Substituted ergolines

Abstract

The present disclosure relates in some aspects to substituted ergolines, such as 14-monosubstituted and 2,14-disubstituted lysergamides, and quaternized derivatives thereof. In some aspects, the disclosure relates to methods of synthesizing the compounds, compositions containing the compounds, and methods of using the compounds, including their administration to subjects. In some aspects, features of the compounds include neuromodulatory activity, for example, activation of serotonin receptors. In some further aspects, the compounds are useful as therapeutic agents, such as anti-inflammatory agents.

Description

[0001] SUBSTITUTED ERGOLINES INVENTORS: David E. Nichols, Joel M. Smith CROSS-REFERENCE

[0001] Priority is claimed under PCT Art.8(1) and Rule 4.10 to U.S. Prov. App. No.63 / 526,915, filed July 14, 2023, and incorporated by reference for all purposes as if fully set forth herein. FIELD OF THE INVENTION

[0002] Certain substituted ergolines are disclosed, such as 14-monosubstituted and 2,14-disubstituted lysergamides, and quaternized derivatives thereof. In aspects, the disclosure relates to methods of synthesizing the compounds, compositions containing the compounds, and methods of using the compounds, including their administration to subjects. In aspects, features of the compounds include neuromodulatory activity, for example, activation of serotonin receptors. In some aspects, the compounds are useful as therapeutic agents, e.g., anti-inflammatory agents. BACKGROUND OF THE INVENTION

[0003] Ergolines are a class of molecule derived from lysergic acid, a semi-synthetic product derived by hydrolysis of naturally occurring compounds produced by the parasitic rye fungus Claviceps purpurea . One of the most notable ergolines is lysergic acid diethylamide, or LSD, synthesized by Albert Hoffman in 1938. LSD was found to possess unique physiological properties, including the ability to induce an intense state of altered consciousness. Early research suggested LSD could be used as an adjunct to psychotherapy to improve patient outcomes. Modern research supports the early findings, and LSD has been demonstrated to have clinical potential for a diverse array of mental illnesses such as depression, anxiety, and addiction.

[0004] Beyond mental health, psychedelics such as LSD may be promising for treating inflammatory, neurological, and neurodegenerative diseases and disorders. However, there exists an ongoing need for the development of novel therapeutic compounds that can be used to treat a broad range of disease indications, especially chronic conditions that lack effective treatments. Many psychedelics, including LSD and its analogs, are federally illegal in the U.S. under Schedule I of the Controlled Substances Act. Novel compounds that minimize side effects, optimize efficacy, and allow for greater access are especially valuable. Provided herein are compounds, compositions, methods, uses, and kits to meet these needs and others, and having such advantages and improvements as will become apparent from the disclosure below. INCORPORATION BY REFERENCE

[0005] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated by reference individually, and as if each is fully set forth herein. However, no such citation is as an admission that a cited reference comes from an area that is analogous or directly applicable to the invention, nor should any citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or is part of the common general knowledge in the art. BRIEF SUMMARY OF THE INVENTION

[0006] The following presents a simplified summary of some embodiments of the invention in order to provide a basic understanding of the invention. This summary is not an extensive overview of the invention. It is not intended to identify key or critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some embodiments of the invention in a simplified form as a prelude to the more detailed description that is presented later.

[0007] In a first aspect, provided is a compound of Formula (1): , or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein: R1is H or –C(O)–C1-C6alkyl; R2is H, C1-C6alkyl, or halo; R6is C1-C6alkyl or C2-C6alkenyl; R14is C1-C6alkyl, C1-C6alkoxy, or halo; and R' and R'' are both C1-C6alkyl; or R' and R'' are taken together to form an optionally substituted heterocyclyl.

[0008] In some embodiments, R1is H or –C(O)–C1-C6alkyl.

[0009] In some embodiments, R6is C1-C6alkyl. In some embodiments, R6is methyl or ethyl. In some embodiments, R6is C2-C6alkenyl. In some embodiments, R6is allyl.

[0010] In some embodiments, R2is H or C1-C6alkyl. In some embodiments, R2is methyl. In some embodiments, R2is halo. In some embodiments, R2is bromo

[0011] In some embodiments, R14is C1-C6alkyl, methyl, or halo. In some embodiments, R14is Cl. In some embodiments, R14is C1-C6alkoxy. In some embodiments, R14is methoxy

[0012] In some embodiments, R' and R'' are both C1-C6alkyl. In some embodiments, R' and R'' are both ethyl or are both methyl. In some embodiments, R' is methyl and R'' is n-propyl. In some embodiments, R' is methyl and R'' is isopropyl.

[0013] In some embodiments, R' and R'' are taken together to form an optionally substituted heterocyclyl. In some embodiments, R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is optionally substituted by C1-C6alkyl. In some embodiments, R' and R'' are taken together to form an unsubstituted azetidinyl. In some embodiments, R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is substituted by C1-C6alkyl. In some embodiments, R' and R'' are taken together to form or , wherein the asterisk (*) indicates the point of connection to the remainder of the compound.

[0014] In another aspect, provided is a compound of Formula (2): , or a prodrug, hydrate, or solvate thereof, wherein: R1is H or –C(O)–C1-C6alkyl; R2is H, C1-C6alkyl, or halo; R6is C1-C6alkyl or C2-C6alkenyl; R6 'is C1-C6alkyl; R14is C1-C6alkyl, C1-C6alkoxy, or halo; and R' and R'' are both C1-C6alkyl; or R' and R'' are taken together to form an optionally substituted heterocyclyl.

[0015] In some embodiments, R1is H or –C(O)–C1-C6alkyl.

[0016] In some embodiments, R6is C1-C6alkyl. In some embodiments, R6is methyl or ethyl. In some embodiments, R6is C2-C6alkenyl. In some embodiments, R6is allyl.

[0017] In some embodiments, R2is H or C1-C6alkyl. In some embodiments, R2is methyl. In some embodiments, R2is halo. In some embodiments, R2is bromo.

[0018] In some embodiments, R14is C1-C6alkyl. In some embodiments, R14is methyl. In some embodiments, R14is halo. In some embodiments, R14is Cl. In some embodiments, R14is C1-C6alkoxy. In some embodiments, R14is methoxy.

[0019] In some embodiments, R' and R'' are both C1-C6alkyl. In some embodiments, R' and R'' are both ethyl. In some embodiments, R' and R'' are both methyl. In some embodiments, R' is methyl and R'' is n-propyl. In some embodiments, R' is methyl and R'' is isopropyl.

[0020] In some embodiments, R' and R'' are taken together to form an optionally substituted heterocyclyl. In some embodiments, R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is optionally substituted by C1-C6alkyl. In some embodiments, R' and R'' are taken together to form an unsubstituted azetidinyl. In some embodiments, R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is substituted by C1-C6alkyl. In some embodiments, R' and R'' are taken together to form or , wherein the asterisk (*) indicates the point of connection to the remainder of the compound.

[0021] In some embodiments, provided is a compound selected from Table 1 , Table 2 , or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0022] In some embodiments, the compound .

[0023] In some embodiments, the compound .

[0024] Also provided is a pharmaceutical composition comprising a therapeutically effective amount of the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration. In some embodiments, the composition is provided in unit dosage form. In some embodiments, the composition comprises the compound in a total amount of between about 0.01 and 100 mg.

[0025] In some embodiments, the composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immuno- stimulants, 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.

[0026] Also provided is a method of modulating neurotransmission in a subject, comprising administering to the subject the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the pharmaceutical composition of any of the disclosed embodiments. In embodiments, modulating neurotransmission comprises agonizing the 5-HT2Areceptor.

[0027] Also provided is a method of increasing neuroplasticity in a subject, comprising administering to the subject the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the pharmaceutical composition of any of the disclosed embodiments.

[0028] Also provided is a method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the pharmaceutical composition of any of the disclosed embodiments.

[0029] In some embodiments, the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission.

[0030] In some embodiments, the medical condition is a mental, behavioral, or neurodevelopmental disorder.

[0031] In some 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 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.

[0032] In embodiments, a compound is administered together with one or more sessions of psychotherapy.

[0033] In some embodiments, the medical condition is inflammation or an inflammatory disorder. In some 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.

[0034] In some embodiments, the inflammatory disorder is an acute inflammatory disorder. In some embodiments, the inflammatory disorder is a chronic inflammatory disorder. In some embodiments, the inflammatory disorder is a steroid-resistant disorder.

[0035] In some 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.

[0036] In some embodiments, the inflammatory disorder is dermatitis. In some 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.

[0037] In some embodiments, the subject has a compromised immune system. In some embodiments, the subject has an autoimmune disorder. In embodiments, the subject has a contraindication to a corticosteroid.

[0038] In some 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%. In some embodiments, the inflammatory biomarker is an inflammatory response gene product. In some embodiments, the inflammatory response gene product is mRNA. In some embodiments, the mRNA is Arg-1 , ICAM1 , VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β mRNA. In some embodiments, the inflammatory response gene product is a protein. In some embodiments, the protein is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β.

[0039] In some embodiments, the medical condition is an ophthalmic disorder. In some embodiments, the ophthalmic disorder is an inflammatory disorder.

[0040] In embodiments, the medical condition is a neurodegenerative disorder. In some embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis or Charcot’s disease, chronic traumatic encephalopathy, corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease or Parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury.

[0041] Also provided is a compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment of a medical condition.

[0042] Also provided is the use of the compound of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a medicament for the treatment of a medical condition.

[0043] Also provided is the pharmaceutical composition of any of the disclosed embodiments for use in the treatment of a medical condition.

[0044] Use of the pharmaceutical composition of any of the disclosed embodiments for the manufacture of a medicament for the treatment of a medical condition.

[0045] The foregoing has outlined broadly and in summary certain pertinent features of the disclosure so that the detailed description of the invention that follows may be better understood, and so that the present contribution to the art can be more fully appreciated. Hence, this summary is to be considered as a brief and general synopsis of only some of the objects and embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are lawfully entitled. Additional features of the invention are described hereinafter. It should be appreciated by those in the art that all disclosed specific compositions and methods are only exemplary, and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods will be appreciated to be also within the scope and spirit of the invention as set forth in the claims.

[0046] The headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner. BRIEF DESCRIPTION OF THE FIGURES

[0047] To further clarify various aspects of the invention, a more particular description is rendered by reference to certain exemplary embodiments illustrated in the figures. It will be appreciated that these figures depict only illustrated embodiments of the invention and should not be considered limiting of its scope. They are merely provided as exemplary illustrations of certain concepts of some embodiments of the invention. These figures, and the elements depicted therein, are not necessarily drawn to consistent scale or to any scale. Certain aspects of the invention are therefore further described and explained with additional specificity and detail, but still by way of example only, with reference to the accompanying figures in which:

[0048] FIG.1 shows the dose-response curve from a cell-based agonist IP-1 assay for 14-Me-LSD for 5-HT2Aand 5-HT2B, as described in Example 3.

[0049] FIG.2 shows the dose-response curve from a cell-based agonist IP-1 assay for 2-Br-14-Me-LSD for 5-HT2Aand 5-HT2B, as described in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0050] While various aspects and features of certain embodiments are summarized above, the following detailed description illustrates several exemplary embodiments in further detail to enable one of skill in the art to practice such embodiments, and to make and use the full scope of the invention claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications. The scope of the invention includes all embodiments and formulations thereof, not only those expressly described below, and it will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as described in the claims. The headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner. A. General Definitions and Terms

[0051] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an active agent” includes reference to a combination of two or more active agents, and reference to “an excipient” includes reference to a combination of two or more excipients. While the term “one or more” may be used, its absence (or its replacement by the singular) does not signify the singular only, but simply underscores the possibility of multiple agents or ingredients in particular embodiments. The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). The term “or” is used herein to mean, and is used interchangeably with, the term “and / or,” unless context clearly indicates otherwise.

[0052] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the disclosure are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments (equivalently and as shorthand, “in embodiments”), the numerical parameters set forth in the description and claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. The term “substantially,” where it is applied to modify a feature or limitation herein, will be read in the context of the disclosure and in light of the knowledge in the art to provide the appropriate certainty, e.g., by using a standard that is recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the art. Where no such certainty can be established from the context, the term may be understood as also meaning “about,” e.g., within ±1%, within ±5%, or within ±10%.

[0053] Where “about” is used to modify one number in a series or range, it is understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range; thus, the term “about 1, 2, or 3” is understood to mean “about 1, about 2, or about 3” and the term “about 1 to 10” means “about 1 to about 10.”

[0054] In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0055] A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations; the current list as of the date of this filing is hereby incorporated by reference as if fully set forth herein.

[0056] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, who as a shorthand may be referred to simply as “one of skill.” Further definitions that may assist a reader in understanding the disclosed embodiments follow; however, it will be appreciated that such definitions are not intended to limit the scope of the invention, which shall be properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill) in view of the language used in the claims. Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0057] Generally, the nomenclature used and procedures performed herein are those known in fields relating to one or more aspects of the invention, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or medicinal chemistry, and are those that will be well known and commonly employed in such fields. Standard techniques and procedures will be those generally performed according to conventional methods in the art.

[0058] “Alkyl” will be understood to include straight or branched radicals having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” can also be used. In some embodiments, an alkyl group comprises from 1 to 10 carbon atoms, from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 3 carbon 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. In embodiments, an alkyl group will be optionally substituted. In embodiments, an alkyl group will be substituted at one or more positions. In embodiments, an alkyl group will not be substituted at any positions.

[0059] “Alkenyl” refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl, and cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, and cyclobuta-1,3-dien-1-yl; and the like. An alkenyl group can be substituted or unsubstituted.

[0060] “Alkynyl” refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include ethynyl; propynyls such as prop-1-yn-1-yl, and prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, and but-3-yn-1-yl; and the like. An alkynyl group can be substituted or unsubstituted.

[0061] “Aryl” refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In some embodiments, an aryl group comprises from 6 to 20 carbon atoms, or between 6 to 12 carbon atoms. An aryl group can be substituted or unsubstituted.

[0062] “Cycloalkyl” refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decahydronaphthalene and adamantane. When cycloalkyl is a monocyclic C3-8cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a monocyclic C3-6cycloalkyl, exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group can be substituted or unsubstituted.

[0063] “Cycloalkenyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring. However, if there is more than one double bond, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. Cycloalkenyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Representative cycloalkenyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. A cycloalkenyl group may be unsubstituted or substituted.

[0064] “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 to 6 carbon atoms (i.e., a C3-C6cycloalkylmethyl), 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms . In some embodiments, the cycloalkylmethyl group is a cyclopropylmethyl group. A cycloalkylmethyl group can be substituted or unsubstituted.

[0065] “Halogen” refers to fluorine, chlorine, bromine, and iodine.

[0066] “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, but not limited to, —S(O)— and —S(O)2—. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, 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, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C1-6 alkyl or oxo (═O), among many others.

[0067] “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. Alkyl-heterocycloalkyl groups can be substituted or unsubstituted.

[0068] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. A heteroaryl includes groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0069] “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 C0-6, 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. In some instances, the alkyl component can be absent. The heteroaryl component is as defined within. Alkyl-heteroaryl groups can be substituted or unsubstituted.

[0070] “Alkoxy” refers to the formula —OR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0071] “Alkylthio” or “thioalkyl” refers to the formula —SR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein. A non-limiting list of alkylthio are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio. An alkylthio may be substituted or unsubstituted.

[0072] “Acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, connected via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0073] “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, dihaloalkyl refers to an alkyl substituted by two halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl groups include difluoromethyl (—CHF2), bromofluoromethyl (—CHBrF), trifluoromethyl (—CF3), and 2-fluoroethyl (—CH2CH2F). Additional examples of haloalkyl groups include —CHF2, —CH2F, —CH2CF3, —CH2CHF2, —CH2CH2F, —CH(CH3)(CF3), —CH(CH3)(CHF2), and —CH(CH3)(CH2F). A haloalkyl may be substituted or unsubstituted.

[0074] “Hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxy- propyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0075] “Haloalkoxy” refers to an —O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). The halogens may be the same or different in each instance. Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0076] “Sulfenyl” refers to an —SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A sulfenyl may be substituted or unsubstituted.

[0077] “Sulfinyl” refers to an —S(═O)—R group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0078] “Sulfonyl” refers to an —SO2R group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0079] “O-carboxy” refers to a —RC(═O)O— group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carboxy may be substituted or unsubstituted.

[0080] “Ester” and “C-carboxy” refer to a —C(═O)OR group in which R can be the same as defined with respect to O-carboxy. Ester and C-carboxy groups may be substituted or unsubstituted.

[0081] “Thiocarbonyl” refers to a —C(═S)R group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0082] “Trihalomethanesulfonyl” refers to an X3CSO2— group wherein each X is a halogen.

[0083] “Trihalomethanesulfonamido” refers to an X3CS(O)2N(RA)— group wherein each X is a halogen, and RAis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0084] “S-sulfonamido” refers to a —SO2N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An S-sulfonamido may be substituted or unsubstituted.

[0085] “N-sulfonamido” refers to a RSO2N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-sulfonamido may be substituted or unsubstituted.

[0086] “O-carbamyl” refers to a —OC(═O)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carbamyl may be substituted or unsubstituted.

[0087] “N-carbamyl” refers to an ROC(═O)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-carbamyl may be substituted or unsubstituted.

[0088] “O-thiocarbamyl” refers to a —OC(═S)—N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-thiocarbamyl may be substituted or unsubstituted.

[0089] “N-thiocarbamyl” refers to an ROC(═S)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-thiocarbamyl may be substituted or unsubstituted.

[0090] “C-amido” group refers to a —C(═O)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A C-amido may be substituted or unsubstituted.

[0091] “N-amido” refers to a RC(═O)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-amido may be substituted or unsubstituted.

[0092] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. In some embodiments, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. If no substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group.

[0093] Still additional definitions and abbreviations are provided elsewhere herein. B. Compounds

[0094] In one aspect, provided is a compound of Formula (1): , or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein: R1is H or –C(O)–C1-C6alkyl; R2is halo, H, or C1-C6alkyl; R6is C1-C6alkyl or C2-C6alkenyl; R14is C1-C6alkyl, C1-C6alkoxy, or halo; and R' and R'' are both C1-C6alkyl; or R' and R'' are taken together to form an optionally substituted heterocyclyl.

[0095] In some embodiments of Formula (1), R1is H or –C(O)–C1-C6alkyl. In some embodiments, R1is H. In some embodiments, R1is –C(O)–C1-C6alkyl. For example, in some embodiments, R1is acetyl. In some embodiments, R1is propanoyl. In some embodiments, R1is butyryl. In some embodiments, R1is valeryl.

[0096] In some embodiments of Formula (1), R2is halo, H, or C1-C6alkyl. In some embodiments, R2is halo. In some embodiments, R2is F, Cl, Br, or I. In some embodiments, R2is F. In some embodiments, R2is Cl. In some embodiments, R2is Br. In some embodiments, R2is I. In some embodiments, R2is H. In some embodiments, R2is C1-C6alkyl. In some embodiments, R2is methyl.

[0097] In some embodiments of Formula (1), R6is C1-C6alkyl or C2-C6alkenyl. In some embodiments, R6is C1-C6alkyl. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is C2-C6alkenyl. In some embodiments, R6is allyl.

[0098] In some embodiments of Formula (1), R14is C1-C6alkyl, C1-C6alkoxy, or halo. In some embodiments, R14is C1-C6alkyl. In some embodiments, R14is methyl. In some embodiments, R14is ethyl. In some embodiments, R14is C1-C6alkoxy. In some embodiments, R14is methoxy. In some embodiments, R14is halo. In some embodiments, R14is F, Cl, Br, or I. In some embodiments, R14is F. In some embodiments, R14is Cl. In some embodiments, R14is Br. In some embodiments, R14is I.

[0099] In some embodiments of Formula (1), R' and R'' are both C1-C6alkyl. It will be understood that in embodiments wherein R' and R'' are both C1-C6alkyl, R' and R'' can be the same or different. For example, in an exemplary embodiment wherein R' and R'' are both C1-C6alkyl, R' and R'' are both ethyl. However, in another exemplary embodiment wherein R' and R'' are both C1-C6alkyl, R' is methyl and R'' is isopropyl. In some embodiments, R' and R'' are both methyl. In some embodiments, R' and R'' are both ethyl. In some embodiments, R' is methyl and R'' is n-propyl. In some embodiments, R' is methyl and R'' is isopropyl.

[0100] In some embodiments of Formula (1), R' and R'' are taken together to form a heterocyclyl, wherein the heterocyclyl is optionally substituted by alkyl. In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by alkyl. In some embodiments, R' and R'' are taken together to form a heterocyclyl, wherein the heterocyclyl is optionally substituted by alkyl. In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by C1-C6alkyl. In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is unsubstituted. For example, in some embodiments, R' and R'' are taken together to form a 4-membered heterocyclyl, such as an azetidine. In some embodiments, R' and R'' are taken together to form a 5-membered heterocyclyl, such as a pyrrolidine. In some embodiments, R' and R'' are taken together to form a 6-membered heterocyclyl, such as a piperidine. In some embodiments wherein R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, the 4- to 6-membered heterocyclyl contains an additional heteroatom. For example, in some embodiments, R' and R'' are taken together to form a 6-membered heterocyclyl containing an additional heteroatom, such as an oxygen (morpholine), a sulfur (thiomorpholine), or a nitrogen (a piperazine). In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by C1-C6alkyl. In certain preferred embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by methyl. In some embodiments, R' and R'' are taken together to form a 2-methylazetidine. In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by ethyl. In some embodiments, R' and R'' are taken together to form a 2-ethylazetidine. In some embodiments, R' and R'' are taken together to form a dimethylazetidine. In some such embodiments, R' and R'' are taken together to form a 2,4-dimethylazetidine. In some embodiments, R' and R'' are taken together to form or , wherein the asterisk (*) indicates the point of connection to the remainder of the compound. In some embodiments, R' and R'' are taken together to form a tetramethylazetidine.

[0101] In some embodiments, the compound of Formula (1) has the structure of Formula (1A), , or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein R1, R2, R6, R', and R'' are as defined for Formula (1).

[0102] In some embodiments, the compound of Formula (1) has the structure of Formula (1B), , or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein X is halo; and R1, R2, R6, R', and R'' are as defined for Formula (1).

[0103] In some embodiments, X is halo. In some embodiments, X is F, Cl, Br, or I. In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is Br. In some embodiments, X is I.

[0104] In some embodiments, the compound of Formula (1) has the structure of Formula (1C), , or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein R14 'is C1-C6alkyl; and R1, R2, R6, R', and R'' are as defined for Formula (1).

[0105] In some embodiments, R14 'is C1-C6alkyl. In some embodiments, R14 'is methyl.

[0106] In another aspect, provided is a compound of Formula (2), , or a prodrug, hydrate, or solvate thereof, wherein: R1is H or –C(O)–C1-C6alkyl; R2is H, C1-C6alkyl, or halo; R6is C1-C6alkyl or C2-C6alkenyl; R6 'is C1-C6alkyl; R14is C1-C6alkyl, C1-C6alkoxy, or halo; and R' and R'' are both C1-C6alkyl; or R' and R'' are taken together to form an optionally substituted heterocyclyl.

[0107] In some embodiments of Formula (2), R1is H or –C(O)–C1-C6alkyl. In some embodiments, R1is H. In some embodiments, R1is –C(O)–C1-C6alkyl. For example, in some embodiments, R1is acetyl. In some embodiments, R1is propanoyl. In some embodiments, R1is butyryl. In some embodiments, R1is valeryl.

[0108] In some embodiments of Formula (2), R2is H, C1-C6alkyl, or halo. In some embodiments, R2is H. In some embodiments, R2is C1-C6alkyl. In some embodiments, R2is methyl. In some embodiments, R2is halo. In some embodiments, R2is F, Cl, Br, or I. In some embodiments, R2is F. In some embodiments, R2is Cl. In some embodiments, R2is Br. In some embodiments, R2is I.

[0109] In some embodiments of Formula (2), R6is C1-C6alkyl or C2-C6alkenyl. In some embodiments, R6is C1-C6alkyl. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is C2-C6alkenyl. In some embodiments, R6is allyl.

