1,3-dihydro-4-isobenzofuranethanamines

Abstract

The disclosure provides 1,3-dihydroisobenzofuran-substituted phenethylamines, including 5-hydroxy- and 5-alkoxy-substituted 1,3-dihydro-4-isobenzofuranethanamines, pharmaceutical compositions thereof, and methods of their synthesis and use. Disclosed compounds exhibit neuromodulatory and anti-inflammatory activity, for example via activation of serotonin receptors, and are useful as regenerative and neuroprotective therapies, and for treating medical conditions such as neuropsychiatric, neurodegenerative, and inflammatory diseases and disorders. Formula (1).

Description

[0001] 2026-03-18 1.3-DIHYDRO-4-ISOBENZOFURANETHANAMINES INVENTOR: David E. Nichols

[0002] CROSS-REFERENCE

[0003]

[0001] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U.S. Provisional Application No. 63 / 773,790, filed March 18, 2025, and hereby incorporated by reference in its entirety for all purposes.

[0004] FIELD OF THE INVENTION

[0005]

[0002] The disclosure relates to benzofused phenethylamine compounds, compositions thereof, and methods of their use. The compounds exhibit neuromodulatory and anti-inflammatory activity, for example via activation of serotonin receptors, and are useful as regenerative and neuroprotective therapies, and for treating medical conditions such as neuropsychiatric, neurodegenerative, and inflammatory diseases and disorders.

[0006] BACKGROUND OF THE INVENTION

[0007]

[0003] Serotonergic agents, including compounds such as psilocybin, LSD, and MDMA, are currently being investigated for a range of therapeutic applications due to their effects on neurological function, mood, and cognition. Serotonin receptor agonists in particular have demonstrated potential in the treatment of various medical conditions. However, existing and investigational therapeutic approaches are limited, including by inadequate efficacy, significant adverse effect profiles, poor long-term tolerability, and hallucinogenic effects.

[0008]

[0004] There accordingly remains an ongoing need for therapeutic compounds with improved efficacy and reduced adverse effects, and which expand therapeutic accessibility across a variety of indications.

[0009]

[0005] The phenethylamine pharmacophore is a chemical scaffold found in biologically active molecules, including neurotransmitters such as dopamine, and in many serotonergic agents. One class of phenethylamine compounds, known as the “2C” or “2C-x” compounds, are ring-substituted phenethylamines containing methoxy groups at the 2- and 5-positions of the benzene ring, with an additional substituent at the 4-position. Certain 2C compounds are potent serotonin 2A (5-HT2A) receptor agonists and the structure-activity relationship of many has been explored. However, adverse effects have been reported in connection with 2C compounds, including sympathomimetic effects such as hypertension, tachycardia, and seizures, as well as gastrointestinal effects and poor tolerability (see, e.g., Dean et al., J Med Toxicol., 2013; 9(2): 172-178).

[0010]

[0006] Moreover, existing phenethylamine compounds are poorly optimized for pharmaceutical development across numerous pharmacological and physicochemical parameters, such as receptor activity and selectivity, behavioral liability, and efficacy, such as for treating neurodegeneration and inflammation.

[0011]

[0007] Provided herein are compounds, compositions, methods, and kits to meet these and other needs.

[0012] INCORPORATION BY REFERENCE

[0013]

[0008] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each is fully set forth herein. No such citation is an admission that a reference comes from an area that is analogous or directly applicable to the disclosure or is prior art or general knowledge in any jurisdiction.2026-03-18

[0014] BRIEF SUMMARY OF THE INVENTION

[0015]

[0009] The following summarizes certain embodiments of the disclosure.

[0016]

[0010] In some aspects are provided compounds of Formula (1):

[0017] OR2Rb

[0018]

[0019] wherein:

[0020] R2is H or Ci-C6alkyl;

[0021] R4is isobutyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl,— (CH2)o-3—C(0)—0—Ci-Ce alkyl, CN, NO2, or halogen; and

[0022] RNis H or— CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12 aryl optionally substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl; and

[0023] Rais H or Ci-Ce alkyl; and Rbis H;

[0024] or Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl;

[0025] or RNand Rbtogether with the intervening atoms form a 4- to 8-membered heterocyclyl, and Rais H or Ci-Ce alkyl;

[0026] or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0027]

[0011] In some aspects are provided compounds of Formula (2):

[0028] OR2

[0029]

[0030]

[0012] In some aspects are provided compounds of Formula (3):

[0031]

[0032] wherein:

[0033] X, Y, and Z are each independently H, F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl; or2026-03-18 X and Y are taken together to form a 4- to 6-membered heterocyclyl, and Z is H, F, Cl, Br, I, OH, Ci-C6alkoxy, C3-C6 cycloalkyl, or phenyl; or

[0034] Y and Z are taken together to form a 4- to 6-membered heterocyclyl, and X is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, C3-C6 cycloalkyl, or phenyl.

[0035]

[0013] In some aspects are provided compounds selected from the group consisting of:

[0036]

[0037]

[0014] In some aspects are provided compounds selected from the group consisting of:

[0038]

[0039]

[0015] In some aspects are provided compounds selected from the group consisting of:2026-03-18

[0040]

[0041]

[0016] In some embodiments, the compound is:

[0042]

[0043]

[0017] In some embodiments, the compound is:

[0044]

[0045]

[0018] In some embodiments, the compound is:

[0046]

[0047]

[0019] In some further aspects are provided pharmaceutical compositions comprising a therapeutically effective amountof a disclosed compound, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0048]

[0020] Also provided are methods of modulating neurotransmission, methods of increasing neuroplasticity, and methods of treating a medical condition, such as further described herein.

[0049]

[0021] The foregoing summary is not intended to limit the scope of the disclosure or the claims. Additional embodiments are described below.

[0050] BRIEF DESCRIPTION OF THE FIGURES

[0051]

[0022] The following figures illustrate certain exemplary embodiments of the disclosure:

[0052]

[0023] FIG. 1A shows the dose-response curve from a cell-based agonist calcium flux assay for exemplary compound 2CIB-2OH-5DHF at 5-HT2A and 5-HT2B, as described in Example 4.2026-03-18

[0024] FIG. 1B shows the dose-response curve from a cell-based agonist calcium flux assay for exemplary compound 2CIB-5DHF at 5-HT2A and 5-HT2B, as described in Example 4.

[0053]

[0025] FIG. 1C shows the dose-response curve from a cell-based agonist calcium flux assay for exemplary compound 2CIB-2OH-5DHF-NBOH at 5-HT2A and 5-HT2B, as described in Example 4.

[0054]

[0026] FIG. 2A shows the HTR count (30 min intervals) of exemplary compound 2CIB-2OH-5DHF at 0, 0.03, 0.3, 3, and 30 milligrams per kilogram (mpk), as described in Example 12.

[0055]

[0027] FIG. 2B shows the HTR count (5 min fractions) of exemplary compound 2CIB-2OH-5DHF at 0, 0.03, 0.1, 0.3, 1, 3, 10, and 30 mpk over 30 minutes, as described in Example 12.

[0056]

[0028] FIG 2C shows the distance traveled (cm) induced by exemplary compound 2CIB-2OH-5DHF at 0.03, 0.1, 0.3, 1, 3, 10, and 30 mpk, as described in Example 12.

[0057]

[0029] FIG 2D shows the distance traveled (cm / 5 min) induced by exemplary compound 2CIB-2OH-5DHF at 0, 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg / kg, measured at 5-minute intervals from 5 to 30 minutes post-injection, as described in Example 12.

[0058]

[0030] FIG 2E shows the change in body temperature (°C) induced by exemplary compound 2CIB-2OH-5DHF at O, 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg / kg, as described in Example 12.

[0059]

[0031] FIG 3 shows the HTR count (30 min intervals) of reference compound DOI at 0, 0.03, 0.3, 3, and 30 mpk, with data obtained following the methods as described in Example 12.

[0060] DETAILED DESCRIPTION OF THE INVENTION

[0061]

[0032] The following detailed description illustrates exemplary embodiments to enable one having ordinary skill in the art (“one of skill”) to practice the disclosure to its full scope. Many modifications, substitutions, and variations can be made by one of skill without departing from the scope of the disclosure as claimed. The disclosure should be accorded the widest scope consistent with the principles and features described herein.

[0062] A. General Definitions and Terms

[0063]

[0033] As used in the specification and claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “an active agent” includes a combination of two or more active agents, and “an excipient” includes a combination of two or more excipients. While the term “one or more” may be used, its absence (or its replacement by the singular) does not signify the singular only, but simply underscores the possibility of, for example, multiple agents or ingredients in some embodiments.

[0064]

[0034] “Or” means, and is interchangeable with, “and / or” unless context clearly indicates otherwise. The specific use of the term “and / or” does not signify that any uses of “or” are disjunctive only; rather, such use simply underscores the possibility that the term “and / or” may be conjunctive in particular embodiments, but otherwise may be disjunctive, like “or.” The term “and” will be understood to be conjunctive.

[0065]

[0035] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., they do not limit lists to recited elements), and are interchangeable with the phrase “including but not limited to.”

[0036] Where ranges are used, the disclosure includes embodiments in which the endpoints are included,2026-03-18 embodiments in which both endpoints are excluded, and embodiments in which one endpoint is included and the other is excluded. It should be assumed that both endpoints are included unless indicated otherwise. It is also understood that unless otherwise indicated or otherwise evident from the context and understanding of one of skill, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. It is further understood that where a series of numerical values is stated herein, the disclosure includes embodiments that relate analogously to any intervening value or range defined by any two values in the series, and that the lowest value may be taken as a minimum and the greatest value may be taken as a maximum. Numerical values, as used herein, include values expressed as percentages.

[0066]

[0037] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, will 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 term “about.” In embodiments, the numerical parameters are approximations that can vary depending on the particular embodiment or the properties sought to be obtained. In embodiments, “about” includes numbers that fall within a range of ±10% of a number, in embodiments within ±5% of a number, in embodiments within ±2% of a number, in embodiments within ±1 % of a number, in embodiments within ±0.5% of a number, and in embodiments within ±0.1 % of a number, unless otherwise stated or evident from the context (such as where a number would impermissibly exceed 100% of a possible value).

[0067]

[0038] Where “about” is used to modify one number in a series or range, it should be understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range. Thus, “about 1, 2, or 3” means “about 1, about 2, or about 3” and “about 1 to 10” means “about 1 to about 10.”

[0068]

[0039] “Substantially,” when used to modify a feature or limitation, should be interpreted in the context of the disclosure and in light of the knowledge in the art to provide the appropriate certainty, such as by using an art-recognized standard to understand it as a term of degree, or by ascertaining the scope as would one of skill.

[0069]

[0040] 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 embodiments are approximations, the numerical values set forth in the examples are reported as precisely as practicable. Numerical values in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0070]

[0041] A list of the abbreviations used by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry; the current list as of the date of this filing is incorporated by reference.

[0071]

[0042] The nomenclature and terminology used and the procedures performed herein are those used in fields relating to one or more aspects of the disclosure, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or medicinal chemistry. Techniques and procedures described herein are generally those available to and performable by one of skill. While materials and methods similar or equivalent2026-03-18 to those disclosed can be used in some embodiments, certain materials and methods are described.

[0072]

[0043] Unless explicitly defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one of skill. Further definitions that may assist a reader in understanding the disclosed and exemplary embodiments are below; however, it will be appreciated that such definitions are not intended to limit the scope of the disclosure, which shall be properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill) in view of the language used in the claims. Terminology is for the purpose of describing particular embodiments and not intended to be limiting.

[0073]

[0044] Terms having a specific meaning within the regulatory law of a jurisdiction in which this application is filed or may be in force generally should be given such meaning unless context dictates otherwise.

[0074]

[0045] “In embodiments” is equivalent to, and used only as shorthand for, “in some embodiments.”

[0075]

[0046] “Alkyl” will be understood to include straight or branched radicals having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon (C=C) bonds, groups having one or more triple carbon-carbon (C=C) bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” can also be used. In some embodiments, an alkyl group comprises from 1 to 10 carbon atoms (“C atoms”), from 1 to 6 C atoms, from 1 to 4 C atoms, or from 1 to 3 C atoms. For any alkyl, the alkyl may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkenyl, alkynyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, and — SONH2.

[0076]

[0047] “Alkenyl” refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one C=C double bond derived by the removal of one H atom from a single C 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.

[0077]

[0048] “Alkynyl” refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one C=C triple bond derived by the removal of one H atom from a single C 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.2026-03-18

[0049] “Aryl” refers to a monovalent aromatic hydrocarbon radical derived by the removal of one H atom from a single C atom of a parent aromatic ring system. Typical aryl groups include groups derived from aceanthry-lene, 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 embodiments, an aryl group comprises from 6-20 C atoms, or between 6-12 C atoms.

[0078]

[0050] “Cycloalkyl” refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3-12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3-6 C atoms, 4-6 C atoms, 5-6 C atoms, 3-8 C atoms, 4-8 C atoms, 5-8 C atoms, 6-8 C atoms, 7-8 C atoms, 3-9 C atoms, 4-9 C atoms, 5-9 C atoms, 6-9 C atoms, 7-9 C atoms, 8-9 C atoms, 3-10 C atoms, 4-10 C atoms, 5-10 C atoms, 6-10 C atoms, 7-10 C atoms, 8-10 C atoms, 9-10 C atoms, 3-11 C atoms, 4-11 C atoms, 5-11 C atoms, 6-11 C atoms, 7-11 C atoms, 8-11 C atoms, 9-11 C atoms, 10-11 C atoms, 3-12 C atoms, 4-12 C atoms, 5-12 C atoms, 6-12 C atoms, 7-12 C atoms, 8-12 C atoms, 9-12 C atoms, 10-12 C atoms, and 11-12 C atoms. Monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic cycloalkyls include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyls include norbornane, bicyclooctane, decahydronaphthalene, and adamantane. When cycloalkyl is a monocyclic C3-8 cycloalkyl, exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a monocyclic C3-6 cycloalkyl, exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0079]

[0051] “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 C atoms, 4-6 C atoms, 5-6 C atoms, 3-8 C atoms, 4-8 C atoms, 5-8 C atoms, 6-8 C atoms, 7-8 C atoms, 3-9 C atoms, 4-9 C atoms, 5-9 C atoms, 6-9 C atoms, 7-9 C atoms, 8-9 C atoms, 3-10 C atoms, 4-10 C atoms, 5-10 C atoms, 6-10 C atoms, 7-10 C atoms, 8-10 C atoms, 9-10 C atoms, 3-11 C atoms, 4-11 C atoms, 5-11 C atoms, 6-11 C atoms, 7-11 C atoms, 8-11 C atoms, 9-11 C atoms, 10-11 C atoms, 3-12 C atoms, 4-12 C atoms, 5-12 C atoms, 6-12 C atoms, 7-12 C atoms, 8-12 C atoms, 9-12 C atoms, 10-12 C atoms, and 11-12 C atoms. 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.

[0080]

[0052] “Cycloalkylmethyl” refers to a radical having a methylene component and a cycloalkyl component, where the methylene component links the cycloalkyl component to the point of attachment. The cycloalkyl component is as defined above, and can include any number of carbons, such as 3-6 C atoms (i.e., a C3-C62026-03-18 cycloalkylmethyl), 4-6 C atoms, 5-6 C atoms, 3-8 C atoms, 4-8 C atoms, 5-8 C atoms, 6-8 C atoms, 7-8 C atoms, 3-9 C atoms, 4-9 C atoms, 5-9 C atoms, 6-9 C atoms, 7-9 C atoms, 8-9 C atoms, 3-10 C atoms, 4-10 C atoms, 5-10 C atoms, 6-10 C atoms, 7-10 C atoms, 8-10 C atoms, 9-10 C atoms, 3-11 C atoms, 4-11 C atoms, 5-11 C atoms, 6-11 C atoms, 7-11 C atoms, 8-11 C atoms, 9-11 C atoms, 10-11 C atoms, 3-12 C atoms, 4-12 C atoms, 5-12 C atoms, 6-12 C atoms, 7-12 C atoms, 8-12 C atoms, 9-12 C atoms, 10-12 C atoms, and 11-12 C atoms. In embodiments, the cycloalkylmethyl group is a cyclopropylmethyl.

[0081]

[0053] “Halogen” refers to fluorine, chlorine, bromine, and iodine.

[0082]

[0054] “Heterocycloalkyl” refers 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 includes bicyclic compounds which include a heteroatom. Bicyclic compounds includes spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds The heteroatoms can also be oxidized, such as — S(O)— and — S(O)2— . Heterocycloalkyl groups can include any number of ring atoms, such as, 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. 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 3-4. The heterocycloalkyl group can include groups such as aziridine, azetidinyl, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1 ,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothia-zolidine, 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 indoline. Heterocycloalkyl groups may be substituted, such as substituted with C1-6 alkyl or oxo (=0), among many others.

[0083]

[0055] “Alkyl-heterocycloalkyl” refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of attachment. The alkyl component can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6, and C5-6. In some instances, the alkyl component can be absent. The heterocycloalkyl component is as defined above.

[0084]

[0056] “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, O or S. Heteroaryl groups can include any number of ring atoms, such as, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. 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. Heteroaryl groups include 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. Heteroaryl groups can be fused to2026-03-18 aromatic ring systems, such as a phenyl ring, to form members including 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.

[0085]

[0057] “Alkyl-heteroaryl” refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of attachment. The alkyl component can include any number of carbons, such as Co-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6, and C5-6. The alkyl component can be absent.

[0086]

[0058] “Alkoxy” refers to the formula —OR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl. 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.

[0087]

[0059] “Alkylthio” or “thioalkyl” refers to the formula —SR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl. A non-limiting list of alkylthio are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio.

[0088]

[0060] “Acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, connected via a carbonyl group as a substituent, e.g., formyl, acetyl, propanoyl, benzoyl, or acryl.

[0089]

[0061] “Haloalkyl” refers to any alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen (e.g., a fluorine, a chlorine, a bromine, or an iodine). Where an alkyl radical is substituted by more than one halogen, it may be referred to using a prefix corresponding to the number of halogen substitutions. For example, di haloalkyl refers to an alkyl substituted by two halo groups, which may be the same halogen. Haloalkyl groups include difluoromethyl (— CHF2), bromofluoromethyl (— CHBrF), trifluoro- methyl (— 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).

[0090]

[0062] “Haloalkylthio” refers to any alkylthio group as defined above, wherein one or more hydrogen atoms are replaced by a halogen (e.g., a fluorine, a chlorine, a bromine, or an iodine). Where an alkylthio 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, dihaloalkylthio refers to an alkylthio substituted by two halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkylthio groups include — SCF3, — CHF2, -CH2F, -CH2CF3, - CH2CHF2, - CH2CH2F, -CH(CH3)(CF3), -CH(CH3)(CHF2), and -CH(CH3)(CH2F).

[0091]

[0063] “Hydroxyalkyl” refers to an alkyl in which one or more of the H atoms are replaced by a hydroxy group. Hydroxyalkyl groups include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl.

[0092]

[0064] “Haloalkoxy” refers to an — O-alkyl group in which one or more of the H atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). The halogens may be the same or different in each2026-03-18 instance. Such groups include chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy.

[0093]

[0065] “Sulfenyl” refers to an —SR group in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0094]

[0066] “Sulfinyl” refers to an — S(=O)— R group in which R can be the same as defined for sulfenyl.

[0095]

[0067] “Sulfonyl” refers to an — SO2R group in which R can be the same as defined for sulfenyl.

[0096]

[0068] “O-carboxy” refers to a — RC(=0)0— group in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0097]

[0069] “C-carboxy” and “ester” refer to a — C(=0)0R group in which R can be the same as for O-carboxy.

[0098]

[0070] “Thiocarbonyl” refers to a — C(=S)R group in which R can be the same as defined for O-carboxy.

[0099]

[0071] “Trihalomethanesulfonyl” refers to an X3CSO2— group wherein each X is a halogen.

[0100]

[0072] “Trihalomethanesulfonamido” refers to an X3CS(O)2N(RA)— group wherein each X is a halogen, and RA is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0101]

[0073] “S-sulfonamido” refers to a — SO2N(RARB) group in which RA and Rscan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0102]

[0074] “N-sulfonamido” refers to a RS02N(RA)— group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0103]

[0075] “O-carbamyl” refers to a — 0C(=0)N(RARB) group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0104]

[0076] “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.

[0105]

[0077] “O-thiocarbamyl” refers to a — OC(=S)— N(RARB) group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0106]

[0078] “N-thiocarbamyl” refers to an R0C(=S)N(RA)— group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0107]

[0079] “C-amido” group refers to a — C(=0)N(RARB) group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0108]

[0080] “N-amido” refers to a RC(=0)N(RA)— group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl.

[0109]

[0081] 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.

[0110]

[0082] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed forthat 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 indicated2026-03-18 substituents. When there are more than one substituents, the substituents may be the same or different. In some embodiments, an optionally substituted group has one substituent. In other embodiments, an optionally substituted group has two substituents. In other embodiments, an optionally substituted group has three substituents. In other embodiments, 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, 0-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group.

[0111]

[0083] Any group having a definition herein can be interpreted as defined herein.

[0112]

[0084] Still additional definitions and abbreviations are provided elsewhere herein.

[0113] B. Compounds

[0114]

[0085] Disclosed herein are certain benzofused phenethylamines, including 1 ,3-dihydroisobenzofuran-substituted phenethylamines. In some embodiments, the compounds are 5-hydroxy- and 5-alkoxy-substituted 1,3-dihydro-4-isobenzofuranethanamines.

[0115]

[0086] In some aspects, the disclosure relates to compounds of Formula (1):

[0116]

[0117] wherein:

[0118] R2is H or Ci-C6alkyl;

[0119] R4is H, F, Cl, Br, I, CN, NO2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, Ci- Ce alkoxy, Ci-Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl, or — (CH2)o-3-C(0)-0- Ci-Ce alkyl; and

[0120] RNis H or— CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12 aryl optionally substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl; and

[0121] Rais H or Ci-Ce alkyl; and Rbis H;

[0122] or Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl;

[0123] or RNand Rbtogether with the intervening atoms form a 4- to 8-membered heterocyclyl, and Rais H or Ci-Ce alkyl;2026-03-18 or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0124]

[0087] In some embodiments of Formula (1), R2is H or Ci-Ce alkyl. In some embodiments, R2is H. In some embodiments, R2is Ci-Ce alkyl. In some embodiments, R2is methyl.

[0125]

[0088] In some embodiments of Formula (1), R4is H, F, Cl, Br, I, CN, NO2, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl, or — (CH2)O-3-C(0)-0-CI-C6alkyl. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CN. In embodiments, R4is NO2. In embodiments, R4is Ci-Ce alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is propyl. In embodiments, R4is butyl. In embodiments, R4is isobutyl. In embodiments, R4is pentyl. In embodiments, R4is neopentyl. In embodiments, R4is C2-C6 alkenyl. In embodiments, R4is vinyl. In embodiments, R4is allyl. In embodiments, R4is C2-C6 alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is Ci-Ce haloalkyl. In embodiments, R4is trifluoromethyl. In embodiments, R4is Ci-Ce alkoxy. In embodiments, R4is methoxy. In embodiments, R4is Ci-Ce haloalkylthio. In embodiments, R4is 2-fluoroethylthio. In embodiments, R4is Ci-Ce alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio. In embodiments, R4is butylthio. In embodiments, R4is isobutyl- thio. In embodiments, R4is C3-C6 cycloalkylmethyl. In embodiments, R4is cyclopropylmethyl. In embodiments, R4is — (CH2)o-3-C(0)-0-Ci-Ce alkyl. In embodiments, R4is — COO-Ci-Ce alkyl. In embodiments, R4is — CH2COO-Ci-Ce alkyl. In embodiments, R4is — (CH2)2COO-Ci-Ce alkyl. In embodiments, R4is — (CFhhCOO-Ci-Ce alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is — CH2COOCH2CH3.

[0126]

[0089] In some embodiments of Formula (1), Rais H or Ci-Ce alkyl. In embodiments, Rais H. In embodiments, Rais Ci-Ce alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl.

[0127]

[0090] In some embodiments of Formula (1), RNis H or — CH2-Ar, wherein Ar is 6- to 12-membered heterocyclyl or Ce-Ci 2 aryl optionally substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl. In embodiments, RNis H. In embodiments, RNis — CH2-Ar. In embodiments, RNis — CH2-Ar, and Ar is 6- to 12-membered heterocyclyl optionally substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl. In embodiments, RNis — CH2-Ar, and Ar is unsubstituted 6- to 12-membered heterocyclyl. In embodiments, RNis — CH2-Ar, and Ar is 6- to 12-membered heterocyclyl substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl. In embodiments, RNis — CH2-Ar, and Ar is benzodioxolyl (e.g., 1 ,3-benzodioxolyl). In embodiments, RNis — CH2-Ar, and Ar is benzo- furanyl (e.g., 1 -benzofuranyl). In embodiments, RNis — CH2-Ar, and Ar is C6-C12 aryl optionally substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl. In embodiments, RNis — CH2-Ar, and Ar is unsubstituted C6-C12 aryl. In embodiments, RNis — CH2-Ar, and Ar is phenyl. In embodiments, RNis — CH2-Ar, and Ar is naphthyl. In embodiments, RNis — CH2-Ar, and Ar is Ce-Ci 2 aryl substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by F, Cl, Br, or I. In embodiments, RNis — CH2-Ar, and Ar is 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, or 2-iodophenyl. In embodiments, RNis — CH2-Ar, and Ar is 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, or 3-iodophenyl. In embodiments, RNis — CH2-Ar,2026-03-18 and Ar is phenyl substituted by OH. In embodiments, RNis — CH2-Ar, and Ar is 2-hydroxyphenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by Ci-Ce alkoxy. In embodiments, RNis — CH2-Ar, and Ar is 2-methoxyphenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by phenyl. In embodiments, RNis — CH2-Ar, and Ar is biphenyl (e.g., 2-biphenyl). In embodiments, RNis — CH2-Ar, and Ar is 2-(4-hydroxyphenyl)phenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by C3-C6 cyclo- alkyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by cyclopropyl (e.g., 2-cyclopropylphenyl).

[0128]

[0091] In some embodiments of Formula (1), Rbis H.

[0129]

[0092] In some embodiments of Formula (1), Rband RNtogether with the intervening atoms form a 4- to 8-membered heterocyclyl. In some embodiments, Rband RNtogether with the intervening atoms form an azetidinyl. In some embodiments, Rband RNtogether with the intervening atoms form a pyrrolidinyl. In some embodiments, Rband RNtogether with the intervening atoms form a piperidinyl. In some embodiments, Rband RNtogether with the intervening atoms form an azepanyl.

[0130]

[0093] In some embodiments of Formula (1), Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl. In some embodiments, Raand Rbtogether with the intervening atoms form a cyclopropyl. In some embodiments, Raand Rbtogether with the intervening atoms form a cyclobutyl. In some embodiments, Raand Rbtogether with the intervening atoms form a cyclopentyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclohexyl.

[0131]

[0094] In some embodiments, the compound has the structure of Formula (2):

[0132] OR2

[0133]

[0134] wherein:

[0135] Rais H or Ci-Ce alkyl; and

[0136] R4is H, F, Cl, Br, I, CN, NO2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci- Ce alkoxy, Ci-Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl, or — (CH2)o-3-C(0)-0- Ci-Ce alkyl;

[0137] or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0138]

[0095] In some embodiments of Formula (2), Rais H or Ci-Ce alkyl. In some embodiments, Rais H. In some embodiments, Rais Ci-Ce alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl.

[0139]

[0096] In some embodiments of Formula (2), R4is H, F, Cl, Br, I, CN, NO2, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl, or — (CH2)o-3-C(0)-0-Ci-Ce alkyl. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CN. In embodiments, R4is NO2. In embodiments, R4is Ci-Ce alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R42026-03-18 is propyl. In embodiments, R4is butyl. In embodiments, R4is isobutyl. In embodiments, R4is pentyl. In embodiments, R4is neopentyl. In embodiments, R4is C2-C6 alkenyl. In embodiments, R4is vinyl. In embodiments, R4is allyl. In embodiments, R4is C2-C6 alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is Ci-Ce haloalkyl. In embodiments, R4is trifluoromethyl. In embodiments, R4is Ci-Ce alkoxy. In embodiments, R4is methoxy. In embodiments, R4is Ci-Ce haloalkylthio. In embodiments, R4is 2-fluoroethyl-thio. In embodiments, R4is Ci-Ce alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio. In embodiments, R4is butylthio. In embodiments, R4is isobutylthio. In embodiments, R4is C3-C6 cycloalkylmethyl. In embodiments, R4is cyclopropylmethyl. In embodiments, R4is — (CH2)o-3-C(0)-0-Ci-Ce alkyl. In embodiments, R4is — COO-Ci-Ce alkyl. In embodiments, R4is — CH2COO-Ci-Ce alkyl. In embodiments, R4is — (CH2)2COO-Ci-Ce alkyl. In embodiments, R4is — (CH2)3COO-Ci-Ce alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is — CH2COOCH2CH3.

[0140]

[0097] In some embodiments, the compound has the structure of Formula (3):

[0141]

[0142] wherein:

[0143] Rais H or Ci-Ce alkyl;

[0144] R4is H, F, Cl, Br, I, CN, NO2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci- Ce alkoxy, Ci-Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl, or — (CH2)o-3-C(0)-0- Ci-Ce alkyl; and

[0145] X, Y, and Z are each independently H, F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl; or

[0146] X and Y are taken together to form a 4- to 6-membered heterocyclyl, and Z is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, C3-C6 cycloalkyl, or phenyl; or

[0147] Y and Z are taken together to form a 4- to 6-membered heterocyclyl, and X is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, C3-C6 cycloalkyl, or phenyl.

[0148]

[0098] In some embodiments of Formula (3), Rais H or Ci-Ce alkyl. In embodiments, Rais H. In embodiments, Rais Ci-Ce alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl.

[0149]

[0099] In some embodiments of Formula (3), R4is H, F, Cl, Br, I, CN, NO2, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl, or — (CH2)o-3-C(0)-0-Ci-Ce alkyl. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CN. In embodiments, R4is NO2. In embodiments, R4is Ci-Ce alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is propyl. In embodiments, R4is butyl. In embodiments, R4is isobutyl. In embodiments, R4is pentyl. In2026-03-18 embodiments, R4is neopentyl. In embodiments, R4is C2-C6 alkenyl. In embodiments, R4is vinyl. In embodiments, R4is allyl. In embodiments, R4is C2-C6 alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is Ci-Ce haloalkyl. In embodiments, R4is trifluoromethyl. In embodiments, R4is C1-C6 alkoxy. In embodiments, R4is methoxy. In embodiments, R4is Ci-Ce haloalkylthio. In embodiments, R4is 2-fluoro-ethylthio. In embodiments, R4is Ci-Ce alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio. In embodiments, R4is butylthio. In embodiments, R4is isobutylthio. In embodiments, R4is C3-C6 cycloalkylmethyl. In embodiments, R4is cyclopropylmethyl. In embodiments, R4is — (CH2)o-3-C(0)-0-Ci-Ce alkyl. In embodiments, R4is — COO-Ci-Ce alkyl. In embodiments, R4is — CH2COO-Ci-Ce alkyl. In embodiments, R4is — (CH2)2COO-Ci-Ce alkyl. In embodiments, R4is — (CH2)3COO-Ci-Ce alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is — CH2COOCH2CH3.

