J. Med. Chem. 1991;34(1):276— 281; Kedrowski et al. 2007. Organic Lett., 9(17), 3205-3207; Heravi & Zadsirjan. Curr Org Syn. 2016; 13(6):800— 833; Keri et al. European J. Med. Chem., 2017;138:1002— 1033; Perez-Silanes et al. J. Heterocyclic Chem. 2001;38(5): 1025-1030; and references cited therein).

[0319] D. Pharmaceutical Compositions

[0320]

[0186] In some further aspects are provided compositions, such as pharmaceutical compositions, comprising a disclosed compound, such as a compound of any disclosed Formula or subformula, or any embodiment.

[0321]

[0187] “Pharmaceutical compositions” are compositions (thus equivalently herein, unless context demands otherwise, “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 comprise multiple carriers, diluents, and / or excipients. 2025-11-28

[0188] Compositions can be prepared by standard pharmaceutical formulation techniques as disclosed in, e.g., Remington: Science & Practice of Pharm. (2020) 23th ed., Acad. Press., Cambridge, Mass.; Merck Index (1996) 12th ed., Merck Pub. Grp., Whitehouse, N. J.; Pharm. Principles Solid Dosage Forms (1993), Tech. Pub. Co., Lancaster, Pa.; Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Wms. & Wilkins, B’more, Md.; & Poznansky et al. Drug Delivery Sys. (1980), R. L. Juliano, ed., Oxford, N. Y., pp. 253-315).

[0322]

[0189] “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.

[0323]

[0190] In some embodiments, compositions comprising a 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).

[0324]

[0191] The disclosed compositions can be 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 any other appropriate fraction of the composition administered.

[0325]

[0192] 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 include ampules and vials with liquid compositions therein. Unit dosage forms further include compounds for transdermal administration, such as “patches” that contact the epidermis (including the mucosa) of a subject for an extended or brief period of time.

[0326]

[0193] In embodiments, disclosed compositions are formulated in a pharmaceutically acceptable oral dosage form. Oral dosage forms include oral liquid dosage forms (e.g., tinctures, drops, emulsions, syrups, elixirs, suspensions, solutions, and the like) and oral solid dosage forms. Disclosed compositions also may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0327]

[0194] In some embodiments, a disclosed composition is formulated as an oral solid dosage form. Oral solid dosage forms may include lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, 2025-11-28 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 embodiments, the pharmaceutical formulation is in the form of a powder. In embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-melt tablet. Additionally, disclosed composition may be administered as a single capsule or in multiple capsule dosage form. In embodiments, the composition is administered in two, three, four, or more capsules or tablets.

[0328]

[0195] Oral solid dosage forms may comprise 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 may comprise 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).

[0329]

[0196] Supplementary active compounds include preservatives, antioxidants, and antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents. Preservatives can be used to inhibit microbial growth or increase stability of the active ingredient thereby prolonging the shelf life of the formulation. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate. Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as alpha lipoic acid.

[0330]

[0197] Disclosed compositions may be formulated as an oral liquid dosage form. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. Oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill for 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 include water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.

[0331]

[0198] 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, 2025-11-28 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 polyfethylene 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.

[0332]

[0199] Compositions also may comprise a disclosed compound and at least one dispersing agent or suspending agent for oral administration to a subject. Such compositions 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. 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.

[0333]

[0200] Disclosed compositions also may be prepared as formulations suitable for intramuscular (IM), subcutaneous (SC), intraperitoneal (IP), or intravenous (IV) injection, such as physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0334]

[0201] Disclosed compositions also may be prepared as topical dosage forms, including transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. Such compositions may comprise penetrants and carriers. Penetrants for transmucosal administration include detergents, bile salts, and fusidic acid derivatives. Carriers for transdermal administration include Vaseline®, lanolin, PEG, alcohols, transdermal enhancers, and combinations thereof.

[0335] E. Pharmaceutical Combinations

[0336]

[0202] Disclosed compositions are not limited to a single disclosed compound, nor limited to a single carrier, diluent, and / or excipient. Also provided are compositions comprising multiple compounds (including additional active compounds), and / or multiple carriers, diluents, and excipients. Pharmaceutical compositions 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. 2025-11-28

[0203] In embodiments, such a composition is prepared 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.

[0337]

[0204] “Therapeutic effects” include 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.

[0338]

[0205] “Synergistic effects” include increases in potency, bioactivity, bioaccessibility, bioavailability, and / or therapeutic effect, that are greater than the additive contributions of the components acting alone. Numerous methods known to those of skill 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.” Such methods include isobologram (or contour) analysis (Huang, Front Pharmacol. 2019; 10:1222); the equation of Loewe additivity (Loewe & Muischnek, Arch Exp Pathol Pharmacol. 1926;114: 313-326); the Sigmoid-Emax equation (Holford & Scheiner, Clin Pharmacokinet. 1981;6: 429-453); and the median-effect equation (Chou & Talalay, Adv Enzyme Regul.

[0339] 1984;22:27-55); for example to provide a concentration-effect curve or combination index curve. The above may be applied to experimental data to generate a graph to aid in assessing the effects of a combination.

[0340]

[0206] In some embodiments, a disclosed 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.

[0341]

[0207] In embodiments, an additional active compound is a tryptamine, such as having the general structure below, wherein RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7are as defined herein or as generally known in the art: 2025-11-28

[0342]

[0343]

[0208] In embodiments, RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7are each independently hydrogen, deuterium, halogen (F, Cl, Br, or I), OH, or phosphoryloxy, or any of alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted. Any two of RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7and the intervening atoms also can be taken together to form a cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted. The tryptamine also may be a quaternary salt, where an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is alkyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted.

[0344]

[0209] In some embodiments, the tryptamine is selected from the group consisting of psilocybin, psilocin, psilacetin, DBT, DET, DiPT, a,0-DMS, DMT, 2,a-DMT, a, N-DMT, DPT, EiPT, AET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-TMT, 4-HO-DMT, 5-HO-DMT (i.e., bufotenine), 4-HO-DPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPT, 4-HO-pyr-T, ibogaine, MBT, 4,5-MDO-DiPT, 5,6-MDO-DiPT, 4,5-MDO-DMT, 5,6-MDO-DMT, 5,6-MDO-MiPT, 2-Me-DET, 5-Br-DMT, 5-CI-DMT, 5-F-DMT, 4,5-MDO-DMT, 4,5-MDO-DiPT, 2-Me-DMT, melatonin, 5-MeO-DET, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-DMT, 4-MeO-MiPT, 5-MeO-MiPT, 5,6-MeO-MiPT, 5-MeO-NMT, 5-MeO-pyr-T, 5-MeO-TMT, 5-MeS-DMT, MiPT, a-MT (i.e., AMT), NET, NMT, pyr-T, tryptamine, or a, N,0-TMS, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof. As known in the art, the systematic naming of tryptamines, such as herein, involves the use of prefixes and suffixes to indicate substitutions on the indole ring and / or the side chain of the tryptamine core structure. For example, EiPT stands for ethyl isopropyl tryptamine, also known as N-ethyl-N-isopropyltryptamine (i.e., N-ethyl-N-[2-(1 H-indol-3-yl)ethyl]propan-2-amine). Examples of these and other tryptamines that may in embodiments be in a composition are known to those of skill, and include the compounds disclosed in Shulgin & Shulgin, TiHKAL: The Continuation, Transform Press (1997) (“TiHKAL”).

[0345]

[0210] In embodiments, an additional tryptamine will be a “complex tryptamine” or other indolamine such as, e.g., iboga alkaloids such as ibogaine, and their analogs, metabolites, and derivatives, and beta-carbolines.

[0346]

[0211] In embodiments, the additional active compound is a phenylalkylamine, such as having the structure below, wherein RN1, RN2, Ra, Rp, and each of R2-R6are as defined herein or as generally known in the art:

[0347]

[0348] 2025-11-28

[0212] In embodiments, RN1, RN2, Ra, Rp, and each of R2-6are independently hydrogen, deuterium, or halogen (F, Cl, Br, or I), or any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted. In embodiments, R3and R4are joined together to form an optionally substituted heterocyclyl, such as a dioxole (like MDMA), a furan, a tetrahydrofuran, a thiophene, a pyrrole, a pyridine, a pyrrolidine, an ethylene oxide, an ethylenimine, a trimethylene oxide, a pyran, a piperidine, an imidazole, a thiazole, a dioxane, a morpholine, or a pyrimidine. In embodiments, R3and R4are joined together to form an optionally substituted aryl, such as a phenyl. In embodiments, the phenethylamine comprises a quaternary ammonium cation wherein each of RN1, RN2, and an additional RN3are independently an alkyl group or an aryl group, with all other substituents as above. In embodiments, the phenethylamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is alkyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted.