[0110] In some embodiments of Formula (2), R6’is C1-C6alkyl. In some embodiments, R6’is methyl.

[0111] In some embodiments of Formula (2), R14is C1-C6alkyl, C1-C6alkoxy, or halo. In some embodiments, R14is C1-C6alkyl. In some embodiments, R14is methyl. In some embodiments, R14is ethyl. In some embodiments, R14is C1-C6alkoxy. In some embodiments, R14is methoxy. In some embodiments, R14is halo. In some embodiments, R14is F, Cl, Br, or I. In some embodiments, R14is F. In some embodiments, R14is Cl. In some embodiments, R14is Br. In some embodiments, R14is I.

[0112] In some embodiments of Formula (2), R' and R'' are both C1-C6alkyl. It will be understood that in embodiments wherein R' and R'' are both C1-C6alkyl, R' and R'' can be the same or different. For example, in an exemplary embodiment wherein R' and R'' are both C1-C6alkyl, R' and R'' are both ethyl. However, in another exemplary embodiment wherein R' and R'' are both C1-C6alkyl, R' is methyl and R'' is isopropyl. In some embodiments, R' and R'' are both methyl. In some embodiments, R' and R'' are both ethyl. In some embodiments, R' is methyl and R'' is n-propyl. In some embodiments, R' is methyl and R'' is isopropyl.

[0113] In some embodiments of Formula (2), R' and R'' are taken together to form a heterocyclyl, wherein the heterocyclyl is optionally substituted by alkyl. In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by alkyl. In some embodiments, R' and R'' are taken together to form a heterocyclyl, wherein the heterocyclyl is optionally substituted by alkyl. In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by C1-C6alkyl. In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is unsubstituted. For example, in some embodiments, R' and R'' are taken together to form a 4-membered heterocyclyl, such as an azetidine. In some embodiments, R' and R'' are taken together to form a 5-membered heterocyclyl, such as a pyrrolidine. In some embodiments, R' and R'' are taken together to form a 6-membered heterocyclyl, such as a piperidine. In some embodiments wherein R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, the 4- to 6-membered heterocyclyl contains an additional heteroatom. For example, in some embodiments, R' and R'' are taken together to form a 6-membered heterocyclyl containing an additional heteroatom, such as an oxygen (morpholine), a sulfur (thiomorpholine), or a nitrogen (a piperazine). In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by C1-C6alkyl. In certain preferred embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by methyl. In some embodiments, R' and R'' are taken together to form a 2-methylazetidine. In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by ethyl. In some embodiments, R' and R'' are taken together to form a 2-ethylazetidine. In some embodiments, R' and R'' are taken together to form a dimethylazetidine. In some such embodiments, R' and R'' are taken together to form a 2,4-dimethylazetidine. In some embodiments, R' and R'' are taken together to form or , wherein the asterisk (*) indicates the point of connection to the remainder of the compound. In some embodiments, R' and R'' are taken together to form a tetramethylazetidine.

[0114] In some embodiments of Formula (2), X - is a pharmaceutically acceptable anion. The anion can be any anion known to the person of skill in the art to be suitable for use in pharmaceutical compositions and formulations, including exemplary anions disclosed in embodiments herein for pharmaceutically acceptable salts (See Berge et al. (1977) “Pharmaceutical Salts,” J. Pharm. Sci.66:1-19.). For example, in some embodiments, X - is a halide (e.g., fluoride, chloride, bromide, iodide). In some embodiments, X - is bromide or iodide. In some embodiments, X - is bromide. In some preferred embodiments, X - is iodide. In some embodiments, X - is an organic sulfonate (e.g., 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, camphorsulfonate). In some embodiments, X - is an organic carboxylate (e.g., benzoate, alkanoate, tartrate). In some preferred embodiments, X - is tartrate.

[0115] In some embodiments, the compound is selected from Table 1. Table 1: Exemplary Compounds

[0002]

[0116] In some embodiments, the compound is selected from Table 2. Table 2: Exemplary Compounds

[0003]

[0117] T he disclosure will be understood to also encompass pharmaceutically acceptable salts of disclosed compounds. The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, and which may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. One of ordinary skill in the art can select from among a wide variety of available counterions those that are pharmaceutically acceptable. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenyl- propionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc and the like. (See Berge, et al., J. Pharm. Sci.1997, 66, 1-19.)

[0118] Certain compounds disclosed herein 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 in the present disclosure.

[0119] A disclosed compound can exist in solid or liquid form. In the solid state, the compound may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline compounds. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The subject matter described herein includes such solvates.

[0120] The skilled artisan will further appreciate that certain compounds described herein that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs.” The subject matter disclosed herein includes such polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

[0121] 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. Optically active (R)– and (S)–, (–)– and (+)–, or (D)– and (L)–isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard tests described herein and other similar tests which are well known in the art. Examples of methods that can be used to obtain optical isomers of the compounds according to the present disclosure include selective crystallization, enzymatic resolution, asymmetric synthesis (including asymmetric chemical synthesis and asymmetric enzymatic synthesis), kinetic resolution, and chiral chromatography (including chiral liquid chromatography, gas chromatography, and high-performance liquid chromatography). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, tautomeric forms are included.

[0122] 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. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine such as2H,3H,11C,13C,14C,15N,17O,18O, and36Cl respectively. In one non-limiting embodiment, isotopically labeled compounds can be used in metabolic studies (with14C), reaction kinetic studies (with, e.g.,2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. An18F-labeled compound may be particularly desirable for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0123] The disclosure also includes prodrugs of disclosed compounds. A “prodrug” is a precursor of a biologically active pharmaceutical agent, which may undergo a chemical or a metabolic conversion to become the biologically active agent. A prodrug can be converted ex vivo to the biologically active pharmaceutical agent by chemical transformative processes. In vivo, a prodrug is converted to the biologically active pharmaceutical agent by the action of a metabolic process, an enzymatic process or a degradative process that removes the prodrug moiety to form the biologically active pharmaceutical agent. Typical examples of prodrugs include compounds with biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Commonly used functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides. These functional groups can be attached to the drug molecule via a linker that is designed to be cleaved under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage. The choice of functional group depends on factors such as stability, ease of synthesis, enzymatic activity, and desired rate of prodrug conversion.

[0124] Generally, the individual disclosed compounds will be administered as part of a pharmaceutical composition or formulation, and are prepared for inclusion in such composition or formulations as isolated or purified compounds. The terms “isolated,” “purified,” or “substantially pure,” as used herein, refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced. An “isolated,” “purified,” or “substantially pure” preparation of a compound is accordingly defined as a preparation having a chromatographic purity (of the desired compound) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method.

[0125] Preferably the substantially pure compound used in the disclosure is substantially free of any other active compounds which are not intended to be administered to a subject. In this context “substantially free” can be taken to mean that no active compound(s) other than the active compound intended to be administered to a subject are detectable by HPLC or other similar detection method, or are below a desired threshold of detection such as defined above.

[0126] In some aspects, features of disclosed compounds provide various advantages. Such advantages may be related to modulation of neurotransmission, pharmacokinetics, such as properties related to absorption, distribution, metabolism, and excretion of a disclosed compound, and subjective effects, such as upon administration to a subject. In embodiments, such advantages are determined relative to a comparator.

[0127] In some embodiments, the comparator is a lysergamide lacking a substituent at the 2- and / or 14-positions. For example, in some embodiments, the comparator is LSD. In some embodiments, the comparator is 2-Br-LSD. In some embodiments, the comparator is LSZ. C. Methods of Preparing Disclosed Compounds

[0128] In some aspects, provided herein are methods of preparing disclosed compounds, such as compounds of Formula (1), Formula (2), and any subformula thereof.

[0129] Specific examples of the synthesis of disclosed compounds are provided in Examples 1 and 2.

[0130] In one example, a compound of Formula (1) wherein R14is methyl is prepared according to the following reaction sequence:

[0131] In some embodiments, wherein a disclosed compound contains a 2-halo substituent (i.e., a compound of Formula (1) or (2) wherein R2is F, Cl, Br or, I), the compound can be prepared by halogenation of the corresponding compound containing a hydrogen at the 2-position (i.e., a compound wherein R2is H). This is shown in the exemplary reaction scheme below for the preparation of a compound of Formula (1) wherein R2is F, Cl, Br, or I:

[0132] Halogenation can be performed according to methods known to the skilled artisan. (see, e.g., Troxler and Hofmann, Helvetica Chimica Acta, 1957, 40(7), 2160-2170.)

[0133] In some embodiments, disclosed compounds are prepared by amide coupling (e.g., pyBOP coupling) of a suitable lysergic acid precursor, according to the following exemplary scheme:

[0134] The lysergic acid precursor can be prepared according to known methods, in particular those disclosed in Knight et al. J. Org. Chem.2023, 88, 4, 2158–2165.

[0135] In some embodiments, wherein a disclosed compound contains an N(1)-substituent (i.e., a compound of Formula (1) or (2) wherein R1is –C(O)–C1-C6alkyl), the compound can be prepared by halogenation of the corresponding compound containing a hydrogen at the N(1)-position (i.e., a compound wherein R1is H). This is shown in the exemplary reaction scheme below for the preparation of a compound of Formula (1) wherein R1is –C(O)–C1-C6alkyl:

[0136] Although an acid anhydride is depicted above as an exemplary acylating reagent, the skilled artisan will understand that any suitable acylating agent can substitute (e.g., an acid chloride). Suitable acylation methods are known to those of skill in the art.

[0137] Disclosed compounds of Formula (2) can be prepared by quaternization of a corresponding compound of Formula (1):

[0138] Precursors and reaction conditions suitable for quaternization are known in the art. In this reaction sequence, wherein R6 ’—X represents a suitable alkylating agent comprising an alkyl moiety and a leaving group (X). For example, in some embodiments, the alkylating agent is methyl iodide.

[0139] For disclosed compounds wherein R' and R'' are taken together to form an azetidine, such as an unsubstituted azetidine or an alkyl-substituted azetidine, the intermediate azetidine, alkylylazetidine, or dialkylazetidines are prepared according to known procedures in the art (see, e.g., Dall'Asta & Pedrazzoli, Experientia, 1970, 26, 1188-1189; Marinetti et al., Eur. J. Org. Chem., 2000, 1815-1920).

[0140] Additional synthetic methods that may be useful for the synthesis of disclosed compounds and any necessary starting materials may be found in Nichols et al., J. Med. Chem.2002, 45, 4344-4349; and general references well-known in the art (see, e.g., Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed.1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols.1-8 (John Wiley & Sons, 1971-96); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1-17, Wiley Interscience; Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991; “Theilheimer’s Synthetic Methods of Organic Chemistry,” Volumes 1-45, Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Interscience, 1991; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995). D. Pharmaceutical Compositions

[0141] In some aspects, provided herein are compositions, such as pharmaceutical compositions, comprising a disclosed compound. “Pharmaceutical compositions” are compositions that include the disclosed compound(s) together in an amount (for example, in a unit dosage form) with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments will not have a single carrier, diluent, or excipient alone, but will include multiple carriers, diluents, and / or excipients. Compositions can be prepared by standard pharmaceutical formulation techniques such as disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th 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., Inc., Lancaster, Pa.; Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; & Poznansky et al. Drug Delivery Sys. (1980), R.L. Juliano, ed., Oxford, N.Y., pp.253-315).

[0142] “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.

[0143] In some embodiments, pharmaceutical compositions comprising a disclosed compound can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal. In some embodiments, the compounds employed in the methods of this disclosure are effective as oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. (See, e.g., Remington, 2020.)

[0144] The disclosed compositions are preferably formulated in a unit dosage form, each dosage containing a therapeutically effective amount of the active ingredients, for example in the dosage amounts disclosed below. The term “unit dosage form” refers to a physically discrete unit suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect(s), in association with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are often used for ease of administration and uniformity of dosage. Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof (e.g., one half a “full” dose for a “booster” dose as described below), of the pharmaceutical composition administered.

[0145] Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Unit dosage forms also include ampules and vials with liquid compositions disposed therein. Unit dosage forms further include compounds for transdermal administration, such as “patches” that contact the epidermis (including the mucosa) for an extended or brief period of time.

[0146] In embodiments, a disclosed composition is formulated in a pharmaceutically acceptable oral dosage form. Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like) and oral solid dosage forms. A disclosed pharmaceutical composition may be prepared as a formulation suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0147] In embodiments, disclosed pharmaceutical compositions may be formulated into a topical formulation (e.g., a topical 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, for example, 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, gelling agents, and other such ingredients as will be generally known to one of skill.

[0148] In some embodiments, the topical formulation comprises a penetration enhancer. Without being bound by theory, penetration enhancers are generally characterized by their ability to increase the permeability of biological barriers, such as scalp skin. In some embodiments, including a penetration enhancer in the formulation increases the bioavailability of the active agent(s) by improving the ability of the active agent(s) to diffuse into the skin tissue. Penetration enhancers include, for example, 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, 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 some embodiments, the penetration enhancer is selected from a group comprising lower chain alcohol with a carbon chain length of 1 to 5, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxychoiate, sodium taurodeoxyeholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, fysophosphatidylchoiine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulphate, Polyoxyethylene-9-lauryl ether, Polyoxythylene-20-cetyiether, Benzalkonium chloride, cetylpyridinium chloride, Vitamin E TPGS, Caprylocaproyl poiyoxylglycerides, Stearoyl Macrogolglycerides, Propylene Glycol Dicaprylocaprate or mixtures thereof.

[0149] In some embodiments, a topical formulation may comprise a penetration enhancer at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of the formulation , on a weight or volume basis.

[0150] In some embodiments, the topical formulation comprises a carrier. Carriers can be designed to give controlled release profiles, improved circulation times and better penetration across the epithelium. In some embodiments, the carrier is a hydrophobic drug carrier. Hydrophobic drug carriers can have the advantage of exhibiting slow sustained release and may adhere well to biological surfaces. Hydrophobic drug carriers can have slow (i.e., extended) release kinetics, or may also be constructed to have a rapid or immediate release profile. New techniques include the development of hydrophilic coatings on hydrophobic nanoparticles to improve their transport across tissue surfaces while retaining the slow-release profiles. These include polyethylene glycol and chitosan coatings (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, without limitation, 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. Selection of a pharmacologically acceptable carrier can depend on the mode of administration. Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed.1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed.2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10th ed.2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003).

[0151] 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 sarconsinates, 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 emulsifiers are synthetic or natural polymers. In certain embodiments, the emulsifier includes silicon. In certain embodiments, the emulsifier is a silicone (e.g., dimethicone, phenyltrimethicone, PEG dimethicone, PPG dimethicone, etc.).

[0152] In embodiments, the topical formulation comprises an antioxidant. 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., β-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., thiorodoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, and lauryl, palmitoyl, oleyl, γ-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), in very low tolerated doses (e.g., pmol to μmol / kg), and furthermore (metal)chelators (e.g., α-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin), α-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., γ-linolenic 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, α-glycosylrutin, ferulaic acid, furfurylideneglucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, nordihydroguajak resin acid, 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).

[0153] In embodiments, the topical formulation comprises a thickener. The thickener may be crosslinked polyacrylic acids and derivatives thereof, polysaccharides and derivatives thereof, such as xanthan gum, agar agar, alginates or tyloses, cellulose derivatives (e.g., carboxymethylcellulose or hydroxycarboxymethylcellulose), fatty alcohols, monoglycerides and fatty acids, polyvinyl alcohol and PVP.

[0154] In embodiments, the topical formulation comprises a cosmetically and / or dermo-cosmetically active substance. A cosmetically and / or dermo-cosmetically active substance may be a color-imparting active substance, skin- or hair-pigmenting composition, tinting composition, tanning composition, bleach, keratin-hardening substance, antimicrobial active substance, light filter active substance, repellent active substance, substance having hyperemic activity, substance having keratolytic or keratoplastic activity, anti- phlogistic agent, substance having keratinizing activity, antioxidant active substance or substance active as a free radical scavenger, skin-moisturizing substance or skin humectant, refatting active substance, substance having antierythematous or antiallergic activity, branched fatty acid, and any mixture thereof.

[0155] In embodiments, the topical formulation comprises a perfume oil. Natural fragrances are extracts of blossoms (lily, lavender, rose, jasmine, neroli, ylang-ylang), stalks and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, caraway, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), woods (pinewood, sandalwood, guajak wood, cedar wood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Typical synthetic fragrance compounds are products of the type consisting of the esters, ethers, aldehydes, ketones, alcohols and hydrocarbons. Essential oils of low volatility, which are generally used as aroma components, are also suitable as perfume oils, e.g., sage oil, chamomile oil, clove oil, balm oil, mint oil, cinnamon leaf oil, lime tree blossom oil, juniper oil, vetiver oil, oliban oil, galbanum oil, labolanum oil and lavandin oil. Bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, α-hexylcinnamaldehyde, geraniol, benzyl- acetone, cyclamenaldehyde, linalool, Boisambrene®Forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allylamyl glycolate, cyclovertal, lavandin oil, muscatel sage oil, G39 damascone, Bourbon geranium oil, cyclohexyl salicylate, Vertofix®Coeur, iso-E-Super®, Fixolide®NP, evemyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romillate, irotyl and floramat.

[0156] In embodiments, the topical formulation comprises a solvent, and optionally a cosolvent. Any solvent(s) and cosolvent(s) may be collectively referred to as a “solvent system.” Without being bound by theory, the solvent system chosen can affect the stability, bioavailability, and 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 should be stable and compatible with the active agent(s) and any other excipients) in the formulation. In some embodiments, wherein the solvent system comprises more than one solvent, the ratio of cosolvents is optimized, for example to increase the penetration or bioavailability of an active agent. Preferred solvent systems are also safe and non-toxic for human consumption. In some embodiments, potential adverse effects, such as irritation or allergic reactions, are considered and minimized during selection of solvents included in a solvent system of the disclosure. Solvents that may be included in topical formulations may include, without limitations, 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 the formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of solvents in the formulation divided by the total weight of the formulation).

[0157] In embodiments, the topical formulation comprises a viscosity modifying agent. In some embodiments, the viscosity modifying agent is a thickener. Common thickeners include but are not limited to: acrylates, carbomers, cellulose matrices, silicones, carrageenans, gums, resins, polysaccharides, and high melting point waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosins, resins, paraffins, and petroleum jelly. In some embodiments, the viscosity modifying agent is a carbohydrate. Exemplary carbohydrates include monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Exemplary polysaccharides include cellulose, methylcellulose, hydroxypropylmethylcellulose, chitin, galactoarabinan, polygalactose, and polyarabinose. Exemplary glycerides includes hydroxystearic acid monoglyceride, hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid monoglyceride, linolenic acid diglyceride, erucic acid monoglyceride, erucic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglyceride, malic acid monoglyceride, malic acid monoglyceride, malic acid diglyceride, and mixture thereof. In some embodiments, the viscosity modifying agent is a polymer. The polymer may be a natural or synthetic polymer. Natural polymers include polysaccharides, nucleic acid, and proteins. Synthetic polymers include polyesters, polyureas, polycarbonates, polyvinyl alcohol, polyamides, polyethers, polyesters, polyamines, polytyrosines, polyanhydrides, polyphosphazenes, polyacrylamides, polyacrylates, polymethacrylates, polyvinylpyrrolidone (PVP), etc. Exemplary thickening agents include alginate derivatives, preneutralized carbomer 430, hydrophilic silicas, polysaccharides, xanthan gum, guar guar, agar agar, carboxymethylcellulose, hydroxyethylcellulose, polyacrylates, polyacrylamides, PVP, and salts.

[0158] In embodiments, the topical formulation comprises an adhesion modifying agent. In embodiments, the topical formulation comprises an adhesive polymer. Adhesive polymers have physicochemical properties that allow prolonged binding to tissue surfaces. In some embodiments, inclusion of an adhesive polymer in the formulation increases the amount of time that an active agent is in contact with, and can diffuse across, a barrier (e.g., skin). In some embodiments, the adhesive polymer is 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. Common tackifiers include but are not limited to gums, resins (natural or modified), carbomers, or other natural or synthetic polymers.

[0159] In embodiments, the topical formulation comprises a preservative. Preservatives can be used to inhibit microbial growth or increase stability of the formulation, thereby prolonging the shelf life of the formulation. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates (e.g., sodium benzoate), vitamin A, vitamin C (ascorbic acid), citric acid, vitamin E, and tocopherol.

[0160] In embodiments, the topical formulation comprises an antioxidant. Without being bound by theory, antioxidants generally can delay or inhibit the oxidative decomposition of components of the topical formulations, which may thereby improve the stability and extend the shelf-life thereof. In embodiments, the antioxidant is α-tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, methionine, citric acid, ascorbic acid, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, propyl gallate, cysteine, or a combination thereof. In some embodiments, the antioxidant is a cyclodextrin, D-α-tocopherol, rosmarinic acid, or a combination thereof.

[0161] In embodiments, the topical formulation comprises a solubilizing agent. Without being bound by theory, solubilizing agents generally form complexes with active ingredients which can have different physicochemical properties than the active ingredient alone. The properties of the complexes can 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. In some embodiments, the water-soluble enhancing agent is 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 propylene glycol. In some embodiments, the solubilizing agent is xanthan gum. In some embodiments the solubilizing agent is a non-ionic surfactant. In some embodiments, the non-ionic surfactant is 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. In some embodiments, the organic liquid is 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. In embodiments, the phospholipid is hydrogenated soy phosphatidylcholine, distearoyl- phosphatidylglycerol, L-alpha-dimyristoyl-phosphatidylcholine, or L-alpha-dimyristoyl-phosphatidylglycerol. In some embodiments, the solubilizing agent is lecithin.

[0162] In embodiments, the topical formulation comprises a colorant. Suitable colorants and / or dyes and / or pigments include colors such as e.g., white, black, yellow, blue, green, pink, red, orange, violet, indigo, brown, and combinations thereof, pigments such as, e.g., Timica Extra Large Sparkles, titanium dioxide and chromium oxide greens, ultramarine blues and pinks and ferric oxides. Colorants and / or dyes and / or pigments may be present, individually or in total (if more than one colorant and / or dye and / or pigment is included), in disclosed formulations in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of colorants and / or dyes and / or pigments in the formulation divided by the total weight of the formulation). Colorants may be present, individually or in total (if more than one colorant is included), in disclosed formulations in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of colorants in the formulation divided by the total weight of the formulation).

[0163] In embodiments, the topical formulation comprises a binder. Suitable binders include, without limitations, 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, and colloidal silica. Binders may be present, individually or in total (if more than one binder is included), in disclosed formulations in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of binders in the formulation divided by the total weight of the formulation).

[0164] In embodiments, the topical formulation comprises a humectant. Humectants, such as low molecular weight polyethylene glycol (e.g., PEG6-PEG12), may be present, individually or in total (if more than one humectant is included), in the formulation in an 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% (calculated as the total weight of humectants in the formulation divided by the total weight of the formulation).

[0165] In embodiments, the topical formulation comprises a surfactant. The surfactants that can be included in the formulation may be anionic, nonionic, or amphoteric compounds. Suitable examples of anionic surfactants are one or more of higher alkyl sulfates such as potassium or sodium lauryl sulfate, higher fatty acid monoglyceride monosulfates, such as the salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, alkyl sulfonates such as sodium dodecyl benzene sulfonate, higher fatty sulfoacetates, higher fatty acid esters of 1,2 dihydroxypropane sulfonate. Examples of water soluble nonionic surfactants are condensation products of ethylene oxide with various hydrogen-containing compounds that are reactive therewith and have long hydrophobic chains (e.g., aliphatic chains of about 12 of 20 carbon atoms), which condensation products contain hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides and other fatty moieties, and with propylene oxide and polypropylene oxides, e.g., Pluronic materials such as Pluronic F127. Exemplary suitable alkyl polyglycoside (APG) surfactant(s) that may be used in the formulation may comprise APG C8-C10, APG C10-C16, decyl glucoside, coco-glucoside, anionic APG carboxylate, sodium lauryl glucose carboxylate, lauryl glucoside, D-glucopyranose (oligomeric, CIO-16 glycosides, carboxymethyl ethers, sodium salts), C12-C16 fatty alcohol glycoside, and combinations thereof. Exemplary APG surfactant(s) that may be used may have an industry designation of Plantaren® 2000 N UP / MB, Plantapon® LGC Sorb, Plantaren® 1200 N UP / MB, and Plantaren® 818 UP / MB. Surfactants may be present, individually or in total (if more than one surfactant is included) in the formulation in an amount ranging from about 0.01 wt% to about 10 wt% (calculated as the total weight of surfactants in the formulation divided by the total weight of the formulation ).

