5-carboxamido and 5-carboxyalkyl phenethylamines

Abstract

Provided herein are novel compounds, such as phenethylamines bearing a 5-carboxamido or 5-carboxyalkyl substituent. In some aspects, also provided are pharmaceutical compositions containing the compounds, methods of synthesizing the compounds, and methods of using such compounds, including their administration to subjects. In some aspects, useful features of the compounds include neuromodulatory and / or anti-inflammatory activity, for example via activation of serotonin receptors. In some further aspects, the compounds are useful as therapeutic agents for treating medical conditions, such as psychiatric disorders and inflammatory conditions.

Description

[0001] 5-CARBOXAMIDO AND 5-CARBOXYALKYL PHENETHYLAMINES

[0002] INVENTOR: David E. Nichols

[0003] CROSS-REFERENCE

[0004]

[0001] Priority is claimed under PCT Art. 8(1) and Rule 4.10 to U.S. Provisional Appl. Nos. 63 / 612,233, filed December 19, 2023, and 63 / 659,282, filed June 12, 2024, both incorporated by reference for all purposes as if fully set forth herein.

[0005] FIELD OF THE INVENTION

[0006]

[0002] The disclosure relates to phenethylamine compounds having a 5-carboxamido or 5-carboxyalkyl substituent, and compositions thereof, methods of their synthesis, and methods of their use, including in humans, such as for treating medical conditions, including psychiatric disorders and inflammatory conditions.

[0007] BACKGROUND OF THE INVENTION

[0008]

[0003] Psychedelics such as psilocybin and LSD are currently being investigated for various medical uses, owing to their psychedelic, anxiolytic, and antidepressant effects. Beyond mental health, psychedelics and related serotonin receptor agonists 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 remain federally illegal in the United States under Schedule I of the Controlled Substances Act. Novel compounds that minimize side effects, optimize efficacy, and allow for greater access are especially valuable.

[0009]

[0004] Provided are compounds, compositions, methods, uses, and kits to meet these needs and others, having such advantages and improvements as will be readily apparent through the disclosure below.

[0010] INCORPORATION BY REFERENCE

[0011]

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

[0012] BRIEF SUMMARY OF THE INVENTION

[0013]

[0006] The following is a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. It is not an extensive overview of the invention, nor intended to identify key or critical elements of the invention or to delineate its full scope. Its sole purpose is to present some embodiments and aspects of the invention in a simplified form as a prelude to the detailed description below.

[0014]

[0007] In a first aspect, provided is compound of Formula (1 ): wherein:

[0015] R is — NH2, -NH-CrC6alkyl, or -O-CrC6alkyl;

[0016] R2is H or CrC6alkyl;

[0017] R4is Br, F, Cl, I, H, CN, NO2, Cj-Cg alkyl, C2-C6alkenyl, C2-C6alkynyl, C^Cg haloalkyl, Cj-Cg alkoxy, C^Cg haloalkylthio, C^Cg alkylthio, C3-C6cycloalkylmethyl, or — (CH2)0.3-C(O)-O-C1-C6alkyl; n is 1 , 2, 3, or 0; and

[0018] Rais H or CpCg alkyl;

[0019] Rbis H; and

[0020] RNis H or — CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12aryl optionally substituted by F, Cl, Br, I, OH, CrC6alkoxy, or phenyl; or

[0021] Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl; and RNis H or — CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12aryl optionally substituted by F, Cl, Br, I, OH, CrC6alkoxy, or phenyl; or

[0022] Rais H or CpCe alkyl; and

[0023] RNand Rbtogether with the intervening atoms form a 4- to 8-membered heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0008] In some embodiments, the compound has the structure of Formula (2): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0024]

[0009] In some embodiments, the compound has the structure of Formula (3): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof, wherein R' is CrCe alkyl.

[0025]

[0010] In some embodiments, the compound has the structure of Formula (4): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0026]

[0011] In some embodiments, the compound has the structure of Formula (5): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0027]

[0012] In some embodiments, R, if present, is -NH2. In some embodiments, R, if present, is -NH-CH3. In some embodiments, R, if present, is -O-CrCs alkyl. In some embodiments, R, if present, is -OCH3.

[0028]

[0013] In some embodiments, Ra, if present, is H. In some embodiments, Ra, if present, is CpCe alkyl. In some embodiments, Ra, if present, is -CH3. In some embodiments, Ra, if present, is -CH2CH3.

[0029]

[0014] In some embodiments, Rb, if present, is H. In some embodiments, RN, if present, is H. In some embodiments, RN, if present, is -CH2-Ar.

[0030]

[0015] In some embodiments, Ar, if present, is phenyl substituted by -OH. In some embodiments, Ar, if present, is phenyl substituted by -OCH3. In some embodiments, Ar is or ; wherein the * indicates the point of attachment to the remainder of RN.

[0031]

[0016] In some embodiments, R2, if present, is H. In some embodiments, R2, if present, is methyl.

[0032]

[0017] In some embodiments, n, if present, is 1. In some embodiments, n, if present, is 0. In some embodiments, n, if present, is 2. In some embodiments, n, if present, is 3.

[0033]

[0018] In some embodiments, R4is Br, F, Cl, or I. In some embodiments, R4is CrC6alkyl. In some embodiments, R4is isobutyl. In some embodiments, R4is ethyl. In some embodiments, R4is C2-C6alkenyl. In some embodiments, R4is allyl. In some embodiments, R4is C3-C6cycloalkylmethyl. In some embodiments, R4is cyclopropylmethyl.

[0034]

[0019] In another aspect, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0035]

[0020] In another aspect, provided is a compound selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0036]

[0021] In another aspect, provided is a compound selected from the group consisting of:

[0037] or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0038]

[0022] In another aspect, provided is a compound selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0039]

[0023] 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, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0040]

[0024] 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 formulated for topical administration. In some embodiments, the composition is formulated as an aerosol, emulsion, spray, ointment, salve, gel, paste, lotion, liniment, oil, or cream.

[0041]

[0025] In some embodiments, the composition comprises one or more pharmaceutically acceptable excipients selected from the group consisting of penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, and gelling agents.

[0042]

[0026] 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.

[0043]

[0027] 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, 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.

[0044]

[0028] In another aspect, provided is a method of modulating neurotransmission in a subject, comprising administering to the subject the compound or pharmaceutical composition of any of the disclosed embodiments. In some embodiments, modulating neurotransmission comprises agonizing the 5-HT2Areceptor.

[0045]

[0029] In another aspect, provided is a method of increasing neuroplasticity or neurogenesis in a subject, comprising administering to the subject the compound or pharmaceutical composition of any of the disclosed embodiments. In some embodiments, increasing neuroplasticity or neurogenesis comprises increasing neuritogenesis, spinogenesis, or synaptogenesis.

[0046]

[0030] In another aspect, provided is a method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any of the disclosed embodiments.

[0047]

[0031] In some embodiments, the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission.

[0048]

[0032] In some embodiments, the medical condition is a mental, behavioral, or neurodevelopmental disorder. 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.

[0049]

[0033] In embodiments, the compound is administered together with one or more sessions of psychotherapy.

[0050]

[0034] 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.

[0051]

[0035] 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.

[0052]

[0036] 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.

[0053]

[0037] In some embodiments, the inflammatory disorder is dermatitis. In some embodiments, the 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.

[0054]

[0038] In some embodiments, the subject has a compromised immune system. In embodiments, the subject has an autoimmune disorder. In some embodiments, the subject has a contraindication to a corticosteroid.

[0055]

[0039] 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% compared to the level of the biomarker before treatment.

[0056]

[0040] In some embodiments, the inflammatory biomarker is an inflammatory response gene product.

[0057]

[0041] In embodiments, the inflammatory response gene product is mRNA. In embodiments, the mRNA is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1 , Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mp9, or TGF-ft mRNA.

[0058]

[0042] 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-1 , Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-0.

[0059]

[0043] In some embodiments, the medical condition is an ophthalmic disorder. In some embodiments, the ophthalmic disorder is an inflammatory disorder.

[0060]

[0044] In some 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.

[0061]

[0045] In another aspect, provided is a compound or pharmaceutical composition of any of the disclosed embodiments for use in the treatment of a medical condition.

[0062]

[0046] In another aspect, provided is the use of the compound or pharmaceutical composition of any of the disclosed embodiments for the manufacture of a medicament for the treatment of a medical condition.

[0063]

[0047] In another aspect, provided is a method of preparing a compound having the structure of Formula (1): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof, comprising: i. reacting a compound of Formula (1 A):

[0064] (1A), with a compound of Formula (1 B), in the presence of a catalyst, to form a compound of Formula (1 C), ii. subjecting the compound of Formula (1 C) to acidic conditions to form a compound of Formula (1) wherein RNis H; ill. and optionally subjecting the compound of Formula (1) wherein RNis H to reductive amination conditions to form a compound of Formula (1) wherein RNis — CH2-Ar; or according to such further steps disclosed herein, to provide a compound of Formula (1) having such substituents as otherwise defined.

[0065]

[0048] In some embodiments, — BY3is — BF3.

[0066]

[0049] In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the catalyst is a palladium(ll) catalyst.

[0067]

[0050] 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.

[0068]

[0051] 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.