[0150]

[0100] In some embodiments of Formula (3), X, Y, and Z are each independently H, F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl (i.e., “Ph”). In embodiments, X is F, Cl, Br, I, OH, Ci-Ce alkoxy, or Ph; and Y and Z are both H. In embodiments, Y is F, Cl, Br, I, OH, Ci-Ce alkoxy, or Ph; and X and Z are both H. In embodiments, Z is F, Cl, Br, I, OH, Ci-Ce alkoxy, or Ph; and X and Y are both H. In embodiments, X and Y are each independently F, Cl, Br, I, OH, Ci-Ce alkoxy, or Ph; and Z is H. In embodiments, X and Z are each independently F, Cl, Br, I, OH, Ci-Ce alkoxy, or Ph; and Y is H. In embodiments, Y and Z are each independently F, Cl, Br, I, OH, Ci-Ce alkoxy, or Ph; and X is H.

[0151]

[0101] In some embodiments, X is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl. In embodiments, X is F, Cl, Br, or I. In embodiments, X is H. In embodiments, X is F. In embodiments, X is Cl. In embodiments, X is Br. In embodiments, X is I. In embodiments, X is OH. In embodiments, X is Ci-Ce alkoxy. In embodiments, X is methoxy. In embodiments, X is phenyl. In embodiments, X is 4-hydroxyphenyl. In embodiments, X is C3-Ce cycloalkyl. In embodiments, X is cyclopropyl.

[0152]

[0102] In some embodiments, Y is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl. In embodiments, Y is F, Cl, Br, or I. In embodiments, Y is H. In embodiments, Y is F. In embodiments, Y is Cl. In embodiments, Y is Br. In embodiments, Y is I. In embodiments, Y is OH. In embodiments, Y is Ci-Ce alkoxy. In embodiments, Y is methoxy. In embodiments, Y is phenyl. In embodiments, Y is 4-hydroxyphenyl. In embodiments, Y is C3-Ce cycloalkyl. In embodiments, Y is cyclopropyl.

[0153]

[0103] In some embodiments, Z is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl. In embodiments, Z is F, Cl, Br, or I. In embodiments, Z is H. In embodiments, Z is F. In embodiments, Z is Cl. In embodiments, Z is Br. In embodiments, Z is I. In embodiments, Z is OH. In embodiments, Z is Ci-Ce alkoxy. In embodiments, Z is methoxy. In embodiments, Z is phenyl. In embodiments, Z is 4-hydroxyphenyl. In embodiments, Z is C3-Ce cycloalkyl. In embodiments, Z is cyclopropyl.

[0154]

[0104] In some embodiments, X and Y are taken together to form a 4- to 6-membered heterocyclyl. In some

[0155] embodiments, X and Y are taken together to form

[0156]

[0157] (methylenedioxy), wherein * and ** indicate the points2026-03-18 of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively. In some embodiments, X and Y are taken together to form a dihydrofuranyl. In embodiments, X

[0158] and Y are taken together to form

[0159]

[0160] , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively. In some embodiments, X and Y are taken together to form a furanyl. In embodiments, X and Y are taken together to form ** **

[0161] ' \2°

[0162]

[0163] O— ' or ' — ' , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.

[0164]

[0105] In some embodiments, Y and Z are taken together to form a 4- to 6-membered heterocyclyl. In some

[0165] embodiments, Y and Z are taken together to form

[0166]

[0167] O—7(methylenedioxy), wherein * and ** indicate the points of connection between Y and the rest of the compound, and between Z and the rest of the compound, respectively. In some embodiments, Y and Z are taken together to form a dihydrofuranyl. In embodiments, Y ** **

[0168]

[0169] \ °

[0170] and Z are taken together to form O'"7or ' — ’ , wherein * and ** indicate the points of connection between Y and the rest of the compound, and between Z and the rest of the compound, respectively.

[0171]

[0106] In some embodiments of any of the disclosed compounds, such as any of Formulas (1 )- (3), Rais not H. In some embodiments, Rais not Ci-Ce alkyl. In some embodiments, Rais not methyl. In embodiments, Rais not ethyl. In embodiments, R2is not H. In embodiments, R2is not Ci-Ce alkyl. In embodiments, R2is not methyl. In embodiments, R4is not H. In embodiments, R4is not F. In embodiments, R4is not Cl. In embodiments, R4is not Br. In embodiments, R4is not I. In embodiments, R4is not CN. In embodiments, R4is not NO2. In embodiments, R4is not Ci-Ce alkyl. In embodiments, R4is not methyl. In embodiments, R4is not ethyl. In embodiments, R4is not propyl. In embodiments, R4is not butyl. In embodiments, R4is not isobutyl. In embodiments, R4is not pentyl. In embodiments, R4is not neopentyl. In embodiments, R4is not C2-C6 alkenyl. In embodiments, R4is not vinyl. In embodiments, R4is not allyl. In embodiments, R4is not C2-C6 alkynyl. In embodiments, R4is not ethynyl. In embodiments, R4is not Ci-Ce haloalkyl. In embodiments, R4is not trifluoromethyl. In embodiments, R4is not Ci-Ce alkoxy. In embodiments, R4is not methoxy. In embodiments, R4is not Ci-Ce haloalkylthio. In embodiments, R4is not 2-fluoroethylthio. In embodiments, R4is not Ci- Ce alkylthio. In embodiments, R4is not methylthio. In embodiments, R4is not ethylthio. In embodiments, R4is not propylthio. In embodiments, R4is not butylthio. In embodiments, R4is not isobutyl- thio. In embodiments, R4is not C3-C6 cycloalkylmethyl. In embodiments, R4is not cyclopropylmethyl. In embodiments, R4is not— (CH2)o- 3-C(0)-0-Ci-Ce alkyl. In embodiments, R4is not — COO-Ci-Ce alkyl. In embodiments, R4is not — CH2COO- Ci-Ce alkyl. In embodiments, R4is not— (CH2)2COO-Ci-Ce alkyl. In embodiments, R4is not— (CH2)3COO-CI-2026-03-18 Ce alkyl. In embodiments, R4is not — CH2COOCH3. In embodiments, R4is not — CH2COOCH2CH3. In embodiments, Rais not H. In embodiments, Rais not Ci-Ce alkyl. In embodiments, Rais not methyl. In embodiments, Rais not ethyl. In some embodiments of Formula (1), Rbis not H.

[0172]

[0107] In some embodiments, the compound has the structure of any of Formulae (l)-(XVII I), wherein R2and R4are as defined for Formula (1), as below in TABLE 1.

[0173] TABLE 1. Exemplary Compounds of Formulae (l)-(XVIII)

[0174] R2 xo OH

[0175] R4\ 7R4" \ /

[0176] (|) '-O (||) '-0 (in)

[0177] R2 xo OH / '^x'X^NH2X^^NH2

[0178] R4X\ / R4Z\ / R4Z\^ 7

[0179] ^0 (IV) *-O (V)U0 (vi) R2OH AJ^X.NH2..i v

[0180] R4" \ /

[0181] ^“0 (VII)L~0 (VIII)V-O (ix) R2r"’\ ^0 r— \ OH r-\ T NH 1 NH 1 NH

[0182] R4" \^ / R4" \ / R4" \ 7

[0183] ^-0 (X)U0 (XI)U'O (xil) R2OH z^^ J^^NH

[0184] R4R4Z\ / R4^ \ /

[0185] ^0 (XIII) ^-0 (XIV) '—0 (XV)

[0186]

[0187] 2026-03-18

[0188]

[0189]

[0108] In some embodiments, the compound is selected from TABLE 3, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof. In the embodiments of Table 3, and elsewhere in this disclosure, the following variables have the following abbreviations.

[0190] TABLE 2. Variable Abbreviations for Compounds in Table 3

[0191] Structure, wherein *

[0192] indicates the point of

[0193] connection

[0194] OH Br Abbreviation NB NBOH NBOMe NBBr

[0195] * p I * p l * r 1 Ph O— / o- / NBPh NBCp NBMD NMe7BF NMe7DHBF

[0196]

[0197] TABLE 3. Exemplary Compounds of Formula (1)

[0198] OR2Rbu

[0199] i I n

[0200] f| 1R

[0201] A Ra

[0202] R\ 7

[0203] No. R2R4RaRbRN

[0204] 1 -CH3— H — H — H — H 2 -CH3— F — H — H — H 3 -CH3-Cl — H — H — H 4 -CH3-Br — H — H — H 5 -CH3-I — H — H — H 6 -CH3-CH3— H — H — H 7 -CH3-CH2CH3— H — H — H 8 -CH3-CH2CH(CH3)2— H — H — H 9 -CH3-CH2CH=CH2— H — H — H 10 -CH3— CN — H — H — H 11 -CH3-NO2— H — H — H

[0205]

[0206] 12 -CH3-CF3— H — H — H2026-03-18

[0207] OR2Rbu

[0208] I I n

[0209] n iR

[0210] A ^>1 Ra

[0211] R4

[0212] '-0

[0213] No. R2R4RaRbRN 13 -CH3-OCH3— H — H — H 14 -CH3-SCH3— H — H — H 15 -CH3-SCH2CH3— H — H — H 16 -CH3- SCH2CH2F — H — H — H 17 -CH3— CH2Cp — H — H — H 18 -CH3-CH2COOCH3— H — H — H 19 -CH3— H — H — H — H 20 -CH3— F — H — H — H 21 -CH3-Cl — H — H — H 22 -CH3— Br — H — H — H 23 -CH3-I — H — H — H 24 -CH3-CH3— H — H — H 25 -CH3-CH2CH3— H — H — H 26 -CH3-CH2CH(CH3)2— H — H — H 27 -CH3-CH2CH=CH2— H — H — H 28 -CH3— CN — H — H — H 29 -CH3-NO2 — H — H — H 30 -CH3-CF3— H — H — H 31 -CH3-OCH3— H — H — H 32 -CH3-SCH3— H — H — H 33 -CH3-SCH2CH3— H — H — H 34 -CH3- SCH2CH2F — H — H — H 35 -CH3— CH2Cp — H — H — H 36 -CH3-CH2COOCH3— H — H — H 37 -CH3— H -CH3— H — H 38 -CH3— F -CH3— H — H 39 -CH3-Cl -CH3— H — H 40 -CH3-Br -CH3— H — H 41 -CH3-I -CH3— H — H 42 -CH3-CH3-CH3— H — H 43 -CH3-CH2CH3-CH3— H — H 44 -CH3-CH2CH(CH3)2-CH3— H — H 45 -CH3-CH2CH=CH2-CH3— H — H 46 -CH3-CN -CH3— H — H

[0214]

[0215] 47 -CH3-NO2 -CH3— H — H2026-03-18

[0216] OR2Rbu

[0217] I I n

[0218] n iR

[0219] A ^>1 Ra

[0220] R4

[0221] '-0

[0222] No. R2R4RaRbRN 48 -CH3-CF3-CH3— H — H 49 -CH3-OCH3-CH3— H — H 50 -CH3-SCH3-CH3— H — H 51 -CH3-SCH2CH3-CH3— H — H 52 -CH3- SCH2CH2F -CH3— H — H 53 -CH3— CH2Cp -CH3— H — H 54 -CH3-CH2COOCH3-CH3— H — H 55 -CH3— H -CH3— H — H 56 -CH3— F -CH3— H — H 57 -CH3-Cl -CH3— H — H 58 -CH3— Br -CH3— H — H 59 -CH3-I -CH3— H — H 60 -CH3-CH3-CH3— H — H 61 -CH3-CH2CH3-CH3— H — H 62 -CH3-CH2CH(CH3)2-CH3— H — H 63 -CH3-CH2CH=CH2-CH3— H — H 64 -CH3— CN -CH3— H — H 65 -CH3-NO2 -CH3— H — H 66 -CH3-CF3-CH3— H — H 67 -CH3-OCH3-CH3— H — H 68 -CH3-SCH3-CH3— H — H 69 -CH3-SCH2CH3-CH3— H — H 70 -CH3- SCH2CH2F -CH3— H — H 71 -CH3— CH2Cp -CH3— H — H 72 -CH3-CH2COOCH3-CH3— H — H 73 -CH3— H -CH2CH3— H — H 74 -CH3— F -CH2CH3— H — H 75 -CH3-Cl -CH2CH3— H — H 76 -CH3-Br -CH2CH3— H — H 77 -CH3-I -CH2CH3— H — H 78 -CH3-CH3-CH2CH3— H — H 79 -CH3-CH2CH3-CH2CH3— H — H 80 -CH3-CH2CH(CH3)2-CH2CH3— H — H 81 -CH3-CH2CH=CH2-CH2CH3— H — H

[0223]

[0224] 82 -CH3-CN -CH2CH3— H — H2026-03-18

[0225] OR2Rbu

[0226] I I n

[0227] n iR

[0228] A ^>1 Ra

[0229] R4

[0230] '-0

[0231] No. R2R4RaRbRN 83 -CH3-NO2-CH2CH3— H — H 84 -CH3-CF3-CH2CH3— H — H 85 -CH3-OCH3-CH2CH3— H — H 86 -CH3-SCH3-CH2CH3— H — H 87 -CH3-SCH2CH3-CH2CH3— H — H 88 -CH3-SCH2CH2F -CH2CH3— H — H 89 -CH3— CH2Cp -CH2CH3— H — H 90 -CH3-CH2COOCH3-CH2CH3— H — H 91 -CH3— H -CH2CH3— H — H 92 -CH3— F -CH2CH3— H — H 93 -CH3-Cl -CH2CH3— H — H 94 -CH3— Br -CH2CH3— H — H 95 -CH3-I -CH2CH3— H — H 96 -CH3-CH3-CH2CH3— H — H 97 -CH3-CH2CH3-CH2CH3— H — H 98 -CH3-CH2CH(CH3)2-CH2CH3— H — H 99 -CH3-CH2CH=CH2-CH2CH3— H — H 100 -CH3— CN -CH2CH3— H — H 101 -CH3-NO2-CH2CH3— H — H 102 -CH3-CF3-CH2CH3— H — H 103 -CH3-OCH3-CH2CH3— H — H 104 -CH3-SCH3-CH2CH3— H — H 105 -CH3-SCH2CH3-CH2CH3— H — H 106 -CH3-SCH2CH2F -CH2CH3— H — H 107 -CH3— CH2Cp -CH2CH3— H — H 108 -CH3-CH2COOCH3-CH2CH3— H — H 109 — H — H — H — H — H 110 — H — F — H — H — H 111 — H -Cl — H — H — H 112 — H -Br — H — H — H 113 — H -I — H — H — H 114 — H -CH3— H — H — H 115 — H -CH2CH3— H — H — H 116 — H -CH2CH(CH3)2— H — H — H

[0232]

[0233] 117 — H -CH2CH=CH2— H — H — H2026-03-18

[0234] OR2Rbu

[0235] I I n

[0236] n iR

[0237] A ^>1 Ra

[0238] R4

[0239] '-0

[0240] No. R2R4RaRbRN 118 — H — CN — H — H — H 119 — H -NO2— H — H — H 120 — H -CF3— H — H — H 121 — H -OCH3— H — H — H 122 — H -SCH3— H — H — H 123 — H -SCH2CH3— H — H — H 124 — H -SCH2CH2F — H — H — H 125 — H — CH2Cp — H — H — H 126 — H -CH2COOCH3— H — H — H 127 — H — H — H — H — H 128 — H — F — H — H — H 129 — H -Cl — H — H — H 130 — H — Br — H — H — H 131 — H -I — H — H — H 132 — H -CH3— H — H — H 133 — H -CH2CH3— H — H — H 134 — H -CH2CH(CH3)2— H — H — H 135 — H -CH2CH=CH2— H — H — H 136 — H -CN — H — H — H 137 — H -NO2— H — H — H 138 — H -CF3— H — H — H 139 — H -OCH3— H — H — H 140 — H -SCH3— H — H — H 141 — H -SCH2CH3— H — H — H 142 — H -SCH2CH2F — H — H — H 143 — H — CH2Cp — H — H — H 144 — H -CH2COOCH3— H — H — H 145 -CH3— H — H — H NB 146 -CH3— F — H — H NB 147 -CH3-Cl — H — H NB 148 -CH3-Br — H — H NB 149 -CH3-I — H — H NB 150 -CH3-CH3— H — H NB 151 -CH3-CH2CH3— H — H NB

[0241]

[0242] 152 -CH3-CH2CH(CH3)2— H — H NB2026-03-18

[0243] OR2Rbu

[0244] I I n

[0245] n iR

[0246] A ^>1 Ra

[0247] R4

[0248] '-0

[0249] No. R2R4RaRbRN 153 -CH3-CH2CH=CH2— H — H NB 154 -CH3— CN — H — H NB 155 -CH3-NO2— H — H NB 156 -CH3-CF3— H — H NB 157 -CH3-OCH3— H — H NB 158 -CH3-SCH3— H — H NB 159 -CH3-SCH2CH3— H — H NB 160 -CH3-SCH2CH2F — H — H NB 161 -CH3— CH2Cp — H — H NB 162 -CH3-CH2COOCH3— H — H NB 163 -CH3— H — H — H NB 164 -CH3— F — H — H NB 165 -CH3-Cl — H — H NB 166 -CH3— Br — H — H NB 167 -CH3-I — H — H NB 168 -CH3-CH3— H — H NB 169 -CH3-CH2CH3— H — H NB 170 -CH3-CH2CH(CH3)2— H — H NB 171 -CH3-CH2CH=CH2— H — H NB 172 -CH3-CN — H — H NB 173 -CH3-NO2— H — H NB 174 -CH3-CF3— H — H NB 175 -CH3-OCH3— H — H NB 176 -CH3-SCH3— H — H NB 177 -CH3-SCH2CH3— H — H NB 178 -CH3-SCH2CH2F — H — H NB 179 -CH3— CH2Cp — H — H NB 180 -CH3-CH2COOCH3— H — H NB 181 -CH3— H — H — H NBOH 182 -CH3— F — H — H NBOH 183 -CH3-Cl — H — H NBOH 184 -CH3-Br — H — H NBOH 185 -CH3-I — H — H NBOH 186 -CH3-CH3— H — H NBOH

[0250]

[0251] 187 -CH3-CH2CH3— H — H NBOH2026-03-18

[0252] No. R2R4RaRbRN 188 -CH3-CH2CH(CH3)2— H — H NBOH 189 -CH3-CH2CH=CH2— H — H NBOH 190 -CH3— CN — H — H NBOH 191 -CH3-NO2— H — H NBOH 192 -CH3-CF373l± ■ — H — H NBOH 193 -CH3-OCH3— H — H NBOH 194 -CH3-SCH3(hO -\ /

[0253] 73 1 V V — H — H NBOH 195 -CH3-SCH2CH3— H — H NBOH 196 -CH3-SCH2CH2F — ( H 73 — — H NBOH \ DJ

[0254] 197 -CH3— CH2Cp — H ZI — H NBOH 198 -CH3-CH2COOCH3— H 73 — H NBOH z

[0255] 199 -CH3— H — H — H NBOH 200 -CH3— F — H — H NBOH 201 -CH3-Cl — H — H NBOH 202 -CH3— Br — H — H NBOH 203 -CH3-I — H — H NBOH 204 -CH3-CH3— H — H NBOH 205 -CH3-CH2CH3— H — H NBOH 206 -CH3-CH2CH(CH3)2— H — H NBOH 207 -CH3-CH2CH=CH2— H — H NBOH 208 -CH3-CN — H — H NBOH 209 -CH3-NO2— H — H NBOH 210 -CH3-CF3— H — H NBOH 211 -CH3-OCH3— H — H NBOH 212 -CH3-SCH3— H — H NBOH 213 -CH3-SCH2CH3— H — H NBOH 214 -CH3-SCH2CH2F — H — H NBOH 215 -CH3— CH2Cp — H — H NBOH 216 -CH3-CH2COOCH3— H — H NBOH 217 — H — H — H — H NBOH 218 — H — F — H — H NBOH 219 — H -Cl — H — H NBOH 220 — H -Br — H — H NBOH 221 — H -I — H — H NBOH

[0256]

[0257] 222 — H -CH3— H — H NBOH2026-03-18

[0258] No. R2R4RaRbRN 223 — H -CH2CH3— H — H NBOH 224 — H -CH2CH(CH3)2— H — H NBOH 225 — H -CH2CH=CH2— H — H NBOH 226 — H — CN — H — H NBOH 227 — H -NO273l± ■ — H — H NBOH 228 — H -CF3— H — H NBOH 229 — H -OCH3(hO -\ /

[0259] 73 1 V V — H — H NBOH 230 — H -SCH3— H — H NBOH 231 — H -SCH2CH3— ( H 73 — — H NBOH \ DJ

[0260] 232 — H -SCH2CH2F — H ZI — H NBOH 233 — H — CH2Cp — H 73 — H NBOH z

[0261] 234 — H -CH2COOCH3— H — H NBOH 235 — H — H — H — H NBOH 236 — H — F — H — H NBOH 237 — H -Cl — H — H NBOH 238 — H — Br — H — H NBOH 239 — H -I — H — H NBOH 240 — H -CH3— H — H NBOH 241 — H -CH2CH3— H — H NBOH 242 — H -CH2CH(CH3)2— H — H NBOH 243 — H -CH2CH=CH2— H — H NBOH 244 — H -CN — H — H NBOH 245 — H -NO2— H — H NBOH 246 — H -CF3— H — H NBOH 247 — H -OCH3— H — H NBOH 248 — H -SCH3— H — H NBOH 249 — H -SCH2CH3— H — H NBOH 250 — H -SCH2CH2F — H — H NBOH 251 — H — CH2Cp — H — H NBOH 252 — H -CH2COOCH3— H — H NBOH 253 -CH3— H — H — H NBOMe 254 -CH3— F — H — H NBOMe 255 -CH3-Cl — H — H NBOMe 256 -CH3-Br — H — H NBOMe

[0262]

[0263] 257 -CH3-I — H — H NBOMe2026-03-18

[0264] No. R2R4RaRbRN 258 -CH3-CH3— H — H NBOMe 259 -CH3-CH2CH3— H — H NBOMe 260 -CH3-CH2CH(CH3)2— H — H NBOMe 261 -CH3-CH2CH=CH2— H — H NBOMe 262 -CH3— CN 73l± ■ — H — H NBOMe 263 -CH3-NO2— H — H NBOMe 264 -CH3-CF3(hO -\ /

[0265] 73 1 V V — H — H NBOMe 265 -CH3-OCH3— H — H NBOMe 266 -CH3-SCH3— ( H 73 — — H NBOMe \ DJ

[0266] 267 -CH3-SCH2CH3— H ZI — H NBOMe 268 -CH3-SCH2CH2F — H 73 — H NBOMe z

[0267] 269 -CH3— CH2Cp — H — H NBOMe 270 -CH3-CH2COOCH3— H — H NBOMe 271 -CH3— H — H — H NBOMe 272 -CH3— F — H — H NBOMe 273 -CH3-Cl — H — H NBOMe 274 -CH3— Br — H — H NBOMe 275 -CH3-I — H — H NBOMe 276 -CH3-CH3— H — H NBOMe 277 -CH3-CH2CH3— H — H NBOMe 278 -CH3-CH2CH(CH3)2— H — H NBOMe 279 -CH3-CH2CH=CH2— H — H NBOMe 280 -CH3-CN — H — H NBOMe 281 -CH3-NO2— H — H NBOMe 282 -CH3-CF3— H — H NBOMe 283 -CH3-OCH3— H — H NBOMe 284 -CH3-SCH3— H — H NBOMe 285 -CH3-SCH2CH3— H — H NBOMe 286 -CH3-SCH2CH2F — H — H NBOMe 287 -CH3— CH2Cp — H — H NBOMe 288 -CH3-CH2COOCH3— H — H NBOMe 289 -CH3— H — H — H NBBr 290 -CH3— F — H — H NBBr 291 -CH3-Cl — H — H NBBr

[0268]

[0269] 292 -CH3-Br — H — H NBBr2026-03-18

[0270] OR2Rbu

[0271] I I n

[0272] n iR

[0273] A ^>1 Ra

[0274] R4

[0275] '-0

[0276] No. R2R4RaRbRN 293 -CH3-I — H — H NBBr 294 -CH3-CH3— H — H NBBr 295 -CH3-CH2CH3— H — H NBBr 296 -CH3-CH2CH(CH3)2— H — H NBBr 297 -CH3-CH2CH=CH2— H — H NBBr 298 -CH3— CN — H — H NBBr 299 -CH3-NO2— H — H NBBr 300 -CH3-CF3— H — H NBBr 301 -CH3-OCH3— H — H NBBr 302 -CH3-SCH3— H — H NBBr 303 -CH3-SCH2CH3— H — H NBBr 304 -CH3-SCH2CH2F — H — H NBBr 305 -CH3— CH2Cp — H — H NBBr 306 -CH3-CH2COOCH3— H — H NBBr 307 -CH3— H — H — H NBBr 308 -CH3— F — H — H NBBr 309 -CH3-Cl — H — H NBBr 310 -CH3— Br — H — H NBBr 311 -CH3-I — H — H NBBr 312 -CH3-CH3— H — H NBBr 313 -CH3-CH2CH3— H — H NBBr 314 -CH3-CH2CH(CH3)2— H — H NBBr 315 -CH3-CH2CH=CH2— H — H NBBr 316 -CH3-CN — H — H NBBr 317 -CH3-NO2— H — H NBBr 318 -CH3-CF3— H — H NBBr 319 -CH3-OCH3— H — H NBBr 320 -CH3-SCH3— H — H NBBr 321 -CH3-SCH2CH3— H — H NBBr 322 -CH3-SCH2CH2F — H — H NBBr 323 -CH3— CH2Cp — H — H NBBr 324 -CH3-CH2COOCH3— H — H NBBr 325 -CH3— H — H — H NBPh 326 -CH3— F — H — H NBPh

[0277]

[0278] 327 -CH3-Cl — H — H NBPh2026-03-18

[0279] OR2Rbu

[0280] I I n

[0281] n iR

[0282] A ^>1 Ra

[0283] R4

[0284] '-0

[0285] No. R2R4RaRbRN 328 -CH3— Br — H — H NBPh 329 -CH3-I — H — H NBPh 330 -CH3-CH3— H — H NBPh 331 -CH3-CH2CH3— H — H NBPh 332 -CH3-CH2CH(CH3)2— H — H NBPh 333 -CH3-CH2CH=CH2— H — H NBPh 334 -CH3— CN — H — H NBPh 335 -CH3-NO2— H — H NBPh 336 -CH3-CF3— H — H NBPh 337 -CH3-OCH3— H — H NBPh 338 -CH3-SCH3— H — H NBPh 339 -CH3-SCH2CH3— H — H NBPh 340 -CH3-SCH2CH2F — H — H NBPh 341 -CH3— CH2Cp — H — H NBPh 342 -CH3-CH2COOCH3— H — H NBPh 343 -CH3— H — H — H NBPh 344 -CH3— F — H — H NBPh 345 -CH3-Cl — H — H NBPh 346 -CH3-Br — H — H NBPh 347 -CH3-I — H — H NBPh 348 -CH3-CH3— H — H NBPh 349 -CH3-CH2CH3— H — H NBPh 350 -CH3-CH2CH(CH3)2— H — H NBPh 351 -CH3-CH2CH=CH2— H — H NBPh 352 -CH3-CN — H — H NBPh 353 -CH3-NO2— H — H NBPh 354 -CH3-CF3— H — H NBPh 355 -CH3-OCH3— H — H NBPh 356 -CH3-SCH3— H — H NBPh 357 -CH3-SCH2CH3— H — H NBPh 358 -CH3-SCH2CH2F — H — H NBPh 359 -CH3— CH2Cp — H — H NBPh 360 -CH3-CH2COOCH3— H — H NBPh 361 -CH3— H — H — H NBCp

[0286]

[0287] 362 -CH3— F — H — H NBCp2026-03-18

[0288] OR2Rbu

[0289] I I n

[0290] n iR

[0291] A ^>1 Ra

[0292] R4

[0293] '-0

[0294] No. R2R4RaRbRN 363 -CH3-Cl — H — H NBCp 364 -CH3— Br — H — H NBCp 365 -CH3-I — H — H NBCp 366 -CH3-CH3— H — H NBCp 367 -CH3-CH2CH3— H — H NBCp 368 -CH3-CH2CH(CH3)2— H — H NBCp 369 -CH3-CH2CH=CH2— H — H NBCp 370 -CH3— CN — H — H NBCp 371 -CH3-NO2— H — H NBCp 372 -CH3-CF3— H — H NBCp 373 -CH3-OCH3— H — H NBCp 374 -CH3-SCH3— H — H NBCp 375 -CH3-SCH2CH3— H — H NBCp 376 -CH3-SCH2CH2F — H — H NBCp 377 -CH3— CH2Cp — H — H NBCp 378 -CH3-CH2COOCH3— H — H NBCp 379 -CH3— H — H — H NBCp 380 -CH3— F — H — H NBCp 381 -CH3-Cl — H — H NBCp 382 -CH3-Br — H — H NBCp 383 -CH3-I — H — H NBCp 384 -CH3-CH3— H — H NBCp 385 -CH3-CH2CH3— H — H NBCp 386 -CH3-CH2CH(CH3)2— H — H NBCp 387 -CH3-CH2CH=CH2— H — H NBCp 388 -CH3-CN — H — H NBCp 389 -CH3-NO2— H — H NBCp 390 -CH3-CF3— H — H NBCp 391 -CH3-OCH3— H — H NBCp 392 -CH3-SCH3— H — H NBCp 393 -CH3-SCH2CH3— H — H NBCp 394 -CH3-SCH2CH2F — H — H NBCp 395 -CH3— CH2Cp — H — H NBCp 396 -CH3-CH2COOCH3— H — H NBCp

[0295]

[0296] 397 -CH3— H — H — H NBMD2026-03-18

[0297] No. R2R4RaRbRN 398 -CH3— F — H — H NBMD 399 -CH3-Cl — H — H NBMD 400 -CH3— Br — H — H NBMD 401 -CH3-I — H — H NBMD 402 -CH3-CH373l± ■ — H — H NBMD 403 -CH3-CH2CH3— H — H NBMD 404 -CH3-CH2CH(CH3)2(hO -\ /

[0298] 73 1 V V — H — H NBMD 405 -CH3-CH2CH=CH2— H — H NBMD 406 -CH3— CN — ( H 73 — — H NBMD \ DJ

[0299] 407 -CH3-NO2— H ZI — H NBMD 408 -CH3-CF3— H 73 — H NBMD z

[0300] 409 -CH3-OCH3— H — H NBMD 410 -CH3-SCH3— H — H NBMD 411 -CH3-SCH2CH3— H — H NBMD 412 -CH3-SCH2CH2F — H — H NBMD 413 -CH3— CH2Cp — H — H NBMD 414 -CH3-CH2COOCH3— H — H NBMD 415 -CH3— H — H — H NBMD 416 -CH3— F — H — H NBMD 417 -CH3-Cl — H — H NBMD 418 -CH3-Br — H — H NBMD 419 -CH3-I — H — H NBMD 420 -CH3-CH3— H — H NBMD 421 -CH3-CH2CH3— H — H NBMD 422 -CH3-CH2CH(CH3)2— H — H NBMD 423 -CH3-CH2CH=CH2— H — H NBMD 424 -CH3-CN — H — H NBMD 425 -CH3-NO2— H — H NBMD 426 -CH3-CF3— H — H NBMD 427 -CH3-OCH3— H — H NBMD 428 -CH3-SCH3— H — H NBMD 429 -CH3-SCH2CH3— H — H NBMD 430 -CH3-SCH2CH2F — H — H NBMD 431 -CH3— CH2Cp — H — H NBMD

[0301]

[0302] 432 -CH3-CH2COOCH3— H — H NBMD2026-03-18

[0303] No. R2R4RaRbRN 433 -CH3— H — H — H NMe7BF 434 -CH3— F — H — H NMe7BF 435 -CH3-Cl — H — H NMe7BF 436 -CH3— Br — H — H NMe7BF 437 -CH3-I 73l± ■ — H — H NMe7BF 438 -CH3-CH3— H — H NMe7BF 439 -CH3-CH2CH3(hO -\ /