[0349]

[0213] In some embodiments, the phenethylamine is selected from the group consisting of mescaline, a-ethylmescaline, escaline, symbescaline, metaescaline, allylescaline, methallylescaline, asymbescaline, cyclopropylmescaline, phenescaline, 4-desoxymescaline, isomescaline, proscaline, metaproscaline, isoproscaline, thiomescaline, thioescaline, thioproscaline, thiobuscaline, a thiomescaline analog (e.g., 3-TM, 4-TM), buscaline, a thioisomescaline (e.g., 2-TIM, 3-TIM, 4-TIM), Aleph (i.e., DOT), a thiometaescaline (e.g., 3-TME, 4-TME, 5-TME), a thiotrisescaline (e.g., 3-T-TRIS, 4-T-TRIS), a thiosymbescaline (e.g., 3-TSB, 4-TSB), Aleph-2, Aleph-4, Aleph-6, Aleph-7, Ariadne, Beatrice (i.e., MDO-D, MDOM), BIS-TOM, BOB, BOD, BOH, BOHD, BOM, 4-Br-3,5-DMA, 2-Br-4,5-MDA, MDEA, 3C-BZ, a 2C-X compound (e.g., 2C-B, 2C-B-AN, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-B-FLY-NBOMe, 2C-B-FLY-NB2EtO5CI, 2C-Bn, 2C-Bu, 2C-B-5-HEMIFLY, 20-0, 2C-C-3, 2C-CN, 2C-CP, 2C-D, 2C-E, 2C-EF, 2C-F, 2C-G, 2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, 2C-G-N, 2C-H, 2C-I, 2CB-lnd, 2C-iP, 2C-N, 2C-NH2, 2C-PYR, 2C-PIP, 20-0, 2C-O-4, 2C-M0M, 2C-P, 2C-Ph, 2C-Se, 2C-T, 2C-T-2, 2C-T-3, 2C-T-4, 2C-T-5, 2C-T-6, 2C-T-7, 2C-T-8, 2C-T-9, 2C-T-10, 2C-T-11, 2C-T-12, 2C-T-13, 2C-T-14, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-18, 2C-T-19, 2C-T-21, 2C-T-21.5, 2C-T-22, 2C-T-23, 2C-T-24, 2C-T-25, 2C-T-27, 2C-T-28, 2C-T-30, 2C-T-31, 2C-T-32, 2C-T-33, 2C-DFM, 2C-TFM, 2C-TFE, 2C-YN, 2C-V, 2C-AL, CPM, psi-2C-T-4, 2C-Se), 3C-BZ, 3C-E, 4-D, beta-D, 2,4-DMA, 2,5-DMA, 3,4-DMA, DMCPA, DME, DMMDA, DMMDA-2, DMPEA, D0AM, DOB, DOBU, DOC, DOEF, DOET, DOI, DOM (i.e., STP), psi-DOM, DON, DOPR, EEE, EEM, EME, EMM, ETHYL-J, ETHYL-K, F-2, F-22, FLEA, GANESHA, a GANESHA analog (e.g., G-3, G-4, G-5, G-N), HOT-2, HOT-7, HOT-17, IDNNA, IRIS, BDB, LOPHOPHINE, 4-MA (i.e., PMA), MADAM-6, MDA, MDMA, MDAL, MDBU, MDBZ, MDCPM, MDDM, MDE, MDHOET, MDIP, MDMC, MDMEO, MDMEOET, MDMP, MDOH, MDPEA, MDPH, MDPL, MDPR, MEDA, MEE, MEM, MEPEA, META-DOB, META-DOT, METHYL-DMA, METHYL-DOB, METHYL-J (i.e., MBDB), METHYL-K, METHYL-MA (i.e., PMMA), METHYL-MMDA-2, MMDA, MMDA-2, MMDA-3a, MMDA-3b, MME, MPM, ORTHO-DOT, PEA, PROPYNYL, tetra- methoxyamphetamine, 3-TASB, 4-TASB, 5-TASB, 3-TE, 4-TE, TMA, TMA-2, TMA-3, TMA-4, TMA-5, TMA-6, 2T-MMDA-3a, 4T-MMDA-2, TMPEA, 2-TOET, 5-TOET, 2-TOM, 2025-11-28 5-TOM, TOMSO, 4-MTA, MDAI, 5-methyl-MDA, 5-APB, 6-APB, and DiFMDA, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof. As known in the art, the systematic naming of phenethylamines, such as herein, involves the use of prefixes and suffixes to indicate substitutions on the phenyl ring and / or side chain of the phenethylamine core structure. For example, MDBZ refers to methylene-dioxybenzylamphetamine (i.e., 3,4-methylenedioxy-N-benzyl-amphetamine). Examples of these and other phenethylamines that may in embodiments be in a composition are known to those of skill, and include the compounds in PiHKAL and in Shulgin AT, The Shulgin Index Vol.1: Psychedelic Phenethylamines & Related Compounds, Transform Press (2011).

[0350]

[0214] In embodiments, the additional active compound is an ergoline or an ergot alkaloid. In embodiments, the additional active compound is a lysergamide, such as having the general structure below, wherein RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are as defined herein or as generally known in the art:

[0351]

[0352]

[0215] In embodiments, RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are each independently hydrogen, deuterium, halogen, or any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted. Further, 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 a cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted. In embodiments, the lysergamide is a quaternary salt, in which an additional R6Ais connected to the nitrogen to which R6is bound; wherein R6Ais alkyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted.

[0353]

[0216] 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-(cyclopropylphenylalkylaminemethanoyl)-lysergic acid diethylamide (1cP-LSD), 1-(1,2-dimethylcyclobutane- 2025-11-28 1-carbonyl)-lysergic acid diethylamide (1D-LSD), 1-propionyl-6-allyl-6-nor-lysergic acid diethylamide (1P-AL-LAD), 1-(cyclopropyl-methanoyl)-6-allyl-6-nor-lysergic acid diethylamide (1cP-AL-LAD), 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide (1 P-ETH-LAD), lysergic acid 2,4-dimethylazetidide (i.e., LA-SS-Az, LSZ), lysergic acid piperidide (LSD-Pip), and lysergic acid methylisopropyl amide (MIPLA).

[0354]

[0217] 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., PiHKAL; TiHKAL; Grob & Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi & Liechti, Arch Toxicol. 2020; 94, 1085-1133; Nichols, Pharmacol Reviews, 2016;68(2):264-355; Glennon, Pharmacol Biochem & Behav. 1999;64:251-256; all are incorporated by reference as if fully set forth herein).

[0355] F. Dose and Dosage

[0356]

[0218] In some embodiments, pharmaceutical compositions comprise a therapeutically effective amount of a disclosed compound, such as for administration to a subject. Administration of compositions in a “therapeutically effective amount,” or an “effective amount” to a subject means administration of an amount of composition sufficient to achieve the desired effect. When an “effective amount” means an amount effective in treating the stated disorder or symptoms in a subject, “therapeutic effect” would be understood to mean the responses(s) in a subject after treatment that are judged to be desirable and beneficial. Depending on the mental health disorder or other medical condition to be treated, or improvement in mental health or functioning sought, and depending on the particular constituent(s) in the compositions under consideration, such responses shall differ, but would be readily understood by those of 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).

[0357]

[0219] In some embodiments, a pharmaceutical composition comprises a disclosed compound in an amount such that a single dose (whether or not formulated as a unit dosage form) is within the disclosed dose ranges.

[0358]

[0220] In some embodiments, the dose is 25 mg or less, including 10 mg or less, 5 mg or less, 1 mg or less, or 0.5 mg or less. In other embodiments, the dose is 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 any dose within these ranges.

[0359]

[0221] In some embodiments, the dose is from about 0.1 mg to about 250 mg, such as about 1 mg to about 100 mg, 5 mg to 50 mg, 10 mg to 50 mg, or 20 mg to 50 mg. In some embodiments, the dose is about 1 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg.