[0069] BRIEF DESCRIPTION OF THE FIGURES

[0070]

[0052] 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:

[0071]

[0053] FIG. 1 shows the dose-response curve from a cell-based agonist calcium flux assay for [5-(2-aminoethyl)-2-bromo-4-methoxyphenyl]acetamide (2CB-5CAM) for 5-HT2Aand 5-HT2B, as described in Example 6;

[0072]

[0054] FIG. 2 shows the dose-response curve from a cell-based agonist calcium flux assay for

[0073] 5-(2-aminoethyl)-2-bromo-4-methoxybenzamide (2CB-5CA) for 5-HT2Aand 5-HT2B, as described in Example 6;

[0074]

[0055] FIG. 3 shows the dose-response curve from a cell-based agonist calcium flux assay for [5-(2-aminoethyl)-4-hydroxy-2-(2-methylpropyl)phenyl]ethanamide (2CIB-2OH-5CAM) for 5-HT2Aand 5-HT2B, as described in Example 6;

[0075]

[0056] FIG. 4 shows the dose-response curve from a cell-based agonist calcium flux assay for [5-(2-aminoethyl)-2-bromo-4-hydroxyphenyl]ethanamide (2CB-2OH-5CAM) for 5-HT2A and 5-HT2B, as described in Example 6;

[0076]

[0057] FIG. 5 shows the effect of 2CB-5CAM administration on PenH Max values in a mouse model of allergic asthma, as described in Example 7;

[0077]

[0058] FIG. 6 shows head-twitch response (HTR) count as a function of 2CB-5CAM dose, as described in Example 8; and

[0078]

[0059] FIG. 7 shows HTR counts as a function of time after administration of 2CB-5CAM at various doses between 0.03 mg / kg and 30 mg / kg, as described in Example 8.

[0079] DETAILED DESCRIPTION OF THE INVENTION

[0080]

[0060] While various embodiments and features of certain aspects are summarized above, this 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 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.

[0081] A. General Definitions and Terms

[0082]

[0061] The singular forms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Thus, “a compound” includes reference to not only one but also to two or more compounds, and “an excipient” includes reference to not only one but also to two or more excipients. While the term “one or more” also may be used, its absence (or its replacement by the singular “a” or “an”) does not signify the singular only, but simply provides emphasis to the possibility of multiples in some particular embodiments.

[0083]

[0062] “Or” means, and is interchangeable with, “and / or” unless context clearly indicates otherwise.

[0084]

[0063] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., they do not limit lists to recited elements), and are interchangeable with the phrase “including but not limited to.”

[0085]

[0064] A shorthand may be used for some terms and, unless context clearly indicates otherwise, will have the same meaning as the full term. For example, a “pharmaceutical composition” may be referred to simply as a “composition,” and other such shorthand terms will be readily appreciated in view of the disclosure.

[0086]

[0065] Unless context indicates a distinction relevant to a described or claimed embodiment, a “composition” and a “formulation” are used interchangeably and equivalently herein.

[0087]

[0066] “In embodiments” may be used equivalently with, and only as shorthand for, “in some embodiments.”

[0067] Numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of embodiments are approximations, the numerical values set forth in the examples are reported as precisely as practicable. Numerical values in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0088]

[0068] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, should be understood as being modified in some instances by the term “about,” even where not so stated explicitly. In alternative embodiments, such numbers should be understood as not being modified by the term “about.” In embodiments, the numerical parameters are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. In other embodiments, “about” refers to plus or minus ten percent (±10%) of the recited unit of measure. Where “about” is used to modify one number in a series or range, it should be understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range. Thus, 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.” The term “substantially,” where it is used to modify a feature or limitation, must be read in the context of the disclosure and in light of the knowledge in the art to provide the appropriate certainty, such as by using a standard 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 relevant art.

[0089]

[0069] A comprehensive list of abbreviations utilized by organic chemists of ordinary skill is in the first issue of each volume of the Journal of Organic Chemistry, typically presented in a table entitled Standard List of Abbreviations; the current list as of the date of this filing is incorporated by reference as if fully set forth herein.

[0090]

[0070] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs (“one of skill”). Generally, the nomenclature used and procedures performed herein are those known in fields relating to one or more aspects of the invention, e.g., biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or medicinal chemistry, and that will be well known and commonly employed in such fields. Standard techniques and procedures are those generally performed according to conventional methods in the art.

[0091]

[0071] Further definitions to assist a reader in understanding the embodiments are below and throughout; however, it will be appreciated that such definitions are not intended to limit the scope of the invention, which is properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill in the relevant art) in view of the language used in the claims. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0092]

[0072] “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, aryl-carbamoyl, 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 be substituted at two or more positions, including three or more, four or more, five or more, or six or more positions. In embodiments, an alkyl group will be substituted at every position. In embodiments, an alkyl group will not be substituted at any positions.

[0093]

[0073] “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.

[0094]

[0074] “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.

[0095]

[0075] “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, tri naphthalene, and the like. In some embodiments, an aryl group comprises from 5 to 20 carbon atoms, or between 6 to 12 carbon atoms. An aryl group can be substituted or unsubstituted.

[0096]

[0076] “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 cycloalkyl, exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group can be substituted or unsubstituted.

[0097]

[0077] “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.

[0098]

[0078] “Alkylene-cycloalkyl” refers to a radical having an alkylene component and a cycloalkyl component, where the alkylene component links the cycloalkyl component to the point of attachment. The cycloalkyl components are as defined above, and can include any number of carbons, such as 3 to 6 carbon atoms (i.e., a C3-C6alkylene-cycloalkyl), 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. An alkylene-cycloalkyl group can be substituted or unsubstituted.

[0099]

[0079] “Halogen” refers to fluorine, chlorine, bromine, and iodine.

[0100]

[0080] “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 include 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 (=0), among many others.

[0101]

[0081] “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.

[0102]

[0082] “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.

[0103]

[0083] “Alkyl-heteroaryl” refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of attachment. The alkyl component can include any number of carbons, such as CO-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent. The heteroaryl component is as defined within. Alkyl-heteroaryl groups can be substituted or unsubstituted.

[0104]

[0084] “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.

[0105]

[0085] “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.

[0106]

[0086] “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.

[0107]

[0087] “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.

[0108]

[0088] “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.

[0109]

[0089] “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.

[0110]

[0090] “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.

[0111]

[0091] “Sulfinyl” refers to an — S(=0)— R group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0112]

[0092] “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.

[0113]

[0093] “O-carboxy” refers to a — RC(=0)0— 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.

[0114]

[0094] “Ester” and “C-carboxy” refer to a — C(=0)0R 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.

[0115]

[0095] “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.

[0116]

[0096] “Trihalomethanesulfonyl” refers to an X3CSO2— group wherein each X is a halogen.

[0117]

[0097] “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.

[0118]

[0098] “S-sulfonamido” refers to a — S02N(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.

[0119]

[0099] “N-sulfonamido” refers to a RS02N(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.

[0120]

[0100] “O-carbamyl” refers to a — 0C(=0)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.

[0121]

[0101] “N-carbamyl” refers to an R0C(=0)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-carbamyl may be substituted or unsubstituted.

[0122]

[0102] “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.

[0123]

[0103] “N-thiocarbamyl” refers to an R0C(=S)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-thiocarbamyl may be substituted or unsubstituted.

[0124]

[0104] “C-amido” group refers to a — C(=0)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A C-amido may be substituted or unsubstituted.

[0125]

[0105] “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.

[0126]

[0106] “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.

[0127]

[0107] Still additional definitions and abbreviations are provided elsewhere herein.

[0128] B. Compounds

[0129]

[0108] The phenethylamine pharmacophore is a well-known chemical scaffold found in biologically active molecules, such as neurotransmitters (e.g., dopamine) and psychoactive drugs. One class of compounds, the “2C” or “2C-X” compounds, are ring-substituted phenethylamines containing methoxy groups on the 2 and 5 positions of the benzene ring, and an additional (often lipophilic) substituent at the 4 position (i.e., R" below).

[0130]

[0109] Certain 2C compounds may have effects that are similar to those of entactogens such as MDMA, as well as effects that are similar to those of psychedelics such as psilocybin. Although some 2C compounds are generally well-tolerated within certain dose ranges, adverse sympathomimetic effects have been reported, including agitation, excited delirium, aggression, violence, dysphoria, hypertension, tachycardia, seizures, and hyperthermia, and many 2C compounds are known to be generally associated with heavy “body load” and gastrointestinal effects (see, e.g., Dean et al., J Med Toxicol, 2013; 9(2): 172-178). For these and other reasons, there is an ongoing need for new chemical entities that retain advantages of certain known phenethylamines, introduce new advantageous properties and biochemical functionalities, and / or mitigate disadvantages of known compounds.

[0131]

[0110] In one aspect, provided is a compound of Formula (1): wherein:

[0132] R is — NH2, — NH-CpCg alkyl, or — O-CpCg alkyl;

[0133] R2is H or CrC6alkyl;

[0134] R4is H, F, Cl, Br, I, CN, NO2, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C^Cg haloalkyl, CrC6alkoxy, C^Cg haloalkylthio, C^Cg alkylthio, C3-C6cycloalkylmethyl, or — (CH2)0.3-C(O)-O-C1-C6alkyl;

[0135] RNis H or — CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12aryl optionally substituted by F, Cl, Br, I, OH, C^CB alkoxy, or phenyl; and

[0136] Rais H or CpCg alkyl; and Rbis H; or Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl; or RNand Rbtogether with the intervening atoms form a 4- to 8-membered heterocyclyl, and Rais H or C Cg alkyl; and n is O, 1 , 2, or 3; or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0111] In some embodiments of Formula (1), R is -NH2, -NH-C^Cg alkyl, or -O-C^Ce alkyl. In embodiments, R is -NH2. In embodiments, R is -NH-C Cg alkyl. In embodiments, R is -NH-CH3. In embodiments, R is -O-CrCsalkyl. In embodiments, R is methoxy (-OCH3).

[0137]

[0112] In some embodiments of Formula (1), R2is H or C^Cg alkyl. In embodiments, R2is H. In embodiments, R2is CrC6alkyl. In embodiments, R2is methyl.