[0304] 73 1 V V — H — H NMe7BF 440 -CH3-CH2CH(CH3)2— H — H NMe7BF 441 -CH3-CH2CH=CH2— / cr

[0305] ( H 73 — — H NMe7BF \ DJ

[0306] 442 -CH3— CN — H ZI — H NMe7BF 443 -CH3-NO2— H 73 — H NMe7BF z

[0307] 444 -CH3-CF3— H — H NMe7BF 445 -CH3-OCH3— H — H NMe7BF 446 -CH3-SCH3— H — H NMe7BF 447 -CH3-SCH2CH3— H — H NMe7BF 448 -CH3-SCH2CH2F — H — H NMe7BF 449 -CH3— CH2Cp — H — H NMe7BF 450 -CH3-CH2COOCH3— H — H NMe7BF 451 -CH3— H — H — H NMe7BF 452 -CH3— F — H — H NMe7BF 453 -CH3-Cl — H — H NMe7BF 454 -CH3-Br — H — H NMe7BF 455 -CH3-I — H — H NMe7BF 456 -CH3-CH3— H — H NMe7BF 457 -CH3-CH2CH3— H — H NMe7BF 458 -CH3-CH2CH(CH3)2— H — H NMe7BF 459 -CH3-CH2CH=CH2— H — H NMe7BF 460 -CH3-CN — H — H NMe7BF 461 -CH3-NO2— H — H NMe7BF 462 -CH3-CF3— H — H NMe7BF 463 -CH3-OCH3— H — H NMe7BF 464 -CH3-SCH3— H — H NMe7BF 465 -CH3-SCH2CH3— H — H NMe7BF 466 -CH3-SCH2CH2F — H — H NMe7BF

[0308]

[0309] 467 -CH3— CH2Cp — H — H NMe7BF2026-03-18

[0310] No. R2R4RaRbRN 468 -CH3-CH2COOCH3— H — H NMe7BF -CH3— H — H — H NMe7BF -CH3— F — H — H NMe7DHBF -CH3-Cl — H — H NMe7DHBF -CH3— Br 73l± ■ — H — H NMe7DHBF -CH3-1 — H — H NMe7DHBF -CH3-CH3(hO -\ /

[0311] 73 1 V V — H — H NMe7DHBF -CH3-CH2CH3— H — H NMe7DHBF -CH3-CH2CH(CH3)2— / cr

[0312] ( H 73 — — H NMe7DHBF -CH3-CH2CH=CH2— H ZI — H NMe7DHBF -CH3— CN — H 73 — H NMe7DHBF -CH3-NO2— H — H NMe7DHBF -CH3-CF3— H — H NMe7DHBF -CH3-OCH3— H — H NMe7DHBF -CH3-SCH3— H — H NMe7DHBF -CH3-SCH2CH3— H — H NMe7DHBF -CH3-SCH2CH2F — H — H NMe7DHBF -CH3— CH2Cp — H — H NMe7DHBF -CH3-CH2COOCH3— H — H NMe7DHBF -CH3— H — H — H NMe7DHBF -CH3— F — H — H NMe7DHBF -CH3-Cl — H — H NMe7DHBF -CH3-Br — H — H NMe7DHBF -CH3-1 — H — H NMe7DHBF -CH3-CH3— H — H NMe7DHBF -CH3-CH2CH3— H — H NMe7DHBF -CH3-CH2CH(CH3)2— H — H NMe7DHBF -CH3-CH2CH=CH2— H — H NMe7DHBF -CH3-CN — H — H NMe7DHBF -CH3-NO2— H — H NMe7DHBF -CH3-CF3— H — H NMe7DHBF -CH3-OCH3— H — H NMe7DHBF -CH3-SCH3— H — H NMe7DHBF -CH3-SCH2CH3— H — H NMe7DHBF

[0313]

[0314] -CH3-SCH2CH2F — H — H NMe7DHBF2026-03-18

[0315]

[0316]

[0109] For any of the exemplary compounds in TABLE 3, additional compounds include those in which the substituent on the phenyl ring at RNis located at a different position on the ring. For example, while in some embodiments the phenyl ring comprises a substituent (e.g., a hydroxy or methoxy group) in the ortho position relative to the point of substitution indicated by the asterisk, in other embodiments the substituent is located at the meta or para position. Thus, a 2-hydroxybenzyl (NBOH) may in other embodiments be a 3-hydroxybenzyl (NB3OH) or a 4-hydroxybenzyl (NB4OH). Likewise, a 2-methoxybenzyl (NBOMe) may in other embodiments be a 3-methoxybenzyl (NB30Me) or a 4-methoxybenzyl (NB40Me). Similarly, a 2-bromobenzyl (NBBr) may in other embodiments be a 3-bromobenzyl (NB3Br) or a 4-bromobenzyl (NB4Br), and the bromine in any of the foregoing may in other embodiments be another halogen. Similarly, polycyclic and fused-ring benzyls such as a 2,3- methylenedioxybenzyl (NBMD) may in other embodiments be a 3,4-methylenedioxybenzyl (NB34MD) or a 4,5- methylenedioxybenzyl (NB45MD). Other exemplary compounds include the cyclopropyl replaced with another cycloalkyl or alkyl (at any of the 2, 3, or 4-position); the methoxy replaced with another alkoxy (at any of the 2, 3, or 4-position), e.g., NBOEt or NB30Et; di-substituted and multi-substituted benzyls; and the like.

[0317]

[0110] For any compound where RNis NMe7BF, i.e., X and Y are taken together to form 'o , in other \ o

[0318] embodiments X and Y are taken together to form \=J . For any compound where RNis NMe7DHBF, i.e., X ** ** \ '"o and Y are taken together to form

[0319]

[0320] , in other embodiments X and Y are taken together to form ' — ' .

[0321]

[0111] In some embodiments, the compound is selected from the following (herein, “Group A” compounds), or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof:

[0322]

[0323] 2026-03-18

[0324]

[0325]

[0112] In some embodiments, the compound is selected from the following (herein, “Group B” compounds), or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof:

[0326]

[0327]

[0113] In some embodiments, the compound is selected from the following (herein, “Group C” compounds), or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof:

[0328]

[0329] 2026-03-18

[0330]

[0114]

[0331]

[0115]

[0332]

[0333]

[0116] (2CIB-2OH-5DHF-NBOH).

[0334] [H7] In some embodiments, the compound is 2CIB-2OH-5DHF, 2CIB-5DHF, or 2CIB-2OH-5DHF-NBOH.

[0335]

[0118] In some embodiments, the compound is 2CIB-2OH-5DHF or 2CIB-5DHF.

[0336]

[0119] In some embodiments, the compound is 2CIB-2OH-5DHF or 2CIB-2OH-5DHF-NBOH.

[0337]

[0120] In some embodiments, the compound is 2CIB-5DHF or 2CIB-2OH-5DHF-NBOH.

[0338]

[0121] Disclosure of a compound also encompasses pharmaceutically acceptable salts of the compound. A “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base. In some embodiments, a pharmaceutically acceptable salt is prepared by reacting a free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid. In some embodiments, the reaction is carried out in water, in an organic solvent, or in a mixture thereof. In some embodiments, the organic solvent is ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. In some embodiments, a pharmaceutically acceptable salt has increased solubility relative to the corresponding free acid or base form. In some embodiments, a pharmaceutically acceptable salt has decreased solubility relative to the corresponding free acid or base form. Exemplary salts include 2-hydroxyethane- sulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamido- benzoate, acefyllinate, acetate, aceturate, adipate, alginate, amino- salicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentane- propionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate),2026-03-18 galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc, and the like (see generally, Berge et al. JPharm Sc / . 1977;66(1):1-19).

[0339]

[0122] Certain disclosed compounds may contain one or more ionizable groups (groups from which a proton can be removed (e.g., — COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)). All possible ionic forms of such molecules and salts thereof are included herein.

[0340]

[0123] In embodiments, a disclosed compound is in solid form. In embodiments, a disclosed compound is in liquid form. In embodiments, a solid compound is in crystalline form, noncrystalline form, or a mixture thereof. In embodiments, a crystalline or noncrystalline compound is in the form of a pharmaceutically acceptable solvate, in which solvent molecules are incorporated into the solid structure. In embodiments, a solvate involves a nonaqueous solvent such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate. In embodiments, a solvate is a hydrate, in which water is the incorporated solvent. In embodiments, a hydrate is a stoichiometric hydrate. In embodiments, a hydrate contains variable amounts of water.

[0341]

[0124] In some embodiments, a disclosed compound, including a solvate thereof, exists as a polymorph (i.e., a different crystalline structure of the same elemental composition). In embodiments, a polymorph differs from another polymorph in one or more physical properties, such as density, stability, dissolution properties, melting point, IR spectrum, or X-ray powder diffraction pattern. In embodiments, a polymorph is produced by varying one or more of the reaction conditions, recrystallization solvent, rate of crystallization, or storage temperature.

[0342]

[0125] The compounds described herein may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The disclosure includes all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. In some embodiments, an optically active (R)- or (S)-, (-)-or (+)-, or (D)- or (L)-isomer is prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. In some embodiments, an optical isomer is obtained by selective crystallization. In some2026-03-18 embodiments, an optical isomer is obtained by enzymatic resolution. In some embodiments, an optical isomer is obtained by asymmetric synthesis, including asymmetric chemical synthesis or asymmetric enzymatic synthesis. In some embodiments, an optical isomer is obtained by kinetic resolution. In some embodiments, an optical isomer is obtained by chiral chromatography, including chiral liquid chromatography, gas chromatography, or high-performance liquid chromatography. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, the disclosure includes both E and Z geometric isomers. Likewise, tautomeric forms are included.

[0343]

[0126] The disclosure also includes compounds with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., isotopically enriched. Examples of isotopes that can be incorporated into disclosed compounds include isotopes of H, C, N, 0, and Cl, such as2H,3H,11C,13C,14C,15N,170,180, and36CI respectively. In some embodiments, an isotopically labeled compound is used in metabolic studies (e.g., with14C), reaction kinetic studies (e.g., with2H 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 (e.g., with18F), or in radioactive treatment of patients. In some embodiments, substitution with heavier isotopes such as deuterium, i.e.,2H, affords one or more therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, an isotopically labeled compound is prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent

[0344]

[0127] The disclosure also includes prodrugs of disclosed compounds. A “prodrug” refers to a precursor of a biologically active agent that undergoes conversion in vivo to the biologically active agent. In some embodiments, a prodrug is converted to the biologically active agent by a metabolic, enzymatic, or degradative process that removes a prodrug moiety. In some embodiments, a prodrug comprises the addition of a biologically labile or cleavable group on a functional moiety of the compound. In some embodiments, a prodrug is a compound that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the biologically active agent. In some embodiments, a prodrug comprises an ester, carbonate, carbamate, amide, phosphate, or sulfonamide functional group. In some embodiments, a functional group is attached to the compound via a linker designed to be cleaved under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage.

[0345]

[0128] In some embodiments, a disclosed compound is administered as part of a pharmaceutical composition or formulation, and is prepared for inclusion in such compositions or formulations as an isolated or purified compound. The terms “isolated,” “purified,” or “substantially pure,” as used herein, refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced. In some embodiments, an isolated, purified, or substantially pure preparation of a compound has a chromatographic purity of greater than 90%, as determined by area2026-03-18 normalization of an HPLC profile or other similar detection method. In some embodiments, the chromatographic purity is greater than 95%. In some embodiments, the chromatographic purity is greater than 96%. In some embodiments, the chromatographic purity is greater than 97%. In some embodiments, the chromatographic purity is greater than 98%. In some embodiments, the chromatographic purity is greater than 99%. In some embodiments, the chromatographic purity is greater than 99.5%. In some embodiments, the chromatographic purity is greater than 99.9%.

[0346]

[0129] In some embodiments, a substantially pure compound is substantially free of other active compounds not intended to be administered to a subject. In some embodiments, “substantially free” means that no such other active compounds are detectable by HPLC or a similar detection method. In some embodiments, “substantially free” means that such other active compounds are below a specified threshold of detection.

[0347]

[0130] In some embodiments, the comparator for a disclosed compound is a 2C compound (e.g., 2C-C, 2C-B, 2C-E). In some embodiments the comparator for a disclosed compound is the corresponding 2C compound with an identical substitution pattern, except for the 1 ,3-dihydroisobenzofuran substituent.

[0348]

[0349] , the comparator is 2C-B (4- bromo-2,5-dimethoxyphenethylamine). In some embodiments, wherein the compound is

[0350] 2

[0351]

[0352] (2C-iBu).

[0353]

[0132] In some embodiments, the comparator is a phenethylamine having an identical substitution pattern, except the 1,3-dihydroisobenzofuran substituent.

[0354]

[0133] In some embodiments, the comparator is a phenethylamine having an identical substitution pattern, except the substituent at the 5-position is a hydroxy, methoxy, or other alkoxy. In some embodiments, the comparator is a phenethylamine having an identical substitution pattern, except for the substituents at the 5- position and 2-position. In some embodiments, the comparator is a phenethylamine having an identical substitution pattern, except for the substituents at the 5-position and 4-position. In some embodiments, the comparator is a phenethylamine having an identical substitution pattern, except for the substituents at the 4- position and 2-position. In embodiments, the comparator is a phenethylamine having an identical substitution pattern, except for the substituents at the 5-position and alpha position. In embodiments, the comparator is a phenethylamine having an identical substitution pattern, except the substituent at the 4-position is a different halogen. In embodiments, the comparator is a phenethylamine having an identical substitution pattern, except2026-03-18 the substituent at the 4-position is a different alkyl. In embodiments, the comparator is a phenethylamine having an identical substitution pattern, except for the substituent at the alpha-position.

[0355]

[0134] In embodiments, the comparator is a phenethylamine having a methyl substituent at the alpha-position, i.e., an amphetamine (or “DOx”) compound. In embodiments, the comparator is DOI. In embodiments, the comparator is DOB. In embodiments, the comparator is 2,5-dimethoxy-4-isobutyl- amphetamine (DOIB). In embodiments, the comparator is a phenethylamine having an identical substitution pattern, except for a methyl substituent at the alpha-position.

[0356]

[0135] In embodiments, the comparator is a phenethylamine having an ethyl substituent at the alpha-position, i.e., a “4C-x” (or “Ariadne”-type) compound. In embodiments, the comparator is a phenethylamine having an identical substitution pattern, except for an ethyl substituent at the alpha-position.

[0357]

[0136] In some embodiments, the comparator is a phenethylamine having an identical substitution pattern, except in place of the 1 ,3-dihydroisobenzofuran is a 2,3-dihydrobenzofuran, 2,5-dihydrobenzofuran, 2,3-dihydro-furan, 2,5-dihydrofuran, 1 ,3-dihydroisobenzothiophene, 2,3-dihydrobenzothiophene, 2,5-dihydrobenzothio-phene, 2,3-dihydrothiophene, 2,5-dihydrothiophene, benzothiophene, isobenzothiophene, tetrahydrothiophene, thiochroman, or thiophene. In embodiments, the substituent at the 4-position is a different halogen or a different alkyl. In embodiments, the substituent at the 2-position is a different alkoxy, or is a hydroxy instead of an alkoxy.

[0358]

[0137] Other comparators will be appreciated by one of skill in view of the disclosure and general knowledge.

[0359] C. Methods of Preparing Disclosed Compounds

[0360]

[0138] Specific examples of the synthesis of certain compounds are provided in EXAMPLE 1. The schemes provided are merely illustrative of exemplary synthetic routes that are useful to prepare disclosed compounds.

[0361]

[0139] In general, disclosed compounds can be synthesized using techniques in synthetic organic chemistry that are within the capabilities of one of skill.

[0362]

[0140] Disclosed compounds can be synthesized from a substituted dihydroisobenzofuran precursor (e.g., wherein X is a halogen (e.g., Cl, Br, I); and R2and R4are as defined for Formula (1)):

[0363]

[0364]

[0141] In this exemplary synthesis, a Boc-protected alkylamino side chain is installed using palladium-catalyzed cross coupling with a boron (R-BY3) reagent (e.g., an organotrifluoroborane or the like). Compounds wherein Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl can be synthesized according to the same approach, wherein Raand Rbof the boron reagent (together with the intervening atoms) form a cycle.

[0365]

[0142] For example, potassium [(1 R, 2R)-2-(di hydroisobenzofuran-2-yl)cyclopropyl]trifl uoroborate can be used2026-03-18 to install a cyclopropylamine side chain.

[0366]

[0143] In some embodiments, a suitably substituted dihydroisobenzofuran precursor is commercially available. If no substituted dihydroisobenzofuran precursor having a desired R2or R4group is commercially available, such precursors can be synthesized as described in EXAMPLE 1.

[0367]

[0144] Compounds wherein RNis — CH2-Ar can be synthesized by reductive amination of a disclosed compound wherein RNis H, as follows:

[0368]

[0369]

[0145] The reductive amination may be conducted according to standard techniques. For example, the starting materials may first be reacted to form an imine intermediate, which is then reduced by sodium borohydride in a second step. Alternatively, the reductive amination can be done in one step using sodium triacetoxyborohydride or sodium cyanoborohydride as the reducing agent.

[0370]

[0146] Compounds wherein Rband RNtogether with the intervening atoms form a 4- to 8-membered heterocyclyl can be synthesized from a substituted phenyl precursor (e.g., wherein X is a halogen (e.g., Cl, Br, I); and R2and R4are as defined for Formula (1)):

[0371]

[0372]

[0373]

[0147] In this exemplary synthesis, palladium-catalyzed cross coupling with a pyridine-based boron (R-BY3) reagent (e.g., an organotrifluoroborane, boronic acid, or the like) is used to attach a pyridine moiety to the substituted dihydroisobenzofuran precursor. Subsequent hydrogenation of the pyridine (using, e.g., hydrogen gas and a metal catalyst) results in a substituted dihydroisobenzofuran-piperidine compound of Formula (1).

[0374]

[0148] If no substituted dihydroisobenzofuran precursor having a desired R2or R4group is commercially available, such precursors can be synthesized as described in EXAMPLE 1.

[0375]

[0149] The R4substituent corresponds to the 4-position of 2C-X and DOx phenethylamines. The 4-substituent may be introduced by substitution of the corresponding 4-substituted phenethylamine (e.g., as in the halogenation of 2C-H to yield 2C-B, 2C-I, etc.), or by substitution of the aryl group of a suitable precursor prior to the introduction of the ethylamino side chain (e.g., as with the 2C-T series).

[0376]

[0150] Similar approaches can be used for disclosed compounds, and appropriate modifications, substitutions, changes, and variations of these synthetic procedures can be made by one of skill without undue experimentation. Exemplary synthetic procedures may be found in, e.g., Shulgin and Shulgin, PiHKAL: A2026-03-18 Chemical Love Story, Transform Press (1991).

[0377]

[0151] Additional methods for synthesis of the compounds described herein, and any necessary starting materials, can be identified by one of skill in view of the references cited herein, including, 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,” Vols. 1-17, Wiley Interscience; Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991; “Theilheimer’s Synthetic Methods of Organic Chemistry,” Vols. 1-45, Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Interscience, 1991; Larock, “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995.

[0378] D. Properties of Certain Disclosed Compounds

[0379]

[0152] In some aspects, disclosed compounds have one or more favorable physicochemical properties. Examples of advantageous physicochemical properties include high aqueous solubility and low photoreactivity.

[0380]

[0153] In embodiments, disclosed compounds are highly water soluble. In embodiments, the aqueous solubility of a compound refers to a maximum concentration at which the compound dissolves in water to form a solution at a specific temperature. In embodiments, aqueous solubility is determined at a temperature of about 20 to 25 °C. Aqueous solubility may be assessed by visible or microscopic inspection of undissolved material, spectrophotometric quantification, or lyophilization methods (Letinski et al., BMC Chem. 2021; 15(1):52; Birch et al., An Chimica Acta. 2019; 1086:16-28; Loftsson & Hreinsdottir, AAPSPharmSciTech. 2006; 7(1 ):E29— E32).

[0381]

[0154] In embodiments, a disclosed compound has an aqueous solubility of between about 1 and 50 mM, about 10 and 100 mM, about 25 and 250 mM, or about 50 and 400 mM. In embodiments, a disclosed compound has an aqueous solubility of between about 100 and 125 mM, or between about 350 and 375 mM.

[0382]

[0155] In embodiments, a disclosed compound has an aqueous solubility of about 1 mM, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110 mM or greater than about 110 mM, wherein all values are expressed in mM, and including all values, ranges, or subranges in between. In embodiments, a compound has an aqueous solubility of at least about 100 mM, including at least about 105 mM, 110, 115, 120, 125, 130, 135, 140, 145, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375 mM, or greater than about 375 mM, wherein all values are expressed in mM, and including all values, ranges, and subranges in between.

[0383]

[0156] In embodiments, a compound has an aqueous solubility of about 43.46 mM. In embodiments, the aqueous solubility is about 110.18 mM. In embodiments, the aqueous solubility is about 364.8 mM.

[0384]

[0157] In embodiments, a disclosed compound remains chemically stable in aqueous solution for at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, or greater than at least about 48 hours, including all values, ranges, and subranges in between. In embodiments, a disclosed compound remains chemically stable in aqueous solution for at least about 24 hours, 36 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 42026-03-18 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or greater than about 12 months, including all values, ranges, and subranges in between.

[0385]

[0158] In embodiments, a disclosed compound exhibits greater aqueous solubility relative to one or more structurally related reference compounds or comparators, for example a compound having a common core scaffold and sharing one or more functional groups. In embodiments, a disclosed compound is at least 2x, 5x, or 10x more soluble than one or more reference compounds or comparators.

[0386]

[0159] In embodiments, disclosed compounds are freely soluble or highly soluble in aqueous solutions, such as purified water, buffered saline, or other pharmaceutically acceptable aqueous carriers. In embodiments, high aqueous solubility contributes to improved formulation options, increased bioavailability, and / or ease of administration. In embodiments, high aqueous solubility allows disclosed compounds to be formulated with less of, or without the use of co-solvents, surfactants, or other solubilizing agents.

[0387]

[0160] In embodiments, disclosed compounds have reduced photoliability. “Photoliability” refers to the susceptibility of a compound to undergo chemical degradation upon exposure to light (Ahmad et al., Int’l J Photoenergy, 2016; 2016(1):8135608). In embodiments, disclosed compounds have increased photostability. “Photostability” refers to resistance to degradation and maintenance of chemical structure and potency under light exposure (Coelho et al., Int’l J Pharmaceutics, 2018; 541 (1-2): 19-25; Allain et al., J Pharm Sci., 2019; 108(3):1172-1176). In embodiments, photoliability and photostability are determined according to ICH Q1B (Photostability Testing of New Drug Substances and Products, ICH, Nov. 1996).

[0388]

[0161] In embodiments, a disclosed compound exhibits low absorbance in the ultraviolet (UV) and visible spectral range (e.g., approximately 290-700 nm). In embodiments, a disclosed compound exhibits reduced photoreactivity. In embodiments, reduced photoreactivity reduces the risk of phototoxic effects that may occur in vivo, upon exposure to light during administration, or during storage.

[0389]

[0162] FDA guidelines provide that a compound having a molar extinction coefficient (MEC) at its Amax (maximum absorbance wavelength) of below about 1,000 L moricm-1(i.e., M-1-cm-1) is considered insufficiently photoreactive to produce phototoxic effects under standard physiological or environmental exposure conditions. In embodiments, a disclosed compound has an MEC of less than 1,000 L moU crn-1.

[0390]

[0163] In embodiments, a disclosed compound having an MEC of less than about 1,000 M-1-cm-1has an MEC of less than about 900 M”1-cm-1, 800, 700, 600, 500, 400, 300, 200, or less than about 100 M”1-cm-1, including all values, ranges, and subranges in between. In embodiments, a compound has an MEC of less than about 800 M-1'cm-1. In embodiments, a compound has an MEC of less than about 400 M”1-cm-1. In embodiments, a compound has an MEC of less than about 350 M”1-cm-1. In embodiments, a compound has an MEC of less than about 300 M”1-cm-1. In embodiments, a compound has an MEC of less than about 3,800 M”1-cm-1. In embodiments, a compound has an MEC of less than about 4,000 M”1-cm-1.

[0391]

[0164] In embodiments, a disclosed compound exhibits reduced photoliability relative to one or more reference compounds or comparators. In embodiments, a compound has an MEC that is at least 2x, 3x, 4x, 5x, 6x, 7x, 8x,2026-03-18 9x, or 10x lower than a reference compound or comparator, including values in between.

[0392]

[0165] In embodiments, one or more physical properties of a compound, such as solubility, photoliability, photostability, and / or formulation compatibility, are improved relative to a reference compound or comparator.

[0393]

[0166] In embodiments, a head twitch response (HTR) assay is conducted using known rodent behavioral pharmacology protocols, for example as described in Laberstadt & Geyer. Psychopharmacol (Berl). 2013;227 (4)727-739; Glatfelter et al., ACS Pharmacol. Transl. Sci. 2022;5:321-330; and de la Fuente Revenga et al., Sci. Rep. 2019;9(1): 14247. HTR is defined as a rapid, lateral head movement that occurs in response to administration of 5-HT2A receptor agonists and other serotonergic compounds (Laberstadt & Geyer, 2015).

[0394]

[0167] Certain disclosed compounds are provided which have reduced or have no significant behavioral liability or behavioral effects, or which have reduced or have no significant hallucinogenic (or “psychedelic”) effects. In embodiments, a disclosed compound is characterized as HTR-negative, i.e., does not induce a head twitch response (HTR), such as by not demonstrating a statistically significant increase in HTR counts relative to vehicle control when tested using a standard head-twitch assay in a rodent model.

[0395]

[0168] In embodiments, a compound is HTR-negative in a rodent behavioral model across a dose range of between about 0.01 and 50 mg / kg, 0.01 and 40 mg / kg, or 0.01 and 30 mg / kg. In embodiments, a compound is HTR-negative in a rodent behavioral model at a dose of at least or about 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg 0.04 mg / kg, 0.05 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, or greater than about 40 mg / kg, including all values, ranges, and subranges in between.

[0396]

[0169] In embodiments, a disclosed compound exhibits HTR counts within 2-fold, 1.5-fold, or equivalent to vehicle-treated controls across one or more tested dose amounts. In embodiments, the absence of an HTR indicates reduced or absent activation of the 5-HT2A receptor. In embodiments, the absence of an HTR indicates reduced or absent such activation of the 5-HT2A receptor as mediates hallucinogenic or subjective psychedelic effects in humans, i.e., partial agonism or biased agonism (ligand bias), or functional selectivity. In some embodiments, a compound may preferentially activate non-hallucinogenic 5-HT2A signaling pathways.

[0397]

[0170] In embodiments, compounds that are HTR-negative may exhibit a reduced likelihood of inducing perceptual disturbances, hallucinations, or dissociative symptoms in subjects, including humans. In embodiments, compounds that are HTR-negative are beneficial in populations where perceptual disturbances, hallucinations, dissociative symptoms, or other similar central nervous system effects are contraindicated (e.g., patients with psychosis, dementia, or pediatric populations). In embodiments, the absence of HTR supports functional selectivity or agonism towards non-hallucinogenic 5-HT signaling pathways. In embodiments, compounds that are HTR-negative may be administered chronically, in higher doses, or in outpatient settings.

[0398] E. Pharmaceutical Compositions

[0399]

[0171] In some aspects are provided compositions, such as pharmaceutical compositions, comprising a disclosed compound. “Pharmaceutical compositions” may include a disclosed compound together in an amount2026-03-18 (for example, in a unit dosage form) with a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, a composition may comprise more than one carrier, diluent, and / or excipient.

[0400]

[0172] Compositions can be prepared by pharmaceutical formulation techniques such as disclosed in, e.g., Remington: Science & Practice of Pharm. (2020) 23rd ed., Acad. Press, Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, N.J.; Pharm. Principles of Solid Dosage Forms (1993), Tech. Pub. Co., Lancaster, Pa.; Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lipp. Williams & Wilkins, Baltimore, Md.; & Poznansky et al., Drug Delivery Sys. (1980), R.L. Juliano, ed., Oxford, N.Y., pp. 253-315.

[0401]

[0173] “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.

[0402]

[0174] Pharmaceutical compositions comprising a disclosed compound can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, topical, transdermal, subcutaneous, intravenous, intramuscular, inhaled, intranasal, and ocular. In embodiments, the compounds are effective as oral, mucosal (e.g., buccal, sublingual), rectal, topical, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal compositions, and are formulated for such administration.

[0403]

[0175] In some embodiments, the compounds employed in the methods of this disclosure are effective as ocular (e.g., ophthalmic, intraocular, intravitreal, and periocular, including subconjunctival, retrobulbar, peribulbar, suprachoroidal, and sub-Tenon’s) compositions, and are formulated for such administration.

[0404]

[0176] In some embodiments, a disclosed composition is formulated in a unit dosage form. “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.

[0405]

[0177] In some embodiments, a unit dosage form contains a single dose. In some embodiments, a unit dosage form contains a sub-dose, or a fraction thereof.

[0406]

[0178] In embodiments, a unit dosage form is a capsule, troche, cachet, lozenge, tablet, ampule, or vial. In embodiments, a unit dosage form includes a composition in a freeze-dried or lyophilized state, to which a sterile liquid carrier can be added prior to administration.

[0407]

[0179] In embodiments, a unit dosage form is a “patch” for transdermal administration that contacts the epidermis (including the mucosa) for an extended or brief period of time.

[0408]

[0180] In embodiments, a disclosed composition comprises a preservative. In some embodiments, the preservative inhibits microbial growth or increases stability of the formulation. In some embodiments, the preservative is EDTA, EGTA, benzalkonium chloride, benzoic acid, a benzoate (e.g., sodium benzoate), or a combination thereof. In embodiments, a disclosed composition comprises an antioxidant. In embodiments, the antioxidant is vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherol, citric acid, or a combination thereof.

[0409]

[0181] In embodiments, disclosed compositions may be formulated into a topical formulation (e.g., a topical2026-03-18 dosage form). Topical formulations include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams; and may include a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients for topical formulations include penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, and gelling agents.

[0410]

[0182] In some embodiments, the topical formulation comprises a penetration enhancer, for example to increase the permeability of biological barriers, or to increase the bioavailability of the active agent(s) by improving the ability of the active agent(s) to diffuse into tissue. Penetration enhancers include fatty acids and oils such as castor oil, coconut oil, medium chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petroleum jelly, cocoa butter, shea butter, or other esters, triglycerides, or functional derivatives thereof. In some embodiments, the penetration enhancer is 1,2-lauryl ether, aprotinin, azone, benzalkonium chloride, benzalkonium bromide, cetylpyridinium chloride, cetyltrimethyl ammonium, cyclodextrin, dextran sulfate, glycol, lauric acid, propylene, lysophosphatidylcholine, menthol, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, chitosan, sodium glycocholate, sodium deoxyglycocholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, dimethyl sulfoxide, or a combination thereof. In embodiments, the penetration enhancer is a lower chain alcohol with a carbon chain length of 1-5, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxy-cholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, lysophosphatidylcholine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, benzalkonium chloride, cetylpyridinium chloride, Vitamin E TPGS, caprylocaproyl polyoxylglycerides, stearoyl macrogolglycerides, propylene glycol dicaprylocaprate, or a mixture thereof.