[0360]

[0222] In some embodiments, a disclosed compound is administered according to an intermittent or regular 2025-11-28 dosing schedule. In some embodiments, the compound is administered daily, twice daily, three times daily, every other day, every third day, every fourth day, every fifth day, weekly, every other week, every third week, or monthly. In some embodiments, the administered dose is any disclosed dose amount, such as about 20 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg, and in some embodiments any of these doses is administered according to any of the dosing frequencies described herein.

[0361]

[0223] In some embodiments, a first dose of a compound is administered and is followed, including as a booster dose, by a second dose from about 30 minutes to about 4 hours later, such as about 30, 60, 90, 120, 150, 180, 210, or 240 minutes after the first dose. In some embodiments, the second dose is from about 10% to 100% of the first dose, such as the same amount as the first dose or about half of the amount of the first dose. In some embodiments, a dosing schedule comprising a first dose and a second dose is performed at any of the frequencies described herein, including daily, twice daily, three times daily, every other day, every third day, every fourth day, every fifth day, weekly, every other week, every third week, or monthly.

[0362]

[0224] It will be appreciated that appropriate dosages may vary depending on whether the treatment is therapeutic or prophylactic; the onset, progression, severity, frequency, duration, probability, or susceptibility of the symptom or condition to be treated; the clinical endpoint desired; previous, simultaneous, or subsequent treatments; the subject’s general health, age, gender, race, and medical or familial history; the route of administration; bioavailability; potential adverse systemic, regional, or local effects; the presence of comorbid disorders; and other factors known to the skilled artisan. Dose amount, frequency, or duration may be increased or decreased as indicated by the clinical outcome desired, the status of the pathology or symptom, the presence or absence of adverse effects, or concomitant medications. The skilled artisan, having the benefit of this disclosure, will appreciate the factors that may influence the dosage, frequency, and timing suitable to provide a therapeutic effect or benefit while avoiding or minimizing adverse effects.

[0363]

[0225] 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 formulation administered, and the age, weight, response, and symptom severity of the patient. Accordingly, the dosage ranges disclosed herein are not intended to limit the scope of the disclosure, and in some instances doses below a disclosed lower limit may be adequate, while in other instances doses above a disclosed upper limit may be employed without undue adverse effects, including where such larger doses are divided into multiple smaller doses for administration.

[0364]

[0226] In some embodiments, where a composition is prepared as a single unit dosage form, such as a capsule, tablet, or lozenge, suitable dosage amounts may be inferred from the format of the preparation itself. In other embodiments, where a composition is prepared as a multiple-dose form, such as a liquid suspension or topical preparation, suitable dosage amounts may be inferred from the means of administration or from packaging, labeling, package inserts, marketing materials, training materials, or other information available to a skilled artisan or to the public, including as provided in a pharmaceutical kit. 2025-11-28 G. Pharmaceutical Kits

[0365]

[0227] In another aspect are provided, pharmaceutical kits (“kits”) that comprise a disclosed pharmaceutical composition, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms may be included in multi-dose kits or containers, and compositions may be packaged in single or multiple unit dosage forms to promote uniformity of dosing and ease of administration.

[0366]

[0228] Kits generally comprise suitable packaging and may include one or more containers comprising any compound described herein. Where more than one component is present, each component may be packaged in a separate container, or two or more components may be combined in a single container where cross-reactivity and shelf-life permit. The kits may be provided in unit dosage form, in bulk or multi-dose form, or in sub-unit doses. In some embodiments, kits contain sufficient quantities of a disclosed compound and / or an additional pharmaceutically active compound useful for treating a disease described herein to provide effective treatment for an extended period, such as any of one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or longer. Kits may also include multiple unit doses and instructions for use and may be packaged in quantities appropriate for dispensing or storage in pharmacies, including hospital or compounding pharmacies.

[0367]

[0229] Information pertaining to dosing and proper administration may be printed directly on the kit or on interior packaging, such as a blister pack, and kits may further include package inserts or other printed instructions on exterior packaging to guide therapeutic use of the disclosed compositions.

[0368] H. Methods of Use

[0369]

[0230] In further aspects are provided methods of using the disclosed compounds and compositions.

[0370]

[0231] In embodiments, disclosed compounds are used to modulate neurotransmission. In embodiments, compounds are used to treat a condition, such as a disease or a disorder. In embodiments, 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, compounds are administered as part of psychedelic-assisted therapy. In embodiments, 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, inflammation or an inflammatory disorder, or pain or a pain disorder. In other embodiments, compounds are administered to a subject that is healthy.

[0371]

[0232] Herein, the terms “subject,” “user,” “patient,” and “individual” may be used interchangeably, and may 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 include one who has an indication for which a disclosed compound may be efficacious.

[0372]

[0233] Disclosed compounds may be orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation, or transdermally administered to a subject. When administered through one or more such routes, disclosed compounds are useful in disclosed methods for treating a subject. 2025-11-28 s. Modulating Neurotransmission and Neuroplasticity

[0373]

[0234] In some embodiments, administration of a disclosed compound modulates neurotransmission in a subject, such as following administration of a pharmacologically effective amount to said subject.

[0374]

[0235] 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.

[0375]

[0236] In some embodiments, administration of a disclosed compound or composition results in inhibiting the reuptake of one or more neurotransmitters. In some embodiments, administration of a disclosed compound or composition results in increasing the extracellular concentration of one or more neurotransmitters, including the amount of extracellular serotonin, dopamine, or norepinephrine.

[0376]

[0237] 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.

[0377]

[0238] In embodiments, administration of a disclosed compound or composition results in modulation of one or more monoamine receptors, such as a serotonin receptor, a dopamine receptor, or a norepinephrine receptor. In embodiments, administration of a compound or composition results in agonism or partial agonism of a monoamine receptor, including any one or more of a serotonin, dopamine, and norepinephrine receptor.

[0378]

[0239] In embodiments, administration of a disclosed compound or composition results in activation of a serotonin receptor. In some embodiments, administration of a disclosed compound or composition results in agonism and / or antagonism of a serotonin receptor (HTR). In some embodiments, administration of a disclosed compound or composition results in agonism or partial agonism of an HTR, such as any one or more of an HTRbsuch as HTR1Aand HTR1B, an HTR2, such as HTR2A, HTR2B, and HTR2C, and HTR6.

[0379]

[0240] In some embodiments, a disclosed compound has an in vitro EC50(agonist mode) for any one or more of HTR1A, HTR1B, HTR2AHTR2B, and HTR6that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has an in vitro EC50(agonist mode) for HTR2Athat is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM. 2025-11-28

[0241] In embodiments, administration of a disclosed compound or composition results in increased agonism of HTR2Arelative to other HTRs. In embodiments, administration of a disclosed compound or composition results in increased agonism of HTR2Arelative to any one or more of an HTR such as HTR1Aand HTR1B, another HTR2, such as HTR2Band HTR2C, an HTR5, e.g., HTR5A, HTR6, and an HTR7, e.g., HTR7D.

[0380]

[0242] In some embodiments, a disclosed compound modulates the activity of a dopamine receptor (DR), such as any one or more of DRD1, DRD2, DRD3, DRD4, and DRD5. In some embodiments, a disclosed compound agonizes or partially agonizes a dopamine receptor. In some embodiments, a disclosed compound agonizes or partially agonizes DRD2. In some embodiments, a disclosed compound agonizes or partially agonizes the DRD2 short isoform (DRD2S). In embodiments, a disclosed compound has an in vitro EC50for DRD2S that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM.

[0381]

[0243] Determining agonism and antagonism, and measuring EC50and IC50, respectively, may be determined according to methods available to one of skill. In one example, measuring Gq-mediated calcium flux is a known method for assessing modulation, e.g., activation, of HTR2A, a widely recognized target of psychedelic compounds. See, e.g., Klein et al., ACS Pharmacol Transl Sci. 2020 14;4(2):533-542; Flanagan et al., ACS Pharmacol Transl Sci. 2020;4(2):488-502; Toro-Sazo et al., PLoS One. 2019;14(1 ):e0209804; Halberstadt et al., Psychopharmacology (Berl). 2019;236(2):799-808. As will be recognized, a partial agonist shows reduced maximum efficacy (EMAX) relative to a full agonist (EMAX= 100%), e.g., serotonin in the example of an HTR.