[0138]

[0113] In some embodiments of Formula (1), R4is H, F, Cl, Br, I, CN, NO2, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C^Cg haloalkyl, C^Cg alkoxy, C^Cg haloalkylthio, C^Cg alkylthio, C3-C6cycloalkylmethyl, or — (CH2)0.3-C(O)-O-C1-Cg alkyl. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CN. In embodiments, R4is NO2. In embodiments, R4is CrC6alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is propyl. In embodiments, R4is butyl. In embodiments, R4is isobutyl. In embodiments, R4is pentyl. In embodiments, R4is neopentyl. In embodiments, R4is C2-C3alkenyl. In embodiments, R4is vinyl. In embodiments, R4is allyl. In embodiments, R4is C2-C6alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is Ci-Cg haloalkyl. In embodiments, R4is trifluoromethyl. In embodiments, R4is C^Cg alkoxy. In embodiments, R4is methoxy. In embodiments, R4is CrCshaloalkylthio. In embodiments, R4is 2-fluoroethylthio. In embodiments, R4is CpCg alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio. In embodiments, R4is butylthio. In embodiments, R4is isobutylthio. In embodiments, R4is C3-C6cycloalkylmethyl. In embodiments, R4is cyclopropylmethyl. In embodiments, R4is — (CH^-CODJ-O-CpCg alkyl. In embodiments, R4is — COO-CrC6alkyl. In embodiments, R4is — CH^OO-CrCg alkyl. In embodiments, R4is — (CH2)2COO-C1-C6alkyl. In embodiments, R4is — (CH2)3COO-C1-C6alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is -CH2COOCH2CH3.

[0139]

[0114] In some embodiments of Formula (1), Rais H or C^Cg alkyl. In embodiments, Rais H. In embodiments, Rais CrC6alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl.

[0140]

[0115] In some embodiments of Formula (1), RNis H or — CH2-Ar, wherein Ar is 6- to 12-membered heterocyclyl or C6-C12aryl optionally substituted by F, Cl, Br, I, OH, CrC6alkoxy, or phenyl. In embodiments, RNis H. In embodiments, RNis — CH2-Ar. In embodiments, RNis — CH2-Ar, and Ar is 6- to 12-membered heterocyclyl optionally substituted by F, Cl, Br, I, OH, C^Cg alkoxy, or phenyl. In embodiments, RNis — CH2-Ar, and Ar is unsubstituted 6- to 12-membered heterocyclyl. In embodiments, RNis — CH2-Ar, and Ar is 6- to 12-membered heterocyclyl substituted by F, Cl, Br, I, OH, C^Cg alkoxy, or phenyl. In embodiments, RNis — CH2-Ar, and Ar is benzodioxolyl (e.g., 1 ,3-benzodioxolyl). In embodiments, RNis — CH2-Ar, and Ar is benzofuranyl (e.g., 1 -benzofuranyl). In embodiments, RNis — CH2-Ar, and Ar is C6-C12aryl optionally substituted by F, Cl, Br, I, OH, C^Cg alkoxy, or phenyl. In embodiments, RNis — CH2-Ar, and Ar is unsubstituted C6-C12aryl. In embodiments, RNis — CH2-Ar, and Ar is phenyl. In embodiments, RNis — CH2-Ar, and Ar is naphthyl. In embodiments, RNis — CH2-Ar, and Ar is C6-C12aryl substituted by F, Cl, Br, I, OH, CpCg alkoxy, or phenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by F, Cl, Br, or I. In embodiments, RNis — CH2-Ar, and Ar is 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, or 2-iodophenyl. In embodiments, RNis — CH2-Ar, and Ar is 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, or 3-iodophenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by OH. In embodiments, RNis — CH2-Ar, and Ar is 2-hydroxyphenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by CrC6alkoxy. In embodiments, RNis — CH2-Ar, and Ar is 2-methoxyphenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by phenyl. In embodiments, RNis — CH2-Ar, and Ar is biphenyl (e.g., 2-biphenyl). In embodiments, RNis — CH2-Ar, and Ar is 2-(4-hydroxyphenyl)phenyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by C3-C6cycloalkyl. In embodiments, RNis — CH2-Ar, and Ar is phenyl substituted by cyclopropyl (e.g., 2-cyclopropylphenyl).

[0141]

[0116] In some embodiments of Formula (1), Rbis H.

[0142]

[0117] In some embodiments of Formula (1), Rband RNtogether with the intervening atoms form a 4- to 8-membered heterocyclyl. In embodiments, Rband RNtogether with the intervening atoms form an azetidinyl. In embodiments, Rband RNtogether with the intervening atoms form a pyrrolidinyl. In embodiments, Rband RNtogether with the intervening atoms form a piperidinyl. In embodiments, Rband RNtogether with the intervening atoms form an azepanyl.

[0143]

[0118] In some embodiments of Formula (1), Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclopropyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclobutyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclopentyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclohexyl.

[0144]

[0119] In some embodiments of Formula (1), n is 0, 1, 2, or 3. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0145]

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

[0146]

[0121] In some embodiments of Formula (2), R4is H, F, Cl, Br, I, CN, NO2, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, CrC6haloalkyl, C^Cs alkoxy, C^Cs haloalkylthio, CrC6alkylthio, C3-C6cycloalkylmethyl, or — (CH2)0.3-C(O)-O-C1-C6alkyl. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CN. In embodiments, R4is NO2. In embodiments, R4is CrC6alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is propyl. In embodiments, R4is butyl. In embodiments, R4is isobutyl. In embodiments, R4is pentyl. In embodiments, R4is neopentyl. In embodiments, R4is C2-C6alkenyl. In embodiments, R4is vinyl. In embodiments, R4is allyl. In embodiments, R4is C2-C6alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is CrCc haloalkyl. In embodiments, R4is trifluoromethyl. In embodiments, R4is CrC6alkoxy. In embodiments, R4is methoxy. In embodiments, R4is CrC6haloalkylthio. In embodiments, R4is 2-fluoroethylthio. In embodiments, R4is C^Cg alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio. In embodiments, R4is butylthio. In embodiments, R4is isobutylthio. In embodiments, R4is C3-C6cycloalkylmethyl. In embodiments, R4is cyclopropylmethyl. In embodiments, R4is — (CH^-CfOJ-O-CrCg alkyl. In embodiments, R4is — COO-CrC6alkyl. In embodiments, R4is — CH2COO-C1-C6alkyl. In embodiments, R4is — (CH2)2COO-C1-C6alkyl. In embodiments, R4is — (CH2)3COO-C1-C6alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is -CH2COOCH2CH3.

[0147]

[0122] In some embodiments, the compound has the structure of Formula (3): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof; wherein R' is CpCg alkyl.

[0148]

[0123] In some embodiments of Formula (3), R' is methyl.

[0149]

[0124] In some embodiments of Formula (3), R4is H, F, Cl, Br, I, CN, NO2, C^Cg alkyl, C2-C6alkenyl, C2-C6alkynyl, CrC6haloalkyl, CrC5alkoxy, C^Cg haloalkylthio, CrC6alkylthio, C3-C6cycloalkylmethyl, or — (CH2)0.3-C(O)-O-C1-Cg alkyl. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CN. In embodiments, R4is NO2. In embodiments, R4is CrC6alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is propyl. In embodiments, R4is butyl. In embodiments, R4is isobutyl. In embodiments, R4is pentyl. In embodiments, R4is neopentyl. In embodiments, R4is C2-C6alkenyl. In embodiments, R4is vinyl. In embodiments, R4is allyl. In embodiments, R4is C2-C6alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is C^Cg haloalkyl. In embodiments, R4is trifluoromethyl. In embodiments, R4is CrC6alkoxy. In embodiments, R4is methoxy. In embodiments, R4is C^Cg haloalkylthio. In embodiments, R4is 2-fluoroethylthio. In embodiments, R4is C^Cg alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio. In embodiments, R4is butylthio. In embodiments, R4is isobutylthio. In embodiments, R4is C3-C6cycloalkylmethyl. In embodiments, R4is cyclopropylmethyl. In embodiments, R4is — (CH2)o.3-C(0)-0-C1-C6alkyl. In embodiments, R4is — COO-C,-C6alkyl. In embodiments, R4is — CH2COO-C1-C6alkyl. In embodiments, R4is — (CH2)2COO-C1-C6alkyl. In embodiments, R4is — (CH2)3COO-C1-C6alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is -CH2COOCH2CH3.

[0150]

[0125] In some embodiments, the compound has the structure of Formula (4): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof; wherein Ra, Rb, R4, and n are as defined for Formula (1).

[0151]

[0126] In some embodiments of Formula (4), Rais H or CrC6alkyl. In embodiments, Rais H. In embodiments, Rais C^Cg alkyl. In embodiments, Rais methyl. In embodiments, Rais ethyl.

[0152]

[0127] In some embodiments of Formula (4), Rbis H.

[0153]

[0128] In some embodiments of Formula (4), Rband RNtogether with the intervening atoms form a 4- to 8-membered heterocyclyl. In embodiments, Rband RNtogether with the intervening atoms form an azetidinyl. In embodiments, Rband RNtogether with the intervening atoms form a pyrrolidinyl. In embodiments, Rband RNtogether with the intervening atoms form a piperidinyl. In embodiments, Rband RNtogether with the intervening atoms form an azepanyl.

[0154]

[0129] In some embodiments of Formula (4), Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclopropyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclobutyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclopentyl. In embodiments, Raand Rbtogether with the intervening atoms form a cyclohexyl.

[0155]

[0130] In some embodiments of Formula (4), R4is H, F, Cl, Br, I, CN, N02, CpCg alkyl, C2-C6alkenyl, C2-C6alkynyl, CrC6haloalkyl, C^Cg alkoxy, C^Cg haloalkylthio, CrC6alkylthio, C3-C6cycloalkylmethyl, or — (CH2)0.3-C(O)-O-C1-C6alkyl. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CN. In embodiments, R4is N02. In embodiments, R4is C^Ce alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is propyl. In embodiments, R4is butyl. In embodiments, R4is isobutyl. In embodiments, R4is pentyl. In embodiments, R4is neopentyl. In embodiments, R4is C2-C6alkenyl. In embodiments, R4is vinyl. In embodiments, R4is allyl. In embodiments, R4is C2-C6alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is C^-CB haloalkyl. In embodiments, R4is trifluoromethyl. In embodiments, R4is CrC6alkoxy. In embodiments, R4is methoxy. In embodiments, R4is C^Cg haloalkylthio. In embodiments, R4is 2-fluoroethylthio. In embodiments, R4is CpCe alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio. In embodiments, R4is butylthio. In embodiments, R4is isobutylthio. In embodiments, R4is C3-C6cycloalkylmethyl. In embodiments, R4is cyclopropylmethyl. In embodiments, R4is — (CH2)0.3-C(O)-O-C1-C6alkyl. In embodiments, R4is — COO-C1-C6alkyl. In embodiments, R4is — CH^OO-CrCs alkyl. In embodiments, R4is — (CH2)2COO-C1-C6alkyl. In embodiments, R4is — (CH2)3COO-C1-C6alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is -CH2COOCH2CH3.