[0411]

[0183] In some embodiments, the topical formulation comprises a carrier. In some embodiments, the carrier is a hydrophobic drug carrier. In some embodiments, a hydrophobic drug carrier exhibits sustained release kinetics. In some embodiments, a hydrophobic drug carrier exhibits rapid or immediate release kinetics. In some embodiments, a hydrophobic drug carrier comprises a hydrophilic coating, such as polyethylene glycol or chitosan (see, e.g., de la Fuente et al., Nanomedicine, 2008; 3:845-857). Any of a variety of pharmaceutically acceptable carriers may be used including aqueous media such as water, saline, glycine, hyaluronic acid and the like; solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient. Examples of specific uses of such pharmaceutical carriers can be found in, e.g., Ansel et al., Pharm. Dosage Forms & Drug Delivery Sys. (1999) 7th ed., Lipp. Williams & Wilkins, Philadelphia, Pa.; Gennaro ed., Remington: Science & Practice of Pharm. (2000) 20th ed., Lipp. Williams & Wilkins, Philadelphia, Pa.; Hardman et al., eds., Goodman & Gilman’s Pharmacological Basis of Therapeutics (2001) 10th ed., McGraw-Hill, New York, N.Y.; & Rowe et al., Handbook of Pharm. Excipients (2003) 4th ed., APhA Pub., Washington, D.C.2026-03-18

[0184] In embodiments, the topical formulation comprises an emulsifier. The emulsifier may be an anionic, cationic, or neutral emulsifier. In certain embodiments, the emulsifier is an anionic emulsifier selected from the group consisting of alkyl sulfate, aralkyl sulfates, alkyl ethoxy ether sulfates, alkaryl sulphonates, alkyl succinates, alkyl sulfosuccinates, N-alkoyl sarconsi nates, isethionates, N-acyl taurate, sodium lauryl sulfate, sodium laureth sulfate, sodium oleyl succinate, sodium dodecylbenzenesulfonate, and sodium lauryl sarconsinate. Exemplary non-ionic or neutral emulsifiers include sorbitan ester, ethoxylated sorbitan ester, ethoxylated alkyl ether, ethoxylated fatty acid ether, fatty alcohol, ethoxylated fatty alcohol, and esters of glycerin and fatty acids. In certain embodiments, the emulsifier is a silicone (e.g., dimethicone, phenyltrimethicone, PEG dimethicone, PPG dimethicone).

[0412]

[0185] In embodiments, the topical formulation comprises an antioxidant, for example to delay or inhibit the oxidative decomposition of components of a formulation, including to thereby improve the stability and extend the shelf-life thereof. The antioxidant may be amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g., urocanic acid) and derivatives thereof, peptides such as D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g., anserine), carotenoids, carotenes (e.g., 0-carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, liponic acid and derivatives thereof (e.g., dihydroliponic acid), aurothioglucose, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, and lauryl, palmitoyl, oleyl, y-linoleyl, cholesteryl and glyceryl esters thereof) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (e.g., buthionine sulfoximines, homocysteine sulfoximines, buthionine sulfones, penta-, hexa- and heptathionine sulfoximine), (metal) chelators (e.g., a-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin), a-hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, gallic acid, bile extracts, bilirubin, biliverdin, EDTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g., y-li nolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives thereof (e.g., sodium ascorbate, ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and derivatives (e.g., vitamin E acetate, tocotrienol), vitamin A and derivatives (vitamin A palmitate) and coniferyl benzoate of benzoic resin, rutinic acid and derivatives thereof, a-glycosylrutin, ferulic acid, furfurylideneglucitol, carnosine, butylhydroxy- toluene, butylhydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, zinc and derivatives thereof (e.g., ZnO, ZnSO4), selenium and derivatives thereof (e.g., selenium methionine), stilbenes and derivatives thereof (e.g., stilbene oxide, trans- stilbene oxide). In embodiments, the antioxidant is a-tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, methionine, citric acid, ascorbic acid, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, thioglycerol, propyl gallate, cysteine, or a combination thereof. In embodiments, the antioxidant is a cyclodextrin, D-a-tocopherol, rosmarinic acid, or a combination thereof.

[0413]

[0186] In some embodiments, a topical formulation comprises a solvent, and optionally a cosolvent. Any2026-03-18 solvent(s) and cosolvent(s) may be collectively referred to as a “solvent system.” In some embodiments, the solvent system is selected to improve the stability, bioavailability, or overall efficacy of the formulation. In some embodiments, the solvent system is capable of dissolving or solubilizing the active agent(s) and any included excipients at the desired concentration(s), and is stable and compatible with the active agent(s) and any other excipients in the formulation. In some embodiments, the solvent system comprises more than one solvent, and the ratio of cosolvents is selected to increase the penetration or bioavailability of an active agent. In some embodiments, the solvent system is safe and non-toxic for human use. In some embodiments, solvents included in a solvent system are selected to reduce irritation or allergic reactions. Solvents that may be included in topical formulations include water, ethanol, polyhydric alcohols (e.g., glycerin), 1 ,3-butylene glycol, propylene glycol, hexylene glycol, propane diol, ethylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, other sugars which are liquid at room temperature, water-soluble alkoxylated nonionic polymers such as polyethylene glycol, and combinations thereof. Solvents may be present, individually or in total (if more than one solvent is included), in a formulation in an amount ranging from about 0.1 to 95 wt%.

[0414]

[0187] In embodiments, the topical formulation comprises a viscosity modifying agent. In some embodiments, the viscosity modifying agent is a thickener. In some embodiments, the thickener is crosslinked polyacrylic acid, xanthan gum, agar agar, alginate, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, fatty alcohol, monoglyceride, fatty acid, polyvinyl alcohol, PVP, carbomer, carrageenan, gum, resin, polysaccharide, or a high melting point wax or oil such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, cocoa butter, shea butter, paraffin, or petroleum jelly, or a derivative or combination thereof. In some embodiments, the viscosity modifying agent is a carbohydrate, such as a monosaccharide, disaccharide, oligosaccharide, or polysaccharide (including cellulose, methylcellulose, hydroxypropylmethylcellulose, chitin, galactoarabinan, polygalactose, or polyarabinose). In embodiments, the viscosity modifying agent is a glyceride, such as hydroxystearic acid monoglyceride, isostearic acid monoglyceride, oleic acid monoglyceride, ricinoleic acid monoglyceride, linoleic acid monoglyceride, linolenic acid monoglyceride, erucic acid monoglyceride, tartaric acid monoglyceride, citric acid monoglyceride, malic acid monoglyceride, or a diglyceride thereof, or a mixture thereof. In embodiments, the viscosity modifying agent is a natural or synthetic polymer, such as a polysaccharide, nucleic acid, protein, polyester, polyurea, polycarbonate, polyvinyl alcohol, polyamide, polyether, polyamine, polyanhydride, polyphosphazene, polyacrylamide, polyacrylate, polymethacrylate, or PVP.

[0415]

[0188] In embodiments, the topical formulation comprises an adhesion modifying agent. In some embodiments, the adhesion modifying agent is an adhesive polymer, such as chitosan, gelatin, guar gum, lectins, sodium alginate, soluble starch, tragacanth, xanthan gum, deacetylated gum, polyacrylic acid, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, a thiomer, polycarbophil, hyaluronic acid, dermatan sulfate, or a combination thereof. In some embodiments, the adhesion modifying agent is a tackifier, such as a gum, resin (natural or modified), carbomer, or other natural or synthetic polymer.2026-03-18

[0189] In embodiments, the topical formulation comprises a solubilizing agent, for example to increase the solubility of the active agent(s) in the formulation. In some embodiments, the solubilizing agent is a water-soluble organic solvent, a non-ionic surfactant, a water-insoluble lipid, an organic liquid, a cyclodextrin, or a phospholipid. In some embodiments, the solubilizing agent is a water-soluble enhancing agent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, xanthan gum, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethylsulfoxide, or a combination thereof. In some embodiments, the solubilizing agent is a non-ionic surfactant, such as Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, mono- and di-fatty acid esters of PEG 300, 400, or 1750, or a combination thereof. In some embodiments, the solubilizing agent is an organic liquid, such as beeswax, d-alpha-tocopherol, oleic acid, or a medium-chain mono- or diglyceride. In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the solubilizing agent is a phospholipid, such as hydrogenated soy phosphatidylcholine, distearoyl-phosphatidylglycerol, L-alpha-dimyristoyl-phosphatidylcholine, or L-alpha-dimyristoyl-phosphatidylglycerol. In some embodiments, the solubilizing agent is lecithin.

[0416]

[0190] In embodiments, the topical formulation comprises a colorant. In some embodiments, the colorant is a dye or pigment, including titanium dioxide, chromium oxide green, ultramarine blue, ultramarine pink, ferric oxide, or a combination thereof. In some embodiments, colorants are present in a topical formulation in a total amount of about 0.01 wt% to about 5 wt%.

[0417]

[0191] In embodiments, the topical formulation comprises a binder, such as polyvinylpyrrolidone (PVP), marine colloids, carboxyvinyl polymers, starches, cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (carmellose), hydroxypropylmethylcellulose, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, and salts thereof (e.g., carmellose sodium), natural gums such as karaya, xanthan, carrageenans, gellan gum, locust bean gum, gum arabic and tragacanth, chitosan, colloidal magnesium aluminum silicate, or colloidal silica. In some embodiments, binders are present in a total amount of about 0.01 wt% to about 5 wt%.

[0418]

[0192] In embodiments, the topical formulation comprises a humectant, such as low molecular weight polyethylene glycol (e.g., PEG6-PEG12). In some embodiments, humectants are present in a total amount of up to about 10 wt%, up to about 5 wt%, up to about 3 wt%, up to about 1 wt%, or up to about 0.1 wt%.

[0419]

[0193] In embodiments, the topical formulation comprises a surfactant. The surfactant may be anionic, nonionic, or amphoteric. In some embodiments, the surfactant is a higher alkyl sulfate such as potassium or sodium lauryl sulfate, an alkyl sulfonate such as sodium dodecyl benzene sulfonate, a higher fatty sulfoacetate, or a higher fatty acid ester of 1 ,2-dihydroxypropane sulfonate. I n some embodiments, the surfactant is a nonionic surfactant, such as a condensation product of ethylene oxide with a fatty acid, fatty alcohol, or fatty amide, or a Pluronic material such as Pluronic F127. In some embodiments, the surfactant is an alkyl polyglycoside (APG), such as decyl glucoside, coco-glucoside, lauryl glucoside, C12- C16 fatty alcohol glycoside, or a combination2026-03-18 thereof. In some embodiments, surfactants are present in a total amount of about 0.01 wt% to about 10 wt%.

[0420]

[0194] In embodiments, the topical formulation comprises a gelling agent, such as pectin (including high methoxyl pectin, low methoxyl pectin, amidated pectin, non-amidated pectin, or a combination thereof), starch, or gelatin (including Type A gelatin, Type B gelatin, a hide or skin gelatin, and / or a bone gelatin, used alone or in combination). In embodiments, gelling agents are present in a total amount of about 0.1 wt%to about 20 wt%.

[0421]

[0195] In some embodiments, the topical formulation comprises a cosmetically and / or dermo-cosmetically active substance, such as a color-imparting substance, pigmenting composition, tanning composition, bleach, keratin-hardening substance, antimicrobial substance, light filter substance, repellent substance, anti-phlogistic agent, antioxidant, skin-moisturizing substance, refatting substance, or a substance having antiallergic or antierythematous activity, or any mixture thereof. In some embodiments, the topical formulation comprises a perfume oil, such as a natural fragrance extract or a synthetic fragrance compound.

[0422]

[0196] In embodiments, a composition is formulated as an oral solid dosage form. Oral solid dosage forms include lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and any combinations thereof. Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations. In some embodiments, an oral solid dosage form is a tablet (including a suspension tablet, a fast-melt 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, capsules made from animal-derived gelatin or plant-derived HPMC, and sprinkle capsules), a solid dispersion, a solid solution, a bioerodible dosage form, a pulsatile release dosage form, a multiparticulate dosage form, pellets, or granules. In embodiments, the composition is administered in one, two, three, four, or more capsules or tablets. Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aids, flavoring agents, sweeteners, coating agents, solubilizing agents, and combinations thereof.

[0423]

[0197] In some embodiments, a disclosed composition is formulated as an oral liquid dosage form, such as a tincture, drops, emulsion, syrup, elixir, suspension, or solution. Oral liquid dosage forms may be formulated with pharmaceutically acceptable excipients, solvents (including water, glycerin, simple syrup, alcohol, medium chain triglycerides (MOT), and combinations thereof), diluents, carriers, dispersing agents, suspending agents, wetting agents, preservatives, viscosity enhancing agents, sweetening agents, and / or flavoring agents (see, e.g., Singh et al., Encyclopedia Pharm. Tech., 2nd Ed., 754-757 (2002)). Suspensions may include oils such as peanut oil, sesame oil, cottonseed oil, corn oil, olive oil, MCT, and long chain triglyceride (LCT) oils, as well as 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, propylene glycol, ethers such as polyethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water. In some embodiments, a formulation comprises a dispersing agent or suspending agent for oral administration, and upon admixture with water, a substantially uniform suspension is obtained.2026-03-18

[0198] Compositions include those suitable for intramuscular (IM), subcutaneous (SC), intraperitoneal (IP), or intravenous (IV) 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.

[0424]

[0199] In some embodiments, a disclosed pharmaceutical composition is formulated for ocular administration, including ophthalmic, intraocular, intravitreal, and periocular (including subconjunctival, retrobulbar, peribulbar, suprachoroidal, and sub-Tenon’s) administration. In some embodiments, an ophthalmic formulation is a topical formulation, such as eye drops, a gel, or an ointment, and may comprise any of the excipients described herein for topical formulations, including penetration enhancers and surfactants as described herein.

[0425]

[0200] In some embodiments, an ophthalmic formulation has a viscosity of about 1.0 to 100,000 cP, about 2.0 to 90,000 cP, or about 2.5 to 75,000 cP. In some embodiments, the ophthalmic formulation comprises a viscosity modifying agent at a concentration of about 0.1% to about 10% by weight, or about 1% to about 5% by weight. In some embodiments, the viscosity modifying agent is sorbitol, at a concentration of about 0.1 % to about 10%, or about 2% to about 5% by weight.

[0426]

[0201] In some embodiments, an ophthalmic formulation comprises a hydrating agent. In some embodiments, the hydrating agent is hyaluronic acid (or a salt thereof, e.g., sodium hyaluronate), water, saline solution, PVP, propylene glycol, glycerol, sorbitol, polyethylene glycol, dexpanthenol, pantothenic acid, ectoin, carboxyvinyl polymer, carmellose sodium, or povidone.

[0427]

[0202] In embodiments, the ophthalmic formulation comprises a pH adjuster. In some embodiments, the pH adjuster is used to adjust the pH of the formulation to a range of about pH 4—10, or about pH 5-8. In embodiments, the pH adjuster is hydrochloric acid, citric acid, sodium citrate, acetic acid, sodium acetate, ammonium acetate, succinic acid, tartaric acid, L-sodium tartrate, sodium hydrate, potassium hydrate, sodium carbonate, sodium hydrogen carbonate, lactic acid, calcium lactate, sodium lactate, sodium fumarate, sodium propionate, boric acid, ammonium borate, maleic acid, phosphoric acid, sodium hydrogenphosphate, malic acid, adipic acid, triethanolamine, diisopropanolamine, meglumine, monoethanolamine, sulfuric acid, or aluminum potassium sulfate.

[0428]

[0203] In some embodiments, the ophthalmic formulation comprises a stabilizer. In some embodiments, the stabilizer is sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium formaldehyde sulfoxylate, L-ascorbic acid, erythorbic acid, L-cysteine, thioglycerol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbyl palmitate, alpha-tocopherol, nordihydroguaiaretic acid, disodium edetate, tetrasodium edetate dehydrate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbic acid, or succinic acid.

[0429]

[0204] In some embodiments, a disclosed compound or pharmaceutical composition is incorporated into a contact lens for ocular drug delivery. In some embodiments, the contact lens is a hydrogel contact lens or a molecularly imprinted contact lens. In some embodiments, the contact lens comprises drug and barrier layers formulated for controlled drug release (see, e.g., Franco et al., Polymers, 2021, 13, 1102).2026-03-18

[0205] A disclosed pharmaceutical composition may comprise any excipient at a concentration of about 0.01 %, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.5%, about 1%, about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% of the formulation, on a weight or volume basis, including all values, ranges, and subranges in between.

[0430] F. Pharmaceutical Combinations

[0431]

[0206] Disclosed compositions are not limited to compositions of a single compound, or limited to a single carrier, diluent, and / or excipient. Compositions also include combinations of multiple compounds (including additional active compounds), and / or multiple carriers, diluents, and excipients. Pharmaceutical compositions for example may comprise a compound of Formula (1) together with one or more other active agents in combination, together with one or more pharmaceutically-acceptable carriers, diluents, and / or excipients, and additionally with one or more other active agents. Additional exemplary embodiments include compositions comprising two compounds of Formula (1 ), or compositions comprising any other two disclosed compounds.

[0432]

[0207] In some embodiments, a pharmaceutical composition is prepared to increase an existing therapeutic effect. In some embodiments, a pharmaceutical composition is prepared to provide an additional therapeutic effect. In some embodiments, a pharmaceutical composition is prepared to increase stability or shelf-life. In some embodiments, a pharmaceutical composition is prepared to decrease an unwanted effect or property. In some embodiments, a pharmaceutical composition is prepared to alter pharmacokinetics or pharmacodynamics. In some embodiments, a pharmaceutical composition is prepared to modulate a neurotransmitter system. In some embodiments, a pharmaceutical composition is prepared to provide synergistic effects.

[0433]

[0208] “Therapeutic effects” in embodiments include antioxidant, anti-inflammatory, analgesic, anti-neuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, and stimulant effects.

[0434]

[0209] “Synergistic effects” include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect, that are greater than the additive contributions of the components acting alone.

[0435]

[0210] Methods for determining synergy include isobologram 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 medianeffect equation (Chou & Talalay, Adv Enzyme Regul., 1984; 22:27-55).

[0436]

[0211] In some embodiments, an 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, immuno- stimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents (e.g., psychoplastogens and2026-03-18 neuroplastogens), monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins. In some embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, 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.

[0437]

[0212] In some embodiments, an additional active compound is a tryptamine. A tryptamine may have the structure below, wherein RN1, RN2, Ra, RP, R2, R4, R5, R6, and R7are as defined herein or known in the art:

[0438] RP R

[0439] I i

[0440]

[0441]

[0213] In embodiments, RN1, RN2, Ra, RP, R2, R4, R5, R6, and R7are each independently H, deuterium, halogen (F, Cl, Br, or I), OH, or phosphoryloxy, or are alkyl, alkenyl, alkynyl, alkoxy, 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 can be taken together to form a cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted. In embodiments, the tryptamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted.

[0442]

[0214] In some embodiments, the additional active compound is a tryptamine selected from the group consisting of psilocybin, psilocin, psilacetin, DBT, DET, DiPT, a,O-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,O-TMS, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof. As known to one of skill, the systematic naming of tryptamines, such as those 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-(1H-indol-3-yl)ethyl]propan- 2-amine). Examples of these tryptamines and others that may in embodiments be included in a disclosed composition as an additional active2026-03-18 compound are known to those of skill, and include the compounds disclosed in Shulgin & Shulgin, TiHKAL: The Continuation, Transform Press (1997) (“TiHKAL”).

[0443]

[0215] In embodiments, the additional active compound is a complex tryptamine or other indolamine, including iboga alkaloids such as ibogaine, and its analogs, metabolites, and derivatives. In embodiments, the tryptamine is a beta-carboline, such as beta-carboline, harmaline, harmine, harmane, harmalol, tetrahydroharmine, 9-methyl-p-carboline, pinoline, and 6-MeO-THH.

[0444]

[0216] In some embodiments, the additional active compound is a phenethylamine. A phenethylamine may have the structure below, wherein RN1, RN2, Ra, RP, and each of R2-R6are as defined herein or known in the art:

[0445]

[0446]

[0217] In embodiments, RN1, RN2, Ra, RP, and each of R26are independently H, deuterium, halogen, or are alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted. In some embodiments, R3and R4are joined together to form an optionally substituted heterocyclyl, such as a dioxole (as with 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 some embodiments, R3and R4are joined together to form an optionally substituted aryl, such as a phenyl. In some 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, and with all other substituents as above. In some 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.

[0447]

[0218] In some embodiments, the additional active compound is a phenethylamine 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, 20-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,2026-03-18 2C-O, 2C-O-4, 2C-MOM, 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, DOAM, 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, 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 stands for methylenedioxybenzylamphetamine (i.e., 3,4-methylenedioxy-N-benzylamphetamine). Exemplary phenethylamines that, in embodiments, may be included in a composition as an additional active compound include the compounds in Shulgin & Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991) (“PiHKAL”); and Shulgin AT, The Shulgin Index Vol.1: Psychedelic Phenethylamines & Related Compounds, Transform Press (2011).

[0448]

[0219] In some embodiments, the additional active compound is an ergoline. In some embodiments, the additional active compound is an ergot alkaloid. In some embodiments, the additional active compound is a lysergamide. A lysergamide may have the structure below, wherein RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are as defined herein or known in the art:

[0449] RN1 RN2

[0450]

[0451]

[0220] In some embodiments, RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are each independently H, deuterium, halogen, or any of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of2026-03-18 which may be optionally substituted. Additionally, any two of RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14and the intervening atoms can be taken together to form a cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, any of which may be optionally substituted. In some 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.

[0452]

[0221] 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 -acetyllysergic 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-(cyclopropylmethanoyl)-lysergic acid diethylamide (1cP-LSD), 1-(1,2-dimethylcyclobutane-1 -carbonyl)- lysergic acid diethylamide (1D-LSD), 1-propionyl-6-allyl-6-nor-lysergic acid diethylamide (1P-AL-LAD), 1-(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).

[0453]

[0222] Other tryptamines, phenethylamines, and lysergamides useful as additional active compounds and contemplated for inclusion in disclosed compositions are described in, e.g., PiHKAL; TiHKAL; Grob & Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi & Liechti, Arch Toxicol., 2020; 94:1085-1133; Nichols, Pharmacol Rev., 2016; 68(2):264— 355; Glennon, Pharmacol Biochem Behav, 1999; 64:251-256; each of which is incorporated by reference as if fully set forth herein.

[0454] G. Dose and Dosage

[0455]

[0223] In some embodiments, pharmaceutical compositions comprise a therapeutically effective amount or an effective amount of a disclosed compound, such as for administration to a subject.

[0456]

[0224] Administration of pharmaceutical compositions in a “therapeutically effective amount,” or an “effective amount” to a subject means administration of an amount of composition sufficient to achieve the desired effect. When an “effective amount” means an amount effective in treating the stated disorder or symptoms in a subject, “therapeutic effect” would be understood to mean the responses(s) in a mammal after treatment that are judged to be desirable and beneficial. Depending on the symptom(s), condition, disease, or disorder to be treated, and depending on the particular constituent(s) in the compositions administered, those responses may differ (e.g., for a mental health disorder, by reference to the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for the stated disorder).

[0457]

[0225] In embodiments, a pharmaceutical composition comprises a disclosed compound in an amount so that2026-03-18 a single dose is (in a milligram amount based on the kilogram weight of a subject), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, and amounts within these ranges.

[0458]

[0226] “Disclosed compound,” broadly, and in some embodiments, includes any compound of Formula (1) or any other Formula herein, such as Formula (2), Formula (3), and Formulae (l)-(XVI II); any compound of any of Group A, Group B, or Group C; any compound of Table 1; any specific compound described by structure; any additional active compound, such as any phenethylamine, tryptamine, or lysergamide; and any other compound herein. In embodiments, a disclosed compound is a compound of Formula (1). In embodiments, a disclosed compound is a compound of Formula (2). In embodiments, a disclosed compound is a compound of Formula (3). In embodiments, a disclosed compound is a compound of Formula (I). In embodiments, a disclosed compound is a compound of Formula (II). In embodiments, a disclosed compound is a compound of Formula (III). In embodiments, a disclosed compound is a compound of Formula (IV). In embodiments, a disclosed compound is a compound of Formula (V). In embodiments, a disclosed compound is a compound of Formula (VI). In embodiments, a disclosed compound is a compound of Formula (VII). In embodiments, a disclosed compound is a compound of Formula (VIII). In embodiments, a disclosed compound is a compound of Formula (IX). In embodiments, a disclosed compound is a compound of Formula (X). In embodiments, a disclosed compound is a compound of Formula (XI). In embodiments, a disclosed compound is a compound of Formula (XII). In embodiments, a disclosed compound is a compound of Formula (XIII). In embodiments, a disclosed compound is a compound of Group A. In embodiments, a disclosed compound is a compound of Group B. In embodiments, a disclosed compound is a compound of Group C. In embodiments, a disclosed compound is a compound of Table 3. In embodiments, a disclosed compound is any of 2CIB-2OH-5DHF, 2CIB-5DHF, and 2CIB-2OH-5DHF-NBOH. In embodiments, the compound is 2CIB-2OH-5DHF. In embodiments, the compound is 2CIB-5DHF. In embodiments, the compound is 2CIB-2OH-5DHF-NBOH.

[0459]

[0227] In some embodiments, a pharmaceutical composition comprises a disclosed compound in an amount so that a single dose is between about 0.001 mg / kg and 0.1 mg / kg, such as about 0.001 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, and about 0.1 mg / kg, as well as ranges between these values. In some embodiments, a single dose is between about 0.1 mg / kg and 1.0 mg / kg, such as about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg about 0.8 mg / kg about 0.9 mg / kg, and about 1.0 mg / kg, as well as ranges between these values.2026-03-18

[0228] In some embodiments, a pharmaceutical composition comprises a disclosed compound in an amount so that a single dose is about 20 pg / kg body weight or less (e.g., less than 20 pg / kg, less than 15 pg / kg, less than 10 pg / kg, or less than 5 pg / kg body weight, e.g., from 1 to 20 pg / kg body weight, e.g., from 1 to 5 pg / kg, from 5 to 10 pg / kg, from 10 to 15 pg / kg, or from 15 to 20 pg / kg, e.g., about 5 pg / kg, about 10 pg / kg, about 15 pg / kg, or about 20 pg / kg).

[0460]

[0229] In some embodiments, a pharmaceutical composition comprises a disclosed compound in an amount so that a single dose is about less than about 20 ng / mL (e.g., 0.05 to 20 ng / mL, e.g., 0.1 to 15 ng / mL, 0.5 to 10 ng / mL, or 1 to 5 ng / mL, e.g., 0.05 to 0.1 ng / mL, 0.1 to 0.2 ng / mL, 0.2 to 0.3 ng / mL, 0.3 to 0.4 ng / mL, 0.4 to 0.5 ng / mL, 0.5 to 1 .0 ng / mL, 1.0 to 5 ng / mL, 5 to 10 ng / mL, 10 to 15 ng / mL, or 15 to 20 ng / mL, e.g., about 0.05 ng / mL, 0.1 ng / mL, 0.2 ng / mL, 0.5 ng / mL, 1 .0 ng / mL, 2.0 ng / mL, 2.5 ng / mL, 5.0 ng / mL, 7.5 ng / mL, 10 ng / mL, 12 ng / mL, 15 ng / mL, or 20 ng / mL). In some embodiments, the circulating drug plasma level of the compound is below the limit of detection (e.g., 0.1 ng / mL or less).

[0461]

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

[0462]

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

[0463]

[0232] It will be appreciated that dosages may vary depending upon whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by the skilled artisan (e.g., medical or familial history).

[0464]

[0233] Dose amount, frequency or duration may be increased or reduced, as indicated by the clinical outcome2026-03-18 desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications. One of skill in view of the disclosure will appreciate the factors that may influence the dosage, frequency, and timing useful to provide a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0465]

[0234] In some embodiments, a disclosed compound is administered at a dose below the ED50 for HTR, motor suppression, or hypothermia. In embodiments, a disclosed compound is administered topically or locally at a dose that achieves therapeutic effects without systemic exposure sufficient to induce behavioral effects.

[0466]

[0235] In embodiments, the dose administered is determined by a physician, in light of relevant circumstances, such as the disorder to be treated, the route of administration, the composition administered, the age, weight, and response of the patient, the severity of the patient’s symptoms, and the like. Disclosed dosages are consequently exemplary and not limiting. In some instances, dosages below the lower limit of a disclosed range may be sufficient, and in other cases dosages above a range may be administered.

[0467]

[0236] Doses may be divided into several smaller doses for administration, and taken together or separately.

[0468]

[0237] In some embodiments, such as where a composition is a single unit dosage form, suggested dosage amounts are known by reference to the format of the preparation itself. In some embodiments, such as where a composition is in a multiple dosage form, suggested dosage amounts are known by reference to the means of administration, or by reference to the packaging and labeling, package insert(s), marketing materials, training materials, and / or other information and knowledge available to those of skill or to the public.

[0469] H. Pharmaceutical Kits

[0470]

[0238] In some aspects are provided pharmaceutical kits (“kits”) containing a disclosed pharmaceutical composition, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. Pharmaceutical compositions can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0471]

[0239] Kits may comprise suitable packaging. A kit may comprise one or more containers comprising any disclosed compound. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. A kit may comprise compositions in unit dosage form, bulk packages (e.g., multi-dose packages), or sub-unit doses. For example, kits may comprise sufficient dosages of a compound as disclosed herein and / or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies). Information pertaining to dosing and proper administration (if needed) may be printed onto a multi-dose kit directly (e.g., on a blister pack or other interior packaging holding disclosed compositions). Kits also may comprise package inserts and / or printed2026-03-18 instructions (e.g., on exterior packaging) for administering their contents and their appropriate therapeutic use.

[0472] I. Methods of Use

[0473]

[0240] In some aspects, provided herein are methods of using the disclosed compounds. In some embodiments, disclosed compounds are used to modulate neurotransmission. In some embodiments, disclosed compounds are used to treat a condition, such as a disease or a disorder. In some embodiments, disclosed compounds are used in the manufacture of a medicament for the therapeutic and / or the prophylactic treatment of a condition, such as a disease or a disorder. In some embodiments, disclosed compounds are administered as part of therapy. In some embodiments, disclosed compounds are administered along with psychotherapy, psychological support, or patient monitoring. In some embodiments, disclosed compounds are administered in a therapeutically effective amount to a subject having a condition, such as a disease or a disorder. In some embodiments, the condition is a mental health disorder. In some embodiments, the condition is a neurodegenerative disorder. In some embodiments, the condition is a pain disorder. In some embodiments, disclosed compounds are administered to a subject that is healthy.

[0474]

[0241] Herein, the terms “subject,” “user,” “patient,” and “individual” may be used interchangeably, and refer to any mammal, including murines, simians, mammalian farm animals, mammalian sport animals, and mammalian pets, such as canines and felines, and in some embodiments humans. Such terms will be understood to include one who has an indication for which a compound, composition, or method described herein may be efficacious, or who otherwise may benefit by the disclosure.

[0475]

[0242] Compounds and compositions may be administered to a subject orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, or by inhalation. Compounds and compositions may be administered to a subject topically ortransdermally. Compounds and compositions may be administered to a subject ocularly, including ophthalmically, i.e., via ophthalmic administration, including via topical administration to the surface of the eye. In embodiments, when administered through any such routes, the compounds and compositions are useful in methods for treating a subject in need of such treatment.