[0382]

[0244] In some embodiments, disclosed compounds or compositions thereof, when administered in a pharmacologically effective amount, result in modulation of one or more membrane monoamine transporters, including any one or more of a serotonin membrane transporter (SERT), a dopamine membrane transporter (DAT), a norepinephrine membrane transporter (NET), and a vesicular monoamine transporter. In some embodiments, a disclosed compound blocks the uptake activity of monoamine transporters. In some embodiments, a disclosed compound blocks the uptake activity of one or more of a serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).

[0383]

[0245] In some embodiments, a disclosed compound inhibits the uptake activity of any one or more of SERT, DAT, and NET. In some embodiments, a disclosed compound inhibits the uptake activity of SERT, DAT, and NET. In embodiments, a disclosed compound has an in vitro IC50of less than 10 pM for any one or more of SERT, DAT, and NET. In embodiments, a disclosed compound does not inhibit the uptake activity of SERT. In embodiments, a disclosed compound has an in vitro IC50of less than 10 pM for SERT. In embodiments, a disclosed compound selectively inhibits the uptake activity of SERT. In embodiments, a disclosed compound shows greater potency for inhibiting the uptake activity of SERT relative to DAT and NET.

[0384]

[0246] Determining whether a disclosed compound results in inhibition of the uptake activity of a monoamine transporter, or whether such activity is lacking, may be determined according to available methods, which may include live-cell fluorescent assays or radioactive assays. In some examples, inhibition of monoamine uptake may be determined in rat synaptosomes or human platelets. See, e.g., Segonzac et al., J Neurochem. 2025-11-28 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.

[0385]

[0247] In some embodiments, administration of a disclosed compound or composition according to the methods herein results in an improved pharmacological profile, such as a relative increase in agonism of serotonin receptors compared to dopamine and / or norepinephrine receptors, compared to a corresponding composition, which may be an increase of 5% or more, 10% or more, 25% or more, or 50% or more, and including amounts in between. Measurements of agonism of a receptor will be as understood by those in the art or by reference to the general knowledge in the art.

[0386]

[0248] In some embodiments, an improved pharmacological profile of a compound or composition is 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, 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.

[0387]

[0249] Detecting a change in monoamine levels in a subject, such as an increase or a decrease, can be achieved according to methods known in the art, for example, brain microdialysis (Chefer et al., Curr Protoc Neurosci. 2009; 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) (e.g., Wong & Gjedde, Encyclopedia Neurosci, 2009; 939-952 and Takano, Front Psych. 2018; 9:228).

[0388]

[0250] In some embodiments, a disclosed compound is used to increase neuroplasticity. Neuroplasticity, such 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 may be increased in embodiments through one or more mechanisms, including synaptic plasticity (e.g., the strengthening or weakening of synapses) and structural plasticity (e.g., changes in the physical structure of neurons, such as the growth of new dendritic branches or the formation of new synapses). In embodiments, increasing neuroplasticity contributes to the therapeutic effects of a disclosed compound, such as when administered to in a subject. In embodiments, increasing neuroplasticity by administering a compound to a subject treats a disease or disorder in the subject.

[0389]

[0251] In embodiments, a compound increases neuroplasticity by increasing one or more of neuritogenesis, spinogenesis, and synaptogenesis. In embodiments, administration of a compound or composition increases neuritogenesis, such as by increasing total neurite length, maximum neurite length, number of neurite nodes, and / or number of neurite extremities. In embodiments, administration increases total neurite length. In embodiments, administration increases maximum neurite length. In embodiments, administration increases the number of neurite nodes. In embodiments, administration increases the number of neurite extremities.

[0390]

[0252] In embodiments, a disclosed compound or composition increases the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., number of 2025-11-28 synapses per neuron), and / or total dendritic length, such as measured using a Sholl analysis or other technique known to those of skill (e.g., Ly et al. ACS Pharmacol Transl Sci. 2020;4(2):452-460).

[0391] b. Treatment

[0392]

[0253] In some embodiments, a disclosed compound is used to treat a medical condition, such as a disease or disorder. In embodiments, a disclosed compound is used in the manufacture of a medicament 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.

[0393]

[0254] In embodiments, a disclosed compound or composition comprising the compound is 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.

[0394]

[0255] In some embodiments are provided methods of treating and / or preventing a condition in a subject, the method comprising administering to the mammal a therapeutically effective amount of a disclosed compound or composition. In embodiments, “treating” or “treatment” refers to treating a disease or disorder in a subject, and preferably in a human, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e., arresting its development; (c) relieving a disorder, i.e., causing regression thereof; (d) protecting from or relieving a symptom or pathology caused by or related to a disorder; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a disorder; and (f) preventing or inhibiting of a worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder. In embodiments, treatment includes prevention. In other embodiments, treatment does not include prevention. Relevant 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.

[0395]

[0256] In embodiments, a disclosed compound is used to treat a central nervous system (CNS) disorder. Broadly, CNS disorders include diseases of the nervous system (e.g., movement disorders, neurodegenerative disorders) as well as mental, behavioral, and neurodevelopmental disorders, such as those in the DSM-5, Merck Manual, ICD-11, or other such diagnostic resources known to one of skill.

[0396] i. Mental, Behavioral, or Neurodevelopmental Disorders

[0397]

[0257] In embodiments, a disclosed compound is used to treat a mental, behavioral, or neurodevelopmental disorder. In embodiments, 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 embodiments, a compound, when administered in a therapeutically effective amount, provides one or more therapeutic effects for the treatment of a mental, behavioral, or neurodevelopmental disorder. Administration of a “compound” will be understood to include administration of a composition comprising the compound. 2025-11-28

[0258] 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 neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.

[0398]

[0259] 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.

[0399]

[0260] In embodiments, a disclosed compound is used to treat a mental health disorder. In embodiments, compounds are administered, such as in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating the mental health disorder. In embodiments, a compound, when administered in a therapeutically effective amount, provides one or more therapeutic effects for the treatment of a mental health disorder. In embodiments, a compound is used to reduce the symptoms of a mental health disorder. Symptoms of a mental health disorder may be determined by reference to the general knowledge in the art.

[0400]

[0261] 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 2025-11-28 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.

[0401]

[0262] In some embodiments, a disclosed compound is used to treat a neurodevelopmental disorder, such as 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 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.

[0402]

[0263] In some embodiments, a disclosed compound is used to treat schizophrenia or another primary psychotic disorder, such as 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.

[0403]

[0264] In some embodiments, a disclosed compound is used to treat catatonia, such as 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.

[0404]

[0265] In embodiments, a disclosed compound is used to treat a mood disorder, such as categorized according to the specific types of mood episodes and their pattern over time. The primary types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. In some embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder), a depressive disorder, or a substance-induced mood disorder. In some embodiments, the mood disorder is a depressive disorder. In embodiments, the depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder (formally known as dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, seasonal affective disorder, mixed depressive and anxiety disorder, or an unspecified depressive disorder. In embodiments, depression is assessed through the Patient Health Questionnaire-9 (PHQ-9) screening tool, Montgomery-Asberg 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 2025-11-28 Depression Inventory (RDI), Hamilton Rating Scale for Depression (HRSD), and Carroll Rating Scale (CRS).

[0405]

[0266] In some embodiments, a disclosed compound is used to treat an anxiety or fear-related disorder, such as a mental disorder that induces excessive or abnormal fear, dread, or worry. In some embodiments, the anxiety disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or a substance-induced anxiety disorder.

[0406]

[0267] In some embodiments, a disclosed compound is used to treat an obsessive-compulsive or related disorder, such as characterized by repetitive thoughts and behaviors, including 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.

[0407]

[0268] In some embodiments, a disclosed compound is used to treat a disorder associated with stress, such as having 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.

[0408]

[0269] In embodiments, a disclosed compound is used to treat a dissociative disorder, such as 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.

[0409]

[0270] In some embodiments, a disclosed compound is used to treat a feeding or eating disorder, such as involving abnormal eating or feeding behaviors that are not explained by another health condition, and not developmentally appropriate or culturally sanctioned, or involving preoccupation with food and 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 2025-11-28 recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.

[0410]

[0271] In some embodiments, a disclosed compound is used to treat an elimination disorder, such as 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).

[0411]

[0272] In some embodiments, a disclosed compound is used to treat a disorder of bodily distress or bodily experience, such as involving 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.