[0156]

[0131] In some embodiments of Formula (4), n is 0, 1, 2, or 3. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0157]

[0132] In some embodiments, the compound has the structure of Formula (5): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof; wherein R4and n are as defined for Formula (1).

[0158]

[0133] In some embodiments of Formula (5), R4is H, F, Cl, Br, I, CN, NO2, CpCs alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cg haloalkyl, CrC3alkoxy, C^Cs haloalkylthio, CrC6alkylthio, C3-C6cycloalkylmethyl, or — (CH2)0.3-C(O)-O-C1-C6alkyl. In embodiments, R4is H. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is CN. In embodiments, R4is NO2. In embodiments, R4is CrC6alkyl. In embodiments, R4is methyl. In embodiments, R4is ethyl. In embodiments, R4is propyl. In embodiments, R4is butyl. In embodiments, R4is isobutyl. In embodiments, R4is pentyl. In embodiments, R4is neopentyl. In embodiments, R4is C2-C6alkenyl. In embodiments, R4is vinyl. In embodiments, R4is allyl. In embodiments, R4is C2-C6alkynyl. In embodiments, R4is ethynyl. In embodiments, R4is CrC5haloalkyl. In embodiments, R4is trifluoromethyl. In embodiments, R4is CrC6alkoxy. In embodiments, R4is methoxy. In embodiments, R4is C^CB haloalkylthio. In embodiments, R4is 2-fluoroethylthio. In embodiments, R4is C^CB alkylthio. In embodiments, R4is methylthio. In embodiments, R4is ethylthio. In embodiments, R4is propylthio. In embodiments, R4is butylthio. In embodiments, R4is isobutylthio. In embodiments, R4is C3-C6cycloalkylmethyl. In embodiments, R4is cyclopropylmethyl. In embodiments, R4is — (CH2)I 3-C(O)-O-C1-C6alkyl. In embodiments, R4is — COO-C,-C6alkyl. In embodiments, R4is — CH2COO-CrCsalkyl. In embodiments, R4is — (CH2)2COO-C1-C6alkyl. In embodiments, R4is — (CH2)3COO-C1-C5alkyl. In embodiments, R4is — CH2COOCH3. In embodiments, R4is -CH2COOCH2CH3.

[0159]

[0134] In some embodiments of Formula (5), n is 0, 1, 2, or 3. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0160]

[0135] In some embodiments, the compound has the structure of any of Formulae (l)-(VI), wherein R, R2, R4, RN, and n are as defined for Formula (1):

[0161]

[0136] In some embodiments, the compound is selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0162] Table 1. Exemplary Compounds of Formula (1)

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0137] In some embodiments, the compound is selected from the group consisting of:

[0169] or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0170]

[0138] In some embodiments, the compound is selected from the group consisting of:

[0171] or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0172]

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

[0173]

[0140] In some embodiments, the compound is selected from the group consisting of:

[0174]

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

[0175]

[0142] In some embodiments, the compound is selected from the group consisting of:

[0176] or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

[0177]

[0143] The individual compounds of the disclosed compositions will be understood to also encompass pharmaceutically acceptable salts of such compounds. The term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, 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 the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. 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.

[0178]

[0144] Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, 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, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, 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, and the like. (Berge SM, Bighley LM, Monkhouse DC. Pharmaceutical Salts. J Pharmaceutical Sciences. 1977;66(1 ):1-19.)

[0179]

[0145] 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.

[0180]

[0146] A disclosed compound can exist in solid or liquid form. In a solid form, a 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.

[0181]

[0147] 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.

[0182]

[0148] 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 invention 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 disclosed compounds 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.

[0183]

[0149] 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., an isotopically enriched compound (or “isotopolog” or “isotopic derivative”). 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 compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine such as2H,3H,11C,13C,14C,15N,17O,18O, and36CI 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. In particular, 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, e.g., increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopologs of a disclosed compound can generally be prepared by carrying out the procedures disclosed in the schemes or in the Examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0184]

[0150] 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. In some embodiments, a prodrug of a disclosed compound comprises a biologically labile group on a functional moiety (e.g., an amine) of the 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.

[0185]

[0151] An individual compound of the disclosure may be administered as part of a pharmaceutical composition or formulation, but may be 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.

[0186]

[0152] Preferably the substantially pure compound used in the invention 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.

[0187]

[0153] 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 the compound; subjective effects, such as psychoactive effects experienced by a subject after administration of the compound; and other therapeutic effects, such as anti-inflammatory effects. In some embodiments, such advantages are determined relative to a comparator.

[0188]

[0154] In embodiments, the comparator for a disclosed compound is a 2C compound (e.g.,

[0189] 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-ethyl-2,5-dimethoxyphenethylamine (2C-E), 4-isobutyl-2,5- dimethoxyphenethylamine (2C-iBu)). In embodiments, the comparator for a disclosed compound is a phenylalkylamine compound with an identical substitution pattern, except for the 5-substituent.

[0190]

[0155] In some embodiments, the presence of a 5-carboxamido or 5-carboxyalkyl substituent confers advantageous properties to a disclosed compound.

[0191]

[0156] Without being bound by theory, a disclosed compound bearing a 5-carboxyalkyl (e.g.,

[0192] 5-carboxymethyl) substituent may engage certain amino acid residues in a serotonin (e.g., S-HT^) receptor. As used herein, “engage” refers to non-covalent interactions between a compound and a receptor, leading to association, interaction, and / or binding between the compound and receptor. In some embodiments, the non-covalent interaction is a hydrogen-bonding, ionic, or van der Waals interaction. In some embodiments, a disclosed compound having a 5-carboxyalkyl substituent engages certain amino acid residues of one or more transmembrane helices of a serotonin receptor. In some embodiments, a disclosed compound engages certain amino acid residues in transmembrane helix 6 (TM6) of the 5-HT2receptor. For example, in some embodiments, a disclosed compound engages an asparagine residue on TM6 (e.g. , N343 of TM6) of the 5-HT2Areceptor. In some embodiments, engaging amino acid residues (e.g., N343 in TM6) of the 5-HT2Areceptor confers advantageous properties, such as increased receptor binding affinity, increased potency, biased signaling, improved selectivity for one receptor subtype (e.g., 5-HT2A) over another (e.g., 5-HT2B), and / or improved therapeutic efficacy (e.g., as anti-inflammatory agents).

[0193]

[0157] In some embodiments, a disclosed compound having a 5-carboxamido substituent may be useful as a locally active therapeutic agent. Systemic administration of therapeutically active agents may directly or indirectly affect multiple organs and tissues throughout the body. Consequently, systemic administration of a compound may give rise to a greater number or extent of adverse effects (e.g., side effects) at a therapeutically active dose. For example, certain psychedelics have been shown to exert potent anti-inflammatory effects, but are also psychoactive or have other effects on the central nervous system (CNS) that may be undesired or unnecessary in the context of treating certain medical conditions (e.g., peripheral medical conditions, such as eye, skin, or muscle inflammation). Hence, it may be desired to administer a compound that exhibits minimal penetration into the CNS, but has therapeutic effects (e.g., anti-inflammatory effects) in tissues and organs in which the compound is directly administered, or in tissues and organs proximal to the site of administration. Such compounds may be referred to as “locally active,” because their action is localized to the area to which (or close to which) they are applied.

[0194]

[0158] Without being bound by theory, a disclosed compound having a 5-carboxyalkyl or 5-carboxamido substituent may be a substrate for an enzyme (e.g., an esterase enzyme). Inactivation (e.g., hydrolysis) of such compounds by esterase enzymes may prevent systemic action or penetration into the CNS, thereby localizing their therapeutic effects to (or proximal to) the site of administration. In some embodiments, administration of a disclosed compound having a 5-carboxyalkyl or 5-carboxamido substituent in a topical formulation exerts therapeutic (e.g., anti-inflammatory) effects locally, without causing psychoactive or other effects associated with penetration into the CNS.

[0195] C. Methods of Preparing Disclosed Compounds

[0196]

[0159] In another aspect, provided are methods for preparing disclosed compounds, such as by chemical synthesis. In some embodiments, the synthesis of a disclosed compound is conducted as described in EXAMPLES 1-4, with any necessary modifications known and understood to those of ordinary skill.

[0197]

[0160] In general, disclosed compounds can be synthesized using known techniques in synthetic organic chemistry that are within the capabilities of one of ordinary skill in the art. The schemes provided herein are merely illustrative of exemplary synthetic routes that may be useful for preparing disclosed compounds.

[0198]

[0161] In some embodiments, a method of synthesizing a disclosed compound comprises reacting a substituted phenyl precursor with an alkylamine precursor to form a substituted phenylalkylamine. In some embodiments, the substituted phenyl precursor comprises a halogen. In some embodiments, the substituted phenyl precursor comprises an iodo group. In some embodiments, the alkylamine precursor is an n-alkylamine precursor. In some embodiments, the alkylamine precursor is an n-ethylamine, n-propylamine, or n-butylamine precursor. In some embodiments, the alkylamine precursor comprises a primary amine. In some embodiments, the alkylamine precursor comprises a protected amine, i.e., an anime comprising a bond to an alkyl moiety and a bond to a protecting group.