[0166] In embodiments, the topical formulation comprises a gelling agent. Exemplary gelling agent(s) used in disclosed formulations may comprise pectins, starches, and gelatin forms derived from animals or from plants (e.g., pork gelatin). The pectin in the formulation may include, e.g., high methoxyl pectin, low methoxyl pectin, or a combination thereof. In some embodiments, the pectin is amidated pectin. In other embodiments, the pectin is non-amidated pectin. In certain embodiments, the pectin is a combination of amidated pectin and non-amidated pectin. The gelatin in the formulation may include Type A gelatin, Type B gelatin, a hide or skin gelatin (e.g., calf skin, pig skin) and / or a bone gelatin (e.g., calf bone, pig bone) used alone or in combination. Gelling agent(s) may be present, individually or in total (if more than one gelling agent is included) in the formulation in an amount ranging from about 0.1 wt% to about 20 wt% (calculated as the total weight of gelling agents in the formulation divided by the total weight of the formulation).

[0167] In some embodiments, a disclosed composition is formulated as an oral solid dosage form. Oral solid dosage forms may include but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combinations thereof. Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations. Accordingly, in some embodiments, the disclosed oral solid dosage forms may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-melt tablet. Additionally, pharmaceutical formulations may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.

[0168] Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof. Oral solid dosage forms also can comprise one or more pharmaceutically acceptable additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).

[0169] Supplementary active compounds include preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents. Preservatives can be used to inhibit microbial growth or increase stability of the active ingredient thereby prolonging the shelf life of the formulation. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate. Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as alpha lipoic acid.

[0170] In some embodiments, a disclosed composition is formulated as an oral liquid dosage form. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients. Solvents may be, for example, water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.

[0171] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. Liquid formulations also may be prepared as single dose or multi-dose beverages. Suspensions may include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include carrier oils such as MCT and long chain triglyceride (LCT) oils. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations may include alcohols, (such as ethanol, isopropyl alcohol, hexadecyl alcohol), glycerol, and propylene glycol. Ethers, such as poly(ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations. Suspension can thus include an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion, or a water-in-oil emulsion.

[0172] In some embodiments, formulations are provided comprising the disclosed compositions and at least one dispersing agent or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained. The aqueous dispersion can comprise amorphous and non-amorphous particles consisting of multiple effective particle sizes such that a drug is absorbed in a controlled manner over time.

[0173] Dosage forms for oral administration can be aqueous suspensions selected from the group including pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, e.g., Singh et al., Encyclopedia Pharm. Tech., 2nd Ed., 754-757 (2002). In addition to disclosed compounds, liquid dosage forms may comprise additives, e.g., one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, or (g) flavoring agents.

[0174] Disclosed compositions also may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0175] In some embodiments, a disclosed pharmaceutical composition may be formulated in an ophthalmic formulation. Ophthalmic formulations of the disclosure include topical formulations, such as eye drops, gels, and ointments; and may comprise excipients suitable for topical formulations, e.g., 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, gelling agents, and other such ingredients described herein and as will be generally known to one of skill in the art.

[0176] A disclosed ophthalmic formulation may contain one or more viscosity- modifying agents and have a viscosity that feels comfortable to the eye and does not cause blurring of the vision. For example, an ophthalmic formulation may have a viscosity of 1.0 to 100,000 cP (e.g., from about 2.0 to 90,000 cP or from about 2.5 to 75,000 cP). Viscosity-modifying agents are substances that have the ability to cause thickening (increase the viscosity) of ophthalmic formulations. Viscosity modifying agents include xanthan gum, edetate, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene glycol, propylene glycol alginate, chitosan, and tragacanth. Hydrogels may also be used as viscosity-enhancing excipients, particularly in artificial tears. Compatible viscosity-adjusting agents can be used in all formulations mentioned herein. Concentrations of viscosity-modifying agents in ophthalmic formulations of the disclosure can range from about 0.1 percent to about 10 percent by weight (e.g., between 1 percent and 5 percent by weight). Sorbitol may be used as a combined tonicity-adjusting and viscosity-modifying excipient. Sorbitol may be used in ophthalmic formulations of the disclosure in a concentration range from about 0.1 to about 10 percent (e.g., from 2 percent to 5 percent by weight).

[0177] The ophthalmic formulation may comprise a penetration enhancer, for example to aid penetration of the active compound(s) into and across the skin or eyelid skin. Exemplary penetration enhancers for ophthalmic formulations include, e.g., any of an aliphatic alcohol, fatty acid (including salts thereof), fatty acid ester, polyalcohol alkyl ether, polyoxyethylene alkyl ether, glyceride, polyalcohol medium chain fatty acid ester, polyoxyethylene sorbitan fatty acid ester, alkyl lactate ester, terpene, and organic amine. In some embodiments, the penetration enhancer is any of ethanol, glycerol, diethylene glycol, propylene glycol, polyethylene glycol and higher aliphatic alcohols (e.g., a saturated or unsaturated higher aliphatic alcohol having 12 to 22 carbon atoms such as oleyl alcohol, lauryl alcohol and stearyl alcohol), capric acid, myristic acid, palmitic acid, lauric acid, stearic acid, isostearic acid, oleic acid, linoleic acid, and linolenic acid (including salts thereof); an ester of a fatty acid such as myristic acid, palmitic acid, lauric acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, pivalic acid, caproic acid, heptanoic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, crotonic acid, sorbic acid, maleic acid, fumaric acid, and sebacic acid with a lower aliphatic alcohol such as methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, heptanol and octanol, isopropyl myristate, isopropyl palmitate, diisopropyl adipate and diethyl sebacate; an ether of a polyalcohol such as glycerol, ethylene glycol, propylene glycol, 1,3-butylene glycol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, methyl glucoside, oligo- saccharide and reduced oligosaccharide with alkyl alcohol; polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether and polyoxyethylene oleyl ether, glycerol ester of fatty acid having 6 to 18 carbon atoms (e.g., monoglyceride, diglyceride, triglyceride and a mixture thereof), glyceryl monolaurate, glyceryl monomyristate, glyceryl monostearate, glyceryl monooleate, glyceryl dilaurate, glyceryl dimyristate, glyceryl distearate, glyceryl trilaurate, glyceryl trimyristate and glyceryl tristearate, ethylene glycol monocaprylate, propylene glycol monocaprylate, glycerin monocaprylate, mono 2-ethylene glycol ethylhexanoate, mono 2-propylene glycol ethylhexanoate, di(2-propylene)glycol ethylhexanoate, propylene glycol, dicaprylate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate, methyl lactate, ethyl lactate, methyl 2-methoxy propionate, ethyl 2-methoxypropionate, monoethanolamine, triethanolamine, creatinine and meglumine. In embodiments, the ophthalmic formulation comprises a hydrating agent. Hydrating agents may also facilitate penetration of the active compound(s) through the cell or junctions of the barriers including mucosal, mucocutaneous, and stratum corneum layers. Exemplary hydrating agents include, e.g., hyaluronic acid (or a salt thereof, e.g., sodium hyaluronate), water, saline solution, and PVP, propylene glycol, glycerol, sorbitol, polyethylene glycol, dexpanthenol, panthothenic acid, ectoin, carboxyvinyl polymer, carmellose sodium, and povidone.

[0178] In some embodiments, the ophthalmic formulation comprises a surfactant. Surfactants may facilitate dissolution and / or absorption of formulation components, and include, e.g., any of an anionic surfactant, cationic surfactant, nonionic surfactant and amphoteric surfactant. Exemplary surfactants include, e.g., any of a fatty acid salt, alkyl sulfate, polyoxyethylene alkyl sulfate, alkylsulfo carboxylate salt, alkylether carboxylate salt, amine salt, quanternary ammonium salt, polysorbate 80, poloxamer, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, alkyl betaine, dimethylalkylglycine, and lecithin.

[0179] In some embodiments, the ophthalmic formulation comprises a gum and / or resin, e.g., any of a sodium polyacrylate, cellulose ether, calcium alginate, carboxyvinyl polymer, ethylene-acrylic acid copolymer, vinyl pyrrolidone polymer, vinyl alcohol-vinyl pyrrolidone copolymer, nitrogen-substituted acrylamide polymer, polyacrylamide, cationic polymer such as cationic guar gum, dimethylacrylic ammonium polymer, acrylic acid-methacrylic acid copolymer, polyoxyethylene-polypropylene copolymer, polyvinyl alcohol, pullulan, agar, gelatine, chitosan, polysaccharide from tamarindo seed, xanthan gum, carageenan, high-methoxyl pectin, low-methoxyl pectin, guar gum, acacia gum, microcrystalline cellulose, arabinogalactan, karaya gum, tragacanth gum, alginate, albumin, casein, curdlan, gellan gum, dextran, cellulose, polyethyleneimine, high polymerized polyethylene glycol, cationic silicone polymer, synthetic latex, acrylic silicone, trimethylsiloxysilicate, and fluorinated silicone resin.

[0180] In some embodiments, the ophthalmic formulation comprises a pH adjuster. A pH adjuster may be used to adjust the pH of the formulation to a desired range, such as pH 4-10, pH 5-8, or any range that maximizes the penetration through the skin of the compound(s) in the composition. In some embodiments, the pH adjuster is any of 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 hydrogencarbonate, 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, and aluminum potassium sulfate.

[0181] In some embodiments, the ophthalmic formulation comprises a stabilizer. Exemplary stabilizers include, e.g., 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 and / or succinic acid.

[0182] Additional ophthalmic formulations of the disclosure include contact lenses. In some embodiments, a disclosed compound or pharmaceutical composition is incorporated into a contact lens for ocular drug delivery. The contact lens may be a hydrogel contact lens or a molecularly imprinted contact lens. Another exemplary contact lens drug delivery system known to those of skill in the art is the experimental SIGHT (Sustained Innovative Glaucoma and Ocular Hypertension Treatment) treatment, which seeks to treat mild to moderate glaucoma and ocular hypertension (see Clinical Trial NCT04747808). The SIGHT drug-eluting lens for glaucoma treatment incorporates the FDA-approved drug bimatoprost into contact lenses that are formulated for controlled drug release. The SIGHT lens comprises drug and barrier layers on the lens surface to control the diffusion release kinetics of the drug. Ophthalmic formulations of the disclosure include those of similar material design as the SIGHT lens, as well as others generally known to those of skill in the art (e.g., as described in Franco, et al., Polymers , 2021, 13, 1102).

[0183] A disclosed pharmaceutical composition may comprise any excipient (e.g., a surfactant, carrier, antioxidant, and the like) at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, or about 80% of the formulation, on a weight or volume basis. E. Pharmaceutical Combinations

[0184] It should be readily appreciated that the disclosed compositions are not limited to combinations of a single compound, or (when formulated as a pharmaceutical composition) limited to a single carrier, diluent, and / or excipient alone, but may also include combinations of multiple compounds (including additional active compounds), and / or multiple carriers, diluents, and excipients. Pharmaceutical compositions of this disclosure thus may comprise a compound of Formula (1) together with one or more other active agents (or their derivatives and analogs) in combination, together with one or more pharmaceutically-acceptable carriers, diluents, and / or excipients, and additionally with one or more other active compounds.

[0185] In some embodiments, a formulation of the disclosure will be prepared so as to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects.

[0186] “Therapeutic effects” that may be increased or added in embodiments of the disclosure include, but are not limited to, antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, and stimulant effects.

[0187] “Synergistic effects” should be understood to include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect, that are greater than the additive contributions of the components acting alone. Numerous methods known to those of skill in the art exist to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby producing “1+1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol., 2019; 10:1222), or the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol.114: 313-326). A synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet.6: 429-453) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55). The corresponding graphs associated with the equations referred to above are the concentration-effect curve and combination index curve, respectively. Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.

[0188] In embodiments, a disclosed pharmaceutical composition comprises an additional active compound. In some embodiments, the additional active compound is selected from the group consisting of: amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents (e.g., psychoplastogens), monoamine oxidase inhibitors, tryptamines, terpenes, 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.

[0189] In some embodiments, an additional active compound is a tryptamine. As understood by those in the art, tryptamines are compounds having the general structure below, wherein RN1, RN2, Rɑ, Rβ, R2, R4, R5, R6, and R7are as defined herein and as generally understood in the art:

[0190] In some embodiments, RN1, RN2, Rɑ, Rβ, R2, R4, R5, R6, and R7are each independently hydrogen, deuterium, halogen (F, Cl, Br, or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Additionally, any two of RN1, RN2, Rɑ, Rβ, R2, R4, R5, R6, and R7and the intervening atoms can be taken together to form an optionally substituted optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In embodiments, the tryptamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0191] In some embodiments, the additional active compound is a tryptamine selected from the group consisting of O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 6-allyl-N,N-diethyl- norlysergamide (AL-LAD), N,N-dibutyltryptamine (DBT), N,N-diethyltryptamine (DET), N,N-diisopropyl- tryptamine (DiPT), 5-methoxy-α-methyltryptamine (α,O-DMS), N,N-dimethyl- tryptamine (DMT), 2,α-dimethyltryptamine (2,α-DMT), α,N-dimethyltryptamine (α,N-DMT), N,N-dipropyltryptamine (DPT), N-ethyl-N-isopropyltryptamine (EiPT), α-ethyltryptamine (AET), 6,N,N-triethylnorlysergamide (ETH-LAD), 3,4-dihydro-7-methoxy-1-methylcarboline (Harmaline), 7-methoxy-1-methylcarboline (Harmine), N,N-dibutyl-4-hydroxytryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl-4- hydroxytryptamine (4-HO-DiPT), 4-hydroxy-N,N,N-trimethyltryptamine (4-HO-TMT), N,N-dimethyl-4-hydroxytryptamine (4-HO-DMT), N,N-dimethyl-5-hydroxytryptamine (5-HO-DMT, bufotenine), N,N-dipropyl-4- hydroxytryptamine (4-HO-DPT), N-ethyl-4-hydroxy-N-methyltryptamine (4-HO-MET), 4-hydroxy-N-isopropyl-N-methyltryptamine (4-HO-MiPT), 4-hydroxy-N-methyl-N-propyl- tryptamine (4-HO-MPT), 4-hydroxy-N,N-tetramethylenetryptamine (4-HO-pyr-T), 12-methoxyibogamine (Ibogaine), N-butyl-N-methyltryptamine (MBT), N,N-diisopropyl-4,5- methylenedioxytryptamine (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylenedioxytryptamine (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxy- tryptamine (4,5-MDO-DMT), N,N-dimethyl-5,6-methylenedioxytryptamine (5,6-MDO-DMT), N-isopropyl-N- methyl-5,6-methylenedioxytryptamine (5,6-MDO-MiPT), N,N-diethyl-2-methyltryptamine (2-Me-DET), 2,N,N-trimethyl-tryptamine (2-Me-DMT), N-acetyl-5-methoxytryptamine (melatonin), N,N-diethyl-5-methoxy- tryptamine (5-MeO-DET), N,N-diisopropyl-5-methoxytryptamine (5-MeO-DiPT), N,N,diallyl-5-methoxy- tryptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-isopropyl-4-methoxy-N- methyltryptamine (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyltryptamine (5-MeO-MiPT), 5,6-dimethoxy- N-isopropyl-N-methyltryptamine (5,6-MeO-MiPT), 5-methoxy-N-methyl- tryptamine (5-MeO-NMT), 5-methoxy-N,N-tetramethylenetryptamine (5-MeO-pyr-T), 6-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl- tryptamine (5-MeO-TMT), N,N-dimethyl-5-methylthiotryptamine (5-MeS-DMT), N-isopropyl-N-methyltryptamine (MiPT), α-methyltryptamine (α-MT), N-ethyltryptamine (NET), N-methyltryptamine (NMT), 6-propylnorlysergamide (PRO-LAD), N,N-tetra- methylenetryptamine (pyr-T), Tryptamine (T), 7-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (Tetrahydroharmine), or α,N-dimethyl-5- methoxytryptamine (α,N,O-TMS), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.

[0192] In some embodiments, an additional tryptamine will be a “complex tryptamine” or other indolamine and including such examples as iboga alkaloids such as ibogaine, and their analogs, metabolites, and derivatives, and beta-carbolines.

[0193] In some embodiments, the additional active compound is a phenethylamine. As understood by those in the art, phenethylamines are compounds having the general structure below, wherein RN1, RN2, Rɑ, Rβ, and each of R2-R6are as taught herein and as generally understood in the art:

[0194] In some embodiments, RN1, RN2, Rɑ, Rβ, and each of R2-6are independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. 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 optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0195] In some embodiments, the additional active compound is a phenethylamine selected from the group consisting of α-ethyl-3,4,5-trimethoxy-phenethylamine (AEM), 4-allyloxy-3,5- dimethoxyphenethylamine (AL), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH), 2,5-dimethoxy-4-ethylthioamphetamine (ALEPH-2), 2,5-dimethoxy-4-isopropylthioamphetamine (ALEPH-4), 2,5-dimethoxy-4-phenylthio-amphetamine (ALEPH-6), 2,5-dimethoxy-4-propylthio- amphetamine (ALEPH-7), 2,5-dimethoxy-α-ethyl-4- methylphenethylamine (ARIADNE), 3,4-diethoxy-5-methoxy-phenethylamine (ASB), 4-butoxy-3,5- dimethoxyphenethylamine (B), 2,5-dimethoxy-4,N-dimethylamphetamine (BEATRICE), 2,5-bismethylthio- 4-methyl-amphetamine (BIS-TOM), 4-bromo-2,5,ß-trimethoxyphenethylamine (BOB), 2,5,ß-trimethoxy-4- methylphenethylamine (BOD), ß-methoxy-3,4-methylenedioxyphenethylamine (BOH), 2,5-dimethoxy- ß-hydroxy-4-methylphenethylamine (BOHD), 3,4,5,ß-tetramethoxy- phenethylamine (BOM), 4-bromo-3,5-dimethoxyamphetamine (4-Br-3,5-DMA), 2-bromo-4,5-methylenedioxyamphetamine (2-Br-4,5-MDA), 3,4-methylenedioxy-N-ethyl- amphetamine (MDEA), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-benzyloxy-3,5- dimethoxyamphetamine (3C-BZ), 4-chloro-2,5-dimethoxyphenethylamine (2C-C), 2,5-dimethoxy-4-methyl-phenethylamine (2C-D), 2,5-dimethoxy-4-ethyl-phenethylamine (2C-E), 3,5-dimethoxy-4-ethoxyamphetamine (3C-E), 2,5-dimethoxy-4-fluorophenethylamine (2C-F), 2,5-dimethoxy-3,4-dimethylphenethylamine (2C-G), 2,5-dimethoxy-3,4-trimethylene- phenethylamine (2C-G-3), 2,5-dimethoxy-3,4-tetramethylenephenethylamine (2C-G-4), 3,4-norbornyl-2,5- dimethoxyphenethylamine (2C-G-5), 1,4-dimethoxynaphthyl-2-ethylamine (2C-G-N), 2,5-dimethoxy- phenethylamine (2C-H), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), 2,5-dimethoxy-4-nitro-phenethylamine (2C-N), 2,5-dimethoxy-4-isopropoxyphenethylamine (2C-O-4), 2,5-dimethoxy-4-propylphenethylamine (2C-P), 4-cyclopropylmethoxy- 3,5-dimethoxyphenethylamine (CPM), 2,5-dimethoxy-4-methyl- selenophenethylamine (2C-SE), 2,5-dimethoxy-4-methylthiophenethylamine (2C-T), 2,5-dimethoxy-4-ethyl- thiophenethylamine (2C-T-2), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,6-dimethoxy-4- isopropylthiophenethylamine (psi-2C-T-4), 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), 4-cyclopropylmethylthio-2,5-dimethoxyphenethylamine (2C-T-8), 4-(t)-butylthio- 2,5-dimethoxy- phenethylamine (2C-T-9), 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine (2C-T-13), 4-cyclopropylthio-2,5-dimethoxyphenethylamine (2C-T-15), 4-(s)-butylthio-2,5-dimethoxy- phenethylamine (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine (2C-T-21), 3,5-dimethoxy-4-trideuteromethyl- phenethylamine (4-D), ß,ß-dideutero-3,4,5- trimethoxy- phenethylamine (ß-D), 3,5-dimethoxy- 4-methyl-phenethylamine (DESOXY), 2,4-dimethoxy- amphetamine (2,4-DMA), 2,5-dimethoxyamphetamine (2,5-DMA), 3,4-dimethoxyamphetamine (3,4-DMA), 2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine (DMCPA), 3,4-dimethoxy-ß- hydroxyphenethylamine (DME), 2,5-dimethoxy-3,4-methylenedioxy- amphetamine (DMMDA), 2,3-dimethoxy-4,5-methylenedioxyamphetamine (DMMDA-2), 3,4-dimethoxy- phenethylamine (DMPEA), 4-amyl-2,5-dimethoxyamphetamine (DOAM), 4-bromo-2,5-dimethoxy- amphetamine (DOB), 4-butyl-2,5-dimethoxyamphetamine (DOBU), 4-chloro-2,5-dimethoxyamphetamine (DOC), 2,5-dimethoxy-4-(2-fluoroethyl) amphetamine (DOEF), 2,5-dimethoxy-4-ethyl- amphetamine (DOET), 4-iodo-2,5- dimethoxyamphetamine (DOI), 2,5-dimethoxy-4- methylamphetamine (DOM (STP)), 2,6-dimethoxy-4-methylamphetamine (psi-DOM), 2,5-dimethoxy-4-nitroamphetamine (DON),2,5-dimethoxy- 4-propylamphetamine (DOPR), 3,5-dimethoxy-4-ethoxyphenethylamine (E), 2,4,5-triethoxyamphetamine (EEE), 2,4-diethoxy-5-methoxyamphetamine (EEM), 2,5-diethoxy-4-methoxyamphetamine (EME), 4,5-dimethoxy-2-ethoxyamphetamine (EMM), 2-ethylamino-1-(3,4-methylenedioxyphenyl)butane (ETHYL-J), 2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane (ETHYL-K), 6-(2-amino-propyl)-5-methoxy-2-methyl-2,3- dihydrobenzofuran (F-2), 6-(2-aminopropyl)-2,2-dimethyl- 5-methoxy-2,3-dihydrobenzofuran (F-22), N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine (FLEA), 2,5-dimethoxy-3,4-(trimethylene) amphetamine (G-3), 2,5-dimethoxy-3,4-(tetra-methylene)amphetamine (G-4), 3,6-dimethoxy-4-(2-amino- propyl)benzonorbornane (G-5), 2,5-dimethoxy-3,4-dimethyl-amphetamine (GANESHA), 1,4-dimethoxynaphthyl-2-isopropyl-amine (G-N), 2,5-dimethoxy-4-ethylthio-N-hydroxyphenethylamine (HOT-2), 2,5-dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine (HOT-7), 4-(s)-butylthio-2,5-dimethoxy- N-hydroxy-phenethylamine (HOT-17), 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA), 2,3,4-trimethoxy-phenethylamine (IM), 3,5-dimethoxy-4-isopropoxyphenethylamine (IP), 5-ethoxy-2-methoxy- 4-methylamphetamine (IRIS), 2-amino-1-(3,4-methylenedioxyphenyl)butane (J, BDB), 3-methoxy- 4,5-methylenedioxyphenethylamine (LOPHOPHINE), 3,4,5-trimethoxy- phenethylamine (M), 4-methoxy- amphetamine (4-MA, PMA), 2,N-dimethyl-4,5- methylenedioxyamphetamine (MADAM-6), 3,5-dimethoxy-4-methallyloxyphenethylamine (MAL), 3,4-methylenedioxyamphetamine (MDA), N-allyl-3,4-methylenedioxyamphetamine (MDAL), N-butyl-3,4-methylenedioxyamphetamine (MDBU), N-benzyl-3,4-methylenedioxy- amphetamine (MDBZ), N-cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM), N,N-dimethyl-3,4-methylenedioxyamphetamine (MDDM), N-ethyl-3,4-methylenedioxy- amphetamine (MDE), N-(2-hydroxyethyl)-3,4-methylenedioxyamphetamine (MDHOET), N-isopropyl-3,4-methylenedioxyamphetamine (MDIP), N-methyl-3,4-methylenedioxy- amphetamine (MDMA), 3,4-ethylenedioxy-N-methylamphetamine (MDMC), N-methoxy-3,4- methylenedioxyamphetamine (MDMEO), N-(2-methoxyethyl)-3,4-methylenedioxyamphetamine (MDMEOET), 3,4-methylenedioxy- α,α,N-trimethyl- phenethylamine (MDMP), N-hydroxy-3,4- methylenedioxyamphetamine (MDOH), 3,4-methylenedioxyphenethylamine (MDPEA), α,α-dimethyl-3,4-methylenedioxyphenethylamine (MDPH), 3,4-methylenedioxy-N-propargyl- amphetamine (MDPL), 3,4-methylenedioxy-N-propyl-amphetamine (MDPR), 3,4-dimethoxy- 5-ethoxyphenethylamine (ME), 4,5-ethylenedioxy-3-methoxyamphetamine (MEDA), 4,5-diethoxy-2-methoxyamphetamine (MEE), 2,5-dimethoxy-4-ethoxyamphetamine (MEM), 4-ethoxy-3-methoxyphenethylamine (MEPEA), 5-bromo-2,4-dimethoxyamphetamine (META-DOB), 2,4-dimethoxy-5-methylthioamphetamine (META-DOT), 2,5-dimethoxy- N-methylamphetamine (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methylamphetamine (METHYL-DOB), 2-methylamino-1- (3,4-methylenedioxyphenyl)butane (METHYL-J, MBDB), 2-methylamino-1-(3,4-methylenedioxyphenyl) pentane (METHYL-K), 4-methoxy-N-methyl- amphetamine (METHYL-MA, PMMA), 2-methoxy-N-methyl- 4,5-methylenedioxyamphetamine (METHYL-MMDA-2), 3-methoxy-4,5-methylenedioxyamphetamine (MMDA), 2-methoxy- 4,5-methylenedioxyamphetamine (MMDA-2), 2-methoxy-3,4-methylenedioxy- amphetamine (MMDA-3a), 4-methoxy-2,3-methylenedioxyamphetamine (MMDA-3b), 2,4-dimethoxy-5- ethoxyamphetamine (MME), 3,4-dimethoxy-5-(n)-propoxyphenethylamine (MP), 2,5-dimethoxy-4- (n)-propoxyamphetamine (MPM), 4,5-dimethoxy-2-methylthioamphetamine (ORTHO-DOT), 3,5-dimethoxy-4-propoxyphenethylamine (P), 3,5-dimethoxy-4-phenethyloxyphenethylamine (PE), phenethylamine (PEA), 3,5-dimethoxy-4-(2-propynyloxy) phenethylamine (PROPYNYL), 3,5-diethoxy-4- methoxyphenethylamine (SB), 2,3,4,5-tetra- methoxyamphetamine (TA), 4-ethoxy-3-ethylthio-5- methoxyphenethylamine (3-TASB), 3-ethoxy-4-ethylthio-5-methoxyphenethylamine (4-TASB), 3,4-diethoxy- 5-methylthio-phenethylamine (5-TASB), 4-(n)-butylthio-3,5-dimethoxyphenethylamine (TB), 4-ethoxy-5- methoxy-3-methylthiophenethylamine (3-TE), 3,5-dimethoxy-4-ethylthiophenethylamine (TE, 4-TE), 3,4-dimethoxy-2-methylthiophenethylamine (2-TIM), 2,4-dimethoxy-3-methylthio- phenethylamine (3-TIM), 2,3-dimethoxy-4-methylthiophenethylamine (4-TIM), 3,4-dimethoxy- 5-methylthiophenethylamine (3-TM), 3,5-dimethoxy-4-methylthiophenethylamine (4-TM), 3,4,5-trimethoxyamphetamine (TMA), 2,4,5-trimethoxy- amphetamine (TMA-2), 2,3,4-trimethoxyamphetamine (TMA-3), 2,3,5-trimethoxyamphetamine (TMA-4), 2,3,6-trimethoxyamphetamine (TMA-5), 2,4,6-trimethoxyamphetamine (TMA-6), 4,5-dimethoxy-3-ethylthio- phenethylamine (3-TME), 3-ethoxy-5-methoxy-4-methylthio- phenethylamine (4-TME), 3-ethoxy-4-methoxy- 5-methylthiophenethylamine (5-TME), 3,4-methylenedioxy-2-methylthioamphetamine (2T-MMDA-3a), 2-methoxy-4,5-methylene- thiooxyamphetamine (4T-MMDA-2), 2,4,5-trimethoxyphenethylamine (TMPEA), 4-ethyl-5-methoxy-2-methylthioamphetamine (2-TOET), 4-ethyl-2-methoxy-5-methylthio- amphetamine (5-TOET), 5-methoxy-4-methyl-2-methylthioamphetamine (2-TOM), 2-methoxy-4-methyl-5-methylthio- amphetamine (5-TOM), 2-methoxy-4-methyl-5-methyl- sulfinylamphetamine (TOMSO), 3,5-dimethoxy-4- propylthiophenethylamine (TP), 3,4,5-triethoxyphenethylamine (TRIS), 3-ethoxy-5-ethylthio-4-methoxy- phenethylamine (3-TSB), 3,5-diethoxy-4-methylthiophenethylamine (4-TSB), 3,4-diethoxy-5-ethylthio- phenethylamine (3-T-TRIS), 3,5-diethoxy-4-ethylthiophenethylamine (4-T-TRIS), (R)-2,5-dimethoxy-4- iodoamphetamine (R-DOI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.