[0476]

[0243] In some embodiments, a disclosed compound is useful as a locally active therapeutic agent. Systemic administration of therapeutically active agents may directly or indirectly affect multiple organs and tissues throughout the body. Consequently, systemic administration of a compound may give rise to a greater number or extent of adverse effects at a therapeutically active dose. For example, certain serotonin receptor agonists have been shown to exert anti-inflammatory effects, but may also have effects on the central nervous system (CNS) that may be undesired or unnecessary in the context of treating certain medical conditions (e.g., skin or ocular inflammation). In embodiments, a disclosed compound exhibits minimal penetration into the CNS, but has therapeutic effects (e.g., anti-inflammatory effects) in tissues and organs in which the compound is directly administered, or in tissues and organs proximal to the site of administration. Such compounds may be referred to as “locally active,” because their action is localized to the area to which (or close to which) they are applied.

[0477]

[0244] Without being bound by theory, disclosed compounds may be substrates for an enzyme. Inactivation2026-03-18 (e.g., hydrolysis) of such compounds (e.g., by an enzyme) may prevent systemic action, thereby localizing their therapeutic effects to (or close to) the site of administration. In some embodiments, other features of disclosed compounds may prevent systemic action. In some embodiments, features of disclosed compounds may prevent penetration into the CNS (e.g., prevent crossing the blood-brain barrier). In some embodiments, administration of a disclosed compound in a disclosed topical formulation exerts therapeutic (e.g., anti-inflammatory) effects locally, without causing systemic effects. In some embodiments, administration of a disclosed compound in a disclosed topical formulation exerts therapeutic (e.g., anti-inflammatory) effects systemically, without causing psychoactive or other effects associated with penetration into the CNS.

[0478] a. Modulating Neurotransmission

[0479]

[0245] In some embodiments, disclosed compounds modulate neurotransmission in a subject, such as following administration of a therapeutically effective amount to said subject.

[0480]

[0246] In embodiments, modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject. In embodiments, modulating neurotransmission comprises regulating levels of monoamines in, for example, the CNS and peripheral tissues.

[0481]

[0247] In some embodiments, disclosed compounds activate serotonin receptors. In some embodiments, disclosed compounds agonize and / or antagonize serotonin receptors (5-HT receptors, such as the 5-HT2 receptor). The 5-HT2 receptor family includes the 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes (see, e.g., Nichols, Pharmacol. Rev., 2016; 68:264-355). In some embodiments, activation of 5-HT2C receptors functionally opposes effects of 5-HT2A receptor activation. In some embodiments, activation of 5-HT2B receptors in cardiac muscle tissue is associated with cardiac valve disease (Hutcheson et al., Pharmacol Ther., 2011; 132(2):146— 157). In some embodiments, a disclosed compound has reduced agonism of 5-HT2B. In embodiments, disclosed compounds agonize or partially agonize 5-HT receptors, such as any one or more of a 5-HTi receptor, such as 5-HTIA and 5-HTIB, a 5-HT2 receptor, such as 5-HT2A and 5-HT2C, and a 5-HTe.

[0482]

[0248] In some embodiments, a disclosed compound has an in vitro EC50 (agonist mode) for any one or more of 5-HTIA, 5-HTIB, 5-HT2A,5-HT2C, and 5-HTethat 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 5-HT2A that is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM. In embodiments, a disclosed compound has an in vitro EC50 (agonist mode) for 5-HT2C that is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM.

[0483]

[0249] In embodiments, compounds show greater potency at 5-HT2A relative to another 5-HT receptor. In embodiments, compounds show greater potency at 5-HT2A relative to any one or more of a 5-HTi receptor, another 5-HT2 receptor, such as 5-HT2B and 5-HT2C, a 5-HTs receptor, a 5-HTe receptor, and a 5-HT? receptor.

[0484]

[0250] In some embodiments, agonism is measured by determining EC50, and antagonism is measured by determining IC50. In embodiments, modulation of 5-HT2A is assessed by measuring Gq-mediated calcium flux2026-03-18 (Klein et al., ACS Pharmacol Transl Sci., 2020; 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., Psychopharmacol (Be )., 2019; 236(2):799— 808). In embodiments, a disclosed compound is a partial agonist, having reduced maximum efficacy relative to a full agonist (i.e., Emax = 100%), e.g., serotonin, in the context of a 5-HT receptor.

[0485]

[0251] In some embodiments, therapeutic benefits of disclosed compounds derive, at least in part, from selective activation of a serotonin receptor (e.g., 5-HT2A, 5-HT2C). In some embodiments, a disclosed compound has increased selectivity for the 5-HT2A receptor over another serotonin receptor (e.g., the 5-HT2B receptor, or the 5-HT2C receptor). In some embodiments, a disclosed compound has increased selectivity for the 5-HT2A receptor over the 5-HT2B receptor. In some embodiments, a disclosed compound has increased selectivity for the 5-HT2A receptor over the 5-HT2C receptor. In some embodiments, selectivity is defined as functional activity selectivity, calculated by the ratio of EC50 of a disclosed compound for one receptor as compared to another receptor. For example, if a hypothetical compound had a 5-HT2A ECSO of 0.2 M and a 5-HT2B ECSO of 1.0 pM, the compound could be said to have a 5-fold functional activity selectivity for the 5-HT2A receptor over the 5-HT2B receptor. In some embodiments, selectivity is defined as affinity selectivity, calculated by the ratio of binding affinity (e.g., as assessed by Ki) for one receptor as compared to another receptor. For example, if a hypothetical compound had a 5-HT2A Ki of 0.1 pM and a 5-HT2B Ki of 1.0 pM, the compound could be said to have a 10-fold affinity selectivity for the 5-HT2A receptor over the 5-HT2B receptor.

[0486]

[0252] In some embodiments, a disclosed compound has an affinity selectivity of about 1.1 -fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold selectivity for the 5-HT2A receptor over the 5-HT2B receptor. In embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2A receptor over the 5-HT2B receptor, relative to a comparator.

[0487]

[0253] In embodiments, a compound has a functional activity selectivity of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold selectivity for the 5-HT2A receptor over the 5-HT2B receptor. In embodiments, a compound has improved functional activity selectivity for the 5-HT2A receptor over the 5-HT2B receptor, relative to a comparator.

[0488]

[0254] In some embodiments, a disclosed compound has an affinity selectivity of about 1.1 -fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold selectivity for the 5-HT2C receptor over the 5-HT2B receptor. In embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2C receptor over the 5-HT2B receptor, relative to a comparator.

[0489]

[0255] In embodiments, a compound has a functional activity selectivity of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold selectivity for the 5-HT2C receptor over the 5-HT2B receptor. In embodiments, a compound has improved functional activity selectivity for the 5-HT2C receptor over the 5-HT2B receptor, relative to a comparator.

[0490] b, Modulating Neuroplasticity

[0491]

[0256] In some embodiments, a disclosed compound modulates neurotransmission in a subject, such as2026-03-18 following administration of a therapeutically effective amount to the subject. In some embodiments, modulating neurotransmission contributes to the therapeutic effects of a compound in a subject. In some embodiments, modulating neurotransmission by administering a compound to a subject treats a disease or disorder therein.

[0492]

[0257] In some embodiments, neurotransmission is quantified by measuring general action potential firing activity (Obien et al., Front Neurosci., 2015; 8:423; Morin et al., J Biosci Bioeng., 2005; 100(2):131— 143). In some embodiments, general action potential firing activity parameters include spike rate, burst rate, and / or spike contrast. In some embodiments, neurotransmission is quantified by measuring burst structure, including burst spike number, burst duration, and / or burst amplitude. In some embodiments, neurotransmission is quantified by measuring oscillatory behavior, including the standard deviation of spike rate, burst rate, and / or burst amplitude. In some embodiments, neurotransmission is quantified by measuring synchronicity of activity of a neuron population. In some embodiments, synchronicity is measured as the coefficient of variation in spike rate, burst rate, and / or burst duration across a neuron population. In some embodiments, synchronicity is measured as synchronicity share, synchronicity distance, and / or spike simplex.

[0493]

[0258] In some embodiments, a disclosed compound modulates spike rate (the number of action potentials per second). In some embodiments, a disclosed compound modulates burst rate (the number of bursts per second). In some embodiments, a disclosed compound modulates spike contrast (a measure of variability in neuronal activity, measured as the difference between the number of spikes occurring in the first half and second half of a recording duration). In some embodiments, a disclosed compound modulates burst spike number (the number of spikes per burst). In some embodiments, a disclosed compound modulates burst duration (the mean duration of detected bursts). In some embodiments, a disclosed compound modulates burst amplitude (the peak value of an integral function with a decay calculated over the timestamps of bursts).

[0494]

[0259] In some embodiments, a disclosed compound modulates oscillatory behavior (the standard deviation of a parameter over time within an experimental episode). In some embodiments, a disclosed compound modulates synchronicity of activity in a neuron population. In some embodiments, a disclosed compound modulates synchronicity share (the average number of units involved in population bursts). In some embodiments, a disclosed compound modulates synchronicity distances (the average distance of burst starts within a population burst from the population burst center). In some embodiments, a disclosed compound modulates spike simplex (a measure of connectivity and complexity in a neuronal network).

[0495]

[0260] In some embodiments, administration of a disclosed compound increases neuroplasticity. In some embodiments, increasing neuroplasticity contributes to the therapeutic effects of administering a disclosed compound to a subject. In some embodiments, increasing neuroplasticity comprises increasing synaptic plasticity, which involves the strengthening or weakening of synapses between neurons. In some embodiments, increasing neuroplasticity comprises increasing structural plasticity, which involves changes in the physical structure of neurons, such as the growth of new dendritic branches or the formation of new synapses. In some embodiments, increasing neuroplasticity by administering a disclosed compound to a subject treats a disease2026-03-18 or disorder in the subject.

[0496]

[0261] In some embodiments, neuroplasticity comprises neuritogenesis (the generation and extension of neurites to form axons and dendrites). In some embodiments, neuroplasticity comprises spinogenesis (the formation of dendritic spines on the dendrites of neurons). In some embodiments, neuroplasticity comprises synaptogenesis (the formation of synapses). In some embodiments, a disclosed compound increases neuritogenesis. In some embodiments, neuritogenesis is measured in terms of total neurite length, maximum neurite length, number of neurite nodes, and / or number of neurite extremities. In some embodiments, a disclosed compound increases total neurite length. In some embodiments, a disclosed compound increases maximum neurite length. In some embodiments, a disclosed compound increases the number of neurite nodes. In some embodiments, a disclosed compound increases the number of neurite extremities.

[0497]

[0262] In some embodiments, administration of a disclosed compound increases the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., number of synapses per neuron), and / or the total dendritic length. In some embodiments, these parameters are measured using a Sholl analysis (Ly et al., ACS Pharmacol Transl Sci., 2020; 4(2):452— 460).

[0498] c. Treatment

[0499]

[0263] In some aspects are provided methods of treating a medical condition, such as a disease or a disorder, by administering a disclosed compound or composition. In some embodiments, disclosed compounds and compositions are accordingly used to treat a medical condition, such as a disease or disorder.

[0500]

[0264] Herein, unless context indicates otherwise, the terms “disease,” “disorder,” and “condition” are used interchangeably and are intended to be interpreted broadly to encompass any pathological or non-pathological state. These terms may include subjects with or without a formal diagnosis, including those who do not meet established diagnostic criteria as well as those who do. For example, an inflammatory “disease,” “disorder,” or “condition” may refer to states associated with or characterized by inflammation, including diagnosable inflammatory diseases, acute or chronic inflammatory disorders, inflammatory syndromes, subclinical inflammatory states, and both localized and systemic inflammatory responses. These terms further encompass states in which inflammation is a contributing factor, consequence, or mechanistic component, whether or not inflammation is the primary clinical focus, and whether or not the condition is formally recognized as an inflammatory disease. In some embodiments, reference to a “disease,” “disorder,” or “condition” refers to a specific, diagnosable medical entity, including those classified by established diagnostic criteria or medical coding systems (e.g., ICD, DSM). As an example, in some embodiments, reference to an inflammatory “disease,” “disorder,” or “condition” refers to a disease, disorder, or condition having a specific clinical diagnosis, including formally recognized medical conditions characterized by inflammation.

[0501]

[0265] In some embodiments, disclosed compounds and compositions are administered to a subject by one or more routes of administration, including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, ophthalmic, intraocular, periocular, topical, and transdermal routes.2026-03-18

[0266] In some embodiments are provided methods of treating and / or preventing a condition in a mammal, such as a human, the method comprising administering to the mammal a therapeutically effective amount of a disclosed compound or a disclosed pharmaceutical composition.

[0502]

[0267] “Treating” and “treatment” includes causing a desired biological or pharmacological effect, and may include any one or more of, or a specific subset of, including depending on whether “treatment” includes “prevention”: (a) preventing a condition from occurring in a subject who may be predisposed to the condition but has not yet received a diagnosis; (b) inhibiting a condition, i.e. arresting its development; (c) relieving a condition, i.e., causing regression thereof; (d) protecting from or relieving a symptom or pathology caused by or related to a condition; (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 condition; and (f) preventing or inhibiting of a worsening or progression of symptoms or pathologies associated with a condition or comorbid with a condition. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, are understood in the art. In some embodiments, treatment includes prevention. In some other embodiments, treatment does not include prevention.

[0503]

[0268] In embodiments, disclosed compounds are used to treat a central nervous system (CNS) disorder. Broadly, CNS disorders include those of the nervous system (e.g., movement disorders, neurodegenerative disorders) as well as mental, behavioral, and neurodevelopmental disorders, such as in the DSM-5, Merck Manual, I CD- 11 , or other such diagnostic resources known to one of skill.

[0504] i. Mental, Behavioral, or Neurodevelopmental Disorders

[0505]

[0269] In embodiments, disclosed compounds are used to treat a mental, behavioral, or neurodevelopmental disorder. In embodiments, disclosed compounds are administered in a therapeutically effective amount to a subject having a mental, behavioral, or neurodevelopmental disorder, thereby treating said disorder.

[0506]

[0270] 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 cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning. A "mental health disorder" generally refers to a disease condition that involves changes in emotion, mood, thinking, and / or behavior.

[0507]

[0271] Unless otherwise defined herein, a mental, behavioral, or neurodevelopmental disorder will be understood to refer to the disorder as defined in the 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.

[0508]

[0272] In some embodiments, the mental, behavioral, or neurodevelopmental disorder is a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder is a disorder of intellectual development, a developmental speech or language disorder, autism spectrum disorder, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder (ADHD), or stereotypic movement disorder.2026-03-18

[0273] In some embodiments, the disorder is schizophrenia or another primary psychotic disorder, including schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder. In some embodiments, the disorder is catatonia, including catatonia associated with another mental disorder or induced by substances or medications.

[0509]

[0274] In some embodiments, the disorder is a mood disorder. 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 depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder, 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.

[0510]

[0275] In some embodiments, the disorder is an anxiety or fear-related disorder, including generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or a substance-induced anxiety disorder.

[0511]

[0276] In embodiments, the disorder is an obsessive-compulsive or related disorder, including 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.

[0512]

[0277] In some embodiments, the disorder is a disorder associated with stress, including post-traumatic stress disorder (PTSD), complex post-traumatic stress disorder (ePTSD), prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder. In some embodiments, the disorder is a dissociative disorder, including dissociative neurological symptom disorder, dissociative amnesia (including amnesia with and without dissociative fugue), trance disorder, possession trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization-derealization disorder.

[0513]

[0278] In some embodiments, the disorder is a feeding creating disorder, including anorexia nervosa (including anorexia with significantly low body weight, dangerously low body weight, or in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or ruminationregurgitation disorder. In embodiments, the disorder is an elimination disorder, including enuresis (nocturnal, diurnal, and nocturnal and diurnal enuresis) or encopresis (with or without constipation or overflow incontinence). In some embodiments, the disorder is a disorder of bodily distress or bodily experience, including bodily distress disorder (including mild, moderate, and severe) or body integrity dysphoria.

[0514]

[0279] In some embodiments, the disorder is a disorder due to substance use or addictive behaviors. In some embodiments, the substance use disorder is alcohol use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalant use disorder, opioid use disorder, sedative use disorder, hypnotic use disorder, anxiolytic use disorder, stimulant use disorder, and tobacco use disorder. In some embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorder, gaming disorder).2026-03-18

[0280] In some embodiments, the disorder is an impulse control disorder, including pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder. In some embodiments, the disorder is a disruptive behavior or dissocial disorder, including oppositional defiant disorder (including with and without chronic irritability-anger) or conduct-dissocial disorder (including childhood-onset and adolescent-onset).

[0515]

[0281] In some embodiments, the disorder is a personality disorder, including antisocial, avoidant, borderline, dependent, histrionic, narcissistic, obsessive-compulsive, paranoid, schizoid, or schizotypal personality disorder, or masochistic or sadistic behavior, psychopathy, or sociopathy.

[0516]

[0282] In some embodiments, the disorder is a neurocognitive disorder, including delirium, mild neurocognitive disorder, an amnestic disorder, or dementia. In some embodiments, the neurocognitive disorder is associated with another disease or disorder or with a psychoactive substance (including medications and illicit or illegal substances). In embodiments, the dementia is associated with Alzheimer's disease, Parkinson's disease, cerebrovascular disease, or Lewy body disease. In some embodiments, a compound is used to treat a behavioral or psychological disturbance associated with dementia.

[0517]

[0283] In some embodiments, the disorder is a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium, including with or without psychotic symptoms.

[0518]

[0284] In some embodiments, the disorder is a sleep-wake disorder, including an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder. In some embodiments, the disorder is a sexual dysfunction, including hypoactive sexual desire dysfunction, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse. In embodiments, the disorder is a paraphilic disorder, including 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. In some embodiments, the disorder is a factitious disorder, including factitious disorder imposed on self or imposed on another.

[0519]

[0285] In some embodiments, measures of therapeutic efficacy include reports by a subject or an observer, or responses to a questionnaire. Non-limiting representative examples of applicable measures include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire-9 (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 Inventory (BDI / BDI-I I), Hamilton Depression Rating Scale (HDRS), Zung Self-Rating Depression Scale (SDS), Major Depression Inventory (MDI), Center for Epidemiologic Studies Depression Scale (CES-D), Rome Depression Inventory (RDI), Carroll Rating Scale (CRS), Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), Montreal2026-03-18 Cognitive Assessment (MoCA), Neuropsychiatric Inventory Questionnaire (NPI-Q), Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), Opioid Risk Tool (ORT-OUD), Drug Abuse Screen Test (DAST-10), and related subject- or observer-reported measures.

[0520] ii. Neurodegenerative Disorders

[0521]

[0286] In some embodiments, disclosed compounds are used to treat a neurodegenerative disorder. In some embodiments, disclosed compounds are administered in a therapeutically effective amount to a subject having a neurodegenerative disorder, thereby treating said disorder. In embodiments, disclosed compounds and compositions are used to reduce the symptoms of a neurodegenerative disorder.

[0522]

[0287] The disclosed compounds are useful in different embodiments for treating neurodegenerative disorders characterized by a gradual loss of structure and function of neurons within the central nervous system (CNS) or peripheral nervous system (PNS), including progressive, chronic, and debilitating conditions.

[0523]

[0288] In some embodiments, disclosed compounds are used to treat disorders involving the degeneration, impairment, or death of neuronal cells, leading to a decline in cognitive, motor, and / or sensory abilities.

[0524]

[0289] In some embodiments, disclosed compounds are used to treat neurodegenerative disorders classified according to primary clinical features, e.g., dementia, parkinsonism, or motor neuron disease. In embodiments, compounds are used to treat neurodegenerative disorders classified according to anatomic distribution of neurodegeneration, e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations. In embodiments, compounds are used to treat neurodegenerative disorders classified according to principal molecular abnormality (Dugger & Dickson. Cold Spring Harb Perspect Biol. 2017: 9(7); a028035). Disorders treated may involve various etiologies, including presence of pathogenic proteins, age, environmental stressors, and genetic predisposition (Armstrong. Folia Neuropathologica. 2020: 58(2); 93-112).

[0525]

[0290] In embodiments, a neurodegenerative disorder is associated with dementia, as described herein.

[0526]

[0291] In some embodiments, the neurodegenerative disorder is any 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 including mild TBI.

[0527] iii. Pain Disorders

[0528]

[0292] In some embodiments, disclosed compounds are used to treat a pain disorder. In some embodiments, disclosed compounds are administered in a therapeutically effective amount to a subject having a pain disorder, thereby treating said disorder. In embodiments, disclosed compounds and compositions are used to reduce the symptoms of a pain disorder.

[0529]

[0293] A “pain disorder” refers to a class of medical conditions characterized by the experience of persistent2026-03-18 or recurrent physical or psychological pain, either localized or widespread, that significantly impairs an individual’s daily functioning and quality of life. These disorders may involve various etiologies, including nociceptive, neuropathic, psychogenic, idiopathic or radicular origins.

[0530]

[0294] Disclosed compounds are useful in some embodiments to treat neuropathic pain. In embodiments, a compound is used to treat psychogenic pain. In embodiments, a compound is used to treat idiopathic pain. In embodiments, a compound is used to treat radicular pain.

[0531]

[0295] Pain disorders may manifest as acute or chronic pain, and they can affect different parts of the body, such as musculoskeletal, neurological, gastrointestinal, or visceral systems. Pain can be expressed as, but is not limited to, post-herpetic pain, trigeminal pain, occipital pain, or pudendal pain. In embodiments, a disclosed compound is used to treat pain associated with chemotherapy (e.g., chemotherapy associated neuropathy). In embodiments, a compound is used to treat arthritis, back pain, central pain, chronic fatigue syndrome, cluster headaches, migraine headaches, phantom limb pain, complex regional pain syndrome, compression mononeuropathy, diabetic neuropathy, fibromyalgia, focal neuropathy, herniated disc pain, or sciatica.

[0532]

[0296] Pain may be assessed using the Pain, Enjoyment, and General Activity Scale (PEG), the Numeric Rating Scale (NRS), the Visual Analog Scale (VAS), Behavioral Pain Scale (BPS), and the Faces Pain Scale-Revised (FPS-R).

[0533] iv. Inflammatory Disorders

[0534]

[0297] Disclosed compounds are useful in some embodiments to treat an inflammatory condition. Without being bound by theory, certain 5-HT2A receptor agonists have demonstrated anti-inflammatory activity, including suppression of TNF-a-induced inflammation and inhibition of pro-inflammatory gene expression (see, e.g., Yu et al., J Pharmacol Exp Then, 2008; 327:316-323; Nau et al., PLoS One, 2013; 8(10):e75426; Flanagan & Nichols, Inf Rev Psychiatry, 2018; 30(4):363— 375; Flanagan et a\., ACS Pharmacol Transl Sci., 2024; 7(2):478— 492; Nichols, Neuropharmacol., 2022; 219:109232). In embodiments, a disclosed compound suppresses pro-inflammatory markers while leaving the broader immune response substantially intact.

[0535]

[0298] In some embodiments, a disclosed compound has anti-inflammatory activity. In some embodiments, a disclosed compound modulates specific inflammation mediators. In embodiments, administration of a disclosed compound reduces inflammation in chronically inflamed tissue. In embodiments, the anti-inflammatory effect is exerted without broadly suppressing the immune system. In embodiments, a disclosed compound is useful to treat inflammatory disease in contexts where steroids are contraindicated or the condition is steroid resistant.

[0536]

[0299] In some embodiments, administration of a disclosed compound decreases an inflammatory response. In embodiments, the inflammatory response is quantified by a change in the level of an inflammation response biomarker. In embodiments, the level of an inflammation response biomarker represents the expression level of an inflammation response gene. In embodiments, the level of an inflammation response biomarker is compared to a baseline level of the same biomarker. In embodiments, increased expression of an inflammation response gene is associated with chronic inflammation. In embodiments, decreased expression of an inflammation2026-03-18 response gene is associated with chronic inflammation.

[0537]

[0300] In some embodiments, a disclosed compound exhibits potent anti-inflammatory properties. In some embodiments, administration of a disclosed compound suppresses several pro-inflammatory markers (e.g., mRNA encoding IL6, IL1b, GMCSF, Arg1, and IL5). In some embodiments, administration of a disclosed compound suppresses pro-inflammatory markers to baseline levels. Without being bound by theory, disclosed compounds may exert their anti-inflammatory effects due to functional selectivity at the 5-HT2A receptor, whereby the compound engages certain amino acid residues within receptor, stabilizing it in a conformation that triggers anti-inflammatory signal transduction pathway effectors.

[0538]

[0301] In some embodiments, the biomarker of inflammation response gene expression is mRNA. In some embodiments, the biomarker of inflammation response gene expression is a protein. In some embodiments, the inflammation response gene is, or encodes, TNFa, Arg-1, IL-4, IL-5, IL-6, IL-8, IL-9, IL-1[3, ll-IA, IL-12, IL-13, IFNa, IFNb, IFNg, TGF- / 3, IL-15, IL-17, IL-20, IL-22, LTA, IL-23, IL-18, VCAM1, ICAM1, MCP1 (CSF2), MMP-9, Muc5ac, Gm-csf, CCL2, CCL5, CCL3, CCL4, CCL11, CD11a (ITGAL), CD3 (CD3D, CD3E, CD3G, CD3Z), CD4, CD8 (CD8A, CD8B), or CRP. In some embodiments, the inflammation response gene encodes an inflammatory agent. An inflammatory agent is a protein that activates an inflammatory response. Inflammatory agents include, for example, the proteins IL-1 p, TNFa, IL-15, IL-17, Arg-1, and IL-18. In some embodiments, the inflammation response gene encodes an anti-inflammatory agent. An anti-inflammatory agent is a protein that reduces an inflammatory response. Anti-inflammatory agents include, for example, the proteins IL-1, IL-4, IL-10, IL-11, and IL-13. In some embodiments, the inflammation response gene encodes an agent that may be inflammatory or anti-inflammatory. For example, leukemia inhibitory factor, interferon-alpha, IL-6, and transforming growth factor (TGF- ) can act as either inflammatory or anti-inflammatory cytokines under various circumstances (Zhang & An. Int Anesthesiol Clin. 2007; 45(2): 27-37).

[0539]

[0302] In some embodiments, the inflammation response gene is one or more of ICAM1 , VCAM1, CCL2, IL-5, IL-6, IL-9, IL-15, IL-1 p, Arg-1, Gm-csf, Muc5ac, MMP-9, or TGF- . In some embodiments, the biomarker of inflammation response is a gene product of any of the foregoing. In some embodiments, the biomarker is mRNA. In some embodiments, the biomarker is protein.

[0540]

[0303] In some embodiments, the inflammation response biomarker is a cytokine. In embodiments, the cytokine biomarker is IL-2, IFN-y, TNFa, TNFp, GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17, IL-25, IL-33, or TGF-p. In embodiments, the inflammation response biomarker is a chemokine. In embodiments, the chemokine biomarker is CCL-1 to CCL-28, CXCL-1 to CXCL-16, IL-8, MCP1, RANTES, XCL1, XCL2, or CX3CLI. In embodiments, the inflammation response biomarker is an enzyme. In embodiments, the enzyme biomarker is Arg-1. In embodiments, the biomarker of inflammation for a particular inflammatory disease, comorbidity, or patient demographic will be known in view of the art (e.g., Sreedhar et al. General Mechanisms of Immunity and Inflammation, in Watanabe & Arumugam eds. Acad Press; 2017; Germolec et al. Methods Mol Biol. 2018; 1803: 57-79; Calder et al. BrJNutr. 2013; 109 Suppl 1: S1-34).2026-03-18

[0304] In some embodiments, a disclosed compound causes the level of an inflammation response biomarker in a subject to become closer to a baseline level. “Baseline level” refers to the level of a biomarker observed in healthy populations not experiencing inflammation. Baseline levels differ among biomarkers and can be measured by available techniques (Calder et al. Br J Nutr. 2013; 109 Suppl 1 :S1 -34).

[0541]

[0305] In some embodiments, a disclosed compound (e.g., administration of a disclosed compound to a subject, such as in a disclosed pharmaceutical composition, and / or such as according to a disclosed method) reduces the level of an inflammatory biomarker. In embodiments, a compound does not reduce the level of an inflammatory biomarker below baseline. In embodiments, a compound reduces the level of an inflammatory biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In embodiments, a disclosed compound reduces the level of an inflammatory biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) to within about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of its baseline level. In embodiments, a disclosed compound decreases the concentration of one or more inflammatory biomarkers in a sample by about 100 pg / mL, 90 pg / mL, 80 pg / mL, 70 pg / mL, 60 pg / mL, 50 pg / mL, 40pg / mL, 30 pg / mL, 20 pg / mL, 10 pg / mL, 5 pg / mL, or 1 pg / mL. In embodiments, the sample is a tissue sample. In embodiments, the sample is a blood sample. In embodiments, the sample is a plasma sample.

[0542]

[0306] In some embodiments, a disclosed compound increases the level of an anti-inflammatory biomarker. In embodiments, a compound does not increase the level of a pro-inflammation biomarker above baseline. In embodiments, a compound increases the level of a pro-inflammation biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In embodiments, a compound increases the concentration of one or more anti-inflammatory biomarkers in a sample by about 100 pg / mL, 90 pg / mL, 80 pg / mL, 70 pg / mL, 60 pg / mL, 50 pg / mL, 40pg / mL, 30 pg / mL, 20 pg / mL, 10 pg / mL, 5 pg / mL, or 1 pg / mL. In embodiments, the sample is a tissue sample. In embodiments, the sample is a blood sample. In embodiments, the same is a plasma sample.

[0543]

[0307] In some embodiments, the dosage of a disclosed compound used to elicit an anti-inflammatory effect is sub-behavioral. In some embodiments, a disclosed compound is used to elicit an anti-inflammatory effect at dosage between about 0.001 and 0.01 mg / kg, between about 0.01 and 0.05 mg / kg, between about 0.05 mg / kg and 0.1 mg / kg, between about 0.1 mg / kg and 0.2 mg / kg, between about 0.4 mg / kg and 0.3 mg / kg, between about 0.3 mg / kg and 0.4 mg / kg, or between about 0.4 mg / kg and 0.5 mg / kg. In embodiments, administration of a disclosed compound at greater than 0.5 mg / kg is sub-behavioral, e.g., without hallucinogenic effects.

[0544]

[0308] Disclosed compounds are useful in some embodiments to treat an inflammatory condition. In embodiments, a disclosed compound is used to reduce inflammation. In embodiments, a disclosed compound is used in the manufacture of a medicament to treat an inflammatory condition or to reduce inflammation.

[0545]

[0309] In some embodiments, the inflammatory condition is an acute inflammatory disorder. In some embodiments, the inflammatory condition is a chronic inflammatory disorder. In some embodiments, the2026-03-18 inflammatory condition is asthma, chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, septicemia, conjunctivitis, Alzheimer’s disease, or another inflammatory condition described herein.

[0546]

[0310] Disclosed compounds are useful in some embodiments for treating an inflammatory condition in patients with autoimmune disorders or otherwise compromised immune systems. For example, a disclosed compound is useful for treating chronic inflammation in patients with type 1 diabetes, type 2 diabetes, multiple sclerosis, lupus, rheumatoid arthritis, psoriatic arthritis, reactive arthritis, Addison disease, Celiac disease, autoimmune encephalitis, gout, vasculitis, mixed connective tissue disease, undifferentiated connective tissue disease, myositis, scleroderma, Sjogren’s syndrome, uveitis, inflammatory bowel disease (IBD), Guillain-Barre syndrome, psoriasis, Grave’s disease, scleroderma (systemic sclerosis), dermatomyositis, Hashimoto thyroiditis, pernicious anemia, Alzheimer’s disease, heart disease, cardiovascular disease, chronic hepatic and renal disease, fibromyalgia, allergies, or chronic obstructive pulmonary disease. In embodiments, a disclosed compound is useful for treating chronic inflammation in an immunocompromised chemotherapy patient.