[0412]

[0273] In some embodiments, a disclosed compound is used to treat a disorder due to substance use or addictive behaviors, such as 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 embodiments, a disclosed compound is used to treat disorders due to substance use (i.e., a substance use disorder, or “SUD”). In embodiments, the SUD 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 embodiments, the SUD 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 embodiments, the SUD is alcohol use disorder (AUD). In embodiments, the SUD is cannabis use disorder. In embodiments, the SUD is caffeine use disorder. In embodiments, the SUD is phencyclidine use disorder. In embodiments, the SUD is inhalant use disorder. In embodiments, the SUD is opioids use disorder. In embodiments, the SUD is sedatives use disorder. In embodiments, the SUD is hypnotics use disorder. In embodiments, the SUD is anxiolytics use disorder. In embodiments, the SUD is stimulants use disorder. In embodiments, the SUD is tobacco use disorder. In embodiments, the SUD is alcohol use disorder, wherein said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism. In embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder). In embodiments, the SUD is screened using a Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, 2025-11-28 Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), the Opioid Risk Tool - OLID (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).

[0413]

[0274] In some embodiments, a disclosed compound is used to treat an impulse control disorder, such as 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 embodiments, impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts. In embodiments, a disclosed compound is used to treat pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.

[0414]

[0275] In some embodiments, a disclosed compound is used to treat a disruptive behavior disorder or a dissocial disorder, such as 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 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).

[0415]

[0276] In some embodiments, a disclosed compound is used to treat a personality disorder, such as 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 embodiments, a disclosed compound is used to treat a mild, moderate, or severe personality disorders. In embodiments, a compound is used to treat a prominent personality trait or patterns (e.g., negative affectivity, detachment, dissociality, disinhibition, anankastia, borderline pattern). In 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.

[0416]

[0277] In some embodiments, a disclosed compound is used to treat a paraphilic disorder, such as 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 embodiments, a disclosed compound is used to treat exhibitionistic disorder, voyeuristic disorder, pedophilic disorder, coercive sexual sadism disorder, frotteuristic disorder, other paraphilic disorders involving non-consenting individuals, or paraphilic disorders involving solitary behavior or consenting individuals.

[0417]

[0278] In embodiments, a disclosed compound is used to treat a factitious disorder, such as 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 2025-11-28 otherwise present themselves or another person as ill, injured, or impaired. In embodiments, a compound is used to treat factitious disorder imposed on self or a factitious disorder imposed on another.

[0418]

[0279] In some embodiments, a disclosed compound is used to treat a neurocognitive disorder, such as 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 embodiments, a disclosed compound is used to treat delirium. In embodiments, the delirium is associated with another disease or disorder. In embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a disclosed compound is used to treat mild neurocognitive disorder. In embodiments, a disclosed compound is used to treat an amnestic disorder. In embodiments, the amnestic disorder is associated with another disease or disorder. In embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a disclosed compound is used to treat dementia. In 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).

[0419]

[0280] In embodiments, a disclosed compound is used to treat a behavioral or psychological disturbance associated with dementia. In 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).

[0420]

[0281] In some embodiments, a disclosed compound is used to treat a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. In embodiments, the syndrome associated with pregnancy or the puerperium involves significant mental and behavioral features, including a depressive symptom. In embodiments, the disorder includes psychotic symptoms. In 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.

[0421]

[0282] In embodiments, a disclosed compound is used to treat a sleep-wake disorder, such as associated with difficulty initiating or maintaining sleep (e.g., insomnia), excessive sleepiness (e.g., hypersomnolence disorders), respiratory disturbance during sleep (e.g., sleep-related breathing disorders (SRBDs), such as obstructive sleep apnea (OSA), central sleep apnea (CSA), sleep- related hypoventilation disorders, sleep-related hypoxemia disorder, snoring, catathrenia, Cheyne-Stokes breathing, and sleep-disordered breathing), disorders of the sleep-wake schedule (e.g., circadian rhythm sleep-wake disorders), abnormal movements during sleep, or problematic behavioral or psychological events that occur while falling asleep, during sleep, or upon arousal from sleep (e.g., parasomnia disorders). In embodiments, a disclosed compound is used to treat an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder. 2025-11-28

[0283] In some embodiments, a disclosed compound is used to treat sexual dysfunction, such as syndromes where the subject has difficulty experiencing personally satisfying, non-coercive sexual activities. In embodiments, a compound is used to treat hypoactive sexual desire dysfunction, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse.

[0422]

[0284] In embodiments, a compound is administered together with psychotherapy, such as psychosocial or behavioral therapy, e.g., any of (or adapted from any of) cognitive behavioral therapy (e.g., as in Arch Gen Psych. 1999;56:493-502), interpersonal therapy (e.g., as in Psychol Addict Behav. 2009;23(1):168-174), contingency management based therapy (e.g., as in Psychol Addict Behav. 2009;23(1): 168-174; J Consul Clin Psychol. 2005;73(2):354-59; or Case Reports Psych. Vol. 2012; 731638), motivational interviewing based therapy (e.g., J Consul Clin Psychol 2001;69(5):858-862), meditation based therapy, such as transcendental meditation based therapy (e.g., J Consul Clin Psychol. 2000;68(3):515-52), or the therapeutic approach of MAPS for PTSD (e.g., as in Mithoefer 2017) (see also, e.g., Schenberg 2018; Johnson 2008).

[0423]

[0285] In embodiments, a compound is administered together with standardized psychological treatment or support, which refers to any accepted modality of standard psychotherapy or counseling sessions, whether once a week, twice a week, or as needed; whether in person or virtual (e.g., over telemedicine or by means of a web program or mobile app); and whether with a human therapist or a virtual or Al therapist.

[0424]

[0286] In some embodiments, a patient will participate in a treatment protocol or a disclosed method, or be administered a disclosed compound as part of such a method, if the patient meets certain specified inclusion criteria, does not meet certain specified exclusion criteria, does not meet any specified withdrawal criteria during the course of treatment, and otherwise satisfies the requirements of the disclosed embodiment.

[0425]

[0287] In some embodiments, administration of a disclosed compound occurs without or with reduced risk of side effects that would require physician or other clinician supervision, and allows for treatment at home or otherwise outside of a clinic and without the need for such supervision, and / or additionally without the need for or use of adjunctive psychotherapy, psychological support, or other patient monitoring.

[0426]

[0288] In some embodiments, administration of a disclosed compound to a subject comprises a personalized (or or “precision”) approach, for example based on individual characteristics of the subject, 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 (e.g., commonly-found and / or wild-type) sequence. Genetic variation may be recombination events or mutations such as substitution / deletion / insertion events like point and splice site mutations. In embodiments, the genetic variation is in one or more cytochrome P450 (CYP or CYP450) enzymes that affects drug metabolism, including of a compound, such as CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 or CYP3A5, and further including any of 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, 2025-11-28 CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0427]

[0289] In some embodiments, a disclosed compound is administered together with an additional compound that is metabolized by the same CYP enzyme(s) as the disclosed compound, so as to permit a lower dose to be taken, increase the effective bioavailability of one or both, or otherwise affect drug metabolism or pharmacokinetics. In some embodiments, the dose of a disclosed composition is adjusted, such as reduced, when administered to a subject known to be a poor metabolizer of an active compound in the composition (e.g., having a genetic variation in CYP2D6 and / or CYP3A4), or increased when administered to a subject known to be a rapid metabolizer. In some embodiments, a patient is tested using ordinary means known to those of skill to determine if the patient is a poor or rapid metabolizer for one or more such CYP enzymes.

[0428]

[0290] In embodiments, the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5). In another embodiment, the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene, associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs. In embodiments, a genetic variation is an inclusion criteria for the administration of a compound. In embodiments, a genetic variation is an exclusion criteria for the administration of a compound.

[0429]

[0291] In some embodiments, a subject has altered epigenetic regulation of a gene, the expression of which is associated with a mental health disorder or other medical condition for which a compound is administered, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.

[0430] ii. Additional Medical Conditions

[0431]

[0292] Also provided are methods of treating further medical conditions, including neurodegenerative disorders, pain and pain disorders, inflammation and inflammatory disorders, and ischemic injury.

[0432]

[0293] In some embodiments, a disclosed compound is used to treat a neurodegenerative disorder. In embodiments, a compound is administered, such as in a therapeutically effective amount, to a subject having a neurodegenerative disorder. In embodiments, a compound, when administered in a therapeutically effective amount, provides one or more therapeutic effects for the treatment of a neurodegenerative disorder.