[0199]

[0162] Protecting groups are known to those of skill in the art (see, e.g., Green et al., “Protective Groups in Organic Chemistry”, Wiley, 1991 and Harrison et al., “Compendium of Synthetic Organic Methods”, John Wiley and Sons, 1971. For amines, protecting groups include tert-Butoxycarbonyl (Boc), Benzyloxycarbonyl (Cbz), 9-Fluorenylmethoxycarbonyl (Fmoc), Allyloxycarbonyl (Alloc), Trimethylsilylethoxycarbonyl (Teoc), Benzyloxycarbonyl (Z, often synonymous with Cbz), Trifluoroacetyl (Tfa), Acetyl (Ac), and Tosyl (Ts).

[0200]

[0163] In some embodiments, wherein the alkylamine precursor comprises a protected amine, the reaction with the substituted phenyl precursor forms a protected substituted phenylalkylamine. In such embodiments, the protecting group may be subsequently removed under standard conditions known to those of skill, to form the substituted phenylalkylamine of the disclosure.

[0201]

[0164] In some embodiments, the substituted phenyl precursor is reacted with the (optionally protected) alkylamine precursor using a Suzuki reaction. The Suzuki reaction can be initiated using a number of palladium(O) and palladium^ I) catalysts and performed under conditions known in the art (see, e.g., Miyaura and Suzuki, Chem Rev 1995; 95:2457-2483). In some embodiments, the catalyst is a palladium(O) catalyst. In some embodiments, the catalyst is a palladium^ I ) catalyst.

[0202]

[0165] In some embodiments, the catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments, the catalyst is tetrakis(tri(o-tolyl)phosphine)palladium(0). In some embodiments, the catalyst is bis(dibenzylideneacetone)palladium(O). In some embodiments, the catalyst is tris(dibenzylideneacetone) dipalladium(O). In some embodiments, the catalyst is [1 ,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll). In some embodiments, the catalyst is palladium(ll) acetate. In some embodiments, the catalyst is dichlorobis(triphenylphosphine)palladium(ll). In some embodiments, the catalyst is bis(triphenyl- phosphine)palladium(ll) chloride. In some embodiments, the catalyst is bis(benzonitrile)palladium(ll) dichloride.

[0203]

[0166] In embodiments, a disclosed compound is synthesized from a substituted phenyl precursor (e.g., wherein X is a halogen (e.g., Cl, Br, I) as shown below; wherein R2, R4, and R5are as defined for Formula (1)):

[0204]

[0167] In this exemplary synthesis, a Boc-protected alkylamino side chain is installed using palladium-catalyzed cross coupling with a boron (R-BY3) reagent (e.g., an organotrifluoroborane or the like). Compounds wherein Raand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl can be synthesized according to the same approach, wherein Raand Rbof the boron reagent (together with the intervening atoms) form a cycle; for example, potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoro- borate can be used to install a cyclopropylamine side chain. In some embodiments, a suitably substituted phenyl precursor is commercially available. If no substituted phenyl precursor having a desired R2, R4, or R5group is commercially available, such precursors can be synthesized as described in EXAMPLES 1-4.

[0205]

[0168] Compounds wherein RNis — CH2-Ar can be synthesized by reductive amination of a disclosed compound wherein RNis H, as follows:

[0206]

[0169] The reductive amination may be conducted according to standard techniques. For example, the starting materials may first be reacted to form an imine intermediate, which is then reduced by sodium borohydride in a second step. Alternatively, the reductive amination can be done in one step using sodium triacetoxyborohydride or sodium cyanoborohydride as the reducing agent.

[0207]

[0170] Compounds wherein Rband RNtogether with the intervening atoms form a 4- to 8-membered heterocyclyl can be synthesized from a substituted phenyl precursor (e.g., wherein X is a halogen (e.g., Cl, Br, I); and R2, R4, and R5are as defined for Formula (1)):

[0208]

[0171] In this exemplary synthesis, palladium-catalyzed cross coupling with a pyridine-based boron (R-BY3) reagent (e.g., an organotrifluoroborane, boronic acid, or the like) is used to attach a pyridine moiety to the substituted phenyl precursor. Subsequent hydrogenation of the pyridine (using, e.g., hydrogen gas and a metal catalyst) results in a substituted phenylpiperidine compound of Formula (1). If no substituted phenyl precursor having a desired R2, R4, or R5group is commercially available, such precursors can be synthesized according to standard techniques.

[0209]

[0172] The R4substituent corresponds to the 4-position of “classical” 2C-X and DOx phenethylamine psychedelics. Typically, the 4-substituent is introduced by substitution of the corresponding 4-substituted phenethylamine (e.g., as in the halogenation of 2C-H to yield 2C-B, 2C-I, etc.), or by substitution of the aryl group a suitable precursor prior to the introduction of the ethylamino side chain (e.g., as in the case of the 2C-T series). In general, similar approaches can be used for disclosed compounds, and appropriate modifications, substitutions, changes, and variations of these known synthetic procedures can be made by those skilled in the art without undue burden. Exemplary synthetic procedures may be found in, e.g., Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991).

[0210]

[0173] Additional methods for synthesis of the compounds described herein and any necessary starting materials are either described in the art or will be readily apparent to the skilled artisan in view of general references well-known in the art (see, e.g., Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed. 1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute 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) and may be used to synthesize the disclosed compounds. Additional references disclosing synthetic methods that may be useful in the synthesis of disclosed compounds include, e.g., PiHKAL; Glennon et al., J. Med. Chem., 1986; 29(2), 194-199; Nichols et al. 1991. J. Med. Chem., 34(1), 276-281 ; Brandt et al. (2011). Drug Test Anal., 4: 24-32; Heravi & Zadsirjan. 2016. Current Organic Synthesis, 13(6), 780-833; Keri et al. 2017. European J. Med. Chem., 138, 1002-1033; and references therein), such adaptation being that known and understood to those of ordinary skill.

[0211] D. Pharmaceutical Compositions

[0212]

[0174] 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).

[0213]

[0175] “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.

[0214]

[0176] 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, a compound employed in a method of this disclosure is effective as an oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and / or intranasal composition. 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.)

[0215]

[0177] A composition can be formulated in a unit dosage form, each dosage containing a therapeutically effective amount of the active ingredient(s), 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.

[0216]

[0178] 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.

[0217]

[0179] 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 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.

[0218]

[0180] 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.

[0219]

[0181] 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).

[0220]

[0182] 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.

[0221]

[0183] 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.

[0222]

[0184] 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 polyethylene 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.

[0223]

[0185] In some embodiments, a formulation comprises a disclosed composition 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.

[0224]

[0186] Dosage forms for oral administration can be aqueous suspensions selected from the group including pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups (e.g., Singh et al., Encycl Pharm Tech., 2nd Ed., 754-57 (2002)). In addition to the disclosed compounds, the liquid dosage forms may comprise additives, such as one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, or (g) flavoring agents.

[0225]

[0187] A disclosed composition also 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.

[0226]

[0188] In embodiments, a disclosed pharmaceutical composition 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 in the art.

[0227]

[0189] 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 glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, lysophosphatidylcholine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulphate, Polyoxyethylene-9-lauryl ether, Polyoxythylene-20-cetyiether, Benzalkonium chloride, cetylpyridinium chloride, Vitamin E TPGS, Caprylocaproyl polyoxylglycerides, Stearoyl Macrogolglycerides, Propylene Glycol Dicaprylocaprate or mixtures thereof. Penetration enhancers may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of penetration enhancers in the formulation divided by the total weight of the formulation).

[0228]

[0190] 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., Lippincot Williams & Wilkins Publishers, 7th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincot, 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). Carriers may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of carriers in the formulation divided by the total weight of the formulation).

[0229]

[0191] In some embodiments, the topical formulation comprises an emulsifier. The emulsifier may be an anionic, cationic, or neutral emulsifier. Emulsifiers include anionic emulsifiers, such as alkyl sulfate, aralkyl sulfates, alkyl ethoxy ether sulfates, alkaryl sulphonates, alkyl succinates, alkyl sulfosuccinates, N-alkoyl sarcosinates, isethionates, N-acyl taurate, sodium lauryl sulfate, sodium laureth sulfate, sodium oleyl succinate, sodium dodecylbenzenesulfonate, and sodium lauryl sarcosinate. Exemplary non-ionic or neutral emulsifiers include sorbitan ester, ethoxylated sorbitan ester, ethoxylated alkyl ether, ethoxylated faty acid ether, fatty alcohol, ethoxylated faty alcohol, and esters of glycerin and faty acids. Emulsifiers also include synthetic and natural polymers. In embodiments, an emulsifier is a silicone (e.g., dimethicone, phenyltrimethicone, PEG dimethicone, PPG dimethicone, etc.). Emulsifiers may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of emulsifiers in the formulation divided by the total weight of the formulation).

[0230]

[0192] In some embodiments, the topical formulation comprises an antioxidant. Antioxidants include 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., p-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, y-linoleyl, cholesteryl and glyceryl esters thereof) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (e.g., buthionine sulfoximines, homocysteine sulfoximines, buthionine sulfones, penta, hexa and heptathionine sulfoximine), in very low tolerated doses (e.g., pmol to pmol / kg), and furthermore (metal)chelators (e.g., a-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin), a-hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, gallic acid, bile extracts, bilirubin, biliverdin, EDTA and derivatives thereof, unsaturated faty acids and derivatives thereof (e.g., y-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, a-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). Antioxidants may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of antioxidants in the formulation divided by the total weight of the formulation).

[0231]

[0193] In some embodiments, the topical formulation comprises a thickener. Thickeners include 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 polyvinylpyrrolidone. Thickeners may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of thickeners in the formulation divided by the total weight of the formulation).

[0232]

[0194] In some embodiments, the topical formulation comprises a cosmetically and / or dermo-cosmetically active substance. Cosmetically and / or dermo-cosmetically active substances include color-imparting active substances, skin- and hair-pigmenting compositions, tinting compositions, tanning compositions, bleaches, keratin-hardening substances, antimicrobial active substances, light filter active substances, repellent active substances, substances having hyperemic activity, substances having keratolytic and keratoplastic activity, antiphlogistic agents, substances having keratinizing activity, antioxidant active substances or substances active as free radical scavengers, skin-moisturizing substances or skin humectants, refatting active substances, substances having antierythematous or antiallergic activity, branched fatty acids, and mixtures thereof. Cosmetically and / or dermo-cosmetically active substances may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of cosmetically and / or dermo-cosmetically active substances in the formulation divided by the total weight of the formulation).