[0196] In embodiments, the additional active compound is an ergoline. In embodiments, the additional active compound is an ergot alkaloid. In embodiments, the additional active compound is a lysergamide. As understood by one in the art, lysergamides are compounds having the general structure below, wherein RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are as taught herein and as generally understood in the art:

[0197] In some embodiments, RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are each independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Additionally, any two of RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14and the intervening atoms can be taken together to form an optionally substituted optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In some embodiments, the lysergamide is a quaternary salt, in which an additional R6Ais connected to the nitrogen to which R6is bound; wherein R6Ais optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0198] In some embodiments, the additional active compound is a lysergamide selected from the group consisting of lysergic acid diethylamide (i.e., LSD, LSD-25, LAD, Delysid), 6-ethyl-6- nor -lysergic acid diethylamide (ETH-LAD), 6-propynyl-6- nor -lysergic acid diethylamide (PARGY-LAD), 6-allyl-6- nor -lysergic acid diethylamide (AL-LAD), 6-propyl-6- nor -lysergic acid diethylamide (PRO-LAD), 6-isopropyl-6- nor -lysergic acid diethylamide (IP-LAD), 6-cylopropyl-6- nor -lysergic acid diethylamide (CIP-LAD), 6-butyl-6- nor -lysergic acid diethylamide (BU-LAD), 6-(2-fluoroethyl)-6- nor -lysergic acid diethylamide (FLUOROETH-LAD), 1-acetyl-lysergic acid diethylamide (i.e., ALD, ALD-52, N-acetyl-LSD), 1-propionyl-lysergic acid diethylamide (1P-LSD), 1-butyryl-lysergic acid diethylamide (1B-LSD), 1-valeryl-lysergic acid diethylamide (1V-LSD), 1-(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-(cyclopropylmethanoyl)-6-allyl-6- nor -lysergic acid diethylamide (1cP-AL-LAD), 1-propionyl- 6-ethyl-6- nor -lysergic acid diethylamide (1P-ETH-LAD), lysergic acid 2,4-dimethylazetidide (i.e., LA-SS-Az, LSZ), lysergic acid piperidide (LSD-Pip), and lysergic acid methylisopropyl amide (MIPLA).

[0199] Other tryptamines, phenethylamines, and lysergamides useful as additional active compounds for purposes of the disclosure and thus contemplated for inclusion therein will be as generally known in the art (see, e.g., Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997); Grob & Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi & Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacological Reviews, 2016; 68(2), 264-355; Glennon, Pharmacology Biochemistry and Behavior, 1999; 64, 251-256; each of which is incorporated by reference as if fully set forth herein). F. Dose and Dosage

[0200] In some embodiments, pharmaceutical compositions comprise a therapeutically effective amount or an effective amount of a disclosed compound, such as for administration to a subject. Administration of pharmaceutical compositions in a “therapeutically effective amount,” or an “effective amount” to a subject means administration of an amount of composition sufficient to achieve the desired effect. When an “effective amount” means an amount effective in treating the stated disorder or symptoms in a subject, “therapeutic effect” would be understood to mean the responses(s) in a mammal after treatment that are judged to be desirable and beneficial. Hence, depending on the mental health disorder to be treated, or improvement in mental health or functioning sought, and depending on the particular constituent(s) in the disclosed compositions under consideration, those responses shall differ, but would be readily understood by those of ordinary skill, through an understanding of the disclosure herein and the general knowledge of the art (e.g., by reference to the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for the stated disorder).

[0201] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a microgram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 µg / kg or less (including a dose of 0.10 µg / kg or less, 0.05 µg / kg or less, and 0.01 µg / kg or less), at least 0.50 µg / kg, at least 0.55 µg / kg, at least 0.60 µg / kg, at least 0.65 µg / kg, at least 0.70 µg / kg, at least 0.75 µg / kg, at least 0.80 µg / kg, at least 0.85 µg / kg, at least 0.90 µg / kg, at least 0.95 µg / kg, at least 1.0 µg / kg, at least 1.1 µg / kg, at least 1.2 µg / kg, at least 1.3 µg / kg, at least 1.4 µg / kg, at least 1.5 µg / kg, at least 1.6 µg / kg, at least 1.7 µg / kg, at least 1.8 µg / kg, at least 1.9 µg / kg, at least 2.0 µg / kg, at least 2.1 µg / kg, at least 2.2 µg / kg, at least 2.3 µg / kg, at least 2.4 µg / kg, at least 2.5 µg / kg, at least 2.6 µg / kg, at least 2.7 µg / kg, at least 2.8 µg / kg, at least 2.9 µg / kg, or at least 3.0 µg / kg, as well as amounts within these ranges.

[0202] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a microgram dosage amount calculated based on the kilogram weight of the patient) between about 0.01 µg / kg and 0.1 µg / kg, such as about 0.01 µg / kg, about 0.02 µg / kg, about 0.03 µg / kg, about 0.04 µg / kg, about 0.05 µg / kg, about 0.06 µg / kg, about 0.07 µg / kg about 0.08 µg / kg about 0.09 µg / kg, and about 0.1 µg / kg, as well as ranges between these values. In some embodiments, a single dose is between about 0.1 µg / kg and 3.0 µg / kg, such as about 0.1 µg / kg, about 0.2 µg / kg, about 0.3 µg / kg, about 0.4 µg / kg, about 0.5 µg / kg, about 0.6 µg / kg, about 0.7 µg / kg about 0.8 µg / kg about 0.9 µg / kg, about 1.0 µg / kg, about 1.2 µg / kg, about 1.4 µg / kg, about 1.6 µg / kg, about 1.8 µg / kg, about 2.0 µg / kg, about 2.2 µg / kg, about 2.4 µg / kg, about 2.6 µg / kg, about 2.8 µg / kg, about 3.0 µg / kg, as well as ranges between these values.

[0203] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 µg or less (including a dose of 10 µg or less, 5 µg or less, and 1 µg or less), at least 25 µg, at least 30 µg, at least 35 µg, at least 40 µg, at least 45 µg, at least 50 µg, at least 55 µg, at least 60 µg, at least 65 µg, at least 70 µg, at least 75 µg, at least 80 µg, at least 85 µg, at least 90 µg, at least 95 µg, at least 100 µg, at least 105 µg, at least 110 µg, at least 115 µg, at least 120 µg, at least 125 µg, at least 130 µg, at least 135 µg, at least 140 µg, at least 145 µg, at least 150 µg, at least 155 µg, at least 160 µg, at least 165 µg, at least 170 µg, at least 175 µg, at least 180 µg, at least 185 µg, at least 190 µg, at least 195 µg, at least 200 µg, at least 225 µg, at least 250 µg, at least 275 µg, or at least 300 µg, as well as amounts within these ranges.

[0204] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) between about 0.1 µg and 1.0 µg, such as about 0.1 µg, about 0.2 µg, about 0.3 µg, about 0.4 µg, about 0.5 µg, about 0.6 µg, about 0.7 µg, about 0.8 µg, about 0.9 µg, and about 1.0 µg, as well as ranges between these values. In some embodiments, a single dose is between about 1 µg and 10 µg, such as about 1 µg, about 2 µg, about 3 µg, about 4 µg, about 5 µg, about 6 µg, about 7 µg, about 8 µg, about 9 µg, and about 10 µg, as well as ranges between these values. In some embodiments, a single dose is between about 1 µg and 300 µg.

[0205] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, as well as amounts within these ranges.

[0206] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient) between about 0.001 mg / kg and 1.0 mg / kg, between about 0.005 mg / kg and 0.5 mg / kg, or between about 0.01 mg / kg and 0.1 mg / kg, such as about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg about 0.08 mg / kg about 0.09 mg / kg, and about 0.1 mg / kg, as well as ranges between these values. In some embodiments, a single dose is between about 0.1 mg / kg and 1.0 mg / kg, such as about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg about 0.8 mg / kg about 0.9 mg / kg, and about 1.0 mg / kg, as well as amounts and ranges between these values.

[0207] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.09 mg / kg or less, 0.08 mg / kg or less, 0.07 mg / kg or less, 0.06 mg / kg or less, 0.05 mg / kg or less, 0.04 mg / kg or less, 0.03 mg / kg or less, 0.02 mg / kg or less, 0.01 mg / kg or less, 0.005 mg / kg or less, and 0.001 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, and at least 2.0 mg / kg, as well as amounts within these ranges.

[0208] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) between about 0.1 mg and 1.0 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, and about 1.0 mg, as well as ranges between these values. In 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.

[0209] In some embodiments, where a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, and at least 150 mg, as well as amounts within these ranges.

[0210] In some embodiments, where a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenethylamine or another tryptamine, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, as well as amounts within these ranges.

[0211] In some embodiments, where a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenethylamine or a tryptamine, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, as well as amounts within these ranges.

[0212] 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).

[0213] Dose amount, frequency or duration may be increased or reduced, as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications. One of skill together with the teachings of this disclosure will appreciate the factors that may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0214] It will be understood that, in some embodiments, the dose actually administered will be determined by a physician, in light of the relevant circumstances, including the disorder to be treated, the chosen route of administration, the actual composition or formulation administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms, and therefore any dosage ranges disclosed herein are not intended to limit the scope of the disclosure. In some instances, dosage levels below the lower limit of a disclosed range may be more than adequate, while in other cases doses above a range may be employed without causing any harmful side effects, provided for instance that such larger doses also may be divided into several smaller doses for administration, either taken together or separately.

[0215] In some embodiments, especially where a formulation is prepared in single unit dosage form, such as a capsule, tablet, or lozenge, suggested dosage amounts may be known by reference to the format of the preparation itself. In embodiments where a formulation is prepared in multiple dosage form, for instance liquid suspensions and topical preparations, suggested dosage amounts may be known by reference to the means of administration or by reference to the packaging and labeling, package insert(s), marketing materials, training materials, or other information and knowledge available to those of skill or the public.

[0216] Accordingly, another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. Pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration. G. Kits

[0217] Another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. Pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0218] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub- unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and / or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0219] Preferably, information pertaining to dosing and proper administration (if needed) will be printed onto a multi-dose kit directly (e.g., on a blister pack or other interior packaging holding the compositions or formulations of the disclosure); however, kits of the disclosure can further contain package inserts and other printed instructions (e.g., on exterior packaging) for administering the disclosed compositions and for their appropriate therapeutic use. H. Methods of Use

[0220] 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.

[0221] Herein, the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to any mammal, including murines, simians, mammalian farm animals, mammalian sport animals, and mammalian pets, such as canines and felines, although preferably humans. Such terms will be understood to include one who has an indication for which a compound, composition, or method described herein may be efficacious, or who otherwise may benefit by the invention. Disclosed methods of treatment can be modified to treat multiple patients at once, including couples or families. Hence, these terms will be understood to also mean two or more individuals. In general, all of the disclosed compounds, compositions, and methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood.

[0222] In some embodiments, disclosed compounds or compositions thereof are orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation or transdermally administered to a subject. In some embodiments, when administered through one or more such routes, the disclosed compounds and the disclosed compositions and formulations comprising them are useful in methods for treating a patient in need of such treatment. a. Modulating Neurotransmission

[0223] In some embodiments, disclosed compounds modulate neurotransmission in a subject, such as following administration of a therapeutically effective amount to said subject. 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. In embodiments, modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0224] In some embodiments, modulating neurotransmission contributes to the therapeutic effects of a disclosed compound in a subject. In some embodiments, modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0225] Neurotransmission refers to the transfer of information between neurons. Information is emitted by a neuron when an action potential occurs, resulting in the release of neurotransmitters into a synapse. Neurotransmission can thus be quantified by measuring parameters of action potential firing in a population of neurons. In some embodiments, neurotransmission is quantified by measuring the general action potential firing activity (Obien et al. Front Neurosci .2015;8:423; Morin et al. J Biosci Bioeng .2005;100(2):131-143). General action potential firing activity parameters include spike rate, burst rate, and / or spike contrast. In embodiments, neurotransmission is quantified by measuring burst structure. Burst structure parameters include burst spike number, burst duration, and / or burst amplitude. In some embodiments, neurotransmission is quantified by measuring oscillatory behavior. Oscillatory behavior is measured as the standard deviation of spike rate, burst rate, and / or burst amplitude. In some embodiments, neurotransmission is quantified by measuring the synchronicity of activity of a neuron population. Synchronicity is measured as the coefficient of variation in spike rate, burst rate, and / or burst duration across a neuron population. Synchronicity is also measured as synchronicity share, synchronicity distance, and / or spike simplex.

[0226] In some embodiments, a disclosed compound modulates spike rate. Spike rate is the number of action potentials per second. In some embodiments, a disclosed compound modulates burst rate. Neurons may send out a series of action potentials in rapid succession, known as a burst. Burst rate is the number of bursts per second. In some embodiments, a disclosed compound modulates spike contrast. Spike contrast is 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 (i.e. 700 milliseconds). In some embodiments, a disclosed compound modulates burst spike number. Burst spike number is the number of spikes per burst. In some embodiments, a disclosed compound modulates burst duration. Burst duration is the mean duration of detected bursts. In some embodiments, neurotransmission is measured as the burst amplitude. To obtain burst amplitude, an integral function with a decay is calculated over the timestamps of bursts. The burst amplitude is the peak value of the integral, which increases with highly frequent and numerous spiking.

[0227] In some embodiments, a disclosed compound modulates oscillatory behavior. Oscillatory behavior is a measure of variability in a parameter, measured as the standard deviation of a parameter over time within the experimental episode. In some embodiments, a disclosed compound modulates the synchronicity of activity in a neuron population. Synchronicity is a measure of the relative variability in activity across a neuron population. In some embodiments, a disclosed compound modulates synchronicity share. Synchronicity share is the average number of units involved in population bursts, higher values reflecting a higher degree of synchronicity in bursts occurring amongst populations of neurons. In some embodiments, a disclosed compound modulates synchronicity distances. Synchronicity distances are defined as the average distance of burst starts within a population burst from the population burst center, lower values reflecting a stronger synchronicity of a network. In some embodiments, a disclosed compound modulates spike simplex. Spike simplex is a measure of connectivity and complexity in a neuronal network, higher values reflecting higher synchronicity among neurons.

[0228] 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-HT2receptor). The 5-HT2receptor family consists of the three distinct receptor subtypes: 5-HT2A, 5-HT2B, and 5-HT2C.5-HT2Aand 5-HT2Creceptors are more highly expressed in the brain than the 5-HT2Bsubtype. Psilocin and other related psychoactive tryptamines exert their psychoactive effects primarily by acting as 5-HT2Areceptor agonists. However, many of these tryptamines (including psilocin) are also agonists at the 5-HT2Band 5-HT2Creceptors, owing to high sequence homology among the three 5-HT2receptor subtypes (Nichols, Pharmacol. Rev., 2016, 68, 264-355). Activation of all 5-HT2receptor subtypes may result in reduced efficacy or detrimental side effects. For example, activation of 5-HT2Creceptors has been shown to functionally oppose effects of 5-HT2Areceptor activation ( id .), while activation of 5-HT2Breceptors in cardiac muscle tissue has been linked to heart valve disease (Hutcheson, et al., Pharmacol. Ther.2011, 132(2): 146–157). In embodiments, it may be desired for a compound, especially one that may be used regularly or over a relatively long time period, to have reduced activity (e.g., agonism) of 5-HT2B. In some embodiments, disclosed compounds agonize or partially agonize 5-HT receptors, such as any one or more of an 5-HT1receptor, such as 5-HT1Aand 5-HT1B, an 5-HT2receptor, such as 5-HT2A, 5-HT2B, and 5-HT2C, and 5-HT6.

[0229] In some embodiments, a disclosed compound has an in vitro EC50(agonist mode) for any one or more of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT6that is less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, or less than 0.1 µM. In embodiments, a disclosed compound has an in vitro EC50(agonist mode) for 5-HT2Athat is less than 1 µM, less than 0.5 µM, less than 0.1 µM, less than 0.05 µM, less than 0.01 µM, less than 0.005 µM, or less than 0.001 µM. In embodiments, a disclosed compound has an in vitro EC50(agonist mode) for 5-HT2Cthat is less than 1 µM, less than 0.5 µM, less than 0.1 µM, less than 0.05 µM, less than 0.01 µM, less than 0.005 µM, or less than 0.001 µM.

[0230] In some embodiments, disclosed compounds show greater potency at 5-HT2Arelative to another 5-HT receptor. In some embodiments, disclosed compounds show greater potency at 5-HT2Arelative to any one or more of an 5-HT1receptor, another 5-HT2receptor, such as 5-HT2Band 5-HT2C, a 5-HT5receptor, a 5-HT6receptor, and a 5-HT7receptor.

[0231] Determining agonism and antagonism, and measuring EC50and IC50, respectively, may be determined according to methods available to one of skill in the art. In one example, measuring Gq-mediated calcium flux is a known method for assessing modulation, e.g., activation, of 5-HT2A, a widely recognized target of psychedelic compounds. See, e.g., Klein et al., ACS Pharmacol Transl Sci.202014;4(2):533-542; Flanagan et al., ACS Pharmacol Transl Sci. 2020;4(2):488-502; Toro-Sazo et al., PLoS One. 2019;14(1):e0209804; Halberstadt et al., Psychopharmacology (Berl).2019;236(2):799-808. As would be recognized by one of skill, a partial agonist is one that shows reduced maximum efficacy (EMAX) relative to a full agonist (EMAX= 100%), e.g., serotonin in the example of a 5-HT receptor.