[0433]

[0294] In 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 (TBI) including mild traumatic brain injury (mTBI).

[0434]

[0295] In some embodiments, a disclosed compound is used to treat pain and / or inflammation, such as a pain disorder and / or an inflammatory disorder. In some embodiments, a compound is administered, such as in a pharmacologically effective amount, to a subject having pain and / or inflammation, thereby treating said pain and / or inflammation. In some embodiments, a compound, when administered in a pharmacologically effective amount, provides one or more therapeutic effects for the treatment of pain and / or inflammation. 2025-11-28

[0296] In some embodiments, a disclosed compound is used to treat a pain disorder. In embodiments, the pain disorder is any of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesia, hyperalgesia, neuralgia, neuritis, neurogenic pain, phantom limb pain, analgesia, anesthesia dolorosa, causalgia, sciatic nerve pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorders, headache disorders, migraine headaches, chronic cluster headaches, concussion headache, short-lasting unilateral neuralgiform headache attacks, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, or pain associated with cancer.

[0435]

[0297] The International Association for the Study of Pain (I ASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Serotonin modulators, such as 5-HT2A agonists, may ameliorate pain through, e.g., synaptic plasticity that alters the pathologic changes in neural connections seen in chronic pain states, resulting in a reduced pain intensity and duration (Castellanos et al., Reg Anesth Pain Med. 2020;45(7): 486-494).

[0436]

[0298] Pain, such as chronic pain, and improvements thereof, such as a reduction of symptoms, may be measured according to known methods, e.g., by subject reporting, pain diaries, pain scales, applicable questionnaires (assessments of chronic pain and its impact on physical, emotional and social functions), ecological momentary assessments and computerized versions thereof. See, e.g., Salaffi et al., Best Practice & Research Clinic Rheumatol, 2015;29(1): 164-186 and Hawker et al., Arthritis Care Res (Hoboken). 2011;63 Suppl 11: S240-52. Exemplary questionnaires include the Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP), Migraine Diagnosis Questionnaire, the Migraine-Screen Questionnaire (MS-Q), the Fibromyalgia Survey Questionnaire (FSQ).

[0437]

[0299] In some embodiments, a disclosed compound is used to treat an inflammatory disorder. In embodiments, the inflammatory disorder is characterized by inflammation of an organ or tissue. In embodiments, the inflammatory disorder comprises any one or more of skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, bladder inflammation, gastric inflammation, intestinal inflammation, neuroinflammation, and brain inflammation. In embodiments, the inflammatory disorder is a disorder that causes acute inflammation, or that exhibits chronic inflammation as a symptom. In some embodiments, the inflammatory disorder comprises chronic inflammation. In embodiments, a compound is used to reduce inflammation.

[0438]

[0300] 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 2025-11-28 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, Psychoneuroendocrinol. 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 (e.g., Germolec et al., Methods Mol Biol. 2018;1803:57-79; Luo et al., Clin Lab. 2019 1;65(3)).

[0439]

[0301] In some embodiments, a compound is used to treat an ischemic injury. In embodiments, a compound is administered, such as in a pharmacologically effective amount, to a subject having an ischemic injury, thereby treating said ischemic injury. In embodiments, a compound, when administered in a pharmacologically effective amount, provides one or more therapeutic effects for the treatment of an ischemic injury.

[0440]

[0302] In some embodiments, the ischemic injury is a stroke. As used herein, “stroke” is a general term that refers to conditions caused by the occlusion or hemorrhage of one or more blood vessels supplying the brain, leading to cell death. “Ischemic stroke”, as used herein, refers to stroke caused by an occlusion of one or more blood vessels supplying the brain. Types of ischemic stroke include, e.g., embolic stroke, cardioembolic stroke, thrombotic stroke, large vessel thrombosis, lacunar infarction, artery-artery stroke and cryptogenic stroke. “Hemorrhagic stroke” herein refers to stroke caused by hemorrhage of one or more blood vessels supplying the brain. Types of hemorrhagic stroke include subdural stroke, intraparenchymal stroke, epidural stroke and subarachnoid stroke. In some embodiments, the stroke is a hemorrhagic stroke, ischemic stroke, or a transient ischemic attack (TIA). In some embodiments, the ischemic injury is an ischemia-reperfusion injury (IRI; also known as reoxygenation injury). In some embodiments, the ischemic injury is tissue damage that occurs when blood flow returns to an organ after a period of ischemia or lack of oxygen.

[0441]

[0303] In some embodiments, treating an ischemic injury with a disclosed compound results in an improvement measured using an assessment scale. Assessment scales include the Berg Balance Scale, the Modified Rankin Scale, the Stroke Impact Scale (SIS), the Stroke Specific Quality of Life Measure (SS-QOL), the American Heart Association Stroke Outcome Classification (AHA SOC), the Barthel Index, the Functional Independence Measurement (FIM™), the Glasgow Outcome Scale (GOS), and the Health Survey SF36™ & SF12™. Other diagnostic and screening tests include the Action Research Arm Test, the Blessed-Dementia Scale, the Blessed-Dementia Information-Memory-Concentration Test, the DSM-IV criteria for the diagnosis of vascular dementia, the Hachinkski Ischaemia Score, the Hamilton Rating Scale for Depression, the N1NDS-A1REN criteria for the diagnosis of vascular dementia, the Orpington Prognostic Score, the Short Orientation-Memory-Concentration Test, the Thrombosis In Myocardial Infarction grading scheme, MRI imaging, diffusion-weighted (DWI) MRI techniques, and PET imaging. 2025-11-28 Examples

[0442]

[0304] Examples are included for illustrative purposes only and should not limit the scope of the invention. Example 1: In Vitro Receptor and Transporter Interactions

[0443]

[0305] 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 disclosed compound and any comparator compounds. 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).

[0444]

[0306] Methods - Arrestin: Activation of HTR5Aand HTR6, are determined using the PathHunter® 0-Arrestin assay. The assay monitors restoration of p-galactosidase (P-Gal) as a marker of GPCR activation and recruitment of 0-Arrestin to the receptor. 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 pL of concentrated sample is added to cells and incubated at 37°C or room temperature for 90 to 180 minutes. Vehicle concentration is 1%. 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 (Chemi nnovation, CA). Percentage activity is calculated using the following formula: % Activity =100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control).

[0445]

[0307] 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 0-Gal as a functional reporter. 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 pL 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%. Compound activity is analyzed using CBIS data analysis suite (Chemi nnovation, CA). For Gs agonist mode assays, percentage activity is calculated using the formula: % Activity =100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX control -mean RLU of vehicle control). For Gi agonist mode assays, percentage activity is calculated using the formula: % Activity = 100% x (1 - (mean RLU of test sample - mean RLU of MAX control) / (mean RLU of vehicle control - mean RLU of MAX control)).

[0446]

[0308] 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 2025-11-28 compound may result in the release of calcium from intracellular stores and an increase in dye fluorescence that can be measured. Cell lines are expanded from freezer stocks and seeded into multi-well microplates. Then, the plates are incubated at 37°C 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. 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. Compound activity is analyzed using CBIS data analysis suite (Chemi nnovation, CA). For agonist mode, percentage activity is calculated using the formula: % Activity = 100% x (mean RFU of test sample - mean RFU of vehicle control) / (mean MAX RFU control ligand - mean RFU of vehicle control). For antagonist mode, percentage inhibition is calculated using the formula: % Inhibition = 100% x (1 - (mean RFU of test sample - mean RFU of vehicle control) / (mean RFU of EC80 control - mean RFU of vehicle control)).

[0447]

[0309] 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. 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 37°C. 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 Envision™ instrument for fluorescence signal detection.

[0448]

[0310] Compound activity is analyzed using CBIS data analysis (Chemlnnovation, CA). For blocker mode assays, percentage inhibition is calculated using the formula: % Inhibition = 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of positive control - mean RLU of vehicle control)).

[0449]

[0311] 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.

[0450]

[0312] To determine agonist and antagonist activity, cell lines are expanded from freezer stocks, seeded into multi-well microplates, and incubated at 37 °C. Cells are then loaded with dye and incubated again. For agonist determination, cells are incubated with the sample at 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. Compound activity is analyzed using CBIS data analysis suite (Chemlnnovation, CA). For agonist mode assays, percentage activity is calculated using the formula: % Activity = 100% x ( mean 2025-11-28 RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control). For antagonist mode, percentage inhibition is calculated using: % Inhibition = 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of EC80 control - mean RLU of vehicle control)).