[0233]

[0195] In embodiments, the topical formulation comprises a fragrance. Fragrances include natural fragrances, such as 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). Fragrances also include synthetic fragrance compounds, such as synthetic esters, ethers, aldehydes, ketones, alcohols, and hydrocarbons. Fragrances also include essential oils and perfume oils, such as 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, lavandin oil, Bergamot oil, di hydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, a-hexylcinnamaldehyde, geraniol, benzylacetone, cyclamenaldehyde, linalool, Boisambrene@Forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allylamyl glycolate, cyclovertal, lavandin oil, muscatel sage oil, G39 damascene, Bourbon geranium oil, cyclohexyl salicylate, Vertofix@Coeur, iso-E-Super®, FixolideONP, evemyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romillate, irotyl and floramat. Fragrances may be included in a formulation in an amount ranging from about 0.1 wt% to about 10 wt% (calculated as the total weight of fragrances in the formulation divided by the total weight of the formulation).

[0234]

[0196] In some 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.” In some embodiments, the solvent system is selected to dissolve or solubilize any active agent(s) and any included excipients at the desired concentration(s), and will be stable and compatible with the active agent(s) and any other excipient(s) 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 a solvent system. Solvents that may be included in topical formulations include water, ethanol, polyhydric alcohols (e.g., glycerin), 1,3-butylene glycol, propylene glycol, hexylene glycol, propane diol, ethylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, other sugars which are liquid at room temperature, water-soluble alkoxylated nonionic polymers such as polyethylene glycol, and combinations thereof. Solvents may be included, 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).

[0235]

[0197] In some embodiments, the topical formulation comprises a viscosity modifying agent. In some embodiments, the viscosity modifying agent is a thickener. Common thickeners include 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, etc. Exemplary thickening agents include alginate derivatives, preneutralized carbomer 430, hydrophilic silicas, polysaccharides, xanthan gum, guar guar, agar agar, carboxymethylcellulose, hydroxyethylcellulose, polyacrylates, polyacrylamides, polyvinylpyrrolidone, and salts. Viscosity modifying agents may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of viscosity modifying agents in the formulation divided by the total weight of the formulation).

[0236]

[0198] In some embodiments, the topical formulation comprises an adhesion modifying agent. In some 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). Adhesive polymers include 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. Tackifiers include gums, resins (natural or modified), carbomers, or other natural or synthetic polymers. Adhesion modifying agents may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of adhesion modifying agents in the formulation divided by the total weight of the formulation).

[0237]

[0199] In some 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. Preservatives may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of preservatives in the formulation divided by the total weight of the formulation).

[0238]

[0200] In some embodiments, the topical formulation comprises a solubilizing agent. Solubilizing agents may 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. Solubilizing agents include water-soluble organic solvents, non-ionic surfactants, water-insoluble lipids, organic liquids, cyclodextrins, and phospholipids. In embodiments the solubilizing agent is a water-soluble enhancing agent. Water-soluble enhancing agents include polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, xanthan gum, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. In embodiments the solubilizing agent is a non-ionic surfactant. Non-ionic surfactants include 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, and mono- and di-fatty acid esters of PEG 300, 400, or 1750. In embodiments the solubilizing agent is an organic liquid. Organic liquids include beeswax, d-alpha-tocopherol, oleic acid, and medium-chain mono- or diglycerides. In embodiments the solubilizing agent is a cyclodextrin. In embodiments the solubilizing agent is a phospholipid. Phospholipids include hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, and L-alpha-dimyristoyl-phosphatidylglycerol. In embodiments, the solubilizing agent is lecithin. Solubilizing agents may be included in a formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of solubilizing agents in the formulation divided by the total weight of the formulation).

[0239]

[0201] In some embodiments, the topical formulation comprises a colorant. Colorants include pigments such as, e.g., titanium dioxide, chromium oxide greens, ultramarine blues and pinks, and ferric oxides. 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).

[0240]

[0202] In some embodiments, the topical formulation comprises a binder. Binders include 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). Binders also include 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).

[0241]

[0203] In some 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).

[0242]

[0204] In some embodiments, the topical formulation comprises a surfactant. Surfactants include anionic, nonionic, and amphoteric compounds. Anionic surfactants include, for example, higher alkyl sulfates such as potassium or sodium lauryl sulfate, higher fatty acid monoglyceride monosulfates, such as salts of monosulfated monoglycerides of hydrogenated coconut oil fatty acids, alkyl sulfonates such as sodium dodecyl benzene sulfonate, higher fatty sulfoacetates, and higher fatty acid esters of 1,2 dihydroxypropane sulfonate. Nonionic surfactants include 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); condensation products comprising 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. In some embodiments, the surfactant is an alkyl polyglycoside (APG) surfactant, such as 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, 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).

[0243]

[0205] In some embodiments, the topical formulation comprises a gelling agent. Gelling agents include pectins, starches, and gelatin forms derived from animals (e.g., pork gelatin) or from plants. In some embodiments, a pectin is a amidated pectin, non-amidated pectin, high methoxyl pectin, low methoxyl pectin, or a combination thereof. In some embodiments, a gelatin is Type A gelatin, Type B gelatin, a hide or skin gelatin (e.g., calf skin, pig skin), or a bone gelatin (e.g., calf bone, pig bone). Gelling agents 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).

[0244]

[0206] 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.

[0245]

[0207] 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 2.0 to 90,000 cP or from 2.5 and 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).

[0246]

[0208] An 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. Penetration enhancers for ophthalmic formulations include aliphatic alcohols, fatty acids (including salts thereof), fatty acid esters, polyalcohol alkyl ethers, polyoxyethylene alkyl ethers, glycerides, polyalcohol medium chain fatty acid esters, polyoxyethylene sorbitan fatty acid esters, alkyl lactate esters, terpenes, and organic amines. Penetration enhancers also include 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); esters of fatty acids 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; ethers 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, oligosaccharide, and reduced oligosaccharide with an alkyl alcohol; polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether and polyoxyethylene oleyl ether, glycerol esters of fatty acids 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 ethyl hexanoate, mono 2-propylene glycol ethyl hexanoate, di(2-propylene)glycol ethyl hexanoate, 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. Penetration enhancers may be present, individually or in total (if more than one penetration enhancer is included) in the formulation in an amount ranging from about 0.1 wt% to about 80 wt% (calculated as the total weight of penetration enhancers in the formulation divided by the total weight of the formulation).

[0247]

[0209] In some embodiments, the ophthalmic formulation comprises a hydrating agent. Hydrating agents may facilitate penetration of the active compound(s) through the cell or junctions of the barriers including mucosal, mucocutaneous, and stratum corneum layers. Hydrating agents include hyaluronic acid (or a salt thereof, e.g., sodium hyaluronate), water, saline solution, and polyvinylpyrrolidone, propylene glycol, glycerol, sorbitol, polyethylene glycol, dexpanthenol, panthothenic acid, ectoin, carboxyvinyl polymer, carmellose sodium, and povidone. Hydrating agents may be present, individually or in total (if more than one hydrating agent is included) in the formulation in an amount ranging from about 0.1 wt% to about 80 wt% (calculated as the total weight of hydrating agents in the formulation divided by the total weight of the formulation).

[0248]

[0210] 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 tamarind 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. Gums and / or resins may be present, individually or in total (if more than one gum and / or resin is included) in the formulation in an amount ranging from about 0.1 wt% to about 80 wt% (calculated as the total weight of gums and / or resins in the formulation divided by the total weight of the formulation).

[0249]

[0211] 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 of the active compound(s) into the eye or is otherwise desired. pH adjusters include 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. pH adjusters may be present, individually or in total (if more than pH adjuster is included) in the formulation in an amount ranging from about 0.1 wt% to about 80 wt% (calculated as the total weight of pH adjusters in the formulation divided by the total weight of the formulation).

[0250]

[0212] In some embodiments, the ophthalmic formulation comprises a stabilizer. Stabilizers include 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. Stabilizers may be present, individually or in total (if more than stabilizer is included) in the formulation in an amount ranging from about 0.1 wt% to about 80 wt% (calculated as the total weight of stabilizers in the formulation divided by the total weight of the formulation).

[0251]

[0213] 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).

[0252] E. Pharmaceutical Combinations

[0253]

[0214] It will 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 also may include combinations of multiple compounds (including additional active compounds), combinations of multiple solid (or non-solid) forms, and / or combinations of multiple carriers, diluents, and excipients. Pharmaceutical compositions (interchangeably, unless context dictates otherwise, with pharmaceutical “formulations”) thus may comprise a disclosed compound together with one or more other solid (or non-solid) compounds, one or more other active compounds, and / or one or more other pharmaceutically-acceptable carriers, diluents, and / or excipients.

[0254]

[0215] In embodiments, a composition is prepared to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way, such as pharmacokinetics (PK) or pharmacodynamics (PD), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects.

[0255]

[0216] “Therapeutic effects” that may be increased or added in embodiments 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.

[0256]

[0217] “Synergistic effects” 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 synergistic effects.

[0257]

[0218] In some embodiments, a disclosed pharmaceutical composition comprises an additional active compound. 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, plasticity-inducing agents (e.g., psychoplastogens, neuroplastogens), 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, increase plasticity (e.g., neural plasticity), or alter PK or PD. In embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

[0258]

[0219] In some embodiments, the additional active compound is a tryptamine. As will be appreciated in the art, tryptamines are compounds having the general structure below, wherein RN1, RN2, Ra, R!, R2, R4, R5, R6, and R7are as defined herein and as generally understood in the art:

[0259]

[0220] In embodiments, RN1, RN2, Ra, Rfi, R2, R4, R5, R6, and R7are each independently hydrogen (H), deuterium (D), halogen (F, Cl, Br, or I), OH, phosphoryloxy, or any of alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. Additionally, any two of RN1, RN2, Ra, Rfi, R2, R4, R5, R6, and R7and the intervening atoms can be taken together to form a cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. In embodiments, the tryptamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is alkyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted.