[0232] Because certain therapeutic benefits of disclosed compounds may derive, at least in part, from selective activation of a serotonin receptor (e.g., 5-HT2A, 5-HT2C), one potential approach for improved next-generation compounds with increased therapeutic efficacy, improved safety profiles, and reduced side effects may be optimizing for selective serotonin receptor activation. Accordingly, in some embodiments, a disclosed compound has increased selectivity for the 5-HT2Areceptor over another serotonin receptor (e.g., the 5-HT2Breceptor, or the 5-HT2Creceptor). In some embodiments, a disclosed compound has increased selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor. In some embodiments, a disclosed compound has increased selectivity for the 5-HT2Areceptor over the 5-HT2Creceptor. In some embodiments, selectivity is defined as functional activity selectivity, calculated by the ratio of the half-maximal effective concentration (EC50) of a disclosed compound for one receptor (e.g., the 5-HT2Areceptor) as compared to another receptor (e.g., a serotonin receptor, such as the 5-HT2Breceptor, or the 5-HT2Creceptor). For example, if a hypothetical compound had a 5-HT2AEC50of 0.2 µM and a 5-HT2BEC50of 1.0 µM, the compound could be said to have a 5-fold functional activity selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor. In some embodiments, selectivity can be defined as affinity selectivity, defined by the ratio of binding affinity (e.g., as assessed by Ki) for one receptor (e.g., the 5-HT2Areceptor) as compared to another receptor (e.g., a serotonin receptor, such as the 5-HT2Breceptor, or the 5-HT2Creceptor). For example, if a hypothetical compound had a 5-HT2AKiof 0.1 µM and a 5-HT2BEC50of 1.0 µM, the compound could be said to have a 10-fold affinity selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor.

[0233] 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-HT2Areceptor over the 5-HT2Breceptor. In embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor, relative to a comparator.

[0234] In embodiments, a disclosed 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-HT2Areceptor over the 5-HT2Breceptor. In embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor, relative to a comparator.

[0235] 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-HT2Creceptor over the 5-HT2Breceptor. In embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2Creceptor over the 5-HT2Breceptor, relative to a comparator.

[0236] In embodiments, a disclosed 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-HT2Creceptor over the 5-HT2Breceptor. In embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2Creceptor over the 5-HT2Breceptor, relative to a comparator. b. Modulating Neuroplasticity

[0237] In some embodiments, a disclosed compound is used to increase neuroplasticity. Neuroplasticity, also known as neural plasticity or brain plasticity, refers to the brain's ability to change and adapt in response to experiences, learning, and environmental factors. Neuroplasticity occurs through several mechanisms, including synaptic plasticity, which involves the strengthening or weakening of connections (synapses) between neurons. Synaptic plasticity is often associated with learning and memory processes. Another form of plasticity is called structural plasticity, which involves changes in the physical structure of neurons, such as the growth of new dendritic branches or the formation of new synapses. In some embodiments, increasing neuroplasticity contributes to the therapeutic effects of a disclosed compound in a subject. In some embodiments, increasing neuroplasticity by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0238] Neuroplasticity can be defined in terms of neuritogenesis, spinogenesis, and synaptogenesis in neurons. Neuritogenesis refers to the process by which neurons generate and extend their neurites (i.e., to form axons and dendrites). Neuritogenesis is a critical step in neural development and the formation of neuronal circuits. Spinogenesis refers to the formation of dendritic spines, which are small protrusions on the dendrites of neurons. Dendritic spines are crucial for synaptic connections and play a vital role in synaptic transmission and plasticity. Synaptogenesis refers to the formation of synapses, which is crucial for the establishment and refinement of neural circuits, and is a fundamental process underlying learning, memory, and information processing in the brain.

[0239] In some embodiments, a disclosed compound increases neuritogenesis. Neuritogenesis can be measured in terms of total neurite length, maximum neurite length, number of neurite nodes, and / or number of neurite extremities. In some embodiments, a disclosed compound increases total neurite length. In some embodiments, a disclosed compound increases maximum neurite length. In some embodiments, a disclosed compound increases the number of neurite nodes. In some embodiments, a disclosed compound increases the number of neurite extremities.

[0240] In some embodiments, administration of a disclosed compound to a subject results in an increase in the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., number of synapses per neuron), or total dendritic length. These factors can be measured using a Sholl analysis and other techniques known to those of skill in the art (Ly et al. ACS Pharmacol Transl Sci .2020;4(2):452-460). c. Treatment

[0241] In some embodiments, disclosed compounds are used to treat a medical condition, such as a disease or disorder. In embodiments, disclosed compounds are used in the manufacture of a medicament to treat a condition, such as a disease or disorder. Also provided are methods of administering disclosed compounds to a subject having a condition, such as a disease or disorder, thereby treating said condition.

[0242] In some embodiments, disclosed compounds or pharmaceutical compositions comprising the disclosed compounds are administered to a subject by one or more routes of administration, including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes. When administered through one or more of such routes, the compound(s) of the disclosure and the disclosed compositions and formulations comprising them are useful in methods for treating a patient in need of such treatment.

[0243] In some embodiments are provided methods of treating and / or preventing a condition in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a disclosed compound or pharmaceutical composition. In some embodiments, “treating” or “treatment” refers to treating a disease or disorder in a mammal, and preferably in a human, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e. arresting its development; (c) relieving a disorder, i.e., causing regression thereof; (d) protecting from or relieving a symptom or pathology caused by or related to a disorder; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a disorder; and (f) preventing or inhibiting of a worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder. In embodiments, treatment includes prevention. In other embodiments, treatment does not include prevention. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood to one of skill in view of the teachings herein and the knowledge in the art.

[0244] In embodiments, disclosed compounds are used to treat a central nervous system (CNS) disorder. Broadly, CNS disorders include diseases of the nervous system (e.g., movement disorders, neurodegenerative disorders) as well as mental, behavioral, and neurodevelopmental disorders, such as those in the DSM-5, Merck Manual, ICD-11, or other such diagnostic resources known to one of skill. i. Mental, Behavioral, or Neurodevelopmental Disorders

[0245] In some embodiments, disclosed compounds are used to treat a mental, behavioral, or neurodevelopmental disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental, behavioral, or neurodevelopmental disorder, thereby treating said mental, behavioral, or neurodevelopmental disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental, behavioral, or neurodevelopmental disorder.

[0246] The ICD-11, which is incorporated by reference herein in its entirety, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant disturbance in an individual's cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning. Such disorders include, but are not limited to, neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.

[0247] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or “mental health disorder”) generally refers to a disease condition that involves negative changes in emotion, mood, thinking, and / or behavior. In general, mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotion, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of suffering. Although the terms “mental disorder” and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11, or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11, ICD-10, DSM-5, or DSM-IV (each of which is incorporated by reference herein in its entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.

[0248] In some embodiments, a disclosed compound is used to treat a mental health disorder in a subject. In some embodiments, a subject has a mental health disorder. In some embodiments, a subject is at risk of a mental health disorder. The diagnosis of a mental health disorder and determining that a subject is at risk of a neurodevelopmental disorder will be known to those in the art. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating said mental health disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental health disorder. In some embodiments, the compounds and compositions of the disclosure are used to reduce the symptoms of a mental health disorder. The symptoms of the mental health disorder to be treated shall be able to be determined by one of skill in the art, by reference to the general understanding of the art regarding that disorder.

[0249] In some embodiments, measures of therapeutic efficacy include reports by a subject or an observer. In some embodiments, measures of therapeutic efficacy include responses to a questionnaire. Non-limiting representative examples of applicable measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject- or observer-reported measures.

[0250] In some embodiments, a disclosed compound is used to treat a neurodevelopmental disorder in a subject. In some embodiments, a subject has a neurodevelopmental disorder. In some embodiments, a subject is at risk of a neurodevelopmental disorder. The diagnosis of a neurodevelopmental disorder and determining that a subject is at risk of a neurodevelopmental disorder will be known to those in the art. Examples of a neurodevelopmental disorder, treatable using the disclosed compounds, include a disorder of intellectual development, a developmental speech or language disorder, autism spectrum disorder, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.

[0251] In some embodiments, a disclosed compound is used to treat schizophrenia or another primary psychotic disorder. In some embodiments, a subject has schizophrenia or another primary psychotic disorder. In some embodiments, a subject is at risk of schizophrenia or another primary psychotic disorder. The diagnosis of schizophrenia or another primary psychotic disorder and determining that a subject is at risk of schizophrenia or another primary psychotic disorder will be known to those in the art. Examples of a psychotic disorder, treatable using the disclosed compounds, include schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder.

[0252] In some embodiments, a disclosed compound is used to treat catatonia. In some embodiments, a subject has catatonia. In some embodiments, a subject is at risk of catatonia. The diagnosis of catatonia and determining that a subject is at risk of catatonia will be known to those in the art. In some embodiments, catatonia is associated with another mental disorder. In some embodiments, catatonia is induced by substances or medications.

[0253] In some embodiments, a disclosed compound is used to treat a mood disorder. In some embodiments, a subject has a mood disorder. In some embodiments, a subject is at risk of a mood disorder. The diagnosis of a mood disorder and determining that a subject is at risk of a mood disorder will be known to those in the art. Examples of a mood disorder, treatable using the disclosed compounds, include depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. In some embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder), a depressive disorder, or a substance-induced mood disorder. In some embodiments, the mood disorder is a depressive disorder. In some embodiments, the depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder (formally known as dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, seasonal affective disorder, mixed depressive and anxiety disorder, or an unspecified depressive disorder. In some embodiments, depression is assessed through the Patient Health Questionnaire-9 (PHQ-9) screening tool, Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale, Beck Depression Inventory (BDI-II), Zung Self-Rating Depression Scales (SDS), Major Depression Inventory (MDI), Center for Epidemiologic Studies Depression Scale (CED-D), Rome Depression Inventory (RDI), Hamilton Rating Scale for Depression (HRSD), and Carroll Rating Scale (CRS).

[0254] In some embodiments, a disclosed compound is used to treat an anxiety or fear-related disorder. In some embodiments, a subject has an anxiety or fear-related disorder. In some embodiments, a subject is at risk of an anxiety or fear-related disorder. The diagnosis of an anxiety or fear-related disorder and determining that a subject is at risk of an anxiety or fear-related disorder will be known to those in the art. Examples of an anxiety or fear-related disorder, treatable using the disclosed compounds, include generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or a substance-induced anxiety disorder.

[0255] In some embodiments, a disclosed compound is used to treat an obsessive-compulsive or related disorder. In some embodiments, a subject has an obsessive-compulsive or related disorder. In some embodiments, a subject is at risk of an obsessive-compulsive or related disorder. The diagnosis of an obsessive-compulsive or related disorder and determining that a subject is at risk of obsessive-compulsive or related disorder will be known to those in the art. Examples of an obsessive-compulsive or related disorder, treatable using the disclosed compounds, include an 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.

[0256] In some embodiments, a disclosed compound is used to treat a disorder associated with stress. In some embodiments, a subject has a disorder associated with stress. In some embodiments, a subject is at risk of a disorder associated with stress. The diagnosis of a disorder associated with stress and determining that a subject is at risk of a disorder associated with stress will be known to those in the art. In some embodiments, the disorder associated with stress has an identifiable stressor that is a causal factor, like exposure to a stressful or traumatic event, or a series of such events or adverse experiences. Stressors may be within the normal range of life experiences (e.g., divorce, socioeconomic problems), or from a threatening or traumatizing experience. In general, the nature and duration of the symptoms that arise in response to the stressor can distinguish the disorder from everyday stress. Examples of a disorder associated with stress, treatable using the disclosed compounds, include post-traumatic stress disorder, complex post-traumatic stress disorder, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder.

[0257] In some embodiments, a disclosed compound is used to treat a dissociative disorder. In some embodiments, a subject has a dissociative disorder. In some embodiments, a subject is at risk of a dissociative disorder. The diagnosis of a dissociative disorder and determining that a subject is at risk of a dissociative disorder will be known to those in the art. Examples of a dissociative disorder, treatable using the disclosed compounds, include dissociative amnesia (including amnesia with dissociative fugue and without dissociative fugue), trance disorder, possession trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization- derealization disorder.

[0258] In some embodiments, a disclosed compound is used to treat a feeding or eating disorder. In some embodiments, a subject has a feeding or eating disorder. In some embodiments, a subject is at risk of a feeding or eating disorder. The diagnosis of a feeding or eating disorder and determining that a subject is at risk of a feeding or eating disorder will be known to those in the art. Examples of a feeding or eating disorder, treatable using the disclosed compounds, include anorexia nervosa (including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.

[0259] In some embodiments, a disclosed compound is used to treat an elimination disorder. In some embodiments, a subject has an elimination disorder. In some embodiments, a subject is at risk of an elimination disorder. The diagnosis of an elimination disorder and determining that a subject is at risk of an elimination disorder will be known to those in the art. Examples of an elimination disorder, treatable using the disclosed compounds, include enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or encopresis (including both with encopresis constipation or overflow incontinence, and encopresis without constipation or overflow incontinence).

[0260] In some embodiments, a disclosed compound is used to treat a disorder of bodily distress or bodily experience. In some embodiments, a subject has a disorder of bodily distress or bodily experience. In some embodiments, a subject is at risk of a disorder of bodily distress or bodily experience. The diagnosis of a disorder of bodily distress or bodily experience and determining that a subject is at risk of a disorder of bodily distress or bodily experience will be known to those in the art. Examples of a disorder of bodily distress or bodily experience, treatable using the disclosed compounds, include bodily distress disorder (including mild, moderate, and severe bodily distress disorder) or body integrity dysphoria.

[0261] In some embodiments, a disclosed compound is used to treat a disorder due to substance use or addictive behaviors. In some embodiments, a subject has a disorder due to substance use or addictive behaviors. In some embodiments, a subject is at risk of a disorder due to substance use or addictive behaviors. The diagnosis of a disorder due to substance use or addictive behaviors and determining that a subject is at risk of a disorder due to substance use or addictive behaviors will be known to those in the art. In some embodiments, a disclosed compound is used to treat disorders due to substance use (i.e., a substance use disorder, or SUD). In some embodiments, the substance use disorder is associated with alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics or anxiolytics, cocaine, stimulants (e.g., amphetamines, methamphetamines, methcathinone, synthetic cathinones, caffeine), hallucinogens, nicotine, volatile inhalants, MDMA or MDA, dissociative drugs like ketamine and phencyclidine, or another substance (including medications and non-psychoactive substances). Examples of a substance use disorder, treatable using the disclosed compounds, include alcohol use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalants use disorder, opioids use disorder, sedatives use disorder, hypnotics use disorder, anxiolytics use disorder, stimulants use disorder, and tobacco use disorder. In some embodiments, the substance use disorder is alcohol use disorder. In some embodiments, the substance use disorder is cannabis use disorder. In some embodiments, the substance use disorder is caffeine use disorder. In some embodiments, the substance use disorder is phencyclidine use disorder. In some embodiments, the substance use disorder is inhalant use disorder. In some embodiments, the substance use disorder is opioids use disorder. In some embodiments, the substance use disorder is sedatives use disorder. In some embodiments, the substance use disorder is hypnotics use disorder. In some embodiments, the substance use disorder is anxiolytics use disorder. In some embodiments, the substance use disorder is stimulants use disorder. In some embodiments, the substance use disorder is tobacco use disorder. In some embodiments, the substance use disorder is alcohol use disorder, wherein said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism. In some embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder). In some embodiments, a substance use disorder can be screened using a Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), the Opioid Risk Tool - OUD (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).

[0262] In some embodiments, a disclosed compound is used to treat an impulse control disorder. In some embodiments, a subject has an impulse control disorder. In some embodiments, a subject is at risk of an impulse control disorder. The diagnosis of an impulse control disorder and determining that a subject is at risk of an impulse control disorder will be known to those in the art. In some embodiments, impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts. Examples of an impulse control disorder, treatable using the disclosed compounds, include pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.

[0263] In some embodiments, a disclosed compound is used to treat a disruptive behavior disorder or a dissocial disorder. In some embodiments, a subject has a disruptive behavior disorder or a dissocial disorder. In some embodiments, a subject is at risk of a disruptive behavior disorder or a dissocial disorder. The diagnosis of a disruptive behavior disorder or a dissocial disorder and determining that a subject is at risk of a disruptive behavior disorder or a dissocial disorder will be known to those in the art. Examples of a disruptive behavior disorder or a dissocial disorder, treatable using the disclosed compounds, include oppositional defiant disorder (including oppositional defiant disorder with chronic irritability-anger and oppositional defiant disorder without chronic irritability-anger) or conduct-dissocial disorder (including childhood-onset conduct-dissocial disorder and adolescent-onset conduct-dissocial disorder).

[0264] In some embodiments, a disclosed compound is used to treat a personality disorder. In some embodiments, a subject has a personality disorder. In some embodiments, a subject is at risk of a personality disorder. The diagnosis of a personality disorder and determining that a subject is at risk of a personality disorder will be known to those in the art. In some embodiments, a disclosed compound is used to treat a mild, moderate, or severe personality disorders. In some embodiments, a disclosed compound is used to treat a prominent personality trait or patterns (e.g., negative affectivity, detachment, dissociality, disinhibition, anankastia, borderline pattern). Examples of a personality disorder, treatable using the disclosed compounds, include antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, masochistic or sadistic behavior, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, psychopathy, sociopathy, schizoid personality disorder, or schizotypal personality disorder.

[0265] In some embodiments, a disclosed compound is used to treat a paraphilic disorder. In some embodiments, a subject has a paraphilic disorder. In some embodiments, a subject is at risk of a paraphilic disorder. The diagnosis of a paraphilic disorder and determining that a subject is at risk of a paraphilic disorder will be known to those in the art. Examples of a paraphilic disorder, treatable using the disclosed compounds, include 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.

[0266] In some embodiments, a disclosed compound is used to treat a factitious disorder. In some embodiments, a subject has a factitious disorder. In some embodiments, a subject is at risk of a factitious disorder. The diagnosis of a factitious disorder and determining that a subject is at risk of a factitious disorder will be known to those in the art. Subjects with factitious disorders may seek treatment or otherwise present themselves or another person as ill, injured, or impaired. Examples of a factitious disorder, treatable using the disclosed compounds, include a factitious disorder imposed on self or a factitious disorder imposed on another.

[0267] In some embodiments, a disclosed compound is used to treat a neurocognitive disorder. In some embodiments, a subject has a neurocognitive disorder. In some embodiments, a subject is at risk of a neurocognitive disorder. The diagnosis of a neurocognitive disorder and determining that a subject is at risk of a neurocognitive disorder will be known to those in the art. Examples of a neurocognitive disorder, treatable using the disclosed compounds, include delirium, amnestic disorder, dementia, Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, or Lewy body disease. In some embodiments, a neurocognitive disorder, treatable using the disclosed compounds, is associated with a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat delirium. In some embodiments, the delirium is associated with another disease or disorder. In some embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat mild neurocognitive disorder. In some embodiments, a disclosed compound is used to treat an amnestic disorder. In some embodiments, the amnestic disorder is associated with another disease or disorder. In some embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat dementia. In some embodiments, the dementia is associated with Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, Lewy body disease, a psychoactive substance (including medications and illicit or illegal substances). In some embodiments, a disclosed compound is used to treat a behavioral or psychological disturbance associated with dementia. In some embodiments, dementia is assessed using a Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).

[0268] In some embodiments, a disclosed compound is used to treat a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. In some embodiments, a subject has a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. In some embodiments, a subject is at risk of a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. The diagnosis of a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium and determining that a subject is at risk of a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium will be known to those in the art. In some embodiments, the disorder includes psychotic symptoms. In some embodiments, a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, with psychotic symptoms. In embodiments, a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, without psychotic symptoms.

[0269] In some embodiments, a disclosed compound is used to treat a sleep-wake disorder. In some embodiments, a subject has a sleep-wake disorder. In some embodiments, a subject is at risk of a sleep-wake disorder. The diagnosis of a sleep-wake disorder and determining that a subject is at risk of a sleep-wake disorder will be known to those in the art. Examples of a sleep-wake disorder, treatable using the disclosed compounds, include an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder.

[0270] In some embodiments, a disclosed compound is used to treat sexual dysfunction. In some embodiments, a subject has sexual dysfunction. In some embodiments, a subject is at risk of sexual dysfunction. The diagnosis of sexual dysfunction and determining that a subject is at risk of sexual dysfunction will be known to those in the art.. Examples of a sexual dysfunction, treatable using the disclosed compounds, include hypoactive sexual desire dysfunction, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse.

[0271] In some embodiments, a disclosed compound or composition is administered together with psychotherapy, such as psychosocial or behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174; in J Consul Clin Psychol 2005; 73(2): 354-59; or in Case Reports in Psychiatry, Vol.2012, Article ID 731638), motivational interviewing based therapy (e.g., as described in J Consul Clin Psychol 2001; 69(5): 858-62), meditation based therapy, such as transcendental meditation based therapy (e.g., as described in J Consul Clin Psychol 2000; 68(3): 515-52), or the therapeutic approach used by MAPS to treat patients with PTSD (e.g., as in Mithoefer, M (2017). Manual for MDMA-Assisted Psychotherapy in the Treatment of Post-traumatic Stress Disorder).

[0272] In some embodiments, disclosed compounds and compositions may be administered in conjunction with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is neither necessitated nor desired, or no specific type of psychotherapy is necessitated or desired, however any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in specific therapies, as well as to choose between any such therapies (or to decide to forgo any specific therapy), while still receiving clinically significant therapeutic effects, is among the advantages of the invention. Furthermore, a patient can participate in numerous other therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.

[0273] In some embodiments, “psychotherapy” is specifically “psychedelic-assisted psychotherapy.” Psychedelic-assisted psychotherapy, broadly, includes a range of related approaches that involve at least one session where the patient ingests a psychedelic and is monitored, supported, or otherwise engaged by one or more trained mental health professionals while under the effects of the psychedelic (see, e.g., Schenberg 2018). Protocols have been developed for the standardization of procedures which emphasize a high degree of care (see, e.g., Johnson 2008), such as the therapeutic approach used by MAPS to treat patients with PTSD using MDMA (e.g., as described in Mithoefer 2017).

[0274] In some embodiments, the psychotherapy conducted with a disclosed compound is conducted in widely spaced sessions. These sessions can be as frequently as weekly but are more often approximately monthly or less frequently. In most cases, a small number of sessions, on the order of one to three, is needed for a patient to experience significant clinical progress, as indicated, for example, by a reduction in the symptoms of the mental health disorder being treated. In some embodiments, psychotherapy comprises multiple sessions, during some of which a disclosed compound is administered (“drug-assisted psychotherapy”); in others, the patient participates in psychosocial or behavioral therapy without concomitant administration of a drug, or without administration of a disclosed compound.

[0275] In some embodiments, a disclosed compound or composition is administered together with standardized psychological treatment or support, which refers to any accepted modality of standard psychotherapy or counseling sessions, whether once a week, twice a week, or as needed; whether in person or virtual (e.g., over telemedicine or by means of a web program or mobile app); and whether with a human therapist or a virtual or AI “therapist.” As used herein, “therapist” refers to a person who treats a patient using the disclosed compositions and methods, whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, although it will be understood that certain requirements will be appropriate to certain aspects of the drug-assisted therapy (e.g., prescribing, dispensing, or administering a drug, offering psychotherapeutic support). In some embodiments, a “person” may also include an AI.

[0276] In some embodiments, a patient will participate in a treatment protocol or a disclosed method, or be administered a disclosed composition as part of such a method, if the patient meets certain specified inclusion criteria, does not meet certain specified exclusion criteria, does not meet any specified withdrawal criteria during the course of treatment, and otherwise satisfies the requirements of the embodiment of the disclosure as claimed.

[0277] Preferably, where the disclosed pharmaceutical compositions are administered, such administration occurs without or with reduced risk of side effects that would require physician supervision, and therefore allow for treatment at home or otherwise outside of a clinic and without the need for such supervision, and / or additionally without the requirement of adjunctive psychotherapy (although it also may be provided in certain embodiments herein).

[0278] In some embodiments, the disclosed compositions may be administered in conjunction with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is neither necessitated nor desired, or no specific type of psychotherapy is necessitated or desired, however any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in specific therapies, as well as to choose between any such therapies (or to decide to forgo any specific therapy), while still receiving clinically significant therapeutic effects, is among the advantages of the invention. Furthermore, a patient can participate in numerous other therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.

[0279] In some instances, certain personalized approaches (i.e., “personalized” or “precision” medicine) may be utilized, based on individual characteristics, including drug metabolism (e.g., CYP2D6 or CYP3A4) or individual genetic variation. The term “genetic variation” refers to a change in a gene sequence relative to a reference sequence (e.g., a commonly-found and / or wild-type sequence). Genetic variation may be recombination events or mutations such as substitution / deletion / insertion events like point and splice site mutations.