[0451] Example 2: In Vitro Activity at Trace Amine-Associated Receptor 1 (TAAR1)

[0452]

[0313] 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. Neuropsychopharmacol. 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).

[0453]

[0314] 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.

[0454]

[0315] Results & Significance: Activation of TAAR1 is shown to modulate monoaminergic neurotransmission (e.g., Revel et al., PNAS. 2011;108(20):8485— 8490). TAAR1 may be a promising target for treatment of neuropsychiatric disorders. For example, the effects of TAAR1 activation on dopaminergic neurotransmission may provide therapeutic benefit for substance use disorders (Liu & Li, Front Pharmacol. 2018; 9: 279).

[0455] Example 3: In Vitro Metabolic Stability

[0456]

[0316] Purpose: To determine the metabolic stability of a disclosed compound, and optionally any comparator compounds. 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).

[0457]

[0317] Methods: A high-throughput assay is used to determine metabolic stability of a disclosed compound (and any comparator compounds) 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.

[0458]

[0318] Results & Significance: Disclosed compounds may exhibit comparable or substantially higher metabolic stability relative to a comparator.

[0459] Example 4: In Vitro Metabolic Profiling

[0460]

[0319] Purpose: To determine whether disclosed compounds are metabolized and to identify metabolites.

[0461]

[0320] Methods: An in vitro study is conducted to evaluate metabolism and metabolites of 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- 2025-11-28 mass spectrometry. 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 also may be conducted according to the methods in Muller & Rentsch, Anal Bioanal Chem.

[0462] 2012;402:2141-2151 and Pedersen et al. Drug Metab Dispos. 2013;41:1247-1255.

[0463]

[0321] Results & Significance: Compounds that undergo metabolism in vivo may produce pharmacologically active or chemically reactive metabolites that produce unexpected effects or potential toxicities. FDA Guidance for Industry, Safety Testing Drug Metabolites notes the relevance of metabolite profiling early in development, as metabolites unique to or disproportionate in humans may require additional toxicological studies.

[0464] Example 5: In Vitro CYP Enzyme Inhibition

[0465]

[0322] Purpose: To assess the interactions between compounds and cytochrome P450 (CYP450) enzymes, to 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.

[0466]

[0323] 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.

[0467]

[0324] Briefly, the disclosed compound is incubated in different concentrations in a mix containing buffer, enzymes, and substrate. Then, fluorescence is measured using a plate reader and percentage inhibition may be extrapolated out from the readings. Alternatively, the inhibitory effects of the disclosed compound on CYP enzymes may be assessed using high-performance liquid chromatography. Inhibition is evaluated using the Michaelis-Menten method. CYP enzyme inhibition may be conducted according to the methods described in Lin et al., J Pharm Sci. 2007;96(9):2485-95 and Wojcikowski et al., Pharmacol Rep. 2020;72(3):612-621.

[0468]

[0325] 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). For context, MDMA has been shown to inhibit CYP2D6 (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.

[0469] Example 6: In Vitro Evaluation of Membrane Permeability and P-gp Interactions in MDCKII MDR1 Cells

[0326] Purpose: To assess the permeability and transport liability of disclosed compounds. Permeability is 2025-11-28 assessed using MDCK (Madin-Darby canine kidney) cells, and the effects of P-glycoprotein (P-gp) are evaluated to determine drug transport.

[0470]

[0327] 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.

[0471]

[0328] Briefly, the disclosed compound and reference compounds (e.g., comparator compounds) are evaluated in two directions in the absence and presence of a P-gp inhibitor. The MDCKII and MDCKII-MDR1 cells are incubated in a transport buffer on both apical [A] and basolateral [B] sides. Then, the disclosed compound is added to each side of the cells and incubated. The rate of transport of the disclosed compound is determined in the absence or presence of a P-gp inhibitor. Following incubation, where the disclosed compound will permeate the cells in both AB and BA directions, the permeability of the cells is measured using a LC MS / MS system. The efflux ratio of the compound is calculated to determine if it is a P-gp substrate.

[0472]

[0329] Results & Significance: This screening provides insight into the movement of the compound in a biological system. Compounds are classified based on Papp (nm / s) as follows (Cambridge MedChem Consulting, ADME, 2019): >150 = High Permeability; 50-150 = Medium Permeability; <50 = Low Permeability.

[0473]

[0330] Mass balance is calculated using the following equation: %Recovery = 100 x (CD(t) + CR(t)) / Co.

[0474]

[0331] Where CD(t) is the measured concentration in the donor well at time t (expressed as IS ratio), CR(t) is the measured concentration in the receiver well at time t (expressed as IS ratio), Cois the initial concentration in the donor solution (expressed as IS ratio). Cell integrity is calculated using the equation: %lntegrity = 100 x [1-RFUbasolateral / RFUapical]. 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.

[0475] Example 7: In Vivo Assessment Of The Behavioral Effects Of Disclosed Compounds Using HTR

[0332] Purpose: The mouse head-twitch response (HTR) is a behavioral test that reflects 5-HT2Areceptor activation and can be predictive of psychedelic effects in humans (Halberstadt et al., J Psychopharmacol.

[0476] 2011; 25(11): 1548-1561). The HTR is widely used as a behavioral surrogate for human psychedelic effects for its ability to reliably distinguish psychedelic from non-psychedelic 5-HT2Areceptor agonists (Halberstadt & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3).

[0477]

[0333] Methods: An HTR assay is performed in accordance with the methods described in Klein et al., Neuropharmacol, 2018;142:231-239 to assess the effects of disclosed compounds in mice. Male C57BL / 6 J mice (6-8 weeks old) are obtained and housed in a vivarium that meets all requirements for care and treatment of laboratory animals. Mice are housed up to four per cage in a climate-controlled room on a reverse-light cycle (lights on at 1900 h, off at 0700 h) and are provided with ad libitum access to food and water, except during behavioral testing. Testing is conducted between 1000 h— 1800 h. All animal experiments are conducted in accordance with applicable guidelines and are approved by an appropriate animal care committee. 2025-11-28

[0334] A head-mounted magnet and a magnetometer detection coil is used to assess HTR, as previously described (Halberstadt & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3, Halberstadt & Geyer, Neuropharmacol, 2014;77:200-7; Nichols et al., ACS Chem Neurosci. 2015; 6(7): 1165-1175). Briefly, mice are anesthetized and a small neodymium magnet is attached to the dorsal surface of the cranium using dental cement. Following a two-week recovery period, HTR experiments are carried out in a well-lit room with at least 7 days between sessions to avoid carryover effects. Test compounds are dissolved in a suitable solvent, e.g., water containing 5% Tween 80, and administered IP at a volume of 5 or 10 mL / kg body weight immediately prior to testing. Different doses are tested to produce a dose-response curve. Mice are injected with drug or vehicle, and HTR activity is recorded in a glass cylinder surrounded by a magnetometer coil for 30 min. Coil voltage is low-pass filtered (2–10 kHz cutoff frequency), amplified, and digitized (20 kHz sampling rate) using a Powerlab / 8SP with LabChart v 7.3.2 (ADInstruments, Colorado Springs, CO, USA), then filtered off-line (40–200 Hz band-pass). Head twitches are identified manually based on the following criteria: 1) sinusoidal wavelets; 2) evidence of at least two sequential head movements (usually exhibited as bipolar peaks) with frequency 40 Hz; 3) amplitude exceeding the level of background noise; 4) duration < 0.15 s; and 5) stable coil voltage immediately preceding and succeeding each response.

[0478]

[0335] Head twitch counts are analyzed using one-way analyses of variance. Post hoc pairwise comparisons between selected groups are performed using Tukey’s studentized range method. The entire recordings are examined for head twitches. In some cases a shorter block of time is analyzed to accommodate compounds with a brief duration of action, as potency calculations can be confounded by extended periods of inactivity.

[0479]

[0336] ED50values and 95% confidence limits are calculated using nonlinear regression. Relationships between HTR potency and binding affinities are assessed using linear regression and ordinary least-squares regression. For all analyses, significance is demonstrated by surpassing an a-level of 0.05.