[0260]

[0221] In some embodiments, the additional active compound is a tryptamine selected from the group consisting of psilocybin, psilocin, psilacetin, DBT, DET, DiPT, a,O-DMS, DMT, 2,a-DMT, a,N-DMT, DPT, EiPT, AET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-TMT, 4-HO-DMT, 5-HO-DMT (i.e., bufotenine), 4-HO-DPT,

[0261] 4-HO-MET, 4-HO-MiPT, 4-HO-MPT, 4-HO-pyr-T, ibogaine, MBT, 4,5-MDO-DiPT, 5,6-MDO-DiPT,

[0262] 4.5-MDO-DMT, 5,6-MDO-DMT, 5,6-MDO-MiPT, 2-Me-DET, 5-Br-DMT, 5-CI-DMT, 5-F-DMT, 4,5-MDO-DMT,

[0263] 4.5-MDO-DiPT, 2-Me-DMT, melatonin, 5-MeO-DET, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-DMT, 4-MeO-MiPT,

[0264] 5-MeO-MiPT, 5,6-MeO-MiPT, 5-MeO-NMT, 5-MeO-pyr-T, 5-MeO-TMT, 5-MeS-DMT, MiPT, o-MT (i.e., AMT), NET, NMT, pyr-T, tryptamine, or a,N,O-TMS, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof. As known to one of skill, the systematic naming of tryptamines, such as those listed herein, involves the use of prefixes and suffixes to indicate substitutions on the indole ring and / or the side chain of the tryptamine core structure. For example, EiPT stands for ethyl isopropyl tryptamine, also known as N-ethyl-N-isopropyltryptamine (i.e., N-ethyl-N-[2-(1 H-indol-3-yl)ethyl] propan-2-amine). Examples of these tryptamines and others that may in embodiments be included in a disclosed composition as an additional active compound are known to those of skill, and include the compounds disclosed in Shulgin & Shulgin, TiHKAL: The Continuation, Transform Press (1997) (“TiHKAL”).

[0265]

[0222] In some embodiments, the additional active compound is a “complex tryptamine” or other indolamine, including such examples as iboga alkaloids such as ibogaine, and its analogs, metabolites, and derivatives. In some embodiments, the tryptamine is a beta-carboline, such as beta-carboline, harmaline, harmine, harmane, harmalol, tetrahydroharmine, 9-methyl-p-carboline, pinoline, and 6-MeO-THH.

[0266]

[0223] In some embodiments, the additional active compound is a phenethylamine. As will be appreciated in the art, phenethylamines are compounds having the general structure below, wherein RN1, RN2, Ra, R|!, and each of R2-R6are as taught herein and as generally understood in the art:

[0267]

[0224] In some embodiments, RN1, RN2, Ra, Rp, and each of R2-6are independently H, D, halogen, or any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. In some embodiments, R3and R4are joined together to form an optionally substituted heterocyclyl, such as a dioxole (as with MDMA), a furan, a tetrahydrofuran, a thiophene, a pyrrole, a pyridine, a pyrrolidine, an ethylene oxide, an ethylenimine, a trimethylene oxide, a pyran, a piperidine, an imidazole, a thiazole, a dioxane, a morpholine, or a pyrimidine. In embodiments, R3and R4are joined together to form an optionally substituted aryl, such as a phenyl. In embodiments, the phenethylamine comprises a quaternary ammonium cation wherein each of RN1, RN2, and an additional RN3are independently an alkyl group or an aryl group, and with all other substituents as above. In embodiments, the phenethylamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is alkyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted.

[0268]

[0225] In some embodiments, the additional active compound is a phenethylamine selected from the group consisting of mescaline, a-ethylmescaline, escaline, symbescaline, metaescaline, allylescaline, methallylescaline, asymbescaline, cyclopropylmescaline, phenescaline, 4-desoxymescaline, isomescaline, proscaline, metaproscaline, isoproscaline, thiomescaline, thioescaline, thioproscaline, thiobuscaline, a thiomescaline analog (e.g., 3-TM, 4-TM), buscaline, a thioisomescaline (e.g., 2-TIM, 3-TIM, 4-TIM), Aleph (i.e., DOT), a thiometaescaline (e.g., 3-TME, 4-TME, 5-TME), a thiotrisescaline (e.g., 3-T-TRIS, 4-T-TRIS), a thiosymbescaline (e.g., 3-TSB, 4-TSB), Aleph-2, Aleph-4, Aleph-6, Aleph-7, Ariadne, Beatrice (i.e., MDO-D, MDOM), BIS-TOM, BOB, BOD, BOH, BOHD, BOM, 4-Br-3,5-DMA, 2-Br-4,5-MDA, MDEA, 3C-BZ, a 2C-X compound (e.g., 2C-B, 2C-B-AN, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-B-FLY-NBOMe, 2C-B-FLY-NB2EtO5CI, 2C-Bn, 2C-Bu, 2C-B-5-HEMIFLY, 2C-C, 2C-C-3, 2C-CN, 2C-CP, 2C-D, 2C-E, 2C-EF, 2C-F, 2C-G, 2C-G-1 , 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, 2C-G-N, 2C-H, 2C-I, 2CB-lnd, 2C-iP, 2C-N, 2C-NH2, 2C-PYR, 2C-PIP, 2C-O, 2C-O-4, 2C-M0M, 2C-P, 2C-Ph, 2C-Se, 2C-T, 2C-T-2, 2C-T-3, 2C-T-4, 2C-T-5, 2C-T-6, 2C-T-7, 2C-T-8, 2C-T-9, 2C-T-10, 2C-T-11 , 2C-T-12, 2C-T-13, 2C-T-14, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-18, 2C-T-19, 2C-T-21 , 2C-T-21.5, 2C-T-22, 2C-T-23, 2C-T-24, 2C-T-25, 2C-T-27, 2C-T-28, 2C-T-30, 2C-T-31 , 2C-T-32, 2C-T-33, 2C-DFM, 2C-TFM, 2C-TFE, 2C-YN, 2C-V, 2C-AL, CPM, psi-2C-T-4, 2C-Se), 3C-BZ, 3C-E, 4-D, beta-D, 2,4-DMA, 2,5-DMA, 3,4-DMA, DMCPA, DME, DMMDA, DMMDA-2, DMPEA, DOAM, DOB, DOBU, DOC, DOEF, DOET, DOI, DOM (i.e., STP), psi-DOM, DON, DOPR, EEE, EEM, EME, EMM, ETHYL-J, ETHYL-K, F-2, F-22, FLEA, GANESHA, a GANESHA analog (e.g., G-3, G-4, G-5, G-N), HOT-2, HOT-7, HOT-17, IDNNA, IRIS, BDB, LOPHOPHINE, 4-MA (i.e., PMA), MADAM-6, MDA, MDMA, MDAL, MDBU, MDBZ, MDCPM, MDDM, MDE, MDHOET, MDIP, MDMC, MDMEO, MDMEOET, MDMP, MDOH, MDPEA, MDPH, MDPL, MDPR, MEDA, MEE, MEM, MEPEA, META-DOB, META-DOT, METHYL-DMA, METHYL-DOB, METHYL-J (i.e., MBDB), METHYL-K, METHYL-MA (i.e., PMMA), METHYL-MMDA-2, MMDA, MMDA-2, MMDA-3a, MMDA-3b, MME, MPM, ORTHO-DOT, PEA, PROPYNYL, tetramethoxy- amphetamine, 3-TASB, 4-TASB, 5-TASB, 3-TE, 4-TE, TMA, TMA-2, TMA-3, TMA-4, TMA-5, TMA-6, 2T-MMDA-3a, 4T-MMDA-2, TMPEA, 2-TOET, 5-TOET, 2-TOM, 5-TOM, TOMSO, 4-MTA, MDAI, 5-methyl-MDA, 5-APB, 6-APB, and DiFMDA, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof. As known in the art, the systematic naming of phenethylamines, such as those herein, involves the use of prefixes and suffixes to indicate substitutions on the phenyl ring and / or side chain of the phenethylamine core structure. For example, MDBZ stands for methylenedioxybenzylamphetamine (i.e., 3,4-methylenedioxy-N-benzylamphetamine). Examples of these phenethylamines and others that, in embodiments, may be included in a disclosed composition as an additional active compound are known to those of skill, and include the compounds disclosed in Shulgin & Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991 ) (“PiHKAL”); and Shulgin AT, The Shulgin Index Vol.1 : Psychedelic Phenethylamines & Related Compounds, Transform Press (2011).

[0269]

[0226] In embodiments, the additional active compound is an ergoline. In embodiments, the additional active compound is an ergot alkaloid.

[0270]

[0227] In embodiments, the additional active compound is a lysergamide. As will be appreciated 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:

[0271]

[0228] In some embodiments, RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are each independently H, deuterium, halogen, or any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. Additionally, any two of RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14and the intervening atoms can be taken together to form a cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. In some embodiments, the lysergamide is a quaternary salt, in which an additional R8' is connected to the nitrogen to which R6is bound; wherein R6Ais alkyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted.

[0272]

[0229] In some embodiments, the additional active compound is a lysergamide selected from the group consisting of LSD, ETH-LAD, PARGY-LAD, AL-LAD, PRO-LAD, IP-LAD, CIP-LAD, BU-LAD, FLUOROETH-LAD, ALD, ALD-52, N-acetyl-LSD, 1 P-LSD, 1 B-LSD, 1V-LSD, 1cP-LSD, 1 D-LSD, 1 P-AL-LAD, 1cP-AL-LAD, 1 P-ETH-LAD, LA-SS-Az, LSZ, LSD-Pip, and MIPLA, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.