[0280] In some embodiments, the genetic variation is a genetic variation in one or more cytochrome P450 (CYP or CYP450) enzymes that affects drug metabolism, including metabolism of a disclosed composition, and including CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5. Other examples of CYP enzymes include CYP1A1, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0281] In some embodiments, a disclosed composition is taken together with a compound that is metabolized by the same CYP enzyme(s) as the disclosed composition, so as to permit a lower dose to be taken, increase the effective bioavailability of one or both, or otherwise affect drug metabolism or pharmacokinetics. In some embodiments, the dose of a disclosed composition is adjusted, such as reduced, when administered to a subject known to be a poor metabolizer of an active compound in the composition (e.g., having a genetic variation in CYP2D6 and / or CYP3A4), or increased when administered to a subject known to be a rapid metabolizer. In some embodiments, a patient is tested using ordinary means known to those of skill to determine if the patient is a poor or rapid metabolizer for one or more such CYP enzymes.

[0282] In some embodiments, the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which has been implicated in mood and anxiety symptoms in humans. In another embodiment, the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs. The FKBP5 gene has been implicated in responses to stress and trauma, and such SNPs are correlated with susceptibility to certain depression, PTSD, and anxiety disorders. In some embodiments, a genetic variation is an inclusion criteria for the administration of a disclosed compound. In some embodiments, a genetic variation is an exclusion criteria for the administration of a disclosed compound.

[0283] In some embodiments, the mammal being treated has altered epigenetic regulation of a gene, the expression of which is associated with a mental health condition or susceptibility to a mental health treatment, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor. ii. Neurodegenerative Disorders

[0284] In some embodiments, disclosed compounds are used to treat a neurodegenerative disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a neurodegenerative disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a neurodegenerative disorder.

[0285] The term “neurodegenerative disorder” refers to a class of progressive, chronic, and debilitating conditions characterized by the gradual loss of structure and function of neurons within the central nervous system (CNS) or peripheral nervous system (PNS). These disorders involve the degeneration, impairment, or death of neuronal cells, leading to a decline in cognitive, motor, and / or sensory abilities.

[0286] Neurodegenerative disorders can be classified according to primary clinical features, e.g., dementia, parkinsonism, or motor neuron disease, anatomic distribution of neurodegeneration, e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations, or principal molecular abnormality (Dugger B, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology.2017:9(7);a028035). T hese disorders may involve various etiologies, including but not limited to, presence of pathogenic proteins, age, environmental stressors, and genetic predisposition (Armstrong R. Folia Neuropathologica.2020:58(2);93-112).

[0287] In some embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis or Charcot’s disease, chronic traumatic encephalopathy, corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease or Parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury. iii. Pain Disorders

[0288] In some embodiments, disclosed compounds are used to treat a pain disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a pain disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a pain disorder.

[0289] A “pain disorder” refers to a class of medical conditions characterized by the experience of persistent 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 but not limited to nociceptive, neuropathic, psychogenic, idiopathic or radicular origins. In embodiments, a compound is used 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.

[0290] 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 disclosed 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.

[0291] In some embodiments, pain is 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). iv. Inflammatory Disorders

[0292] Inflammation is an essential immune response to tissue insults such as microbial infection, acute injury, chemical irritants or other such dysregulation of normal tissue functioning. The inflammatory process is a feature of the innate immune system, whereby molecular patterns of tissue damage are recognized and responded to by a variety of inflammatory agents such as cytokines and chemokines. These inflammatory agents act directly to remove harmful stimuli and initiate various signaling responses to return damaged tissue to a state of homeostasis. Although this response is often self-terminating, the resolution of inflammation may fail for multiple reasons, extending the inflammation response into a chronic stage (Ahmed AU. Front Biol.2011:6(4): 274–281). Chronic inflammation is often associated with or underlies a variety of pathological conditions, including major cardiovascular and neuropsychiatric disorders (Nichols CD. Cardiovasc Psychiatry Neurol 2009:475108).

[0293] Recent evidence suggests a significant role of the 5-HT2Aserotonin receptor subtype in mediating the termination of the inflammatory response.5-HT2Areceptors are found throughout the body, including in both the central nervous system and peripheral tissues (Flanagan & Nichols. In’l Rev of Psychiatry. 2018;30(4):363-375). In the brain, 5-HT2Areceptors are involved in cognitive function and working memory, mediate the effects of psychedelic compounds, and have been implicated in mechanisms underlying neuropsychiatric disorders such as schizophrenia (Nichols CD. Cardiovasc Psychiatry Neurol.2009;475108). In the periphery, 5-HT2Areceptors are found in multiple immune related tissues such as the spleen, thymus, and circulating lymphocytes, as well as in components of both the innate and adaptive immune systems (Stefulj J, et al. Brain Behav Immun.2000 Sep;14(3):219-24; Cloëz-Tayarani I, et al. Int Immunol.2003 Feb;15(2):233-40). Research on 5-HT2Areceptors at these tissues have elucidated their role in modulating the immune response (Flanagan TW, Nichols CD. Int Rev Psychiatry.2018 Aug;30(4):363-375).

[0294] Due to their significant action on 5-HT2Areceptors in the brain, multiple studies have been performed to assess the effect of psychedelic compounds on the inflammation modulating effects of 5-HT2Areceptors. One such study found that (R)-2,4-dimethoxy-4-iodoamphetamine ((R)-DOI) is able to potently repress TNF-ɑ induced inflammation. This study found the same effect, albeit slightly less potent, induced by the psychedelic compounds 2C-BCB, LA-SS-Az and LSD (Yu et al. J Pharmacol Exp Ther .2008;327:316-323). Notably, the potency required to achieve anti-inflammatory effects of some psychedelic compounds is at levels in the low picomolar range, approximately 500x more potent than conventional corticosteroids at their target. Anti-inflammatory doses of psychedelics also can be below the threshold for producing subjective or behavioral effects, meaning they may exhibit anti-inflammatory effects without triggering a psychedelic “trip.”

[0295] This work, and subsequent in vitro and in vivo studies have demonstrated that (R)-DOI inhibits TNF-α induced expression of genes encoding intracellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), and inflammatory cytokines IL-6 and IL-1β, and chemokines monocyte chemotactic protein-1 (MCP1). (R)-DOI also blocks activation and nuclear translocation of NF-κB, nitric oxide synthase activity, and downregulates asthma-associated protein arginase-1 (Nau F Jr, et al. PLoS One.2013 Oct 2;8(10):e75426; Flanagan & Nichols. Int’l Review Psych.2018.30(4), 363-375; Flanagan et al. ACS Pharmacol Transl Sci .2024;7(2):478–492). Further, some psychedelic compounds potently suppress select key proinflammatory biomarkers, while leaving others unaffected. For the biomarkers where suppression is evident, suppression is potent and returns levels to baseline, not suppressed below baseline levels, even at relatively high doses of drug (Nichols CD. Neuropharmacol.2022;219:109232). Thus, some psychedelics can reduce expression of certain key inflammatory components, while leaving the immune response largely intact. This is a unique mechanism of action among known anti-inflammatory and immunomodulatory agents, and may be advantageous as it is predicted to have fewer side effects such as opportunistic infections that are associated with broad immunosuppressants like corticosteroids ( id. ).

[0296] Although there is great therapeutic potential for psychedelics as anti-inflammatory agents, there is considerable variation in the efficacy of different psychedelics. It has been hypothesized that chemical structural diversity among psychedelics may result in functional selectivity at the 5-HT2Areceptor, whereby certain ligands engage specific subsets of amino acid residues in the binding pocket of the receptor that induce stable conformational states that couple to different anti-inflammatory signal transduction affectors. This hypothesis is supported by the differential peripheral effects of (R)-DOI and (R)-DOTFM, wherein the former induces anti-inflammatory effects in a mouse model of asthma while the latter does not (Flanagan et al. ACS Pharmacol Transl Sci .2024). This finding supports earlier work that determined the primary pharma- cophore for anti-inflammatory phenethylamine 5-HT2Areceptor agonists to be 2,5-dimethoxyphenethylamine (2C-H) (Flanagan TW, et al. ACS Pharmacol Transl Sci .2020 Aug 13;4(2):488-502). However, structure- activity relationships of anti-inflammatory agents with 5-HT2Areceptor agonist properties remain unclear.

[0297] In some embodiments, a disclosed compound is a potent anti-inflammatory agent that acts on specific inflammation mediators, thereby returning chronically inflamed tissue to a healthy state. In some embodiments, the anti-inflammatory effect is enacted without broadly suppressing the immune system, and can therefore be beneficial to treat inflammatory disease where steroids are contraindicated, or the condition is steroid resistant.

[0298] In some embodiments, a disclosed compound decreases an inflammatory response in a subject. In some embodiments, the inflammatory response is quantified by a change in the level of an inflammation response biomarker. In some embodiments, the level of an inflammation response biomarker represents the expression level of an inflammation response gene. For example, an increased level of an inflammation response biomarker in a subject can be compared to a baseline level of the same biomarker, said increase being indicative of increased expression of the inflammation response gene encoding that biomarker. In some embodiments, increased expression of an inflammation response gene can be associated with chronic inflammation. In some embodiments, decreased expression of an inflammation response gene can be associated with chronic inflammation.

[0299] 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-HT2Areceptor, whereby the compound engages certain amino acid residues within receptor, stabilizing it in a conformation that triggers anti-inflammatory signal transduction pathway effectors.

[0300] 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 TNFα, Arg-1, IL-4, IL-5, IL-6, IL-8, IL-9, IL-1β, Il-lA, IL-12, IL-13, IFNα, IFNb, IFNg, TGF-β, IL-15, IL-17, IL-20, IL-22, LTA, IL-23, IL-18, VCAM1, ICAM1, MCP1, MMP-9, Muc5ac, Gm-csf, CCL2, CCL5, CCL3, CCL4, CCL11, CD11a, CD3, CD4, CD8, 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-1β, TNFα, 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-β) can act as either inflammatory or anti-inflammatory cytokines under various circumstances (Zhang JM, An J. Int Anesthesiol Clin.2007 Spring;45(2):27-37).

[0301] In some embodiments, the inflammation response gene is ICAM1. In some embodiments, the biomarker of inflammation response is an ICAM1 gene product. In some embodiments, the biomarker is ICAM1 mRNA. In some embodiments, the biomarker is the ICAM1 protein. In some embodiments, the inflammation response gene is VCAM1. In some embodiments, the biomarker of inflammation response is a VCAM1 gene product. In some embodiments, the biomarker is VCAM1 mRNA. In some embodiments, the biomarker is the VCAM1 protein. In some embodiments, the inflammation response gene is MCP1. In some embodiments, the biomarker of inflammation response is a MCP1 gene product. In some embodiments, the biomarker is MCP1 mRNA. In some embodiments, the biomarker is the MCP1 protein. In some embodiments, the inflammation response gene is IL-5. In some embodiments, the biomarker of inflammation response is a IL-5 gene product. In some embodiments, the biomarker is IL-5 mRNA. In some embodiments, the biomarker is the IL-5 protein. In some embodiments, the inflammation response gene is IL-6. In some embodiments, the biomarker of inflammation response is a IL-6 gene product. In some embodiments, the biomarker is IL-6 mRNA. In embodiments, the biomarker is the IL-6 protein.

[0302] In some embodiments, the inflammation response gene is IL-9. In some embodiments, the biomarker of inflammation response is a IL-9 gene product. In some embodiments, the biomarker is IL-9 mRNA. In some embodiments, the biomarker is the IL-9 protein. In some embodiments, the inflammation response gene is IL-15. In some embodiments, the biomarker of inflammation response is a IL-15 gene product. In some embodiments, the biomarker is IL-15 mRNA. In some embodiments, the biomarker is the IL-15 protein. In some embodiments, the inflammation response gene is IL-1β . In some embodiments, the biomarker of inflammation response is a IL-1β gene product. In some embodiments, the biomarker is IL-1β mRNA. In some embodiments, the biomarker is the IL-1β protein. In some embodiments, the inflammation response gene is Arg-1. In some embodiments, the biomarker of inflammation response is a Arg-1 gene product. In some embodiments, the biomarker is Arg-1 mRNA. In some embodiments, the biomarker is the Arg-1 protein.

[0303] In some embodiments, the inflammation response gene is Gm-csf . In some embodiments, the biomarker of inflammation response is a Gm-csf gene product. In some embodiments, the biomarker is Gm-csf mRNA. In some embodiments, the biomarker is the Gm-csf protein. In some embodiments, the inflammation response gene is Muc5ac . In some embodiments, the biomarker of inflammation response is a Muc5ac gene product. In some embodiments, the biomarker is Muc5ac mRNA. In some embodiments, the biomarker is the Muc5ac protein. In some embodiments, the inflammation response gene is MMP-9. In some embodiments, the biomarker of inflammation response is a MMP-9 gene product. In some embodiments, the biomarker is MMP-9 mRNA. In some embodiments, the biomarker is the MMP-9 protein. In some embodiments, the inflammation response gene is TGF-β . In some embodiments, the biomarker of inflammation response is a TGF-β gene product. In some embodiments, the biomarker is TGF-β mRNA. In some embodiments, the biomarker is the TGF-β protein.

[0304] In some embodiments, the inflammation response biomarker is a cytokine. Cytokines are small signaling proteins that coordinate the interactions of different cell types involved in the amplification and regulation of the inflammatory response. In some embodiments, the cytokine biomarker is IL-2, IFN- ^^, TNFα, TNFβ, 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-β. In some embodiments, the inflammation response biomarker is a chemokine. Chemokines are small signaling proteins that induce the movement of other cell types, such as toward a tissue injury site. In some embodiments, the chemokine biomarker is CCL-1 to CCL-28, CXCL-1 to CXCL-16, IL-8, MCP1, RANTES, XCL1, XCL2, or CX3CL1. In some embodiments, the inflammation response biomarker is an enzyme. In some embodiments, the enzyme biomarker is Arg-1. In some embodiments, the biomarker of inflammation for a particular inflammatory disease, comorbidity, or patient demographic will be known to those of skill in the art ( See: Sreedhar R, et al. General Mechanisms of Immunity and Inflammation. In: Watanabe K & Arumugam S. eds. Japanese Kampo medicines for the treatment of common diseases: Focus on inflammation. Academic Press;2017:Chapter 3; Germolec DR et al. Markers of Inflammation. Methods Mol Biol.2018;1803:57-79; Calder PC, et al. Br J Nutr.2013 Jan;109 Suppl 1:S1-34).

[0305] 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 will be known to those of skill, or can be measured by standard techniques (Calder PC, et al. Br J Nutr.2013 Jan;109 Suppl 1:S1-34).

[0306] In some embodiments, a disclosed compound reduces the level of an inflammatory biomarker. In some embodiments, a disclosed compound does not reduce the level of an inflammatory biomarker below baseline. In some embodiments, a disclosed 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 some 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 some 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 some embodiments, the sample is a tissue sample. In some embodiments, the sample is a blood sample. In some embodiments, the same is a plasma sample.

[0307] In some embodiments, a disclosed compound increases the level of an anti-inflammatory biomarker. In some embodiments, a disclosed compound does not increase the level of a pro-inflammation biomarker above baseline. In some embodiments, a disclosed 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 some embodiments, a disclosed 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 some embodiments, the sample is a tissue sample. In some embodiments, the sample is a blood sample. In some embodiments, the same is a plasma sample.

[0308] 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.

[0309] In embodiments, a disclosed compound is used to treat an inflammatory disorder. 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 disorder or reduce inflammation.

[0310] In some embodiments, the disorder is an acute inflammatory disorder. In some embodiments, the disorder is a chronic inflammatory disorder. In some embodiments, the inflammatory disorder 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.

[0311] In some embodiments, a disclosed compound is useful 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 (MS), 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 (COPD). In some embodiments, a disclosed compound is useful for treating chronic inflammation in an immunocompromised chemotherapy patient.

[0312] In some embodiments, a disclosed compound is useful 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.

[0313] In some embodiments, a disclosed compound is useful 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.

[0314] In embodiments, a disclosed compound is useful 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.

[0315] In some embodiments, the inflammatory disorder is any of acne vulgaris, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, Anemia, appendicitis, arteritis, arthritis, including osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathy such as ankylosing spondylitis, reactive arthritis (Reiter syndrome), psoriatic arthritis, enteroarthritis associated with inflammatory bowel disease, Whipple and Behcet's disease, septic arthritis, gout (also known as gouty arthritis, crystalline synovitis, metabolic arthritis), pseudogout (calcium pyrophosphate deposition disease), and Still's disease. Arthritis can affect a single joint (monoarthritis), two to four joints (oligoarthritis), or five or more joints (polyarthritis).

[0316] In some embodiments, the inflammatory disorder is any of long COVID, a food allergy, post-treatment lyme disease syndrome, and an ulcer. In some embodiments, an inflammatory disorder is any of asthma, atherosclerosis, autoimmune disorder, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, including NF-κB-induced inflammatory cancer; cardiovascular disease, including hypertension, endocarditis, myocarditis, heart valve dysfunction, congestive heart failure, myocardial infarction, diabetic heart abnormalities, vascular inflammation, including arteritis, phlebitis, and vasculitis; arterial occlusive disease, including arteriosclerosis and stenosis; inflammatory cardiac hypertrophy, peripheral arterial disease, aneurysm, embolism, incision, pseudoaneurysm, vascular malformation, vascular nevus, thrombosis, thrombophlebitis, varicose veins, stroke, cardiac arrest, and carditis; celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, congestive heart failure, conjunctivitis, colitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, lacrimal inflammation, and dementia.

[0317] In some embodiments, the inflammatory disorder is a dermatitis disorder. Without being bound by theory, dermatitis refers to inflammation of the skin which can occur chronically due to skin barrier dysfunction, abnormal inflammatory response, and persistent itching (Nakahara T, et al. J Dermatol. 2021;48(2):130-139; Beck LA, et al. JID Innov.2022;2(5):100131). Whereas common among dermatitis disorders include redness, persistent itching, and dry skin, further clinical phenotypes of dermatitis disorders are highly heterogeneous, reflecting the diversity and complexity of the underlying mechanisms leading to the disorder (Renert-Yuval Y, et al. J Allergy Clin Immunol.2021;147(4):1174-1190.e1). Many of the inflammatory agents involved in chronic inflammation are also involved in the inflammatory response to dermatitis disorders, including but not limited to CCL17, CCL18, CCL22, CCL27, IL-4, IL-13, IL-17A, IL-18, IL-19, IL-22, IL-26, IL-33, MMP12, and Th2 (Ahn K, et al. Curr Opin Immunol.2020;66:14-21; Renert-Yuval Y, et al. J Allergy Clin Immunol. 2021;147(4):1174-1190.e1; Furue M, et al. Iran J Immunol.2019;16(2):97-107; Sroka-Tomaszewska J, Trzeciak M. Int J Mol Sci.2021;22(8):4130; Fallon et al., Nat Genetics, 2009, 41: 602-608). Effective treatments of dermatitis disorders often target inflammatory pathways, thereby regulating the inflammatory response and ameliorating the symptoms of the dermatitis disorder (Wollenberg A, et al. Br J Dermatol.2014;170 Suppl 1:7-11).

[0318] In some embodiments, the inflammatory disorder is a dermatitis disorder, including 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.

[0319] In some embodiments, the dermatitis disorder is atopic dermatitis. In some embodiments, the dermatitis disorder is chronic photosensitivity dermatitis. In some embodiments, the dermatitis disorder is eczema. In some embodiments, the dermatitis disorder is atopic eczema. In some embodiments, the dermatitis disorder is contact eczema. In some embodiments, the dermatitis disorder is dryness eczema. In some embodiments, the dermatitis disorder is seborrheic eczema. In some embodiments, the dermatitis disorder is discoid eczema. In some embodiments, the dermatitis disorder is varicose eczema. In some embodiments, the dermatitis disorder is herpetic dermatitis. In some embodiments, the dermatitis disorder is neurodermatitis. In some embodiments, the dermatitis disorder is herpetic dermatitis. In some embodiments, the dermatitis disorder is autosensitizing dermatitis. In some embodiments, the dermatitis disorder is stasis dermatitis. In some embodiments, the dermatitis disorder is purulent dermatitis. In some embodiments, the dermatitis disorder is dyshidrotic eczema. In some embodiments, the dermatitis disorder is follicular eczema. In some embodiments, the dermatitis disorder is spongiotic dermatitis. In some embodiments, the dermatitis disorder is hand dermatitis. In some embodiments, the dermatitis disorder is diaper dermatitis. In some embodiments, the dermatitis disorder is occupational contact dermatitis. In some embodiments, the dermatitis disorder is lichen planus-like atopic dermatitis.

[0320] In some embodiments, the inflammatory disorder is any of dermatitis, including atopic dermatitis, chronic photosensitivity dermatitis, eczema, atopic eczema, contact eczema, dryness eczema, seborrheic eczema, sweating disorders, discoid eczema, venous eczema, herpetic dermatitis, neurodermatitis, and autosensitizing dermatitis, stasis dermatitis, purulent sweaty, lichen planus, psoriasis, including psoriasis vulgaris, nail psoriasis, prickly psoriasis, scalp psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis; rosacea, and scleroderma, including morphea; pharmacologically induced inflammation, including from legal or illegal drugs, and chemicals; chronic neurogenic inflammation, including primary and secondary neural inflammation; dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, emphysema, encephalitis, endocarditis, endometritis, enterocolitis, epicondylitis, epididymis, fasciitis, fibromyalgia, fibrosis, connectitis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valvular dysfunction, hepatitis, purulent spondylitis, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, including lymphangitis, lymphadenitis, bacterial cystitis, bacterial encephalitis, pandemic influenza, viral encephalitis, and viral hepatitis (types A, B, and C); inflammatory bowel disease, including Crohn’s disease; inflammatory heart enlargement, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, umbilitis, ovitis, testitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteomyelitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, Peritonitis, pharyngitis, phlebitis, pleurisy, interstitial pneumonia, polycystic nephritis, polymyositis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal vein, renal failure, reperfusion injury, retinitis, rheumatic fever Rhinitis, fallopianitis, sarcoidosis, salivary glanditis, sepsis, including bacteremia and viremia; sinusitis, spastic colon, stenosis, stomatitis, stroke, inflammation associated with surgical complications, synovitis, tendonitis, tendonitis, tendonitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection, including graft versus host disease (GVHD); a Th1-mediated inflammatory disease, trigonitis, tuberculosis, tumor, urethritis, bursitis, uveitis, vaginitis, vasculitis, including Buerger's disease, cerebral vasculitis, Churg-Strauss arteritis, cryoglobulinemia, essential cryoglobulin vasculitis, giant cells arteritis, golfer vasculitis, Henoch-Schönlein purpura, hypersensitivity vasculitis, Kawasaki disease, microscopic polyarteritis / polyvasculitis, nodular polyarteritis, rheumatoid polymuscular muscle pain (PMR), rheumatic vasculitis, Takayasu arteritis, Wegener's granulomatosis, systemic lupus erythematosus (SLE), relapsing polychondritis, Behcet's disease; ulcerative colitis such as ulcerative proctitis, left side colitis, total colitis, and fulminant colitis; and vulvitis.

[0321] A reduction in inflammation, such as chronic systemic inflammation, may be measured according to various methods available to one of skill. Inflammatory biomarkers may be detected from biological specimens, for example, a subject’s blood, such as plasma or serum, or saliva. In one example, inflammation may be detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell count from a blood test. CRP may also be detected in a saliva sample. Salivary CRP is not synthesized locally in the mouth and may reflect more systemic levels of inflammation compared to other inflammatory biomarkers, such as cytokines (Szabo & Slavish, Psychoneuroendocrin.202;124:105069). Additionally clinical pathology data, e.g., hematology data on erythrocyte parameters, platelet count, total number of leukocytes, and leukocyte differentials and morphology, coagulation data on clotting times and fibrinogen, and clinical chemistry data on total protein, albumin and globulin, liver enzymes, renal parameters, electrolytes, and bilirubin can provide an initial indication of the presence and potentially the location of inflammation, in the absence of specific data on immune tissues. See e.g., Germolec et al. Methods Mol Biol.2018;1803:57-79 and Luo et al. Clin Lab.20191;65(3). v. Ophthalmic Diseases and Disorders

[0322] In some embodiments, a disclosed 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 RR, et al. Lancet Glob Health. 2013;1(6):e339-49). Repeated episodes of either infection or inflammation triggers a chronic inflammatory disease process that can result in vascularization and subsequent vision threatening scarring of the cornea (Vaidyanathan U, 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 AT, et al. Clin Exp Ophthalmol. 2020;48(3):366-401). By contrast, modulation with 5-HT receptor agonists has been shown to have anti-inflammatory and anti-vascularization properties, and the ability to decrease ophthalmic pressure (Foster T, et al. Invest Ophthalmol Vis Sci.2020;61(7):429).