[0547]

[0311] Disclosed compounds are useful in some embodiments for treating an inflammatory condition in patients with a steroid-resistant disease or disorder. In some embodiments, the steroid-resistant disease or disorder is steroid resistant nephrotic syndrome (SRNS), steroid-resistant inflammatory bowel syndrome (IBS), steroid-resistant asthma, steroid-resistant acute graft-versus-host disease, steroid-resistant ulcerative colitis, steroid-resistant Crohn’s disease, steroid-resistant chronic obstructive pulmonary disease (COPD), steroid-resistant pulmonary fibrosis, steroid-resistant leukemias, steroid-resistant rheumatoid arthritis, or steroid-resistant idiopathic nephrosis.

[0548]

[0312] Disclosed compounds are useful in some embodiments for treating an inflammatory condition in a patient with a contraindication to a corticosteroid. Contraindications to corticosteroids can occur, for example, because of hypersensitivity to any component of a corticosteroid formulation, concurrent administration of live or live-attenuated vaccines (e.g., when using immunosuppressive doses), systemic fungal infection, osteoporosis, uncontrolled hyperglycemia, adrenal suppression, Cushing syndrome, diabetes mellitus, glaucoma, cataracts, joint infection, uncontrolled hypertension, herpes simplex keratitis, myopathy, certain psychiatric disturbances and / or disorders, and varicella infection. Additional exemplary contraindications include peptic ulcer disease, congestive heart failure, and viral or bacterial infections not controlled by anti-infective or antibacterial agents.

[0549]

[0313] Disclosed compounds are useful in embodiments for treating 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, ocular inflammation, or brain inflammation.

[0550]

[0314] In some embodiments, the inflammatory condition is a dermatological inflammatory disorder. Dermatological inflammatory disorders include dermatitis and related conditions, wherein the dermatitis is any2026-03-18 of atopic dermatitis, chronic photosensitivity dermatitis, eczema, atopic eczema, contact eczema, dryness eczema, seborrheic eczema, discoid eczema, varicose eczema, venous eczema, herpetic dermatitis, neurodermatitis, autosensitizing dermatitis, stasis dermatitis, purulent dermatitis, dyshidrotic eczema, follicular eczema, spongiotic dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, lichen planus, or lichen planus-like atopic dermatitis; and further including acne vulgaris, sweating disorders, pemphigus vulgaris, psoriasis, or rosacea; wherein psoriasis is any of psoriasis vulgaris, nail psoriasis, scalp psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, or psoriatic arthritis; and further including scleroderma, including morphea, and vulvitis. In some embodiments, the inflammatory condition is a dermatitis disorder relating to chronic skin inflammation due to skin barrier dysfunction or abnormal inflammatory response. In embodiments, the dermatitis disorder involves redness, persistent itching, and dry skin. In embodiments, the dermatitis disorder involves an inflammatory pathway relating to any of CCL17, CCL18, CCL22, CCL27, IL-4, IL-13, IL-17A, IL-18, IL-19, IL-22, IL-26, IL-33, MMP12, and Th2

[0551]

[0315] In some embodiments, the inflammatory condition is pharmacologically or chemically induced inflammation, such as inflammation induced by legal or illegal drugs, toxins, or environmental chemicals.

[0552]

[0316] In some embodiments, the inflammatory condition is a neurogenic or autoimmune inflammatory disorder. Neurogenic and autoimmune inflammatory disorders include chronic neurogenic inflammation, primary or secondary neural inflammation, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Huntington's disease, dementia, myelitis, encephalitis, migraine, fibromyalgia, polymyositis, dermatomyositis, lupus nephritis, systemic lupus erythematosus (SLE), relapsing polychondritis, Behcet's disease, inflammatory neuropathy, and long COVID.

[0553]

[0317] In some embodiments, the inflammatory condition is a metabolic or systemic inflammatory disorder. Metabolic and systemic inflammatory disorders include diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, diabetic heart abnormalities, metabolic syndrome (syndrome X), obesity, insulin resistance, non-alcoholic steatohepatitis, anemia, hypertension, ischemia, ischemic heart disease, heart disease, heart valvular dysfunction, congestive heart failure, myocardial infarction, inflammatory heart enlargement, and atherosclerosis.

[0554]

[0318] In some embodiments, the inflammatory condition is a gastrointestinal (Gl) or hepatic inflammatory disorder. Gl and hepatic inflammatory disorders include acid reflux, gastritis, gastroenteritis, ileitis, colitis, enterocolitis, appendicitis, inflammatory bowel disease, such as Crohn's disease, ulcerative colitis (e.g., ulcerative proctitis, left-sided colitis, total colitis, fulminant colitis), proctitis, ulcer, hepatitis, (e.g., viral hepatitis types A, B, and C), cirrhosis, hyperlipidemic pancreatitis, pancreatitis, spastic colon, and celiac disease.

[0555]

[0319] In some embodiments, the inflammatory condition is a renal or urogenital inflammatory disorder. Renal and urogenital inflammatory disorders include nephritis, glomerulonephritis, interstitial nephritis, polycystic nephritis, renal failure, cystitis, including bacterial cystitis, interstitial cystitis, and cyclophosphamide-induced cystitis, urethritis, prostatitis, epididymitis, pelvic inflammatory disease, cervicitis, vaginitis, trigonitis, ovitis,2026-03-18 testitis, endometritis, and salpingitis.

[0556]

[0320] In some embodiments, the inflammatory condition is a cardiovascular and vascular inflammatory disorder. Cardiovascular and vascular inflammatory disorders include endocarditis, myocarditis, pericarditis, carditis, arteritis, phlebitis, thrombophlebitis, vasculitis, including Buerger's disease, cerebral vasculitis, Churg-Strauss arteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell arteritis, Henoch-Schonlein purpura, hypersensitivity vasculitis, Kawasaki disease, microscopic polyarteritis, nodular polyarteritis, rheumatic vasculitis, Takayasu arteritis, and Wegener's granulomatosis, as well as arteriosclerosis, stenosis, peripheral arterial disease, aneurysm, embolism, pseudoaneurysm, vascular malformation, thrombosis, varicose veins, reperfusion injury, stroke, cardiac arrest, and rheumatic fever.

[0557]

[0321] In some embodiments, the inflammatory condition is an infectious or infection-associated inflammatory condition. Infectious and infection-associated inflammatory conditions include lymphangitis, lymphadenitis, bacterial encephalitis, viral encephalitis, pandemic influenza, sepsis, including bacteremia and viremia, tuberculosis, cellulitis, cholangitis, cholecystitis, chorioamnionitis, mastitis, Whipple disease, and graft rejection, including graft-versus-host disease (GVHD).

[0558]

[0322] In some embodiments, the inflammatory condition is a musculoskeletal or connective tissue inflammatory disorder. Musculoskeletal and connective tissue inflammatory disorders include arthritis, (e.g., osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis), spondyloarthropathy such as ankylosing spondylitis, reactive arthritis (Reiter syndrome), psoriatic arthritis, enteroarthritis associated with inflammatory bowel disease, septic arthritis, gout, pseudogout (calcium pyrophosphate deposition disease), and Still's disease; wherein arthritis may affect a single joint (monoarthritis), two to four joints (oligoarthritis), or five or more joints (polyarthritis); as well as fasciitis, tendonitis, synovitis, bursitis, epicondylitis, osteochondritis, osteomyelitis, osteopenia, osteoporosis, polymyalgia rheumatica (PMR), and connective tissue inflammation.

[0559]

[0323] In some embodiments, the inflammatory condition is an ocular, oral, or ENT inflammatory disorder. Ocular, oral, and ENT inflammatory disorders include keratitis, keratoconjunctivitis, conjunctivitis, iritis, uveitis, blepharitis, retinitis, age-related macular degeneration (AMD), glossitis, gingivitis, stomatitis, pulpitis, sinusitis, rhinitis, allergic rhinitis, tonsillitis, laryngitis, pharyngitis, mastoiditis, otitis, and lacrimal inflammation.

[0560]

[0324] In some embodiments, the inflammatory condition is a pulmonary or thoracic inflammatory disorder. Pulmonary and thoracic inflammatory disorders include asthma, chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, bronchiolitis, interstitial pneumonia, pleurisy, cystic fibrosis, and sarcoidosis.

[0561]

[0325] In some embodiments, the inflammatory condition is an allergic inflammatory condition. Allergic inflammatory conditions include allergies, food allergies, allergic rhinitis, and bullous pemphigoid.

[0562]

[0326] In some embodiments, the inflammatory condition is a neoplastic or immune-mediated inflammatory condition. Neoplastic and immune-mediated inflammatory conditions include NF-kB-induced inflammatory cancer, Th1 -mediated inflammatory disease, and balanitis.

[0563]

[0327] In some embodiments, the inflammatory condition is generalized or trauma-associated inflammation,2026-03-18 such as trauma, traumatic brain injury (TBI), burns, inflammation associated with surgical complications, and nonspecific inflammatory responses.

[0564]

[0328] In some embodiments, a reduction in inflammation is measured by detecting a change in an inflammatory biomarker in a biological specimen, such as blood, plasma, serum, or saliva. In embodiments, the biomarker is high-sensitivity C-reactive protein (CRP) or white blood cell count. In some embodiments, the biomarker is salivary CRP (see, e.g., Szabo & Slavish, Psychoneuroendocrin., 2021; 124:105069). In some embodiments, inflammation is assessed using clinical pathology data, including hematology, coagulation, and clinical chemistry parameters (see, e.g., Germolec et al., Methods Mol Biol., 2018; 1803:57-79).

[0565] v. Ophthalmic Diseases and Disorders

[0566]

[0329] In some embodiments, a compound is used to treat an ophthalmic disease or disorder. Ophthalmic diseases and disorders often result from infection and / or inflammation of ocular tissue, and are the leading cause of corneal blindness and visual morbidity worldwide (Bourne et al. Lancet Glob Health. 2013; 1(6): e339-49). Repeated episodes of infection or inflammation triggers a chronic inflammatory disease process that can result in vascularization and subsequent vision threatening scarring of the cornea (Vaidyanathan et al. Med Hypothesis Discov Innov Ophthalmol. 2019; 8(3): 163-176). Corticosteroids are often used to control the ophthalmic inflammatory response, however, this treatment is immunosuppressive and can result in uncontrolled pathogen replication, loss of an intact corneal epithelial barrier, increased ocular pressure and eventual deterioration of vision (Fung et al. Clin Exp Ophthalmol. 2020; 48(3): 366-401). By contrast, modulation with 5-HT receptor agonists is shown to have anti-inflammatory and anti-vascularization properties, and the ability to decrease ophthalmic pressure (Foster et al. Invest Ophthalmol Vis Sci. 2020; 61 (7): 429).

[0567]

[0330] Disclosed compounds are useful in some embodiments to reduce, or ameliorate, or prevent an ophthalmic disease or disorder, non-limiting examples of which are described herein.

[0568]

[0331] In some embodiments, administration of a disclosed compound reduces intraocular pressure in a subject. In some embodiments, a disclosed compound is used to treat ocular hypertension.

[0569]

[0332] The range for normal intraocular pressure is generally considered to be between 10 and 21 mmHg. This pressure is primarily determined by the balance between how much aqueous humour is produced in the eye and how much is drained away. Factors such as the thickness and stiffness of the cornea also play a role in influencing this pressure. Typically, intraocular pressure averages around 15 to 16 mmHg, with potential variations of up to 6 mmHg. For instance, during nighttime, this pressure often drops due to reduced aqueous humour production. Moreover, intraocular pressure can change in response to several physiological factors, including exercise, heart rate, breathing, fluid consumption, and the use of certain systemic or topical medications. Elevated intraocular pressure can lead to optic nerve damage, a condition known as glaucoma. If there’s no optic nerve damage, the term ocular hypertension is used. Various factors can contribute to increased intraocular pressure, including conditions like orbital swelling, traumatic hyphema, blockage in the pupil, retained surgical materials, inflammation within the eye, or the use of corticosteroids. High intraocular pressure is a2026-03-18 significant risk factor for glaucoma, and conversely, glaucoma frequently involves an increase in intraocular pressure. Symptoms that may arise from elevated intraocular pressure or from a combination of glaucoma and increased pressure include optic nerve damage, bleeding of the optic disc, defects in the nerve fiber layer, notching, a vertically elongated cup, uneven or progressive enlargement of the optic cup, diminished field of vision, seeing halos, blurry vision, and eye discomfort, among others.

[0570]

[0333] Disclosed compounds are useful in some embodiments to treat glaucoma. In some embodiments, the glaucoma is open-angle glaucoma, normal-tension glaucoma, angle-closure glaucoma, congenital glaucoma, neovascular glaucoma, pigmentary glaucoma, exfoliation glaucoma, uveitic glaucoma, or glaucoma caused by another factor (e.g., cataracts, tumors, eye injury).

[0571]

[0334] Disclosed compounds are useful in some embodiments to treat allergic conjunctivitis, including vernal keratoconjunctivitis and atopic keratoconjunctivitis; dry eye syndrome and meibomian gland dysfunction; cataracts; keratoconus; bullous and other keratopathy; Fuch’s endothelial dystrophy; ocular cicatricial pemphigoid; conditions associated with photoreactive keratotomy (PRK) healing and other corneal healing; conditions associated with tear lipid degradation or lacrimal gland dysfunction; uveitis, including anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, non-infectious uveitis, and infectious uveitis; keratitis; scleritis; iritis; cyclitis; ocular graft versus host disease; optic neuritis; ocular Stevens Johnson Syndrome; blepharitis; ocular rosacea, with or without meibomian gland dysfunction; post cataract; persistent corneal erosion; and inflammation associated with corneal trauma, corneal transplantation, and refractive surgery.

[0572]

[0335] In some embodiments, the ophthalmic disease or disorder is an inflammatory disorder. In some embodiments, the ophthalmic disease or disorder is macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis, conjunctivitis, keratitis, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber’s disease, retinal detachment, retinal pigment epithelial detachment, rubeosis iridis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinochoroidal neovascularization, or a combination thereof.

[0573]

[0336] In some embodiments, the ophthalmic disease is macular degeneration. In embodiments, the ophthalmic disease is keratoconjunctivitis. In embodiments, the ophthalmic disease is conjunctivitis. In embodiments, the ophthalmic disease is keratitis. In embodiments, the ophthalmic disease is diabetic retinopathy. In embodiments, the ophthalmic disease is retinopathy of prematurity. In embodiments, the ophthalmic disease is polypoidal choroidal vasculopathy. In embodiments, the ophthalmic disease is ischemic proliferative retinopathy. In embodiments, the ophthalmic disease is retinitis pigmentosa. In embodiments, the ophthalmic disease is cone dystrophy. In embodiments, the ophthalmic disease is proliferative vitreoretinopathy. In embodiments, the ophthalmic disease is retinal artery occlusion. In embodiments, the ophthalmic disease is retinal vein occlusion. In embodiments, the ophthalmic disease is Leber’s disease. In embodiments, the ophthalmic disease is retinal detachment. In embodiments, the ophthalmic disease is retinal pigment epithelial2026-03-18 detachment. In embodiments, the ophthalmic disease is rubeosis iridis. In embodiments, the ophthalmic disease is corneal neovascularization. In embodiments, the ophthalmic disease is retinal neovascularization. In embodiments, the ophthalmic disease is choroidal neovascularization. In embodiments, the ophthalmic disease is retinochoroidal neovascularization.

[0574] vi. Other Administration Considerations

[0575]

[0337] In some embodiments, such as when administered to a subject for the treatment of a mental health disorder, a disclosed compound is administered together with therapy. “Therapy” herein is intended to be understood broadly, and includes psychotherapy, such as psychosocial or behavioral therapy, e.g., any of (or adapted from any of) cognitive behavioral therapy (e.g., as in Crits-Christoph et al. Arch Gen Psychiatry. 1999; 56(6): 493-502), interpersonal therapy (e.g., as in Barry et al. Psychol Addict Behav. 2009; 23(1): 168-174), contingency management based therapy (e.g., as in Barry et al. Psychol Addict Behav. 2009; 23(1): 168-174; in Petry et al. J Consult Clin Psychol. 2005; 73(2): 354-359.; or in Adams et al. Case Reports in Psychiatry.

[0576] 2012; 2012: Article ID 731638), motivational interviewing based therapy (e.g., as in Stotts et al. J Consult Clin Psychol. 2001 ; 69(5): 858-862), meditation based therapy, such as transcendental meditation based therapy (e.g., as in Rohsenow et al. J Consult Clin Psychol. 2000;68(3):515-520), or a therapeutic approach such as used by the Multidisciplinary Association for Psychedelic Studies (MAPS) (e.g., as in Mithoefer. Manual for MDMA-Assisted Psychotherapy in the Treatment of Post-traumatic Stress Disorder. 7th ed. Multidisciplinary Association for Psychedelic Studies; 2015) (see also, e.g., Schenberg. Front Pharmacol. 2018; 9: 733; Johnson et al. J Psychopharmacol. 2008; 22(6): 603-620). Therapy may be conducted periodically, such as more than once a week, every about one week, every about two weeks, every about three weeks, and the like.

[0577]

[0338] In embodiments, a compound is administered together with standardized psychological treatment or support, including any modality of psychotherapy or counseling, including both in person and virtual sessions, and including sessions involving a human therapist as well as a virtual or artificial intelligence (Al) “therapist.”

[0339] In some embodiments, disclosed compounds are administered together with the subject performing or participating in one or more therapeutically beneficial activities, such as breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and the like.

[0578]

[0340] Disclosed compounds in some embodiments are administered without or with reduced risk of side effects that would require supervision or monitoring, and thus do not require such supervision or monitoring.

[0579]

[0341] A disclosed compound may be administered to a subject if the subject meets certain or all inclusion criteria, does not meet certain or all exclusion criteria, does not meet certain or all withdrawal criteria, and / or satisfies one or more other limitations of a disclosed or claimed embodiment, such as a method of use.

[0580]

[0342] In embodiments, a personalized approach (i.e., “personalized” or “precision” medicine) may be utilized, based on individual characteristics, including drug metabolism (e.g., CYP2D6 or CYP3A4) or individual genetic variation. The term “genetic variation” refers to a change in a gene sequence relative to a reference sequence2026-03-18 (e.g., a commonly-found and / or wild-type sequence). Genetic variation may be recombin- ation events or mutations such as substitution / deletion / insertion events like point and splice site mutations.

[0581]

[0343] In embodiments, the genetic variation is a genetic variation in one or more cytochrome P450 (CYP or CYP450) enzymes that affects drug metabolism, such as of a disclosed compound, e.g., CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5. Other CYP enzymes include CYP1A1, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0582]

[0344] In embodiments, a disclosed compound is taken together with a second 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 compound is adjusted, such as reduced, when administered to a subject known to be a poor metabolizer of the compound, or increased when administered to a subject known to be a rapid metabolizer. In embodiments, a subject is tested to determine if the subject is a poor or a rapid metabolizer.

[0583]

[0345] In some embodiments, the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which has been implicated in mood and anxiety symptoms in humans. In embodiments, the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs. The FKBP5 gene is associated with responses to stress and trauma, and such SNPs are correlated with susceptibility to PTSD and depressive and anxiety disorders. In embodiments, a genetic variation is an inclusion criteria for administration of a compound. In embodiments, a genetic variation is an exclusion criteria for administration of a compound.

[0584]

[0346] In some embodiments, the subject being treated, i.e., being administered a disclosed compound, has altered epigenetic regulation of a gene, the expression of which is associated with a mental health condition or susceptibility to a mental health treatment, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.

[0585] J. Examples

[0586]

[0347] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0587] EXAMPLE 1: Synthesis of 4-(2-aminoethyl)-7-isobutyl-1,3-dihydroisobenzofuran-5-ol HCI

[0588]

[0589] 1 2 3 42026-03-18

[0590]

[0591] 9 Step 1: Methyl 3-bromo-5-methoxy-2-methylbenzoate (2)

[0592]

[0348] A solution of 1,3-dibromo-5-methoxy-2-methyl-benzene (Solution 1,

[0593]

[0594] (2000mL) was delivered by Pump 1 (P1) at a rate of 47.192 mL / min to flow reactor 1 (FLR1) which consisted of a PFA static mixer (1mL) and PFA coil reactor (3.175 mm, 4.274mL), maintained at -60°C. A solution of n-BuLi (Solution 2, 1.1 eq, 25.17 g, 1.6 M, 245.35 mL, 11.92%) was delivered by Pump 2 (P2) at a flow rate of 5.548 mL / min to FLR1. The residence time of FLR1 was 0.1 min. The mixture was collected with a bottle which contained CO2 (10 eq). P1 and P2 were started simultaneously and collected after running 0.1 mins. After completion, the mixture was quenched by sat. aq. NH4CI (500 mL) solution. The reaction mixture was partitioned between H2O (100 mL) and DCM (1000 mL). The organic phase was separated, washed with brine (500 mL x 2), dried over Na2SC , filtered, and concentrated under reduced pressure to give a residue. Compound 3-bromo-5-methoxy-2-methyl-benzoic acid (75 g, crude) was obtained as a white solid. Then to a solution of 3-bromo-5-methoxy-2-methyl-benzoic acid (65 g, 265.23 mmol, 1 eq) in MeOH (650 mL) was added H2SO4 (35.60 g, 362.93 mmol, 19.35 mL, 1.37 eq) at 20°C. The mixture was stirred at 70 °C for 12 h. The crude reaction mixture from an independent 10 g scale run was combined with the crude reaction mixture from a separate 65 g scale run for workup. The mixture was concentrated under reduced pressure to give a residue. The residue was partitioned between H2O (200 mL) and MTBE (400 mL). The organic phase was separated, washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound methyl 3-bromo-5-methoxy-2-methyl-benzoate (73 g, crude) was obtained as a white solid.

[0595] Step 2: Methyl 3-bromo-2-(bromomethyl)-5-methoxybenzoate (3)

[0596]

[0349] To a solution of methyl 3-bromo-5-methoxy-2-methyl-benzoate (60 g, 231.57 mmol, 1 eq) in DCE (1.8 L) was add NBS (45.34 g, 254.73 mmol, 1.1 eq). The solution 1 was delivered by P1 at a rate of 1.005 mL / min into FLR1, which comprised a fluorinated ethylene propylene (FEP) coil reactor (3.175 mm, 10.048 mL, 450 nm, 600 W) maintained at 40°C. The residence time of flow reactor 1 was 4 hr. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound methyl 3-Br-2-(Br-methyl)-5-MeO-benzoate (80 g, crude) was obtained as a white solid.

[0597] Step 3: 3-bromo-2-(hydroxymethyl)-5-methoxybenzoic acid (4)2026-03-18

[0350] A solution of methyl 3-bromo-2-(bromomethyl)-5-methoxy-benzoate (80 g, 236.69 mmol, 1 eq) and NaOH (2 M, 800.06 mL, 6.76 eq) in dioxane (800 mL) and H2O (800 mL) was stirred at 20 °C for 12 hr. The reaction mixture was diluted with HCI (2M, 500 mL) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. Compound 3-bromo-2-(hydroxymethyl)-5-methoxy-benzoic acid (60 g, crude) was obtained as a Colorless oil.1H NMR (400 MHz, DMSO-de) 6 ppm 7.61 (d, J = 2.15 Hz, 1 H) 7.37 (d, J = 2.15 Hz, 1 H) 5.27 (s, 2 H) 3.87 (s, 3 H).

[0598] Step 4: 3-bromo-2-(hydroxymethyl)-5-methoxy-phenyl]methanol (5)

[0599]

[0351] To a solution of 3-bromo-2-(hydroxymethyl)-5-methoxy-benzoic acid (60 g, 229.82 mmol, 1 eq) in THF (1200 mL) was added BH3-Me2S (10 M, 229.82 mL, 10 eq) at 0°C under N2. The mixture was stirred at 50 °C for 12 hours under N2 atmosphere. The reaction mixture was quenched by addition MeOH (1 L) at 0 °C, after which the mixture was stirred at 70 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove MeOH and THF. The residue was diluted with H2O (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate=1 / 0 to 1 / 1). Compound [3-bromo-2-(hydroxy- methyl)-5-methoxy-phenyl]methanol (25 g, 101.18 mmol, 44.02% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-de) 6 ppm 7.04 (q, J = 2.51 Hz, 2 H) 5.28 (t, J = 5.58 Hz, 1 H) 4.85 (t, J = 5.27 Hz, 1 H) 4.66 (d, J = 5.65 Hz, 2 H) 4.55 (d, J = 5.14 Hz, 2 H) 3.76 (s, 3 H) 1.17 (s, 1 H).

[0600] Step 5: 4-bromo-6-methoxy-1,3-dihydroisobenzofuran (6)

[0601]

[0352] To a solution of [3-bromo-2-(hydroxymethyl)-5-methoxy-phenyl]methanol (23 g, 93.09 mmol, 1 eq) in DMA (460 mL) was added NaH (9.31 g, 232.71 mmol, 60% purity, 2.5 eq) at 0°C for 30 min under N2 atmosphere, and then was added trimethyl phosphite (28.87 g, 232.71 mmol, 27.50 mL, 2.5 eq) to above solution at 0 °C under N2 atmosphere. The mixture was stirred at 20 °C for 3 h under N2 atmosphere. The reaction mixture was quenched by addition NH4CI (100 mL) at 0 °C, and then diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was combined with a separate 2 g scale batch for purification. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min). Compound 4-bromo-6-methoxy-1,3-dihydroisobenzofuran (12 g, 51.86 mmol, 45.17% yield, 99% purity) was obtained as a white solid.1H NMR (400 MHz, DMSO-de) 6 ppm 7.05 (d, J = 1.67 Hz, 1 H) 6.92 (s, 1 H) 5.07 (s, 2 H) 4.90 (s, 2 H) 3.77 (s, 3 H).

[0602] Step 6: 4-isobutyl-6-methoxy-1 ,3-dihydroisobenzofuran (7)

[0603]

[0353] A mixture of 4-bromo-6-methoxy-1,3-dihydroisobenzofuran (12 g, 52.39 mmol, 1 eq), isobutyl boronic acid (8.01 g, 78.58 mmol, 1.5 eq), CS2CO3 (51.20 g, 157.16 mmol, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (2.14 g, 2.622026-03-18 mmol, 0.05 eq) in Tol. (120 mL) and H2O (12 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 1 hour under N2 atmosphere. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (50 mL). The organic phase was separated, washed with brine (40 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 100 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min). Compound 4-isobutyl-6-methoxy-1 ,3-dihydro- isobenzofuran (9.5 g, 45.13 mmol, 86.15% yield, 98% purity) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) 5 ppm 6.72 (s, 1 H) 6.61 (d, J=1.88 Hz, 1 H) 4.88 - 5.02 (m, 4 H) 3.73 (s, 3 H) 2.33 (d, J=7.25 Hz, 2 H) 1.82 (dquin, J=13.59, 6.79, 6.79, 6.79, 6.79 Hz, 1 H) 0.87 (d, J=6.63 Hz, 6 H).

[0604] Step 7: 4-iodo-7-isobutyl-5-methoxy-1 ,3-dihydroisobenzofuran (8)

[0605]

[0354] To a solution of 4-isobutyl-6-methoxy-1 ,3-dihydroisobenzofuran (5 g, 24.24 mmol, 1 eq) and I2 (6.15 g, 24.24 mmol, 4.88 mL, 1 eq) in EtOH (80 mL) was added AgOTf (6.85 g, 26.66 mmol, 1.1 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 20 °C for 1 hour under N2. The reaction mixture was concentrated by vacuum to remove the EtOH and then diluted by H2O (100 mL) and MTBE (150 mL). The organic phase was separated, washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Commercial hexanes gradient @ 50 mL / min). Compound 4-iodo-7-isobutyl-5-methoxy-1 ,3-dihydroisobenzofuran (5.1 g, 14.13 mmol, 58.27% yield, 92% purity) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) 5 ppm 6.67 (s, 1 H) 5.11 (s, 2 H) 4.85 (s, 2 H) 3.82 (s, 3 H) 2.34 (br d, J = 7.25 Hz, 2 H) 1.84 (dt, J = 13.45, 6.79 Hz, 1 H) 0.87 (d, J = 6.50 Hz, 6 H).

[0606] Step 8: tert-butyl A / -[2-(7-isobutyl-5-methoxy-1 ,3-dihydroisobenzofuran-4-yl)ethyl]carbamate (9)

[0607]

[0355] A mixture of 4-iodo-7-isobutyl-5-methoxy-1 ,3-dihydroisobenzofuran (3.9 g, 11.74 mmol, 1 eq), potassium;2-(tertbutoxycarbonylamino) ethyl-trifluoro-boranuide (4.42 g, 17.61 mmol, 1.5 eq), CS2CO3 (7.65 g, 23.48 mmol, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(1 -adamantyl)-butyl-phosphane (785.02 mg, 1.17 mmol, 0.1 eq) in dioxane (80 mL) and H2O (8 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 14 hours under N2 atmosphere. The reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0-20% ethylacetate / commercial hexanes gradient @ 100 mL / min). Compound tert-butyl N-[2-(7-isobutyl-5-methoxy-1 ,3-dihydroisobenzofuran-4-yl)ethyl]carbamate (1.5 g, 4.03 mmol, 34.37% yield, 94% purity) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 6.83 (br t, J = 5.72 Hz, 1 H) 6.64 (s, 1 H) 4.95 (br d, J = 12.76 Hz, 4 H) 3.76 (s, 3 H) 3.01 (q, J = 6.52 Hz, 2 H) 2.54 (s, 2 H) 2.31 (d, J = 7.27 Hz, 2 H) 1.82 (dt, J = 13.50, 6.78 Hz, 1 H) 1.35 (s, 8 H) 0.87 (d, J = 6.56 Hz, 6 H).

[0608] Step 9: 4-(2-aminoethyl)-7-isobutyl-1,3-dihydroisobenzofuran-5-ol hydrochloride (Target)2026-03-18

[0356] To a solution of tert-butyl N-[2-(7-isobutyl-5-methoxy-1 ,3-dihydroisobenzofuran -4-yl)ethyl]carbamate (1.5 g, 4.29 mmol, 1 eq) in DCM (40 mL) was dropwise added BBra (2 M, 6.44 mL, 3 eq) at -78 °C. Then the mixture was slowly warmed to 0 °C and stirred at 0 °C for 2 hours under N2 atmosphere. The reaction mixture was added to ice saturated NaHCC solution (50 mL) slowly at 0 °C and the solution was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a crude product. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40mm x 5 pm; mobile phase: [H20(0.04% HCI)-ACN]; gradient: 1 %-40% B over 8.0 min). Compound 4-(2-aminoethyl)-7-isobutyl-1 ,3- dihydroisobenzofuran-5-ol (690 mg, 2.51 mmol, 58.56% yield, 99.01% purity, HCI) was obtained as a white solid.1H NMR (400 MHz, DMSO-cfe) 6 ppm 7.27 - 8.38 (m, 3 H) 6.55 (s, 1 H) 5.00 (s, 2 H) 4.92 (s, 2 H) 2.80 - 2.97 (m, 2 H) 2.64 - 2.73 (m, 2 H) 2.25 (d, J=7.21 Hz, 2 H) 1.75 (dquin, J = 13.57, 6.88, 6.88, 6.88, 6.88 Hz, 1 H) 0.86 (d, J=6.60 Hz, 6 H).

[0609] EXAMPLE 2: In Vitro Serotonin Receptor Functional Activity Assays

[0610]

[0364] Purpose: The purpose of this experiment is to evaluate the pharmacological effects of the disclosed compounds on intracellular inositol monophosphate (IP-1) accumulation, as the disclosed compounds target 5-HT2A, 5-HT2B, and 5-HT2C receptors. These receptors are part of the serotonin receptor family, which plays a key role in neuromodulation, mood regulation, and metabolic function. Functional activity at these receptors can be assessed through intracellular second messenger accumulation, which serves as a proxy for receptor activation. The IP-One functional assay provides a reliable and quantitative approach to characterize compound potency and efficacy in modulating serotonin receptor signaling.