[0480]

[0337] Results & Significance: Results show whether a disclosed compound is likely to produce psychedelic effects in humans. When a psychedelic effect is produced, its magnitude is evaluated and compared amongst compounds. Results can be represented as ED50(mg / kg). Differences between the HTR of disclosed compounds and suitable comparator compounds are also determined based on described methods.

[0481]

[0338] 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 for its practice. The description is presented solely for purposes of illustration, and is not intended to be exhaustive or to be limiting. 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.

[0482]

[0339] The scope of the invention shall be defined solely by the following claims and their equivalents.

Claims

2025-11-28CLAIMSThe invention claimed is:

1. A compound of Formula (1):or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, wherein:Rais CrC6alkyl;Rpis H, OH, or CrC6alkoxy;X is Br, F, Cl, I, CrC6alkyl, C2-C8alkenyl, C2-C8alkynyl, C^Cs alkoxy, C^Cs alkylthio, C^Cs haloalkyl, CrC6haloalkoxy, CrC6haloalkylthio, C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; andRNis H, CrC6alkyl, or C^Cs alkylene-C6-C12aryl; wherein:one of R2and R5is methyl, and the other is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, CrC6haloalkyl, CrC6alkylene— 3- to 6-membered cycloalkyl, C^Cs alkylene— 4- to 6-membered heterocycloalkyl, or CpCg alkylene— aryl, or CrC6alkylene— heteroaryl; and R3and R6are both H; orR2and R3together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl;R5is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, C^Cs haloalkyl, C^Cs alkylene— 3- to 6-membered cycloalkyl, CrC6alkylene— 4- to 6-membered heterocycloalkyl, or CrC6alkylene— aryl, or CrC6alkylene— heteroaryl; andR6is H; orR5and R6together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl;R2is C3-C6alkyl, C3-C6alkenyl, C2-C8alkynyl, CrC6haloalkyl, CrC6alkylene— 3- to 6-membered cycloalkyl, C^Cs alkylene— 4- to 6-membered heterocycloalkyl, or C^Cs alkylene— aryl, or C^Cs alkylene— heteroaryl; andR3is H.2025-11-28 2. The compound of claim 1, having the structure of Formula (I):

3. The compound of claim 1, having the structure of Formula (II):4 The compound of claim 1, having the structure of Formula (III):5 The compound of any of claims 2—4, wherein Rais methyl.6 The compound of any of claims 2—4, wherein Rais ethyl.7 The compound of claim 2, wherein R2is methyl.8 The compound of claim 2 or 3, wherein R5is C3-C6alkyl.9 The compound of claim 8, wherein R5is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or n-pentyl.10 The compound of claim 2 or 3, wherein R5is C3-C6alkenyl.11 The compound of claim 10, wherein R5is allyl.12 The compound of any of claims 2—4, wherein X is F, Cl, Br, or I.13 The compound of any of claims 2—4, wherein X is CrCg alkyl.14 The compound of claim 13, wherein X is methyl.15 The compound of claim 13, wherein X is ethyl.16 The compound of any of claims 2—4, wherein X is CrC6alkylthio or CrC6haloalkylthio.2025-11-2817. The compound of claim 16, wherein X is methylthio, ethylthio, or 2-fl uoroethylthio.

18. The compound of any of claims 2—4, wherein X is CrC6haloalkyl.

19. The compound of claim 18, wherein X is trifluoromethyl.

20. The compound of claim 1, having the structure of Formula (IV) or Formula (V):

21. The compound of claim 1, having the structure of Formula (VI) or Formula (VII):

24. The compound of claim 1, having the structure of Formula (XII) or Formula (XIII):2025-11-28 25. The compound of claim 1, wherein the compound is selected from the compounds of TABLE 1.

26. The compound of claim 1, having the structure of:2025-11-2827. The compound of claim 1, in enantiomerically pure form.

28. The compound of claim 27, wherein the enantiomerically pure compound is the (R)-enantiomer.

29. The compound of claim 27, wherein the enantiomerically pure compound is the (S)-enantiomer.

30. The compound of claim 1, in enantiomerically enriched form.

31. The compound of claim 30, having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, and wherein the enriched enantiomer is the (R)-enantiomer.

32. The compound of claim 30, having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, and wherein the enriched enantiomer is the (S)-enantiomer.

33. A prodrug of the compound of claim 1.

34. The prodrug of claim 33, having the structure:OR5wherein R is an amino acid side chain.

35. The prodrug of claim 33, having the structure:2025-11-28wherein X is H or PO3H2.

36. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

37. The pharmaceutical composition of claim 36, formulated for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

38. The pharmaceutical composition of claim 36, in unit dosage form.

39. The pharmaceutical composition of claim 38, comprising the compound in a total amount of between 1 and 200 mg, or between 5 and 100 mg.

40. The pharmaceutical composition of claim 39, comprising the compound in a total amount of between 10 and 75 mg, or between 20 and 50 mg.

41. The pharmaceutical composition of claim 36, wherein the unit dosage form is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

42. The pharmaceutical composition of claim 36, further comprising a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof.

43. The pharmaceutical composition of claim 42, wherein the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic agents, antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, monoamine oxidase inhibitors, terpenes, tryptamines, phenethylamines, phenylalkylamines, lysergamides, sedatives, stimulants, serotonergic agents, and vitamins.

44. The pharmaceutical composition of claim 42, wherein the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase2025-11-28 stability or shelf life, improve bioavailability, induce synergy, or alter pharmacokinetics or pharmacodynamics.

45. The pharmaceutical composition of claim 44, wherein the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

46. A method of modulating neurotransmission in a subject, comprising administering to the subject:a. a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof; orb. the pharmaceutical composition of claim 36.

47. The method of claim 46, wherein modulating neurotransmission comprises activating a monoamine neurotransmitter receptor and / or modulating the uptake activity of a monoamine transporter.

48. The method of claim 47, wherein the monoamine neurotransmitter receptor is any of a serotonin receptor, a dopamine receptor, and a norepinephrine receptor.

49. The method of claim 48, wherein the serotonin receptor is a 5-HT2A receptor.

50. The method of claim 47, wherein the monoamine transporter is a serotonin transporter (SERT).

51. A method of treating a medical condition in a subject, comprising administering to the subject:a. a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof; orb. the pharmaceutical composition of claim 36.

52. The method of claim 51, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission.

53. The method of claim 52, wherein the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission.

54. The method of claim 53, wherein the monoaminergic neurotransmission is any of serotonergic neurotransmission, dopaminergic neurotransmission, and noradrenergic neurotransmission.

55. The method of claim 51, wherein the medical condition is a mental health disorder.

56. The method of claim 55, wherein the mental health disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), adjustment disorder, a depressive disorder, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to another medical condition, premenstrual dysphoric disorder, seasonal affective disorder, persistent depressive disorder (dysthymia), an anxiety disorder, an obsessive-compulsive and related disorder, a phobic disorder,2025-11-28 binge-eating disorder, body dysmorphic disorder, a substance use disorder, an alcohol or drug use disorder, a substance-induced mood disorder, a mood disorder due to another medical condition, a disruptive behavior disorder, an eating disorder, an impulse-control disorder,attention-deficit / hyperactivity disorder (ADHD), a personality disorder, an attachment disorder, and a dissociative disorder.

57. The method of claim 56, wherein the mental health disorder is PTSD.

58. The method of claim 56, wherein the depressive disorder is major depressive disorder (MDD) or treatment-resistant depression (TRD).

59. The method of claim 56, wherein the anxiety disorder is generalized anxiety disorder (GAD).

60. The method of claim 56, wherein the substance use disorder is alcohol use disorder (AUD), nicotine dependence or tobacco use disorder, opioid use disorder (OUD), stimulant use disorder, or sedative, hypnotic, or anxiolytic use disorder.

61. The method of claim 51, wherein the medical condition is a neurodegenerative disorder, pain or a pain disorder, or inflammation or an inflammatory disorder.

62. The method of claim 52, wherein the medical condition is an ischemic injury.

63. The method of claim 62, wherein the ischemic injury is a stroke or an ischemia-reperfusion injury.

64. The method of claim 51, wherein the compound is administered together with one or more sessions of psychotherapy or psychological support.

65. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, or the pharmaceutical composition of claim 36, for use in the treatment of a medical condition.

66. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, or the pharmaceutical composition of claim 36, for use in the manufacture of a medicament for the treatment of a medical condition.

67. A compound, composition, kit, method, or use comprising or characterized by any one or more aspects or embodiments disclosed herein.

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