[0323] In some embodiments, a disclosed compound can be used to reduce, or ameliorate, or prevent an ophthalmic disease or disorder, non-limiting examples of which are described herein.

[0324] 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.

[0325] 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 a 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.

[0326] In some embodiments, a disclosed compound is used 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).

[0327] In some embodiments, a disclosed compound is used 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 (GVHD); 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.

[0328] 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 neo- vascularization, choroidal neovascularization, retinochoroidal neovascularization, or a combination thereof.

[0329] In some embodiments, the ophthalmic disease is macular degeneration. In some embodiments, the ophthalmic disease is keratoconjunctivitis. In some embodiments, the ophthalmic disease is conjunctivitis. In some embodiments, the ophthalmic disease is keratitis. In some embodiments, the ophthalmic disease is diabetic retinopathy. In some embodiments, the ophthalmic disease is retinopathy of prematurity. In some embodiments, the ophthalmic disease is polypoidal choroidal vasculopathy. In some embodiments, the ophthalmic disease is ischemic proliferative retinopathy. In some embodiments, the ophthalmic disease is retinitis pigmentosa. In some embodiments, the ophthalmic disease is cone dystrophy. In some embodiments, the ophthalmic disease is proliferative vitreoretinopathy. In some embodiments, the ophthalmic disease is retinal artery occlusion. In some embodiments, the ophthalmic disease is retinal vein occlusion. In some embodiments, the ophthalmic disease is Leber's disease. In some embodiments, the ophthalmic disease is retinal detachment. In some embodiments, the ophthalmic disease is retinal pigment epithelial detachment. In some embodiments, the ophthalmic disease is rubeosis iridis. In some embodiments, the ophthalmic disease is corneal neovascularization. In some embodiments, the ophthalmic disease is retinal neovascularization. In some embodiments, the ophthalmic disease is choroidal neovascularization. In some embodiments, the ophthalmic disease is retinochoroidal neovascularization. I. Examples

[0330] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. EXAMPLE 1: Synthesis of 14-Methyl-LSD (14-Me-LSD)

[0331] Indole ( 2 )

[0332] To a solution of commercial indole 1 (573 mg, 2.73 mmol) in pyridine (1.59 mL) was added ICl (1M in DCM, 2.73 mL, 2.73 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h before adding Boc2O (1.32 mL, 5.73 mmol) and DMAP (33.3 mg, 0.273 mL). Once complete by1H NMR analysis the mixture was quenched with ice water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with a sat. Na2S2O3solution (15 mL) and brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (19:1 hexanes:EtOAc eluent, silica) to afford 1.05 g (87% yield) of indole 2.

[0333] 1H NMR ( 2 ) (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 2.48 (s, 3H), 1.63 (s, 9H).

[0334] HRMS m / z: [M+H]+calcd for C14H16BrINO2435.9409; found 435.9368

[0335] Alcohol ( 3 )

[0336] To a solution of indole 2 (970.4 mg, 2.225 mmol) in THF (12.30 mL) cooled in an acetone / dry ice bath (–78 °C) was added a solution of i -PrMgCl•LiCl (2.00 mL, 1.11 M, 2.225 mmol) dropwise. The mixture was stirred in the cooling bath for 1 h. Upon consumption of 2 as determined by1H NMR, a solution of methyl 6-formylnicotinate (735.0 mg, 4.451 mmol) in THF (10.00 mL) was cannulated into the reaction dropwise. After addition of methyl 6-formylnicotinate, the bath was swapped to an ice bath, and the reaction mixture was allowed to gradually warm to rt. The reaction was then quenched with a sat. aqueous solution of NH4Cl (10 mL), diluted with water (10 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (3:1 hexanes:EtOAc eluent, silica) to afford 1.057 g (61% yield) of alcohol 3.

[0337] 1H NMR ( 3 ) (500 MHz, CDCl3): δ 9.20 (s, 1H), 8.23 (dd, J = 8.1, 2.1 Hz, 1H), 7.41 (s, 1H), 7.40 – 7.30 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 3.95 (s, 3H), 2.51 (s, 3H), 1.58 (s, 9H).

[0338] HRMS m / z: [M+H]+calcd for C22H24BrN2O5475.0868; found 475.0820

[0339] Pyridine ( 4 )

[0340] To a suspension of NaBH4pellets (175.1 mg, 4.63 mmol) in DCE (11.57 mL) at rt was added TFA (2.83 mL) cautiously with venting of evolved gas. This mixture was stirred until complete dissolution of the NaBH4pellets could be visually observed resulting in a fine off-white turbid solution. After dissolution, alcohol 3 (550 mg, 1.157 mmol ) was added as a solution in DCE (11.57 mL) dropwise. The reaction was allowed to stir for 1 h at rt before heating to 60 °C overnight. After completion as determined by1H NMR analysis, the reaction was cooled to rt and diluted with H2O (20 mL), neutralized with K2CO3, extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (3:2 hexanes:EtOAc eluent, silica) to afford 326 mg (78% yield) of pyridine 4.

[0341] 1H NMR ( 4 ) (600 MHz, CDCl3): δ 9.17 (dd, J = 2.2, 0.8 Hz, 1H), 8.26 (s, 1H), 8.16 (dd, J = 8.2, 2.2 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 7.7, 1.0 Hz, 1H), 4.66 (s, 2H), 3.93 (s, 3H), 2.42 (s, 3H).

[0342] HRMS m / z: [M+H]+calcd for C17H16BrN2O2359.0395; found 359.0374

[0343] Tetrahydropyridine ( 5 )

[0344] To a stirring solution of compound 4 (325.0 mg, 0.904 mmol) in CH2Cl2(9.05 mL) was added MeOTf (0.113 mL, 0.995 mmol) at 0 °C. After 2 h, the reaction was complete as determined by TLC and concentrated under reduced pressure. The crude residue was redissolved in MeOH (9.05 mL) and added solid NaBH4(136.9 mg, 3.619 mmol) portion wise at 0 °C turning the solution canary yellow. This combined mixture was stirred overnight at 0 °C eventually warming to rt and determined to be complete by1H NMR analysis. The reaction was quenched with a 1:1 mixture of a sat. aqueous solution of NaHCO3and acetone (3 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic layers were washed with brine (15 mL), dried with MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (1:1 hexanes:EtOAc then 19:1 DCM:MeOH eluent, silica) to afford 310 mg (91% yield) of tetrahydropyridine 5.

[0345] 1H NMR ( 5 ) (500 MHz, CDCl3): δ 8.35 (s, 1H), 7.21 – 7.14 (m, 2H), 7.01 (s, 1H), 6.84 (d, J = 7.7 Hz, 1H), 3.83 (app d, J = 17.2 Hz, 1H), 3.77 (s, 3H), 3.67 – 3.59 (m, 2H), 3.52 – 3.48 (m, 1H), 2.99 (t, J = 12.0 Hz, 1H), 2.83 (s, 3H), 2.49 – 2.28 (m, 5H).

[0346] HRMS m / z: [M+H]+calcd for C18H22BrN2O2377.0864; found 377.0861

[0347] Carbamate ( 6 )

[0348] To a solution of tetrahydropyridine 5 (1.18 g, 3.13 mmol) in DCM (31.2 mL) was added DMAP (38.2 mg, 0.313 mmol) followed by Boc2O (0.862 mL, 3.75 mmol) at rt. The mixture was stirred at rt for 5h before being determined complete by1H NMR analysis. The reaction was quenched with the addition of H2O (30 mL) and extracted with EtOAc (3 x 30 mL), the combined organic layers were washed with brine (50 mL), dried with MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (EtOAc eluent, silica) to afford 1.08 g (72% yield) of carbamate 6.

[0349] 1H NMR ( 6 ) (500 MHz, CDCl3): δ 7.34 – 7.28 (m, 2H), 6.97 (s, 1H), 6.91 (d, J = 7.9 Hz, 1H), 3.74 (s, 3H), 3.48 (ddd, J = 13.8, 10.9, 3.5 Hz, 2H), 3.35 (dq, J = 17.2, 2.6 Hz, 1H), 3.17 (dt, J = 10.3, 5.1 Hz, 1H), 2.67 (dd, J = 14.0, 10.2 Hz, 1H), 2.56 (s, 3H), 2.49 (s, 3H), 2.19 (dq, J = 6.5, 3.2 Hz, 2H), 1.62 (s, 9H).

[0350] HRMS m / z: [M+H]+calcd for C23H30BrN2O4477.1388; found 477.1375

[0351] Tetrahydropyridines ( 7a and 7b )

[0352] The following procedure is representative of two parallel reactions that were worked up and purified together. In a glovebox, LiTMP (320.6 mg, 2.179 mmol) was weighed out into a flame dried screw cap reaction vial containing a septum and subsequently removed from the glovebox. To this vial under a stream of N2THF (2.20 mL) was added resulting in an amber solution. To this solution was then added a solution of carbamate 6 (208 mg, 0.4357) in THF (2.20 mL) dropwise at –78 °C. The mixture was stirred at –78 °C for 1 h, after which it was determined to be complete by TLC analysis. The reaction was quenched with a sat. aqueous solution of NH4Cl (2.0 mL) at –78 °C and allowed to warm to rt . The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried with MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (1:1 hexanes:EtOAc eluent, silica) to afford 335 mg (79% avg yield) of a mixture of tetrahydropyridine diastereomers 7a and 7b in a 1.5:1 ratio.

[0353] 1H NMR ( 7a ) (600 MHz, CDCl3): δ 7.42 (s, 1H), 7.30 (dd, J = 7.9, 1.1 Hz, 1H), 6.92 (dd, J = 7.9, 1.1 Hz, 1H), 5.91 – 5.85 (m, 1H), 5.70 (dt, J = 10.2, 2.5 Hz, 1H), 3.71 (s, 3H), 3.59 (ddd, J = 14.8, 4.4, 1.2 Hz, 1H), 3.42 (ddt, J = 8.4, 5.5, 2.8 Hz, 1H), 3.28 – 3.15 (m, 2H), 2.87 – 2.76 (m, 1H), 2.67 (dd, J = 11.6, 9.6 Hz, 1H), 2.55 (s, 3H), 2.50 (s, 3H), 1.63 (s, 9H).

[0354] 1H NMR ( 7b ) (600 MHz, CDCl3) δ 7.36 (s, 1H), 7.30 (dd, J = 7.9, 1.1 Hz, 1H), 6.92 (dd, J = 7.9, 1.1 Hz, 1H), 5.91 – 5.85 (m, 1H), 5.75 (ddd, J = 10.3, 3.0, 2.1 Hz, 1H), 3.74 (s, 3H), 3.49 (ddd, J = 14.3, 5.4, 1.1 Hz, 1H), 3.32 – 3.27 (m, 1H), 3.28 – 3.15 (m, 2H), 2.87 – 2.76 (m, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 1.63 (s, 9H).

[0355] HRMS m / z: [M+H]+calcd for C23H30BrN2O4477.1388; found 477.1366

[0356] Ergoline ( 8 , 9a , and 9b )

[0357] In a glovebox, Pd(tBu3P)2(360 mg, 0.7038 mmol) was weighed out into a flame dried screw cap reaction vial containing a septum and subsequently removed from the glovebox. To this reaction vial dioxane (5.0 mL) was added under a stream of N2. In a sperate RBF tetrahydropyridines 7a and 7b (336 mg, 0.7038 mmol) were dissolved in dioxane (30.2 mL) and charged with the previously prepared Pd(tBu3P) solution followed by Cy2NMe (0.452 mL, 2.111 mmol). This mixture was then sparged with N2for 5 min before being heated in an oil bath to 100 °C. After 2 h the reaction was determined to be complete by TLC analysis. Once the reaction had cooled to rt the mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried with MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on Et3N neutralized silica (4:1 hexanes:EtOAc eluent, silica) to afford 220 mg (79% yield) of ergoline compound 8, containing trace amounts of isomers presumed to be 9a and 9b . This mixture was used in the ensuing step without consequence to the result.

[0358] 1H NMR ( 8 ) (600 MHz, CDCl3): δ 7.23 (s, 1H), 7.09 (dd, J = 7.4, 0.9 Hz, 1H), 7.07 – 7.02 (m, 2H), 4.02 – 3.97 (m, 1H), 3.71 (s, 3H), 3.47 (d, J = 17.7 Hz, 1H), 3.37 – 3.28 (m, 2H), 2.89 (dd, J = 15.3, 4.5 Hz, 1H), 2.67 (s, 3H), 2.65 – 2.61 (m, 1H), 2.58 (s, 3H), 1.62 (s, 9H).

[0359] HRMS m / z: [M+H]+calcd for C23H29N2O4397.2127; found 397.2109

[0360] Carboxylic Acid ( 10 )

[0361] To a stirring solution of tetracyclic compounds 8:9a:9b (220 mg, 0.555 mmol) in ethanol (6.94 mL) was added 1 M KOH (6.94 mL) and the mixture was heated in an oil bath at 70 °C for 12 h. Upon completion as determined by HRMS, the mixture was allowed to cool to rt and acidified to pH 6.0 using 1 M HCl. The resulting solution was concentrated, and the residue was suspended pyridine (10 mL). This suspension was then filtered, and the filtrate evaporated afforded crude carboxylic acid 10 as brown oil.

[0362] 14-Me-LSD ( 11 )

[0363] To a solution of crude carboxylic acid 10 (268 mg, 0.949 mmol) in DCM (9.5 mL) and pyridine (0.245 mL, 3.047 mmol) was added diethylamine (0.128 mL, 1.234 mmol) at 0 °C. The reaction was allowed to stir for 30 min at 0 °C before being charged with T3P (0.735 mL, 1.234 mmol, 50% in EtOAc) and stirred overnight eventually warming to rt. The reaction was quenched with the addition of DI H2O (10 mL) and allowed to stir for 30 min after which the layers were separated and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried with MgSO4, and concentrated under reduced pressure. The crude residue was purified using centrifugal thin-layer chromatography (EtOAc then 19:1 DCM:MeOH eluent, silica) to afford 51 mg (27% over two steps) of 14-Me-LSD 11 as a brown oil.

[0364] 1H NMR ( 11 ) (600 MHz, CDCl3): δ 8.11 (s, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.93 (d, J = 1.0 Hz, 1H), 6.89 (s, 1H), 6.30 (s, 1H), 4.01 – 3.95 (m, 1H), 3.52 (dd, J = 14.5, 5.5 Hz, 1H), 3.49 – 3.40 (m, 4H), 3.30 (dddd, J = 9.1, 7.6, 4.5, 2.6 Hz, 1H), 3.16 (ddd, J = 11.1, 4.9, 1.4 Hz, 1H), 2.94 (t, J = 10.9 Hz, 1H), 2.76 (ddd, J = 13.7, 11.6, 1.7 Hz, 1H), 2.63 (s, 3H), 2.45 (s, 3H), 1.24 (t, J = 7.23H), 1.17 (t, J = 7.1 Hz, 3H).

[0365] HRMS m / z: [M+H]+calcd for C21H28N3O 338.2232; found 338.2227

[0366] Maleate salt formulation of 11 : To a solution of 11 (37.5 mg, 0.111 mmol) in EtOAc (0.9 mL) and MeOH (0.1 mL) was added a solution of maleic acid (12.9 mg, 0.111 mmol) in EtOAc (1 mL) at rt. The solution was cooled to –20 °C overnight in a freezer before being evaporated to dryness and triturated with Et2O (3 x 3 mL) to yield 35 mg (69% yield) of 11 as its corresponding maleate salt.

[0367] 1H NMR ( 11·maleate ) (600 MHz, CDCl3): δ 8.02 (s, 1H), 7.12 (d, J = 7.4 Hz, 1H), 7.05 – 6.97 (m, 2H), 6.35 (s, 1H), 4.53 – 4.50 (m, 1H), 4.04 – 3.97 (m, 1H), 3.71 (dd, J = 11.8, 5.1 Hz, 1H), 3.66 (dd, J = 14.3, 5.5 Hz, 1H), 3.57 (t, J = 11.4 Hz, 1H), 3.53 – 3.40 (m, 4H), 3.37 (t, J = 13.3 Hz, 1H), 3.12 (s, 3H), 2.48 (s, 3H), 1.26 (t, J = 6.9 Hz, 3H), 1.18 (t, J = 7.5 Hz, 3H). EXAMPLE 2: Synthesis of 2-Bromo-14-methyl-LSD (2-Br-14-Me-LSD)

[0368] To a solution of 14-Me-LSD 11 (18.7 mg, 0.0554 mmol) in dioxane (1.11 mL) was added solid Br2· dioxane (13.7 mg, 0.0554 mmol) portion wise at approximately 15 °C. After addition of Br2· dioxane the reaction mixture was warmed to rt and stirred for 30 min before it was determined complete by TLC. The reaction was diluted with DCM (5 mL) and quenched by the additon of a sat. aqueous solution of NaHCO3(5 mL) after which the layers were separated and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried with MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (EtOAc eluent, silica) to afford 14.0 mg (60% yield) of 2-Br-14-Me-LSD 12 as a brown oil.

[0369] 1H NMR ( 12 ) (600 MHz, CDCl3): δ 8.27 (s, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 0.9 Hz, 1H), 6.29 (s, 1H), 4.00 – 3.95 (m, 1H), 3.51 – 3.40 (m, 5H), 3.35 (dd, J = 14.7, 5.7 Hz, 1H), 3.28 – 3.23 (m, 1H), 3.18 – 3.13 (m, 1H), 2.93 (t, J = 11.0 Hz, 1H), 2.64 (s, 3H), 2.41 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0370] HRMS m / z: [M+H]+calcd for C21H27BrN3O 416.1337; found 416.1323

[0371] Maleate salt formulation of 12 : To a solution of 12 (37.2 mg, 0.089 mmol) in EtOAc (0.9 mL) and MeOH (0.1 mL) was added a solution of maleic acid (10.4 mg, 0.089 mmol) in EtOAc (1 mL) at rt. The solution was cooled to –20 °C overnight in a freezer before being evaporated to dryness and triturated with Et2O (3 x 3 mL) to yield 33 mg (69% yield) of 12 as its corresponding maleate salt.

[0372] 1H NMR ( 12·maleate ) (600 MHz, CDCl3): δ 8.91 (s, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.4 Hz, 1H), 6.31 (s, 1H), 4.46 – 4.43 (m, 1H), 3.92 – 3.89 (m, 1H), 3.74 – 3.69 (m, 1H), 3.58 (t, J = 11.4 Hz, 1H), 3.50 – 3.36 (m, 4H), 3.12 (s, 3H), 3.10 – 2.98 (m, 2H), 2.40 (s, 3H), 1.25 (t, J = 6.4 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H) EXAMPLE 3: In Vitro Receptor Activity Assays

[0373] Purpose: The agonist activity of disclosed compounds at the human 5-HT2Areceptor expressed in transfected HEK-293 cells, and the human 5-HT2Breceptor expressed in CHO-K1 cells, was determined by measuring their effects on IP1 production using the HTRF detection method.

[0374] Methods: The cells are suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCl, 146 mM NaCl, 1 mM CaCl2, 0.5 mM MgCl2, 5.5 mM glucose and 50 mM LiCl, then distributed in microplates at a density of 1.5x104cells / well and incubated for 30 min at 37 °C in the presence of buffer (basal control), test compound or reference agonist.

[0375] For stimulated control measurement, separate assay wells contain 10 µM 5-HT. Following incubation, the cells are lysed and the fluorescence acceptor (D2-labeled IP1) and fluorescence donor (anti-IP1 antibody labeled with europium cryptate) are added.

[0376] After 60 min at room temperature, the fluorescence transfer is measured at λex = 337 nm and λem = 620 and 665 nm using a microplate reader (Envision, Perkin Elmer). The IP1 concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio).

[0377] The results are expressed as a percent of the control response to 10 µM 5-HT. The standard reference agonist is 5-HT, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50value is calculated.

[0378] Results: Table 3 summarizes the 5-HT2Aagonist activity data for 14-Me-LSD and 2-Br-14-Me-LSD. Table 3. IP-1 Agonist Potency (EC50) Values for Disclosed Compounds

[0379] Dose-response curves for 14-Me-LSD and 2-Br-14-Me-LSD are provided in FIGS.1 and 2 , respectively. These data correspond to the tabular data below: 14-Me-LSD 2-Br-14-Me-LSD

[0380] Results showed that both 14-Me-LSD and 2-Br-14-Me-LSD are potent agonists of the 5-HT2Areceptor. Furthermore, both exemplary compounds exhibit excellent selectivity for 5-HT2Aover 5-HT2Bagonism, with low 5-HT2BEmaxvalues. EXAMPLE 4: In Vitro Receptor Binding Assays

[0381] Methods: Membrane is extracted from 5-HT2A / HEK293, 5-HT2B / CHO-K1, and 5-HT2C / HEK293 cells. The reference compounds and screening compounds are 4-fold serially diluted in 100% DMSO for 8 points. Transfer 1 μL of serial diluted references and screening compounds to the assay plates. Then add 100 μL / well of membrane and 100 μL / well of radioligand3H-LSD or125I-DOI. 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 μL of Perkin Elmer Microscint 20 cocktail to each well of assay plate and count3H trapped on filter plate using Perkin Elmer MicroBeta2 Reader.

[0382] Results: Results are expected to show that disclosed compounds potently bind the 5-HT2Areceptor, and may have improved selectivity for binding the 5-HT2Areceptor over another receptor (e.g., another 5-HT receptor, such as the 5-HT2Breceptor or the 5-HT2Creceptor). EXAMPLE 5: Anti-Inflammatory Properties of Compounds

[0364] The anti-inflammatory properties of disclosed compounds are assessed in a mouse model of allergic asthma according to methods described in Flanagan et al. ACS Pharmacol Trans Sci.2020, 4(2), 488–502.

[0365] Procedure: The respiratory pathogen-free Brown Norway (RijHsd-BN) rats used in this Example 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. Animal protocols are prepared in accordance with the Guide for the Care and Use of Laboratory Animals (Committee for the Update of the Guide for the Care and Use of Laboratory Animals, National Academies Press, Washington, DC (2011)). The rats are allowed to acclimate at least 1 week prior to initiation of sensitization with chicken ovalbumin grade V (OVA).

[0366] For sensitization, Brown Norway rats (7−9 weeks old) are i.p. injected with (500 μL) of 2.0 mg of chicken OVA emulsified in 2.0 mL of Imject Alum [Al(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 a previously described mouse model of acute asthma (Nau et al. Am J Physiol. Lung Cellular Mo Physiol.2015, 308(2), L191−198). 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 × 19.05 × 19.7 cm) acrylic induction chamber. No more than 6 animals are exposed in the chamber per challenge. OVA aerosol was 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.

[0367] 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 Neuro Sci.2016, 36(50), 12661-12676; Pazhoohan et al. PLoS One. 2017, 12(10), e0187249). For measurement of airway responsiveness to 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 is connected on one pole to the main chamber and on the second pole to a reference chamber. The transducer measures pressure differences between both chambers as caused by the respiratory cycle, mainly inhalation and exhalation. Computer software provides a breath-by-breath analysis of pressure signals and transforms pressure differences via computerized calculations to a dimensionless empirically established value, enhanced pause or PenH.