[0611]

[0365] Methods (5-HT2A and 5-HT2C IP-One Functional Activity Assays): Intracellular accumulation of IP-1 is measured using an IP-One HTRF assay kit (Cat.# 62IPAPEJ, Cisbio) at WuXi AppTec Co. Ltd. (Hong Kong) Discovery Biology Unit according to their standard protocols. Briefly, the reference compounds and screening compounds are 3.16-fold serially diluted in 100% DMSO for 10 points using Bravo. 70 nL of compounds are added to the assay plate using Echo555. Added 14 pL / 7500 cells / well of 5-HT2A-expressing HEK293 or 5-HT2C-expressing HEK293 to the assay plate and will incubate for 60 min at 37 °C. After incubation, 3 pL of IP-1 d2 Reagent working solution and 3 pL of IP-1 Tb Cryptate Antibody working solution are added to all wells. The plates are incubated for 1 hour at room temperature and are read for fluorescence at 620 nm and 665 nm on an EnVision Multimode Plate Reader (PerkinElmer). The ratio of the acceptor and donor emission signals (665 / 620) are calculated for each individual well and will be substituted into the standard curve to obtain the log concentration of IP level. After converting to the antilog base IP-1, the average background control signal is subtracted from each well and values are normalized to the maximal response of 5-HT at 3 pM (100%). % MAX is calculated by taking the average normalized maximal response for each compound at the highest concentration tested. The data is then analyzed using the four-parameter nonlinear regression curve-fitting function in GraphPad Prism 5 (GraphPad Software, San Diego, CA) to generate potency (EC50) values. The represented plots will show normalized IP-1 values versus compound concentrations; the corresponding2026-03-18 numerical data are parameter estimates for the concentration-response curve using the four-parameter nonlinear regression curve-fitting function in GraphPad Prism 10.

[0612]

[0366] Methods (5-HT?R IP-One Functional Activity Assays): Intracellular accumulation of IP-1 is measured using an IP-One HTRF) assay kit (Cat.# 62IPAPEJ, Cisbio) at WuXi AppTec Co. Ltd. (Hong Kong) Discovery Biology Unit according to their standard protocols. Briefly, 5-HT2B / HEK293 are plated in a 384-well plate and will incubate at 37 °C and 5% CO2 overnight. The reference compounds and screening compounds are 3.16-fold serially diluted in 100% DMSO for 10 points using Bravo. 70 nL of compounds are added to the cell plate using Echo555 and then will incubate for 60 minutes at 37 °C. After incubation, add 3 pL of IP-1 d2 Reagent working solution and 3 pL of IP-1 Tb Cryptate Antibody working solution to all wells. The plates are incubated for 1 hour at room temperature and are read for fluorescence at 620 nm and 665 nm on an EnVision Multimode Plate Reader (Perkin Elmer). The ratio of the acceptor and donor emission signals (665 / 620) are calculated for each individual well and are substituted into the standard curve to obtain the log concentration of IP level. After converting to the antilog base IP-1, the average background control signal is subtracted from each well and values are normalized to the maximal response of 5-HT at 3 pM (100%). % MAX is calculated by taking the average normalized maximal response at the highest concentration tested. Data is analyzed using the four-parameter nonlinear regression curve-fitting function in GraphPad Prism 5 (GraphPad Software, San Diego, CA) to generate potency (EC50) values. Parameter constraint “Top=100” is used in the analysis of 5-HT2B IP-1. Represented plots show normalized IP-1 values versus compound concentrations; the corresponding numerical data are parameter estimates for the concentration-response curve using the four-parameter nonlinear regression curve-fitting function in GraphPad Prism 10. “Top=100” parameter constraint is not enabled for the represented plot analysis.

[0613]

[0367] Results: Administration of a disclosed compound may act as agonists, antagonists, or modulators of 5-HT2A, 5-HT2B, and 5-HT2C receptor activity, as measured by intracellular IP-1 accumulation. These results will demonstrate that the disclosed compounds enhance neurotransmission, support neuroplasticity, and improve CNS function, while also regulating inflammatory pathways to reduce pain and inflammation. Furthermore, results will strengthen the hypothesis that the disclosed compounds support healthy vascular function and reduce neuroinflammation, offering therapeutic benefits for ophthalmic diseases.

[0614] EXAMPLE 3: In Vitro Serotonin Receptor Binding Affinity Assay

[0615]

[0368] Purpose: The purpose of this experiment is to evaluate the binding affinity and selectivity of disclosed compounds for 5-HT2A, 5-HT2B, and 5-HT2C receptors using an in vitro radioligand binding assay. Understanding these interactions will help assess their potential for modulating neurotransmission, neuroplasticity, and treating CNS, pain, and inflammatory disorders.

[0616]

[0369] Methods (5-HT2A, 5-HT2B, and 5-HT2C In Vitro Receptor Binding Assays): Membrane is extracted from 5-HT2A / HEK293, 5-HT2B / HEK293 and 5-HT2c / HEK293 cells. The reference compounds and screening compounds are 4-fold serially diluted in 100% DMSO for 8 points. Transfer 1 pL of serial diluted references and2026-03-18 screening compound to the assay plates. Then add 100 pL / well of membrane and 100 pL / well of radioligand3H-LSD. Incubate at room temperature for 1 hour. Filter the reaction mixture through the GF / C plate using PerkinElmer Filtermate Harvester and wash the plates. Dry the filter plate for 1 hour at 50 °C. Seal the bottom of the filter plate using Perkin Elmer Unifilter-96 backing seal tape. Add 50 pL of Perkin Elmer Microscint 20 cocktail to each well of assay plate and count3H trapped on filter plate using Perkin Elmer MicroBeta2 Reader.

[0617]

[0370] Results: Results will show that compounds bind to 5-HT2A, 2B, and / or 2C receptors with varying affinities, and are selective for different 5-HT receptor subtypes. Results will confirm that compounds have therapeutic applications for CNS disorders, neuroplasticity, pain, and inflammation-related conditions.

[0618] EXAMPLE 4: Calcium Flux Assay

[0619]

[0371] Purpose: The agonist activity of test compounds at 5-HT2A and 5-HT2B receptors was determined using a calcium flux assay.

[0620]

[0372] Methods: Briefly, Human Embryonic Kidney (293T) cells transiently expressing human 5-HT2A receptors or human 5-HT2B receptors were seeded in 200 pL DMEM supplemented with 1% (v / v) dialyzed fetal bovine serum (Gibco, Cat. #A33820-01) onto black 96-well poly-D-lysine coated plates with clear bottoms (40,000 cells / well) and maintained overnight in a humidified atmosphere at 37 °C and 5% CO2. The following day, media was aspirated and replaced with 100 pL HBSS supplemented with 20 mM HEPES (pH 7.4), loaded with 5 pM Fluo-2 AM HA (ION Biosci., San Marcos, TX) and 2.5 mM water-soluble probenecid (Thermo Fisher Sci., Waltham, MA). Plates were incubated for 1 hour at 37 °C, washed once with 100 pL HBSS-HEPES, and maintained in 100 pL HBSS-HEPES supplemented with 2.5 mM water-soluble probenecid. The plates of dye-loaded cells were placed into a FlexStation 3 microplate reader (Molecular Devices, Sunnyvale, CA) set at 37 °C to monitor fluorescence (excitation, 485 nm; emission, 525 nm; cutoff, 515 nm).

[0621]

[0373] Plates were read for 30 s (2 s interval) to establish baseline fluorescence and then administered 50 pL of 2,7-dimethyl-4-hydroxy-DET and read for an additional 120 s. After obtaining a calcium flux trace, the mean baseline fluorescence (F) was subtracted from peak fluorescence (AF) in each well and the product normalized by F (AF / F). The data were analyzed using the four-parameter nonlinear regression curve-fitting function in GraphPad Prism 10.2.3 (GraphPad Software, San Diego, CA), to generate potency (EC50) and maximal2026-03-18 response values. Maximal response values were normalized to the maximum 5-HT response (100%) and minimum 5-HT response (0%) on the same plate. Each concentration point was tested in triplicate.

[0622]

[0374] Results: Table 4 shows the dose-response curves for exemplary compounds 2CIB-2OH-5DHF, 2CIB-5DHF, and 2CIB-2OH-5DHF-NBOH. FIGs. 1 A-C show the dose response curves of 2CIB-2OH-5DHF (FIG. A), 2CIB-5DHF (FIG. B), and 2CIB-2OH-5DHF-NBOH (FIG. C) from the calcium flux assay.

[0623] TABLE 4. Calcium Flux Assay Results

[0624] Potency (ECso) (Emax)

[0625] Compound

[0626] 5-HT2A 5-HT2B

[0627] 2CIB-2OH-5DHF 5.79 nM (104.4%) 233.3 nM (41.7%) 2CIB-5DHF 12.01 nM (108.2%) 40.01 nM (98.38%) 2CIB-2OH-5DHF-NBOH 0.457 nM (76.60%) 593.7 nM (33.06%)

[0628]

[0629]

[0375] Among compounds tested, 2CIB-2OH-5DHF and 2CIB-2OH-5DHF-NBOH exhibited reduced activation of the 5-HT2B receptor relative to 2CIB-5DHF, as reflected by both their higher ECso values (233.3 nM and 593.7nM, respectively, compared to 40.01 nM for 2CIB-5DHF) and substantially lower Emax values (41.7% and 33.06%, respectively, compared to 98,38% for 2CIB-5DHF). Despite this reduced 5-HT2B engagement, both compounds retained potent 5-HT2A agonist activity, with ECso values of 5.79 nM and 0.457 nM, respectively. This functional selectivity profile can provide significant advantages, such as reduced off-target effects and a lower risk of 5HT2B-mediated valvular heart disease, thereby contributing to an improved therapeutic index.

[0630] EXAMPLE 5: Anti-Inflammatory Properties of Exemplary Compounds

[0631]

[0357] Purpose: The anti-inflammatory properties of disclosed compounds are assessed in rodent models of allergic asthma, in which airway hyperresponsiveness (AHR) is induced by ovalbumin (OVA) sensitization and challenge. Prevention of AHR, quantified via whole-body plethysmography (WBP) following methacholine exposure, serves as a functional in vivo biomarker for anti-inflammatory efficacy. Methods are based on those described in Flanagan et al., ACS Pharmacol Transl Sci., 2020; 4(2):488-502, with modifications as described.

[0632]

[0358] Methods: Respiratory pathogen-free Brown Norway (RijHsd-BN) rats are housed singly in a pathogen-free animal facility with free access to food and water on a 12 h / 12 h light / dark cycle. Protocols are prepared in accordance with the Guide for the Care and Use of Laboratory Animals (Nat’l Acad Press, 2011)). Rats are allowed to acclimate at least 1 week prior to initiation of sensitization with chicken ovalbumin grade V (OVA).

[0633]

[0359] For sensitization, Brown Norway rats (7-9 weeks) are injected with 500 uL of 2.0 mg of chicken OVA emulsified in 2.0 mL of Imject Alum [AI(OH)3 / Mg(OH)2] on days 0 and 7, as described in Elwood et al., J Allergy Clin Immunol., 1991; 88(6):951-60. OVA exposure methods are based on the model described in Nau et al., Am J Physiol Lung Cell Mol Physiol., 2015; 308(2)1191-198 ("Nau et al. 2015").

[0634]

[0360] OVA-alone treated rats are exposed to 3 times weekly exposure of 10.0 mg of OVA slowly dissolved in 10.0 mL of 0.9% sterile saline solution in a 15 L (38.00 x 19.05 x 19.7 cm) acrylic induction chamber. No more2026-03-18 than 6 animals are exposed in the chamber per challenge. OVA aerosol is generated using an ultrasonic nebulizer in conjunction with a Pari Proneb pump at a 1.0% OVA concentration for a total duration of 30 min, as described in Palmans et al., Am J Respir Crit Care Med., 2000; 161 : 627-635.

[0635]

[0361] For drug exposures, rats are exposed in groups of 3-4 rats / group to the appropriate concentration of drug dissolved in a total volume of 4.5 mL of sterile saline using an inExpose nose-only inhalation system 30 min prior to each OVA challenge. Each 4.5 mL of sample is aerosolized using a nebulizer in conjunction with a Pari Proneb pump. Exposures last 15 min. All respiratory parameters are measured 48 h after the final OVA exposure. To minimize the impact of circadian influences, all respiratory recordings are performed between 10 am and 3 pm (Lai et al., Bio-protocol, 2017; 7(12):e2343; Lai et al., J Neurosci., 2016; 36(50):12661-12676; Pazhoohan et al., PLoS One, 2017; 12(10):e0187249).

[0636]

[0362] Separately, Balb / c mice are sensitized to OVA via intraperitoneal injection, then exposed repeatedly to aerosolized OVA to induce acute allergic airway inflammation. Mice are separated into experimental groups, including: (1) naive mice (no OVA sensitization or challenge), (2) OVA mice (sensitized and challenged with OVA), and (3) compound-treated mice administered a disclosed compound (e.g., via intraperitoneal injection) prior to OVA challenge. Respiratory parameters are measured 48 hours after the final OVA exposure.

[0637]

[0363] For measurement of airway responsiveness to methacholine (MeCh), a noninvasive bias flow ventilated whole-body plethysmography system is used in spontaneously breathing, unrestrained rodents. The plethysmograph is ventilated by a continuous flow of 2.5 L / min. A differential pressure transducer connected to the main chamber and a reference chamber measures pressure differences caused by the respiratory cycle. Computer software provides a breath-by-breath analysis of pressure signals and transforms pressure differences to enhanced pause (PenH). PenH has been used as a measure of bronchoconstriction (see, e.g., Nau et al. 2015; Flanagan et al., Life Sci., 2019; 236:116790; Hamelmann et al., Am J Respir Crit Care Med., 1997; 156:766-775; Djuric et al., Brain Behavlmmun., 1998; 12(4):272-84). For the assay, the chamber pressure signal is calibrated by dynamic injection of 5 mL of room air via syringe. Animals are then placed in the chamber, where baseline data is recorded for 5 min following a 10 min habituation period. After measurement of baseline PenH, either aerosolized saline (0.9% NaCI) or an aqueous solution of MeCh in increasing concentrations (4, 8, 16, 32 mg / mL) is nebulized through an inlet of the plethysmography chamber for 3 min, followed by measurements of PenH values for 3 min. A vibrating-mesh nebulizer is used to generate aerosol. Following recordings, to prevent a MeCh gradient there is a wash-out period of 7 min in which the animal is provided with fresh air. Data are expressed as the mean + / - SEM of maximal PenH values per group.

[0638]

[0364] Results: Results will show that disclosed compounds reduce PenH max values and suppress pulmonary inflammation. Treatment with a disclosed compound will mitigate the airway hyperresponsiveness associated with OVA exposure, with treated animals exhibiting PenH values comparable to those of naive animals. Inhibition of PenH is considered a proxy for anti-inflammatory effects due to its correlation with asthma pathophysiology, including eosinophil infiltration, Th2 cytokine production, and airway remodeling.2026-03-18 EXAMPLE 6: In Vivo Model for Assessing Ocular Inflammation Following Application of Compounds

[0365] Purpose: To assess the effects of disclosed compounds on ocular inflammation. Cytokines, e.g., IL-6 (Ghasemi, Ocul Immunol Inflamm., 2018; 26(1 ):37— 50) and IL-8 (Ghasemi et al., Ocul Immunol Inflamm., 2011; 19(6):401— 12), and neuropeptides, e.g., substance P (Bignami et al., Curr Drug Targets, 2016; 17(11):1265— 74), can contribute to ocular inflammation.

[0639]

[0366] Methods: Ocular inflammation is assessed according to known methods with modifications. For example, ocular inflammation can be assessed in induced models of uveitis (see, e.g., PCT Pub. No. WO2015 / 074137A1, which describes an endotoxin-induced model in Example 1 and an LPS-induced model in Example 2), a chemical cauterization model of corneal inflammation (see, e.g., Example 4 of PCT Pub. No. WO2015 / 074137A1), or in human subjects at risk of experiencing or currently experiencing such inflammation.

[0640]

[0367] Results: Application of a compound, such as topical application, can prevent and / or reduce ocular inflammation. Reductions in ocular inflammation may lead to improvements in symptomatology associated with ocular inflammation, including eye redness, pain, and alterations in sight, e.g., blurred vision.

[0641] EXAMPLE 7: In Vivo Model for Assessing Atopic Dermatitis Following Application of Compounds

[0368] Purpose: To assess the therapeutic effects of disclosed compounds in a mouse in vivo model of atopic dermatitis. The model uses the flaky tail mouse strain, which carries a mutation in the gene for the epidermal protein filaggrin, comparable to the mutation underlying human atopic dermatitis (Fallon et al., Nat Genetics, 2009; 41:602-608). Challenging these mice with topically applied ovalbumin results in a condition resembling atopic dermatitis, with eczema and increased skin levels of inflammatory biomarkers. Exemplary measures of efficacy include skin flakiness, skin levels of Type 2 helper T-cell (Th2) and cytokines, e.g., IL4, IL5, and IL10.

[0642]

[0369] Methods: The protocol for application of ovalbumin to the skin of flaky tail mice is described in the literature (op cit.). In brief, abdomens of 3-5 week old mice are shaved 24 hours prior to cutaneous application of ovalbumin suspensions (50 pg in 50 pL PBS), which are applied to the abdomen as described previously.

[0643]

[0370] There are two experimental groups: in the first, mice are pretreated with test compound prior to and during the application of ovalbumin to study the effects of preventing and inhibiting the development of atopic dermatitis. In the second group, mice are treated with test compound following 4-5 weeks of ovalbumin treatment (after atopic dermatitis symptoms have appeared) to study the effects of the compound in treating the symptoms. For each test compound, the compound is administered (e.g., IV, IM, IP, oral gavage) at several doses to study dose dependent effects. Following each experiment, mice are euthanized and skin punch biopsy specimens from each abdomen are harvested, snap frozen in liquid nitrogen, and homogenized with HTAB buffer. Samples are centrifuged, and supernatants are subjected to cytokine profiling by ELISA for the levels of biomarkers (e.g., Th2, IL4, IL5, and IL10) using protein standards for quantification.

[0644]

[0371] Results: Resultswill show that administration of a disclosed compound or composition prevents, inhibits, and / or treats the symptoms of atopic dermatitis.2026-03-18 EXAMPLE 8: In Vivo Model for Assessing Intraocular Pressure Following Application of Compounds

[0372] Purpose: High intraocular pressure (IOP) is a significant risk factor and / or symptom of various ophthalmic diseases and disorders (e.g., glaucoma) and ocular pathologies. The purpose of this protocol is to assess the effects of administering a disclosed compound on intraocular pressure in an in vivo rat model.

[0645]

[0373] Methods: To evaluate the IOP following a single or repeat dose of test article via topical ocular administration in male Brown Norway rats, the test compound will be administered directly to the ocular surface of both eyes using a calibrated positive displacement pipette. Baseline and subsequent IOP measurements will be completed using the TonoLab Rebound Tonometer. IOP measurements will be completed while the animal is fully awake. Three sets of 6 IOP measurements are recorded and averaged for each eye. Animals will receive a “loading dose” series of three administrations (10 pL of a solution of test compound per administration) over a 10-minute period, i.e., 10 pL every 2-3 minutes.

[0646]

[0374] Results: Results will show that administration of a disclosed compound results in a reduction of IOP, which can indicate utility in treating ophthalmic diseases and disorders associated with elevated IOP.

[0647] EXAMPLE 9: In Vitro Metabolic Stability of Disclosed Compounds

[0648]

[0375] Purpose: The purpose of this study is to assess the metabolic stability of compounds in vitro. The liver is a major site of drug metabolism in the body, and liver microsomes, hepatocytes, and liver S9 fractions can be used to determine the in vitro intrinsic clearance of a compound (see, e.g., Ackley et al., Metabolic Stability Assessed by Liver Microsomes and Hepatocytes. In Yan & Caldwell (eds) Optimization in Drug Discovery. Methods Pharmacol Toxicol. Humana Press, and Richardson et al. Drug Metab Lett. 2016; 10(2): 83-90).

[0649]

[0376] Methods: A liver microsomal stability assay is performed according to available methods, e.g., in accordance with the methods described in U.S. Pub. No. 2008 / 0045588 with modifications. Briefly, the assay is conducted at 1 mg / mL liver microsome protein with an NADPH-generating system in 2% NaHCC (2.2 mM NADPH, 25.6 mM glucose 6-phosphate (G6P), 6 units per mL G6P dehydrogenase and 3.3 mM MgCI2). Test compounds are prepared as solutions in 20% acetonitrile-water and added to the assay mixture (final assay cone, of 5 pg / mL) and incubated at 37° C. Final concentration of acetonitrile should be <1%. Aliquots (50 pL) are taken out at 0, 15, 30, 45, and 60 min, and diluted with ice cold acetonitrile (200 pL) to stop the reactions. Samples are centrifuged at 12,000 RPM for 10 min to precipitate proteins. Supernatants are transferred to microcentrifuge tubes and stored for LC / MS / MS analysis of the degradation half-life of the test compounds.

[0650]

[0377] Results: Results will show a measurement of the in vitro intrinsic clearance of disclosed compounds. Such data provides a prediction of the metabolic stability and clearance of the compounds.

[0651] EXAMPLE 10: Effects of Disclosed Compounds on Promoting Neurogenesis and Neuroplasticity

[0378] Purpose: The effects of disclosed compounds on neurogenesis and neuroplasticity are measured in an in vitro dendritogenesis assay, an in vivo spinogenesis assay, and an ex vivo neuroplasticity assay.

[0652]

[0379] Methods (In Vitro Dendritogenesis Assay): Neurons are plated in 96-well format at a density of approximately 15,000 cells / well in wells containing 1% penicillin-streptomycin, 10% heat-inactivated fetal bovine2026-03-18 serum, and 0.5 mM glutamine. After 24 h, the medium is replaced with Neurobasal containing B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 pM glutamate. After 3 days in vitro, the cells are treated with test compounds. Stock solutions of the compounds in DMSO are first diluted 100-fold in Neurobasal before an additional 10-fold dilution into each well (total dilution = 1:1000; 0.1% DMSO concentration). Treatments are randomized. After 1 h, the media is removed and replaced with new Neurobasal media containing B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 pM glutamate. The cells grow for an additional 72 h. At that time, neurons are fixed by removing 80% of the media and replacing it with a volume of 4% aqueous paraformaldehyde equal to 50% of the working volume of the well. Then, the cells are incubated at room temperature for 20 min before the fixative is aspirated and each well washed twice with DPBS. Cells are permeabilized using 0.2% Triton X-100 in DPBS for 20 minutes at room temperature without shaking. Plates are blocked with antibody diluting buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS for 1 h at room temperature. Then, plates are incubated overnight at 4 °C with gentle shaking in ADB containing a chicken anti-MAP2 antibody (1:10,000; EnCor, CPCA-MAP2). The next day, plates are washed three times with DPBS and once with 2% ADB in DPBS. Plates are incubated for 1 h at room temperature in ADB containing an anti-chicken IgG secondary antibody conjugated to Alexa Fluor 488 (1 : 500) and washed five times with DPBS. After the final wash, lOOpL of DPBS is added per well.

[0653]

[0380] The wells are then imaged and analyzed. Plate controls (both positive and negative) are used to ensure that the assay is working properly as well as to visually determine appropriate numerical values for brightness / contrast and thresholding to be applied universally to the remainder of the randomized images.

[0654]

[0381] Next, the brightness / contrast settings are applied, and approximately 1-2 individual pyramidal-like neurons per image (i.e., no bipolar neurons) that do not overlap extensively with other cells or extend far beyond the field of view are selected for analysis. All images are taken and analyzed by an experimenter blinded to treatment conditions. The number of crossings for each neuron at each distinct radius is averaged to produce an average Sholl plot for each treatment. For each treatment, neurons are selected from at least 6 wells spread across 2 plates (9 sites / well x 3 wells / plate x 2 plates).

[0655]

[0382] Methods (In Vivo Spinoqenesis Assay): Female C57BL / 6J mice are treated with VEH (saline) or a disclosed compound (n = 3 / group). After 24 h, the animals are sacrificed via transcardial perfusion with oxygenated Ringer’s solution, followed by a fixative (2% paraformaldehyde, 2.5% glutaraldehyde, 3mM calcium chloride in 0.1 M cacodylate buffer). Brains are carefully removed from the skull and post-fixed overnight in the same fixative. Brains are then rinsed with PBS and 100 pm coronal sections spanning the prefrontal cortex are collected using a vibrating microtome. Regions of the infralimbic cortex are microdissected according to the Allen Brain Atlas (Lein et al. Nature. 2007;445:168-176) and processed further for electron microscopy. Samples are then stained with buffered 1.5% reduced osmium tetroxide for 45 minutes, rinsed thoroughly, further stained with 1% aqueous uranyl acetate overnight at 4°C, dehydrated and embedded in Eponate 12™ epoxy resin.

[0656]

[0383] A blockface that spans from the medical cortical surface to the corpus callosum is then trimmed and2026-03-18 150-250 serial ultrathin sections (55 nm) are collected onto silicon chips using diamond knives (Diatome) on an ultramicrotome. Serial sections on silicon chips are loaded into a scanning electron microscope for imaging. The apical tuft region is identified, and a series of images are collected from a region of interest identified on consecutive sections. Following image alignment, the datasets for each animal constitute volumes of at least 20x20x10 pm in dimension with voxel sizes of 8x8x55 nm. Cross sections of eight random dendrites are samples for the central section of each volume. Skeletons of the dendritic centerline and dendritic spines are traced by human experts. Dendritic spine densities (spines / micron) are calculated for each volume).

[0657]

[0384] Methods (Ex Vivo Neurop lasticitv Assay): This assay is conducted according to known procedures (see, e.g., Olson DE. J Exp Neurosci. 2018; 12: 1179069518800508; Ly et al. Cell Rep. 2018;23:3170-3182; and references therein). In brief, primary cortical neurons are prepared from timed pregnant wild-type C57BL / 6JRccHsd mice at E18. Animals are sacrificed and embryos are dissected in Calcium and Magnesium free Hanks Balanced Salt Solution (CMF-HBSS) containing 15 mM HEPES and 10 mM NaHCOa, pH 7.2. Embryos are decapitated, skin and skull gently removed and hemispheres are separated. After removing meninges and brain stem, the hippocampi are isolated, chopped with a sterile razor blade in Chop solution (Hibernate-E without Calcium containing 2% B-27) and digested in 2 mg / mL papain dissolved in Hibernate-E without Calcium for 30 minutes (± 5 min) at 30°C. Hippocampi are triturated 10-15 times with a fire-polished silanized Pasteur pipette in Hibernate-E without Calcium containing 2% B-27, 0.01% DNasel, 1 mg / mL BSA, and 1 mg / mL Ovomucoid Inhibitor. Undispersed pieces are allowed to settle by gravity for 1 min and the supernatant is centrifuged for 3 min at 228 g. The pellet is resuspended in Hibernate-E containing 2% B-27, 0.01% DNasel, 1 mg / ml BSA, 1 mg / mL Ovomucoid Inhibitor and diluted with Hibernate-E containing 2% B-27. After the second centrifugation step (3 min at 228 g), the pellet is resuspended in nutrition medium (Neurobasal, 2% B-27, 0.5 mM glutamine, 1% Penicillin-Streptomycin).

[0658]

[0385] Cells are counted in a hemacytometer and seeded in nutrition medium on poly-D-lysine pre-coated 96-well plates at a density of 2.6 x 104cells / well. Cells are cultured at 37°C; 95% humidity and 5% CO2. All wells are handled the same way. The experiment is performed in adequate technical replicates for all groups.

[0659]

[0386] On the day of preparation, mouse cortical neurons are seeded on poly-D-lysine pre-coated 96-well plates at a density of 2.6 x 104cells per well. One day later, cells are treated with test compounds for three different time points (4 h, 8 h and 24 h), followed by a complete medium change. Additionally, cells are treated with 40 ng / mL of a positive control (Fibroblast Growth Factor, FGF) or vehicle control (VC) for 48 h. The experiment is carried out with several technical replicates per condition, and vehicle-treated cells as control.

[0660]

[0387] Treated primary neurons are fixed on day 4 by addition of equal volume 4% paraformaldehyde (PFA) to the medium at room temperature (RT) for 30 minutes. Cells are rinsed two times with PBS and are permeabilized with 0.1 % Triton X-100 in PBS for 30 minutes at RT. Next, cells are blocked for 90 min at RT with 20% horse serum, 0.1% Triton X-100 in PBS. Then, samples are incubated with the primary antibody against Beta Tubulin Isotype III at 4°C overnight. The next day, the cells are further incubated for another 30 min at RT.2026-03-18 After three washing steps with PBS, cells are incubated with a fluorescently labeled secondary antibody and DAPI (nucleus) for 1.5 hours at RT in the darkness. Cells are again rinsed four times with PBS and then imaged. From each well, images are taken at 10x magnification. Digital images from cortical neurons are analyzed using a software-supported automatic quantification method to measure the number of neurites, number of branches, total length of neurites and length of the longest neurite. Basic statistical analysis is performed. If appropriate, data are presented as mean ± standard error of mean (SEM) and group differences are evaluated by e.g. one or two-way ANOVA or T-test. ECso may be calculated as described elsewhere.

[0661]

[0388] Results: Results will show that administration of disclosed compounds increase dendritogenesis, spinogenesis, and / or neuroplasticity.

[0662] EXAMPLE 11: Carboxylesterase Reaction Phenotyping Assay

[0663]

[0389] Purpose: To determine whether disclosed compounds are susceptible to metabolism (e.g., hydrolysis) by human carboxylesterase enzymes. In some embodiments, hydrolysis of a disclosed compound by a carboxylesterase prevents systemic action, thereby localizing therapeutic effects to the site of administration.

[0664]

[0390] Methods: Test systems for this assay include hCE1-b, hCE1-c, hCE2 expressed enzymes, and / or human liver / intestinal microsomes which are incubated with and without CE inhibitor. The concentration of the test compound is 1 pM. A positive control substrate (trandolapril for hCE1; irinotecan for hCE2, monitoring for the formation of 7-ethyl- 10-hydroxycamptothecin) is also included. Test compounds are introduced as 100 pL of a 10 mM DMSO stock solution. Analysis is conducted by LC-MS / MS to determine the amount of test compound remaining at each time point for each isoform, half-life, and standard error of half-life.

[0665]

[0391] Results: Results will show that certain disclosed compounds (e.g., those having an ester substituent) are substrates for hCE1 and / or hCE2 and are susceptible to hydrolysis in vivo.

[0666] EXAMPLE 12: Assessment of HTR in Mice Administered Exemplary Compounds of the Disclosure

[0392] Purpose: The mouse head-twitch response (HTR) is a behavioral test that reflects 5-HT2AR activation and is predictive of human psychedelic effects (Halberstadt et al. J Psychopharmacol. 2011 ;25(11):1548- 1561). HTR is widely used as a behavioral surrogate for such effects as it can reliably distinguish psychedelic and nonpsychedelic 5-HT2AR agonists (Halberst. & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3).

[0667]

[0393] Methods: HTR assays were performed in accordance with the methods described in Klein et al., Neuropharmaco\, 2018;142:231-239, with modifications, to assess HTRs and motor activity in male C57BL / 6J mice treated with exemplary compounds of the disclosure. Test compounds: Exemplary compounds were dissolved in saline (0.9% NaCI) and administered in doses ranging from 0 to 30 mg / kg (mpk) intraperitoneally (i.p.) in 5 ul of vehicle per g of animal mass. R-DOI ((-)-R-2,5-dimethoxy-4-iodo-amphetamine) was used as positive control in the same vehicle and route of administration. Animals: C57BL / 6J males were sourced from JAXS farms and maintained in a hygienic environment with controlled temperature and humidity in 12-hour light / dark cycles. Animals were provided free access to food and water except during testing.

[0668]

[0394] Upon arrival at the vivarium, all animals were installed with magnetic ear tags bilaterally as previously2026-03-18 described by de la Fuente et al., J Neurosci Methods. 2020 Jan 16;334: 108595. Animals were allowed to acclimate to the tags for an additional week prior to initiating testing. For testing, each animal was placed individually in a cylinder with a magnetometer for acclimation during each session. After 30 min, either an exemplary compound or a vehicle control was administered to the animals, which were then returned to the magnetometer for an additional 60 min. Both periods (pre- and post-article administration) were recorded.

[0669]

[0395] Exemplary compound 2CIB-2OH-5DHF was administered at doses of 0, 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg / kg, as well as 0 mg / kg (vehicle control), with n=6 per dose.

[0670]

[0396] Data Acquisition & Processing: Recording of changes in voltage signal in response to mouse head movement was performed in non-overlapping ~500-turn enameled wire (30 AWG) coils supported in closed plastic containers (inner dimensions, 11 cm diameter x 14 cm tall) with both terminals of each coil connected to a phono preamplifier (Pyle PP444) as previously described by de la Fuente Revenga et al., Sci Rep 2019 Oct 3;9(1): 14247. The amplified signal output was recorded at a 1000 Hz sampling rate using a Nl USB-6001 (National Instruments) data acquisition system controlled through MATLAB (Mathworks, R2020a version, with Nl myDAQ support package). The analog input range for each channel was ±10 V with an ADC (analog-digital conversion) of 16 bits. Raw signals were bandpass-filtered (70-110 Hz FIR filter). Filtered signals were rectified (absolute value x2), baseline-subtracted, and smoothed with a moving average.

[0671]

[0397] Potential HTR events were identified as maxima in the processed signal, as described by de la Fuente et aL, op cit. For spectral validation, unfiltered data segments (±2x event width around peaks) underwent spectral analysis. Events were confirmed as HTRs if they met: (1) maximum in the 70-110 Hz band of the spectrum exceeding a power threshold value of 0.005V2 / Hz; (2) cumulative sum of all power values in the 70-110 Hz band in excess of 0.05 V2 / Hz; (3) frequency corresponding to the absolute maximum within the operative frequency range of the spectrum >35 Hz; and (4) sum of zero-crossings of the derivative of the spectrum density <40 (between 5-200 Hz). Regarding quality control, events were cross-validated with wavelet analysis (Halberstadt, 2020). Any discrepancies were visually inspected and corrected.

[0672]

[0398] To quantify motor activity, baseline (smoothed vs. recorded) differences were binned. Activity was calculated as the area under the curve (AUG) of the baseline-corrected |V| signal, excluding confirmed HTR events. HTR and activity data for the 30 min preceding and the 60 min following administration were binned in 15 min fractions for representation of time-dependent effects. The sum of the first 30 min post-article2026-03-18 administration was employed to analyze dose-dependence. Statistical analysis included one-way ANOVA w / Dunnett’s post hoc correction for multiple comparisons and twotailed Student’s t-test. ED50 and ID50 were estimated using non-linear regression in Prism 12.0 (GraphPad Software, San Diego, CA, USA). Inverted U-shape dose-responses were fitted to a third order polynomial equation for visualization purposes. Body temperature also was measured and change in body temperature (AT) was calculated relative to baseline.

[0673]

[0399] Results: Exemplary compound 2CIB-2OH-5DHF exhibited a dose-dependent increase in HTR counts over the 30 min observation period, following an inverted U-shaped dose-response profile (FIG.2A). HTR counts remained near vehicle baseline at doses of 0.03-1 mg / kg. An increase in HTR was observed beginning at 3 mg / kg, with peak HTR counts at 10 mg / kg. At 30 mg / kg, HTR counts declined relative to the 10 mg / kg dose. The ED50 for HTR induction was estimated at 3.38 mg / kg. A statistically significant increase in HTR relative to vehicle was observed at 10 mg / kg.

[0674]

[0400] Time-course analysis of HTR counts in 5 min fractions (FIG. 2B) showed that at doses of 0-1 mg / kg, HTR counts remained near baseline throughout the observation period. A modest elevation was observed at 3 mg / kg. At 10 mg / kg HTR counts were elevated above baseline beginning at the earliest time bin and sustained throughout the 30 min period. At 30 mg / kg, HTR counts were moderately elevated but lower than at 10 mg / kg.

[0675]

[0401] By comparison, reference compound R-DOI exhibited a classic sigmoidal dose-response relationship, with HTR counts increasing progressively from baseline at vehicle to approximately 125 counts at the highest tested dose (FIG. 3). The maximum HTR response of 2CIB-2OH-5DHF was substantially lower than of R-DOI.

[0676]

[0402] Regarding motor activity, total distance traveled remained consistent across doses from 0 to 10 mg / kg (FIG. 2C), indicating that HTR measurements at these doses were not confounded by changes in locomotion. At 30 mg / kg, a statistically significant reduction in total distance was observed, with an estimated ED50 for motor suppression of >26 mg / kg. Time-course analysis of distance traveled in 5 min bins (FIG. 2D) confirmed that motor activity at doses of 0-10 mg / kg remained clustered near vehicle levels throughout the observation period, while the 30 mg / kg group exhibited sustained suppression of locomotion across all time bins.

[0677]

[0403] Body temperature was assessed as a measure of thermoregulatory effects (FIG. 2E). No significant change in temperature was observed at doses of 0-10 mg / kg. At 30 mg / kg, a statistically significant decrease in temperature of approximately 3°C was observed, with an estimated ED50 for hypothermia of >20 mg / kg.

[0678]

[0404] Together, these data indicate that 2CIB-2OH-5DHF induces a dose-dependent HTR2026-03-18 with an inverted U-shaped profile and a substantially reduced maximum response relative to R-DOL Motor suppression and hypothermia were observed only at the highest tested dose (30 mg / kg), well above the dose range at which HTR was observed. The separation between the ED50 for HTR (3.38 mg / kg) and the ED50 values for motor suppression (>26 mg / kg) and hypothermia (>20 mg / kg) indicates a behavioral and physiological margin between the dose at which 5-HT2A-mediated behavioral effects emerge and the dose at which adverse motor or thermoregulatory effects are observed. The observed separation between the ED50 for HTR induction (3.38 mg / kg) and the ED50 values for motor suppression (>26 mg / kg) and hypothermia (>20 mg / kg) indicates a wide behavioral and physiological margin. This margin suggests that anti-inflammatory or other therapeutic effects may be achievable at doses below those associated with significant behavioral, motor, or thermoregulatory effects. The attenuated maximum HTR response of 2CIB-2OH-5DHF relative to R-DOI, together with the inverted U-shaped dose-response profile, further supports the compound's suitability for pharmaceutical development at doses that minimize behavioral liability. Disclosed compounds therefore can in some embodiments be administered at a dose below the ED50 for HTR, motor suppression, or hypothermia.

[0679] EXAMPLE 13: Optic Nerve Crush Assay

[0680]

[0405] Purpose: The purpose of this study is to test disclosed compounds for potential neuroprotective effects in an optic nerve crush (ONC) model in rats.

[0681]

[0406] Methods: 2-14 wk old Brown Norway rats are used. Animals receive prophylactic dosing of the compounds (and optionally, one or more comparator compounds) 3 days prior to injury induction. Animals undergo optical coherence tomography (OCT) exams starting at baseline, and again 7, 14, and 21 days after injury. OCT will be used to measure the retinal nerve fiber layer (RNFL), inner plexiform layer (I PL), and total retinal thickness using a 9x9 spider plot. Animals will also undergo pupillary light reflex testing daily for up to 5 days post procedure and prior to anesthesia for OCT. At the conclusion of the study, whole eye samples will be collected and will undergo immunofluorescent staining using Brn3a and RBPMS to stain for retinal ganglion cells (RGCs) and counterstained with DAPI. From these, RGC loss will be calculated. Test compounds may be2026-03-18 administered topically (e.g., BID) or intravenously (e.g., SID) to ONC model animals at one or more doses, alongside vehicle-treated and naive control groups. Dose levels, routes of administration, and group sizes are selected based on the pharmacological profile of the disclosed compound and the results of prior in vitro and in vivo assays described herein. IP dosing may be used for daily dosing, dependent on frequency needed.

[0682]

[0407] Results: Results will show that administration of disclosed compounds demonstrate protective effects, as determined by retinal ganglion cell counts, and other measures described herein.

[0683] EXAMPLE 14: Aqueous Solubility and Photoliability of Disclosed Compounds

[0684]

[0408] Purpose: Aqueous solubility studies are conducted to evaluate the dissolution of exemplary compounds in water. Photostability testing is performed to assess the susceptibility of exemplary compounds to degradation upon exposure to light.

[0685]

[0409] Methods: The aqueous solubility of exemplary compounds is tested by sequentially diluting a known mass in water. Aqueous solubility is determined by the presence or absence of undissolved material upon microscopic inspection. Photoabsorption is determined from a dilution of the resulting solutions and assessed using wavelengths between 290 nm and 700 nm. The molar extinction coefficient (MEC) is calculated based on the wavelength of maximal absorption within this band range. In accordance with FDA guidelines, MEC below 1,000 L moU crn-1is considered insufficiently photoreactive to result in direct phototoxicity.

[0686]

[0410] Results: Results will show the aqueous solubility and MEC for exemplary compounds. One or more exemplary compounds will exhibit higher aqueous solubility and lower MEC values relative to a reference compound. Certain exemplary compounds will exhibit an MEC below 1,000 L moricm-1, indicating a reduced risk of phototoxicity relative to a reference compound having an MEC above 1,000 L moU crn-1. Such physical characteristics will provide advantageous properties, e.g., benefits related to enhanced bioavailability, ease of formulation, and reduced risk of adverse events such as phototoxicity.

[0687] EXAMPLE 15: In Vitro Pharmacology of Disclosed Compounds: Binding, Enzyme, and Uptake Assays

[0411] Purpose: The pharmacology of exemplary compounds is evaluated using in vitro binding, enzyme, and uptake assays to characterize receptor selectivity, off-target binding, and enzymatic activity.

[0688]

[0412] Methods (Binding Assays): In vitro binding assays are performed using human recombinant receptors expressed in mammalian cell lines (e.g., HEK-293, CHO). Assay conditions, including radioligand identity, concentration, nonspecific competitor, temperature, and incubation time, are optimized for each receptor. Assays are conducted in triplicate, and specific binding is quantified by scintillation counting. Specific binding is expressed as a percentage of control-specific binding. Half-maximal inhibitory concentrations (IC50) are determined by non-linear regression analysis using the Hill equation. Inhibition constants (Ki) are calculated using the Cheng-Prusoff equation. The receptor panel includes serotonin receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3), adrenergic receptors (alphalA, alphalD, alpha2A, betal, beta2), dopamine receptors (D1, D2S), muscarinic receptors (M1, M2, M3), opioid receptors (delta, kappa, mu), cannabinoid receptors (CB1, CB2), histamine receptors (H1, H2), nicotinic receptors (N neuronal alpha4beta2), vasopressin receptors (Via),2026-03-18 endothelin receptors (ETA), cholecystokinin receptors (CCK1), adenosine receptors (A2A), steroid hormone receptors (GR, AR), ion channels (BZD central, NMDA, Ca2+ channel L-type, hERG potassium channel, KV channel, Na+ channel site 2), and transporters (norepinephrine transporter, dopamine transporter, 5-HT transporter).

[0689]

[0413] Methods (Enzyme and Uptake Assays): In vitro enzyme and uptake assays are conducted using human recombinant enzymes expressed in mammalian or insect cell lines. Enzymatic activity is measured using appropriate substrates under conditions optimized for each target. The enzyme panel includes cyclooxygenases (C0X1, C0X2), phosphodiesterases (PDE3A, PDE4D2), kinases (Lek kinase), acetylcholinesterase, and monoamine oxidase (MAO-A). Reactions are incubated for a defined duration and quantified using fluorimetry, photometry, scintillation counting, or LANCE technology as appropriate. IC50 and EC50 values, along with Hill coefficients, are determined by nonlinear regression analysis of concentration-response curves.

[0690]

[0414] Results: Results will show that exemplary compounds exhibit high levels of specific binding at 5-HT2A, 5-HT2B, and 5-HT2C receptors, with comparatively lower binding at other receptors, ion channels, and transporters tested. The binding profile will indicate a degree of receptor selectivity for serotonin receptor subtypes. Enzyme and uptake profiling will further characterize the biochemical activity of the compounds across phosphodiesterase, cyclooxygenase, kinase, and neurotransmitter transporter targets.

[0691] EXAMPLE 16: In Vitro Permeability of Disclosed Compounds

[0692]

[0415] Purpose: An in vitro permeability assay is conducted to evaluate the ability of exemplary compounds to traverse cellular barriers that mimic physiological membranes, such as the blood-brain barrier.

[0693]

[0416] Methods: In vitro permeability studies are performed using confluent monolayers of MDR1 -transfected Madin-Darby Canine Kidney (MDR1-MDCKII) cells cultured under standard conditions. Cells are seeded onto permeable supports and maintained until they form tight monolayers suitable for bidirectional transport studies. The assay is conducted at 37°C using Hanks' balanced salt solution (HBSS) adjusted to pH 7.4 on both the apical and basolateral sides. For apical-to-basolateral (A-B) permeability, samples are collected at 0 and 60 minutes. For basolateral-to-apical (B-A) permeability, samples are collected at 0 and 40 minutes. The concentration of each compound in the donor and receiver chambers is determined by HPLC-MS / MS.

[0694]

[0417] The apparent permeability coefficient (Papp) for each compound is calculated using the formula: Papp (cm / s) = (VR x CR,end) / (At x A x (CD, mid - CR, mid)), where VR is the volume of the receiver chamber, CR,end is the concentration of compound in the receiver chamber at the final time point, At is the incubation time, and A is the surface area of cell monolayer. The midpoint donor concentration (CD, mid) is calculated as the average of donor concentrations at time 0 and the end time point, while CR,mid is calculated as one-half of CR,end.

[0695]

[0418] Compound recovery is evaluated using the following formula: Recovery (%) = [(VD x CD, end) + (VR x CR,end)] / (VD x CDO) x 100, where VD and VR are the volumes of the donor and receiver chambers, respectively, CD, end and CR,end are the compound concentrations at the final time point in their respective compartments, and CDO is the initial concentration in the donor chamber. Monolayer integrity is assessed2026-03-18 following the permeability assay using fluorescein as a paracellular marker compound. Fluorescein is added to the apical chamber and sampled in the basolateral chamber after incubation. Monolayers with fluorescein Papp values below 1.5 x 10-6cm / s are considered intact. Only data from wells that meet this integrity threshold are included in the final analysis.

[0696]

[0419] Results: Results will show the A-B permeability, B-A permeability, and percent recovery of exemplary compounds. Exemplary compounds will exhibit A-B permeability greater than B-A permeability, indicating facilitated transport or efficient passive diffusion in the A-B direction. B-A permeability of exemplary compounds will be lower than A-B permeability, indicating that the compounds are not significant substrates for active efflux transporters such as P-glycoprotein (P-gp).

[0697] K. Additional Exemplary Embodiments

[0698]

[0420] The following additional embodiments are exemplary and non-limiting.

[0699]

[0421] In some aspects are provided compounds of Formula (I):

[0700] OR2R

[0701] i ibu

[0702] n

[0703] fl IR

[0704] R4

[0705]

[0706] ^■0 (1),

[0707] wherein: R2is H or Ci-Ce alkyl; R4is H, F, Cl, Br, I, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl, or — (CH2)o-3-C(0)-0-Ci-Ce alkyl; and RNis H or — CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12 aryl optionally substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl; and Rais H or Ci-Ce alkyl; and Rbis H; or Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl; or RNand Rbtogether with the intervening atoms form a 4- to 8-membered heterocyclyl, and Rais H or Ci-Ce alkyl; or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0708]

[0422] In embodiments, R2is Ci-Ce alkyl. In embodiments, R2is methyl. In embodiments, R2is H.

[0709]

[0423] In embodiments, RNis H. In embodiments, RNis — CH2-Ar.

[0710]

[0424] In embodiments, the compound has the structure of Formula (2):

[0711] OR2

[0712] R4\ ?

[0713]

[0714] (2),

[0715] wherein Ra, R2, and R4are as defined herein, such as for Formula (I).

[0716]

[0425] In embodiments, the compound has the structure of Formula (3):2026-03-18

[0717]

[0718] wherein: Ra, R2, and R4are as defined herein, such as for Formula (I); X, Y, and Z are each independently H, F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl; or X and Y are taken together to form a 4- to 6-membered heterocyclyl, and Z is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, C3-C6 cycloalkyl, or phenyl; or Y and Z are taken together to form a 4- to 6-membered heterocyclyl, and X is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, C3-C6 cycloalkyl, or phenyl.

[0719]

[0426] In embodiments, X is OH. In embodiments, X is methoxy. In embodiments, X is F, Cl, Br, or I. In embodiments, X is phenyl. In embodiments, X is C3-C6 cycloalkyl. In embodiments, X is cyclopropyl.

[0720]

[0427] In embodiments, Y and Z are H. In embodiments, X and Y are taken together to form \ O— ' (methylenedioxy), wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively. In embodiments, X and Y are taken together to form

[0721] o

[0722] a dihydrofuranyl. In embodiments, X and Y are taken together to form

[0723]

[0724] 0—4or ' — ' , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively. In embodiments, X and Y are taken together to form a furanyl. In embodiments, X and Y are taken

[0725] \

[0726]

[0727] \x,°

[0728] together to form O— or = / , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.

[0729]

[0428] In embodiments, Rais H. In embodiments, Rais Ci-Ce alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl. In embodiments, R4is F, Cl, Br, or I. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is Ci-Ce alkyl. In embodiments, R4is ethyl. In embodiments, R4is isobutyl. In embodiments, R4is — (CH2)o-3-C(0)-0-Ci-Ce alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is — CH2COOCH2CH3. In embodiments, R4is Ci-Ce alkenyl. In embodiments, R4is allyl. In embodiments, R4is Ci-Ce alkynyl. In embodiments, R4is propargyl.

[0730]

[0429] In some embodiments, the compound is selected from the compounds listed herein in Table 3.

[0731]

[0430] In some embodiments, the compound is selected from the compounds defined herein as Group A.

[0732]

[0431] In some embodiments, the compound is selected from the compounds defined herein as Group B.

[0733]

[0432] In some embodiments, the compound is selected from the compounds defined herein as Group C.

[0734]

[0433] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of the compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, disclosed pharmaceutical compositions are suitable for, or are formulated for, oral, buccal,2026-03-18 sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration. In some embodiments pharmaceutical composition is in unit dosage form. In some embodiments the pharmaceutical composition comprises the compound in a total amount of between about 0.01 and 100 mg. In embodiments, the pharmaceutical composition is formulated for topical administration. In embodiments, the pharmaceutical composition is formulated as an aerosol, emulsion, spray, ointment, salve, gel, paste, lotion, liniment, oil, or cream. In embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients selected from the group consisting of penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, and gelling agents.

[0735]

[0434] In embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of an additional active compound, or a salt, solvate, or stereoisomer thereof. In 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-posttraumatic stress disorder (anti-PTSD) agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, NMDA modulators, NMDA antagonists, and vitamins.

[0736]

[0435] Also provided are methods of modulating neurotransmission in a subject, comprising administering to the subject a compound or composition disclosed in any of the embodiments. In embodiments, modulating neurotransmission comprises agonizing the 5-HT2A or 5-HT2C receptor. In embodiments, modulating neurotransmission comprises agonizing other serotonin receptor subtypes, including agonizing or partially agonizing any one or more of a 5-HTi receptor, such as 5-HTIA and 5-HTIB, a 5-HT2 receptor, such as 5-HT2A and 5-HT2C, and a 5-HTe receptor. Also provided are methods of increasing neuroplasticity in a subject, comprising administering to the subject a compound or composition disclosed in any of the embodiments.

[0737]

[0436] Also provided are methods of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a disclosed compound or composition. In embodiments, the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission. In embodiments, the medical condition is a mental, behavioral, or neurodevelopmental disorder. In embodiments, the medical condition is a neurodevelopmental disorder, schizophrenia or another primary psychotic disorder, catatonia, a mood disorder, an anxiety or fear-related disorders, an obsessive-compulsive or related disorder, a disorder specifically associated with stress, a dissociative disorder, a feeding or eating disorder, an elimination disorder, a disorder of bodily distress or bodily experience, a disorder due to substance use or addictive behavior, an impulse control disorder, a disruptive2026-03-18 behavior or dissocial disorder, a personality disorder, a paraphilic disorder, a factitious disorder, a neurocognitive disorder, a mental or behavioral disorder associated with pregnancy, childbirth or the puerperium, a sleep-wake disorder, or a sexual dysfunction. In embodiments, the compound is administered together with one or more sessions of psychotherapy.

[0738]

[0437] In embodiments, the medical condition is inflammation or an inflammatory disorder. In embodiments, inflammation is 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, ocular inflammation, or brain inflammation. In embodiments, the inflammatory disorder is an acute inflammatory disorder. In embodiments, the inflammatory disorder is a chronic inflammatory disorder. In embodiments, the inflammatory disorder is a steroid-resistant disorder. In embodiments, the inflammatory disorder is selected from the group consisting of asthma, chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, septicemia, conjunctivitis, and Alzheimer’s disease. In embodiments, the inflammatory disorder is dermatitis. In embodiments, dermatitis is atopic dermatitis, chronic photosensitivity dermatitis, eczema, atopic eczema, contact eczema, dryness eczema, seborrheic eczema, discoid eczema, varicose eczema, herpetic dermatitis, neurodermatitis, autosensitizing dermatitis, stasis dermatitis, purulent dermatitis, dyshidrotic eczema, follicular eczema, spongiotic dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

[0739]

[0438] In embodiments, the subject has a compromised immune system. In embodiments, the subject has an autoimmune disorder. In embodiments, the subject has a contraindication to a corticosteroid.

[0740]

[0439] In embodiments, treating inflammation or an inflammatory disorder comprises reducing the level of an inflammatory biomarker by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.

[0741]

[0440] In embodiments, the inflammatory biomarker is an inflammatory response gene product. In embodiments, the inflammatory response gene product is mRNA. In embodiments, mRNA is Arg-1, ICAM1, VCAM1, CCL2, IL-6, IL-1 [3, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-[3 mRNA. In embodiments, the inflammatory response gene product is a protein. In embodiments, the protein is Arg-1, ICAM1 , VCAM1, MCP1, IL-6, IL-1 p, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF- .

[0742]

[0441] In embodiments, the medical condition is an ophthalmic disorder. In embodiments, the ophthalmic disorder is an inflammatory disorder. In embodiments, medical condition is macular degeneration, keratoconjunctivitis, conjunctivitis, keratitis, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber’s disease, retinal detachment, retinal pigment epithelial detachment, rubeosis iridis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, or retinochoroidal neovascularization.2026-03-18

[0442] In embodiments, the medical condition is a neurodegenerative disorder. 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.

[0743]

[0443] In some aspects, the compound or the composition of any one of the disclosed embodiments is for use in the treatment of a medical condition. In some aspects are provided the use of the disclosed compounds and compositions for the manufacture of a medicament for the treatment of a medical condition.

[0744]

[0444] The foregoing description of specific embodiments is presented for purposes of illustration and description, and is not intended to be exhaustive or to limit the disclosure to the precise compositions, formulations, or methods disclosed. Many modifications and variations are possible in view of the above teachings, and the disclosure is intended to enable one of skill to utilize the disclosed subject matter with such modifications as are suited to a particular use. The scope of protection afforded the disclosure shall be defined solely by the following claims and their equivalents.

Claims

2026-03-18CLAIMSThe disclosure claimed is:

1. A compound of Formula (1):wherein:R2is H or Ci-C6alkyl;R4is isobutyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkylthio, Ci-Ce alkylthio, C3-C6 cycloalkylmethyl,— (CH2)o-3—C(0)—0—Ci-Ce alkyl, CN, NO2, or halogen; andRNis H or— CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12 aryl optionally substituted by F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl; andRais H or Ci-Ce alkyl; and Rbis H;or Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl;or RNand Rbtogether with the intervening atoms form a 4- to 8-membered heterocyclyl, and Rais H or Ci-Ce alkyl;or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof. 2 The compound of claim 1 , wherein R2is Ci-Ce alkyl.3 The compound of claim 2, wherein R2is methyl.4 The compound of claim 1 , wherein R2is H.5 The compound of claim 1 , wherein RNis H.6 The compound of claim 1 , wherein RNis — CH2-Ar.7 The compound of claim 1 , having the structure of Formula (2):OR28 The compound of claim 1 , having the structure of Formula (3):2026-03-18wherein:X, Y, and Z are each independently H, F, Cl, Br, I, OH, Ci-Ce alkoxy, or phenyl; orX and Y are taken together to form a 4- to 6-membered heterocyclyl, and Z is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, C3-C6 cycloalkyl, or phenyl; orY and Z are taken together to form a 4- to 6-membered heterocyclyl, and X is H, F, Cl, Br, I, OH, Ci-Ce alkoxy, C3-C6 cycloalkyl, or phenyl.The compound of claim 8, wherein X is OH.The compound of claim 8, wherein X is methoxy.The compound of claim 8, wherein X is F, Cl, Br, or I.The compound of claim 8, wherein X is phenyl.The compound of claim 8, wherein X is C3-C6 cycloalkyl.The compound of claim 8, wherein X is cyclopropyl.The compound of claim 8, wherein Y and Z are H.The compound of claim 8, wherein X and Y are taken together to form(methylenedioxy), wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.The compound of claim 8, wherein X and Y are taken together to form a dihydrofuranyl.w *«The compound of claim 17, wherein X and Y are taken together to form O—7or. wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.The compound of claim 8, wherein X and Y are taken together to form a furanyl.X **\ J) \The compound of claim 19, wherein X and Y are taken together to form O”7or ' — ' , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and2026-03-18 the rest of the compound, respectively.

21. The compound of claim 1 , wherein Rais H.

22. The compound of claim 1 , wherein Rais Ci-Ce alkyl.

23. The compound of claim 22, wherein Rais methyl.

24. The compound of claim 22, wherein Rais ethyl.

25. The compound of claim 1, wherein R4is F, Cl, Br, or I.

26. The compound of claim 25, wherein R4is Br.

27. The compound of claim 25, wherein R4is I.

28. The compound of claim 1 , wherein R4is Ci-Ce alkyl.

29. The compound of claim 28, wherein R4is ethyl.

30. The compound of claim 28, wherein R4is isobutyl.

31. The compound of claim 1 , wherein R4is — (CH2)o-3-C(0)-0-Ci-Ce alkyl.

32. The compound of claim 31 , wherein R4is — CH2COOCH3.

33. The compound of claim 31 , wherein R4is — CH2COOCH2CH3.

34. The compound of claim 1 , wherein R4is Ci-Ce alkenyl.

35. The compound of claim 34, wherein R4is allyl.

36. The compound of claim 1 , wherein R4is Ci-Ce alkynyl.

37. The compound of claim 36, wherein R4is propargyl.

38. The compound of claim 1 , selected from the group consisting of:2026-03-1839. The compound of claim 1 , selected from the group consisting of:

40. The compound of claim 1 , selected from the group consisting of:2026-03-18OH41. The compound of claim 1, wherein the compound is:

42. The compound of claim 1, wherein the compound is:

43. The compound of claim 1, wherein the compound is:

44. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, and a pharmaceutically acceptable carrier, diluent, or excipient.

45. The pharmaceutical composition of claim 44, wherein the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

46. The pharmaceutical composition of claim 44, wherein the composition is in unit dosage form.

47. The pharmaceutical composition of claim 44, comprising the compound in a total amount of between about 0.01 and 100 mg.

48. The pharmaceutical composition of claim 45, formulated for topical administration.

49. The pharmaceutical composition of claim 48, formulated as an aerosol, emulsion, spray, ointment, salve, gel, paste, lotion, liniment, oil, or cream.

50. The pharmaceutical composition of claim 48, comprising one or more pharmaceutically acceptable excipients selected from the group consisting of penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, and gelling agents.

51. The pharmaceutical composition of claim 1 , further comprising a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

52. A method of modulating neurotransmission in a subject, comprising administering to the subject the compound of claim 1 or the pharmaceutical composition of claim 44.2026-03-18 53. The method of claim 52, wherein modulating neurotransmission comprises agonizing the 5-HT2A or 5- HT2c receptor.

54. A method of increasing neuroplasticity in a subject, comprising administering to the subject the compound of claim 1 or the pharmaceutical composition of claim 44.

55. A method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or the pharmaceutical composition of claim 44.

56. The method of claim 55, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission.

57. The method of claim 55, wherein the medical condition is a mental, behavioral, or neurodevelopmental disorder.

58. The method of claim 55, wherein the medical condition is a neurodevelopmental disorder, schizophrenia or another primary psychotic disorder, catatonia, a mood disorder, an anxiety or fear- related disorders, an obsessive-compulsive or related disorder, a disorder specifically associated with stress, a dissociative disorder, a feeding or eating disorder, an elimination disorder, a disorder of bodily distress or bodily experience, a disorder due to substance use or addictive behavior, an impulse control disorder, a disruptive behavior or dissocial disorder, a personality disorder, a paraphilic disorder, a factitious disorder, a neurocognitive disorder, a mental or behavioral disorder associated with pregnancy, childbirth or the puerperium, a sleep-wake disorder, or a sexual dysfunction.

59. The method of claim 55, wherein the medical condition is inflammation or an inflammatory disorder.

60. The method of claim 59, wherein inflammation is 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, ocular inflammation, or brain inflammation.

61. The method of claim 59, wherein the inflammatory disorder is an acute inflammatory disorder.

62. The method of claim 59, wherein the inflammatory disorder is a chronic inflammatory disorder.

63. The method of claim 59, wherein the inflammatory disorder is a steroid-resistant disorder.

64. The method of claim 59, wherein the inflammatory disorder is selected from the group consisting of asthma, chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, septicemia, conjunctivitis, and Alzheimer’s disease.2026-03-18 65. The method of claim 59, wherein the inflammatory disorder is dermatitis.

66. The method of claim 65, wherein dermatitis is atopic dermatitis, chronic photosensitivity dermatitis, eczema, atopic eczema, contact eczema, dryness eczema, seborrheic eczema, discoid eczema, varicose eczema, herpetic dermatitis, neurodermatitis, autosensitizing dermatitis, stasis dermatitis, purulent dermatitis, dyshidrotic eczema, follicular eczema, spongiotic dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

67. The method of claim 55, wherein the medical condition is an ophthalmic disorder.

68. The method of claim 67, wherein the ophthalmic disorder is an inflammatory disorder.

69. The method of claim 55, wherein the medical condition is macular degeneration, keratoconjunctivitis, conjunctivitis, keratitis, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber’s disease, retinal detachment, retinal pigment epithelial detachment, rubeosis iridis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, or retinochoroidal neovascularization.

70. The method of claim 55, wherein the medical condition is a neurodegenerative disorder.

71. The method of claim 70, wherein 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.

72. A compound of claim 1 , or the pharmaceutical composition of claim 44, for use in the treatment of a medical condition.

73. Use of the compound of claim 1 , or the pharmaceutical composition of claim 44, in the manufacture of a medicament for the treatment of a medical condition.

Images