[0368] Numerous experiments (Nau et al. Am J Physiol. Lung Cellular Mol Physiol 2015, 308(2), L191−198; 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, Behav. Immun.1998, 12(4), 272−84) have shown PenH to be a reliable and sensitive measure of bronchoconstriction and a superior measure in assessing the degree of bronchoconstriction compared to other derived parameters such as box pressure or box flow (Djuric et al., Brain, Behav. Immun.1998, 12(4), 272−84), and it faithfully reproduces the results of forced respiratory techniques such as flexiVent (flexiVent, SCIREQ, Montreal, CA) (Nau et al. American Journal of Physiology. Lung Cellular and Molecular Physiology 2015, 308(2), L191−198).

[0369] For the assay, the chamber pressure signal is calibrated by dynamic injection of 5 mL of room air via syringe. Rats are then placed in the chamber, where baseline data is recorded for 5 min following a 10 min habituation period in the plethysmograph. After measurement of baseline PenH, either aerosolized saline (0.9% NaCl Solution) 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 rat is provided with fresh air. Data are expressed as the mean SEM of maximal PenH values per group.

[0370] Results: Results may show that certain disclosed compounds possess potent anti-inflammatory properties, and more specifically they may reduce PenH max values and suppress pulmonary inflammation. EXAMPLE 6: Assessment of Ocular Inflammation Following Application of Compounds

[0364] Purpose: Ocular inflammation and uveitis encompass potentially sight-threatening diseases with local and systemic etiologies. Cytokines, e.g. IL-6 (Ghasemi, Ocul Immunol Inflamm.2018;26(1):37-50) and IL-8 (Ghasemi et al. Ocul Immunol Inflamm.2011 Dec;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.

[0365] 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., WO2015074137A1, 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 WO2015074137A1), or in human subjects at risk of experiencing or currently experiencing such inflammation.

[0366] Results & Significance: Application of a disclosed 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 but not limited to eye redness, pain, and alterations in sight, e.g., blurred vision. EXAMPLE 7: In Vivo Model for Assessing Atopic Dermatitis Following Application of Compounds

[0367] Purpose: Atopic dermatitis, or eczema, is characterized by chronic inflammation, and can result in inflammatory symptoms such as irritation of the skin. In some embodiments, disclosed compounds and compositions are useful for treating atopic dermatitis. The purpose of this experiment is to assess the therapeutic effects (e.g., inhibiting and / or reducing the various end-points associated with atopic dermatitis) of disclosed compounds and compositions in a mouse in vivo model of atopic dermatitis. The model for this study uses the flaky tail mouse strain, which carries a mutation in the gene for the epidermal protein filaggrin, which is comparable to the mutation underlying human atopic dermatitis or eczema (Fallon et al., Nat Genetics, 2009, 41: 602-608). Challenging these mice with topically applied ovalbumin results in a condition resembling atopic dermatitis. Mice typically exhibit eczema and increased skin levels of inflammatory biomarkers following ovalbumin application. Exemplary measures of efficacy include skin flakiness, skin levels of Type 2 helper T-cell (Th2) and cytokines, such as IL4, IL5 and IL10.

[0368] Methods: The protocol for application of ovalbumin to the skin of flaky tail mice has been described in the literature ( id. ). In brief, the abdomens of 3-5 week old mice are shaved 24 hours prior to cutaneous application of ovalbumin suspensions (50 μg in 50 μL PBS), which are applied to the abdomen as described previously ( id. ).

[0369] There are two experimental groups: in the first, the mice are pretreated with a disclosed 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, the mice are treated with a disclosed 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 compound tested, the compound is administered (e.g., intravenously, intramuscularly, by 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.

[0370] Results: Results are expected to show that administration of a disclosed compound or composition prevents, inhibitors, and / or treats the symptoms atopic dermatitis. EXAMPLE 8: In Vitro Metabolic Stability of Compounds

[0371] The purpose of this experiment is to assess the metabolic stability of disclosed compounds in an in vitro assay. 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).

[0372] Methods: A liver microsomal stability assay is performed according to available methods, e.g., in accordance with the methods described in US 2008 / 0045588 with modifications. Briefly, the assay is conducted at 1 mg per mL liver microsome protein with an NADPH-generating system in 2% NaHCO3 (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM MgCl2). Test compounds are prepared as solutions in 20% acetonitrile-water and added to the assay mixture (final assay concentration 5 microgram per mL) and incubated at 37° C. Final concentration of acetonitrile in the assay should be <1%. Aliquots (50 μL) are taken out at times 0, 15, 30, 45, and 60 min, and diluted with ice cold acetonitrile (200 μL) 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.

[0373] Results & Significance: Results provide a measurement of the in vitro intrinsic clearance of disclosed compounds, providing a prediction of the metabolic stability and clearance of the compounds. EXAMPLE 9: In Vivo Model for Assessing Intraocular Pressure Following Application

[0374] 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.

[0375] 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 µL of a solution of test compound per administration) over a 10-minute period, i.e., 10 µL every 2-3 minutes.

[0376] Results: Results may 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. EXAMPLE 10: In Vivo Assessment of Behavioral Effects of Compounds Using HTR

[0383] The mouse head-twitch response (HTR) is a behavioral test that reflects 5-HT2Areceptor activation and can be predictive of psychedelic effects in humans (Halberstadt et al. J Psychopharmacol.2011; 25(11): 1548–1561; Glatfelter et al. ACS Pharmacol. Transl. Sci.2022, 5, 321−330). HTR is widely used as a behavioral surrogate for human psychedelic effects for its ability to reliably distinguish psychedelic from non-psychedelic 5-HT2Areceptor agonists ( id. ).

[0384] Methods: An HTR assay is performed in accordance with the methods described in Glatfelter et al. ACS Pharmacol. Transl. Sci.2022, 5, 321−330 to assess the effects of disclosed compounds in mice. All experiments are performed using adult (2−4 months old) male C57BL / 6J mice weighing 20−30 g. Mice are singlehoused housed in a vivarium with ad libitum access to food and water, under standard 12 h light−dark conditions (lights on from 0700 to 1900 h).

[0385] Test compounds are dissolved in a suitable solvent, e.g., water containing 5% Tween 80, and administered intraperitoneally or subcutaneously a volume of 0.01 mL / g body weight immediately prior to testing. Different doses are tested to produce a dose-response curve. Mice are injected with drug or vehicle, and HTR activity is recorded as follows.

[0386] On the day of an experiment, mice in their home cages are transported from the vivarium to the experimental test room and are given 1 h for acclimation. For the experimental sessions, mice receive test compound or vehicle injections and are placed into cylindrical acrylic arenas (7.5 in diameter) housed inside of mouse locomotor boxes. The arenas have transparent floor panels with white bench paper underneath to provide a light background for contrast. Video cameras are used to record high frame rate (120 frames per sec) overhead videos (960p resolution) of mice that receive injections of the test compounds or their saline vehicle. Video cameras are mounted ca.10 inches above the arena floor, and experimental test sessions are recorded for 30 min post-injection. All experiments occur during the light phase of the light−dark cycle between 0900 and 1700 h local time.

[0387] Mice are randomized to treatment conditions and are repeat-tested once per 1−2 weeks to avoid potential tolerance to the effects of a disclosed compound on HTR. After videos of each experiment are recorded, the video files are transferred to an external hard drive for storage until subsequent computer analysis as described below.

[0388] A commercially available software package (TopScan, Clever Sys Inc.) can be adapted for use in measuring HTR. A custom feature of the TopScan software package monitors the ears of the mice to detect head movements that are classified as HTRs. All videos are analyzed for HTRs according to the developer’s instructions. Briefly, experimental details (mouse ID, treatment, date, experiment #, etc.) are entered into the software and the following three procedures are carried out for each video: (1) a background image file is generated to distinguish the arena and its background from the mouse, (2) an arena file is generated that can be customized to the shape and area of any arena contained in each video, and (3) an animal color model file is used to track the ears and checked to ensure there is clear visualization of the ears for each set of videos. The animal color model is dynamic and can be adapted for different lighting conditions or to detect different color contrasts.

[0389] Using all three of the aforementioned parameters created for each video in the software, and the experimental information entered into the software database, automated software scoring of experimental videos is conducted. After videos are scored, all HTRs identified for each video can be quickly reviewed in the software as a list of short video segments that can be viewed and used to remove any potential non-HTR events or false positives as well as confirm HTRs. Finally, the data can be exported in several different formats for further processing and statistical analyses.

[0390] Two trained observers watch the videos and visually score the number of HTRs in 5 min bins for each 30 min experimental session. The total number of HTRs observed for each 30 min video is tallied. The visual scoring is carried out blind to treatment conditions, and HTRs from the two trained observers are averaged to determine the total number of HTRs per video as well as to assess the relationship to the software-based scoring method.

[0391] Visual scores from the trained observers and computer scores from the software analyses are compared by two-way ANOVA (scoring method × treatment) with Tukey’s post-hoc multiple comparisons test to assess differences between scoring methods and effects of drug treatment. Pearson r correlations are computed to assess relationships between visual scores from trained observers and computer software scores. Potency (ED50) values are determined from dose−response studies using nonlinear regression of the rising phase of the curve. Analyzes are conducted using GraphPad Prism software.

[0392] Results can be represented as ED50(mg / kg). Differences between the mouse HTR of disclosed compounds and suitable comparator compounds can be determined according to methods described herein. Results may show that administration of certain exemplary disclosed compounds, such as compounds unsubstituted at the 2-position (i.e., wherein R2= H; for instance 14-Me-LSD) may result in a HTR; other disclosed compounds, such as compounds having a non-H 2-substituent (i.e., wherein R2is other than H; for instance 2-Br-14-Me-LSD) may not result in a HTR. J. Exemplary Aspects and Embodiments

[0393] Among the various exemplary and non-limiting aspects and embodiments herein are the following.

[0394] In one exemplary aspect, provided is a compound of Formula (1), or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein: R1is H or –C(O)–C1-C6alkyl; R2is H, C1-C6alkyl, or halo; R6is C1-C6alkyl or C2-C6alkenyl; R14is C1-C6alkyl, C1-C6alkoxy, or halo; and R' and R'' are C1-C6alkyl; or R' and R'' are taken together to form an optionally substituted heterocyclyl.

[0395] In embodiments, R1is H. In embodiments, R1is –C(O)–C1-C6alkyl. In embodiments, R6is methyl. In embodiments, R6is ethyl. In embodiments, R6is allyl. In embodiments, R2is H. In embodiments, R2is C1-C6alkyl. In embodiments, R2is methyl. In embodiments, R2is halo. In embodiments, R2is bromo. In embodiments, R14is C1-C6alkyl. In embodiments, R14is methyl. In embodiments, R14is halo. In embodiments, R14is chloro. In embodiments, R14is C1-C6alkoxy. In embodiments, R14is methoxy. In embodiments, R' and R'' are both C1-C6alkyl. In embodiments, R' and R'' are both methyl. In embodiments, R' and R'' are both ethyl. In embodiments, R' is methyl and R'' is n-propyl. In embodiments, R' is methyl and R'' is isopropyl. In embodiments, R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is optionally substituted by C1-C6alkyl. In embodiments, R' and R'' are taken together to form an unsubstituted azetidinyl. In embodiments, R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is substituted by C1-C6alkyl.

[0396] In embodiments, R' and R'' are taken together to form , wherein the asterisk (*) indicates the point of connection to the remainder of the compound.

[0397] In another aspect, provided is a compound of Formula (2), , or a prodrug, hydrate, or solvate thereof, wherein: R1is H or –C(O)–C1-C6alkyl; R2is H, C1-C6alkyl, or halo; R6is C1-C6alkyl or C2-C6alkenyl; R6 'is C1-C6alkyl; R14is C1-C6alkyl, C1-C6alkoxy, or halo; and R' and R'' are both C1-C6alkyl; or R' and R'' are taken together to form an optionally substituted heterocyclyl.

[0398] In embodiments, R1is H. In embodiments, R1is –C(O)–C1-C6alkyl. In embodiments, R6is methyl. In embodiments, R6is ethyl. In embodiments, R6is allyl. In some preferred embodiments, where R6is ethyl or allyl, R6 'is methyl. In some preferred embodiments, where R6is C2-C6alkyl or C2-C6alkenyl, R6 'is methyl. In embodiments, R2is H. In embodiments, R2is C1-C6alkyl. In embodiments, R2is methyl. In embodiments, R2is halo. In embodiments, R2is bromo. In embodiments, R14is C1-C6alkyl. In embodiments, R14is methyl. In embodiments, R14is halo. In embodiments, R14is Cl. In embodiments, R14is C1-C6alkoxy. In embodiments, R14is methoxy. In embodiments, R' and R'' are both C1-C6alkyl. In embodiments, R' and R'' are both methyl. In embodiments, R' and R'' are both ethyl. In embodiments, R' is methyl and R'' is n-propyl. In embodiments, R' is methyl and R'' is isopropyl. In embodiments, R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is optionally substituted by C1-C6alkyl. In embodiments, R' and R'' are taken together to form an unsubstituted azetidinyl. In embodiments, R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is substituted by C1-C6alkyl.

[0399] In embodiments, R' and R'' are taken together to form or , wherein the asterisk (*) indicates the point of connection to the remainder of the compound.

[0400] In another aspect, provided is a compound selected from Table 1 , Table 2 , or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0401] In another aspect, provided is a pharmaceutical composition comprising a therapeutically effective amount of the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some such embodiments, the compound, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, is a pure or substantially pure individual enantiomer, or an enantiomerically enriched mixture having an optical purity of between 0-25%, between 25-50%, between 50-75%, between 75-90%, between 90-95%, or at least 95% enantiomeric excess. In embodiments, the pharmaceutical composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, IV, intraocular, topical, or transdermal administration.

[0402] In embodiments, the pharmaceutical composition is provided in unit dosage form. In some such embodiments, the compound is in a total amount of between 0.1 and 100 mg, or between 1 and 10 mg. In embodiments, the compound is in a total amount of between 0.1 and 1 mg, or between 0.5 and 5 mg. In embodiments, the unit dosage form of the pharmaceutical composition is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

[0403] In embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate 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-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins. In embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, or alter pharmacokinetics or pharmacodynamics. In embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect. In embodiments, the additional active agent is an agent useful in treating an inflammatory disease, such as a non-steroidal anti-inflammatory drug (NSAID), analgesic, anesthetic, peptide, enzyme, coenzyme, steroid, calcium channel blocker, immunosuppressant, proton-pump inhibitor, Certolizumab pegol, antidepressant, opiate, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, leflunomide and sulfasalazine, synthetic DMARDs such as apremilast, biological DMARDs such as etanercept, adalimumab, and secukinumab, other categories of TNF-inhibitors, biguanides such as metformin, sodium phenylbu...

Claims

CLAIMS The invention claimed is:

1. A compound of Formula (1):, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein: R1is H or –C(O)–C1-C6alkyl; R2is halo, H, or C1-C6alkyl; R6is C1-C6alkyl or C2-C6alkenyl; R14is C1-C6alkyl, C1-C6alkoxy, or halo; and R' and R'' are both C1-C6alkyl; or R' and R'' are taken together to form an optionally substituted heterocyclyl.

2. The compound of claim 1, wherein R1is H.

3. The compound of claim 1, wherein R1is –C(O)–C1-C6alkyl.

4. The compound of claim 1, wherein R6is C1-C6alkyl.

5. The compound of claim 4, wherein R6is methyl.

6. The compound of claim 4, wherein R6is ethyl.

7. The compound of claim 1, wherein R6is C2-C6alkenyl.

8. The compound of claim 7, wherein R6is allyl.

9. The compound of claim 1, wherein R2is halo.

10. The compound of claim 9, wherein R2is bromo.

11. The compound of claim 1, wherein R2is H.

12. The compound of claim 1, wherein R2is C1-C6alkyl.

13. The compound of claim 12, wherein R2is methyl.

14. The compound of claim 1, wherein R14is C1-C6alkyl.

15. The compound of claim 1, wherein R14is methyl.

16. The compound of claim 1, wherein R14is halo.

17. The compound of claim 16, wherein R14is Cl.

18. The compound of claim 1, wherein R14is C1-C6alkoxy.

19. The compound of claim 18, wherein R14is methoxy.

20. The compound of claim 1, wherein R' and R'' are both C1-C6alkyl.

21. The compound of claim 20, wherein R' and R'' are both ethyl.

22. The compound of claim 20, wherein R' and R'' are both methyl.

23. The compound of claim 20, wherein R' is methyl and R'' is n-propyl.

24. The compound of claim 20, wherein R' is methyl and R'' is isopropyl.

25. The compound of claim 1, wherein R' and R'' are taken together to form an optionally substituted heterocyclyl.

26. The compound of claim 25, wherein R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is optionally substituted by C1-C6alkyl.

27. The compound of claim 25, wherein R' and R'' are taken together to form an unsubstituted azetidinyl.

28. The compound of claim 25, wherein R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is substituted by C1-C6alkyl.

29. The compound of claim 28, wherein R' and R'' are taken together to formor, wherein the asterisk (*) indicates the point of connection to the remainder of the compound.

30. A compound selected from Table 1 , or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

31. The compound of claim 30, wherein the compound.

32. The compound of claim 30, wherein the compound.

33. A compound of Formula (2):, or a prodrug, hydrate, or solvate thereof, wherein: R1is H or –C(O)–C1-C6alkyl; R2is H, C1-C6alkyl, or halo; R6is C1-C6alkyl or C2-C6alkenyl; R6 'is C1-C6alkyl; R14is C1-C6alkyl, C1-C6alkoxy, or halo; and R' and R'' are both C1-C6alkyl; or R' and R'' are taken together to form an optionally substituted heterocyclyl.

34. The compound of claim 33, wherein R1is H.

35. The compound of claim 33, wherein R1is –C(O)–C1-C6alkyl.

36. The compound of claim 33, wherein R6is C1-C6alkyl.

37. The compound of claim 36, wherein R6is methyl.

38. The compound of claim 36, wherein R6is ethyl.

39. The compound of claim 33, wherein R6is C2-C6alkenyl.

40. The compound of claim 39, wherein R6is allyl.

41. The compound of claim 33, wherein R2is H.

42. The compound of claim 33, wherein R2is C1-C6alkyl.

43. The compound of claim 42, wherein R2is methyl.

44. The compound of claim 33, wherein R2is halo.

45. The compound of claim 44, wherein R2is bromo.

46. The compound of claim 33, wherein R14is C1-C6alkyl.

47. The compound of claim 46, wherein R14is methyl.

48. The compound of claim 33, wherein R14is halo.

49. The compound of claim 48, wherein R14is Cl.

50. The compound of claim 33, wherein R14is C1-C6alkoxy.

51. The compound of claim 50, wherein R14is methoxy.

52. The compound of claim 33, wherein R' and R'' are both C1-C6alkyl.

53. The compound of claim 52, wherein R' and R'' are both ethyl.

54. The compound of claim 52, wherein R' and R'' are both methyl.

55. The compound of claim 52, wherein R' is methyl and R'' is n-propyl.

56. The compound of claim 52, wherein R' is methyl and R'' is isopropyl.

57. The compound of claim 33, wherein R' and R'' are taken together to form an optionally substituted heterocyclyl.

58. The compound of claim 57, wherein R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is optionally substituted by C1-C6alkyl.

59. The compound of claim 57, wherein R' and R'' are taken together to form an unsubstituted azetidinyl.

60. The compound of claim 57, wherein R' and R'' are taken together to form an azetidinyl, wherein the azetidinyl is substituted by C1-C6alkyl.

61. The compound of claim 60, wherein R' and R'' are taken together to formor, wherein the asterisk (*) indicates the point of connection to the remainder of the compound.

62. A compound selected from Table 2 , or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

63. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

64. The pharmaceutical composition of claim 63, wherein the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

65. The pharmaceutical composition of claim 63, wherein the composition is provided in unit dosage form.

66. The pharmaceutical composition of claim 65, comprising the compound in a total amount of between about 0.01 and 100 mg.

67. The pharmaceutical composition of claim 63, further comprising a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

68. The pharmaceutical composition of claim 67, wherein the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, 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.

69. A method of modulating neurotransmission in a subject, comprising administering to the subject the compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

70. The method of claim 69, wherein modulating neurotransmission comprises agonizing the 5-HT2Areceptor.

71. A method of increasing neuroplasticity in a subject, comprising administering to the subject the compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

73. The method of claim 72, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission.

74. The method of claim 72, wherein the medical condition is a mental, behavioral, or neurodevelopmental disorder.

75. The method of claim 73, 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.

76. The method of claim 73, wherein the compound is administered together with one or more sessions of psychotherapy.

77. The method of claim 72, wherein the medical condition is inflammation or an inflammatory disorder.

78. The method of claim 77, 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.

79. The method of claim 77, wherein the inflammatory disorder is an acute inflammatory disorder.

80. The method of claim 77, wherein the inflammatory disorder is a chronic inflammatory disorder.

81. The method of claim 77, wherein the inflammatory disorder is a steroid-resistant disorder.

82. The method of claim 77, 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.

83. The method of claim 77, wherein the inflammatory disorder is dermatitis.

84. The method of claim 83, 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.

85. The method of claim 77, wherein the subject has a compromised immune system.

86. The method of claim 77, wherein the subject has an autoimmune disorder.

87. The method of claim 77, wherein the subject has a contraindication to a corticosteroid.

88. The method of claim 77, wherein 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%.

89. The method of claim 88, wherein the inflammatory biomarker is an inflammatory response gene product.

90. The method of claim 89, wherein the inflammatory response gene product is mRNA.

91. The method of claim 90, wherein the mRNA is Arg-1 , ICAM1 , VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β mRNA.

92. The method of claim 88, wherein the inflammatory response gene product is a protein.

93. The method of claim 92, wherein the protein is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β.

94. The method of claim 77, wherein the medical condition is an ophthalmic disorder.

95. The method of claim 94, wherein the ophthalmic disorder is an inflammatory disorder.

96. The method of claim 77, wherein the medical condition is a neurodegenerative disorder.

97. The method of claim 96, 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.

98. A compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment of a medical condition.

99. Use of the compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a medicament for the treatment of a medical condition.

100. A method of modulating neurotransmission in a subject, comprising administering to the subject the pharmaceutical composition of claim 63.

101. The method of claim 100, wherein modulating neurotransmission comprises agonizing the 5-HT2Areceptor.

102. A method of increasing neural plasticity in a subject, comprising administering to the subject the pharmaceutical composition of claim 63.

103. A method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 63.

104. The method of claim 103, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission.

105. The method of claim 103, wherein the medical condition is a mental, behavioral, or neurodevelopmental disorder.

106. The method of claim 105, 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.

107. The method of claim 105, wherein the composition is administered together with one or more sessions of psychotherapy.

108. The method of claim 103, wherein the medical condition is inflammation or an inflammatory disorder.

109. The method of claim 108, 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.

110. The method of claim 108, wherein the inflammatory disorder is an acute inflammatory disorder.

111. The method of claim 108, wherein the inflammatory disorder is a chronic inflammatory disorder.

112. The method of claim 108, wherein the inflammatory disorder is a steroid-resistant disorder.

113. The method of claim 108, 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, Alzheimer’s disease.

114. The method of claim 108, wherein the inflammatory disorder is dermatitis.

115. The method of claim 114, 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.

116. The method of claim 108, wherein the subject has a compromised immune system.

117. The method of claim 108, wherein the subject has an autoimmune disorder.

118. The method of claim 108, wherein the subject has a contraindication to a corticosteroid.

119. The method of claim 108, wherein 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%.

120. The method of claim 119, wherein the inflammatory biomarker is an inflammatory response gene product.

121. The method of claim 120, wherein the inflammatory response gene product is mRNA.

122. The method of claim 121, wherein the mRNA is ICAM1 , VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β mRNA.

123. The method of claim 120, wherein the inflammatory response gene product is a protein.

124. The method of claim 123, wherein the protein is ICAM1, VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β.

125. The method of claim 108, wherein the medical condition is an ophthalmic disorder.

126. The method of claim 125, wherein the ophthalmic disorder is an inflammatory disorder.

127. The method of claim 108, wherein the medical condition is a neurodegenerative disorder.

128. The method of claim 127, 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.

129. The pharmaceutical composition of any one of claims 63-68 for use in the treatment of a medical condition.

130. Use of the pharmaceutical composition of any one of claims 63-68 for the manufacture of a medicament for the treatment of a medical condition.

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