[0273]

[0230] Other tryptamines, phenethyl amines, and lysergamides useful as additional active compounds in some embodiments and contemplated for inclusion therein will be as generally known in the art (see, e.g., PiHKAL; TiHKAL; Grob & Grigsby, Handbook of Medical Hallucinogens, 2021 ; Luethi & Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacol Rev., 2016; 68(2), 264-355; Glennon, Pharmacol Biochem Behav., 1999; 64, 251-256; each of which is incorporated by reference as if fully set forth herein).

[0274] F. Dose and Dosage

[0275]

[0231] In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount or an effective amount of a disclosed compound, such as for administration to a subject. Administration of disclosed 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).

[0276]

[0232] 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.

[0277]

[0233] 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 0.1 mg / kg, such as about 0.001 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, and about 0.1 mg / kg, as well as ranges between these values. In some embodiments, a single dose is between about 0.1 mg / kg and 1.0 mg / kg, such as about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg about 0.8 mg / kg about 0.9 mg / kg, and about 1 .0 mg / kg, as well as ranges between these values.

[0278]

[0234] 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) about 20 pg / kg body weight or less (e.g., less than 20 pg / kg, less than 15 pg / kg, less than 10 pg / kg, or less than 5 pg / kg body weight, e.g., from 1 to 20 pg / kg body weight, e.g., from 1 to 5 pg / kg, from 5 to 10 pg / kg, from 10 to 15 pg / kg, or from 15 to 20 pg / kg, e.g., about 5 pg / kg, about 10 pg / kg, about 15 pg / kg, or about 20 pg / kg).

[0279]

[0235] 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) about less than about 20 ng / mL (e.g., 0.05 to 20 ng / mL, e.g., 0.1 to 15 ng / mL, 0.5 to 10 ng / mL, or 1 to 5 ng / mL, e.g., 0.05 to 0.1 ng / mL, 0.1 to 0.2 ng / mL, 0.2 to 0.3 ng / mL, 0.3 to 0.4 ng / mL, 0.4 to 0.5 ng / mL, 0.5 to 1 .0 ng / mL, 1.0 to 5 ng / mL, 5 to 10 ng / mL, 10 to 15 ng / mL, or 15 to 20 ng / mL, e.g., about 0.05 ng / mL, 0.1 ng / mL, 0.2 ng / mL, 0.5 ng / mL, 1 .0 ng / mL, 2.0 ng / mL, 2.5 ng / mL, 5.0 ng / mL, 7.5 ng / mL, 10 ng / mL, 12 ng / mL, 15 ng / mL, or 20 ng / mL). In some embodiments, the circulating drug plasma level of the compound is below the limit of detection (e.g., 0.1 ng / mL or less).

[0280]

[0236] 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

[0281] 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

[0282] 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

[0283] 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.

[0284]

[0237] 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 100 mg, such as about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg, as well as ranges between these values.

[0285]

[0238] 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 100 mg and 1 ,000 mg, such as about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, and about 1000 mg, as well as ranges between these values.

[0286]

[0239] 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.

[0287]

[0240] 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 20 mg and 200 mg, such as about 25 mg, about 35 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, and about 200 mg, as well as ranges between these values.

[0288]

[0241] 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 (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.

[0289]

[0242] 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

[0290] 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

[0291] 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

[0292] 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.

[0243] 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).

[0293]

[0244] 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.

[0294]

[0245] 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 invention. 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.

[0295]

[0246] In embodiments, for example where a composition is prepared in single unit dosage form, suggested dose amounts may be known by reference to the format of the preparation itself. In embodiments, for example where a composition is prepared in multiple dosage form, suggested dose 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 available to those of skill or the public.

[0296]

[0247] Accordingly, another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the invention, 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.

[0297] G. Kits

[0298]

[0248] Another aspect of this disclosure provides pharmaceutical kits (as shorthand, “kits”) containing a disclosed pharmaceutical composition, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. Pharmaceutical compositions also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration. Kits may comprise suitable packaging. Kits may comprise one or more containers comprising any compound described herein, along with any additional active compounds. 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).

[0299]

[0249] In some embodiments, information pertaining to dosing and proper administration (if needed) is printed onto a multi-dose kit directly (e.g., on a blister pack or interior packaging). Disclosed kits can further contain package inserts and other printed instructions, including on exterior packaging, for administering the disclosed compositions and for their appropriate therapeutic use.

[0300] H. Methods of Use

[0301]

[0250] In some aspects, provided are methods of using a disclosed compound and compositions thereof. In some embodiments, a disclosed compound is used to modulate neurotransmission. In embodiments, a disclosed compound is used to treat a condition, such as a disease or a disorder. In embodiments, a disclosed compound is used in the manufacture of a medicament for the therapeutic and / or the prophylactic treatment of a condition, such as a disease or a disorder. In embodiments, a disclosed compound is administered as part of therapy. In embodiments, a disclosed compound is administered along with psychotherapy, psychological support, or patient monitoring. In embodiments, a disclosed compound is administered in a therapeutically effective amount to a subject having a condition, such as a disease or a disorder. In embodiments, the condition is a mental, behavioral, or neurodevelopmental disorder. In embodiments, the condition is a neurodegenerative disorder. In embodiments, the condition is inflammation. In embodiments, the condition is an inflammatory disorder. In embodiments, the condition is a pain disorder. In embodiments, a disclosed compound is administered to a subject that is healthy.

[0302]

[0251] 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 therefrom. Disclosed methods can be modified to treat multiple patients, including couples and groups. Hence, in some embodiments, 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.

[0303]

[0252] In embodiments, a disclosed compound or composition thereof is orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation or transdermally administered to a subject. In embodiments, when administered through one or more such routes, the disclosed compounds and the compositions comprising them are useful in methods for treating a patient in need of such treatment. . Modulating Neurotransmission

[0304]

[0253] In embodiments, a disclosed compound modulates 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.

[0305]

[0254] 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 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 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 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.

[0306]

[0255] In embodiments, administration of a disclosed compound modulates spike rate. Spike rate is the number of action potentials per second. In embodiments, administration of 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 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 (e.g., 700 milliseconds). In embodiments, a disclosed compound modulates burst spike number. Burst spike number is the number of spikes per burst. In embodiments, a disclosed compound modulates burst duration. Burst duration is the mean duration of detected bursts. In 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.

[0307]

[0256] In embodiments, administration of 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 embodiments, administration of 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 embodiments, administration of 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 embodiments, administration of 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 embodiments, administration of 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.

[0308]

[0257] In embodiments, modulating neurotransmission contributes to the therapeutic effects of a disclosed compound in a subject. In embodiments, modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject. In some embodiments, modulating neurotransmission comprises modulating monoaminergic neurotransmission. In some embodiments, modulating neurotransmission comprises modulating serotonergic neurotransmission. In some embodiments, modulating neurotransmission comprises modulating dopaminergic neurotransmission. Accordingly, in some embodiments, administration of a disclosed compound treats a medical condition linked to dysregulation or inadequate functioning of neurotransmission, and in specific embodiments, treats a medical condition linked dysregulation or inadequate functioning of serotonergic and / or dopaminergic neurotransmission.

[0309]

[0258] In some embodiments, administration of a compound activates serotonin receptors. In embodiments, disclosed compounds agonize and / or antagonize serotonin receptors (5-HT receptors). In some embodiments, disclosed compounds agonize or partially agonize 5-HT receptors, such as any one or more of an 5-HT, receptor, such as 5-HT1Aand 5-HT1B, an 5-HT2receptor, such as 5-HT2A, 5-HT2B, and 5-HT2C, and 5-HT6.

[0310]

[0259] 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 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has an in vitro EC50(agonist mode) for 5-HT2Athat is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM. In embodiments, a disclosed compound has an in vitro EC50(agonist mode) for 5-HT2Cthat is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM.

[0311]

[0260] In some embodiments, disclosed compounds show greater potency at 5-HT2relative to another 5-HT receptor. In some embodiments, disclosed compounds show greater potency at 5-HT^ relative to any one or more of an 5-HTi receptor, another 5-HT2receptor, such as 5-HT2Band 5-HT2C, a 5-HT5receptor, a 5-HT6receptor, and a 5-HT7receptor.

[0312]

[0261] 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-HT^, a widely recognized target of psychedelic compounds (see, e.g., Klein et al., ACS Pharmacol Transl Sci. 2020 14;4(2):533-542; Flanagan et al., ACS Pharmacol Transl Sci. 2020;4(2):488-502; Toro-Sazo et al., PLoS One. 2019;14(1):e0209804; Halberstadt et al., Psychopharmacology (Berl). 2019;236(2):799-808). As 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.

[0313]

[0262] Because certain therapeutic benefits of disclosed compounds may derive, at least in part, from selective activation of a serotonin receptor (e.g., 5-HT^, 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-HT^ receptor 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 b-HT^ receptor) 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 pM and a 5-HT2BEC50of 1 .0 pM, 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 K,) 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-HT2AK, of 0.1 pM and a 5-HT2BEC50of 1.0 pM, the compound could be said to have a 10-fold affinity selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor.

[0314]

[0263] 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 S-HT^ receptor over the 5-HT2Breceptor, relative to a comparator.

[0315]

[0264] In some 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 some embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2Areceptor over the 5-HT2Breceptor, relative to a comparator.

[0316]

[0265] 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 some embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2Creceptor over the 5-HT2Breceptor, relative to a comparator.

[0317]

[0266] In some 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 some embodiments, a disclosed compound has improved affinity selectivity for the 5-HT2Creceptor over the 5-HT2Breceptor, relative to a comparator. . Modulating Neuroplasticity

[0318]

[0267] In embodiments, administration of a disclosed compound increases 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. Without being bound by theory, 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 embodiments, increasing neuroplasticity contributes to the therapeutic effects of administering a disclosed compound to a subject. In embodiments, increasing neuroplasticity refers to increasing synaptic plasticity. In embodiments, increasing neuroplasticity refers to increasing structural plasticity. In embodiments, increasing neuroplasticity by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0319]

[0268] 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. In embodiments, administration of 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 embodiments, administration of a disclosed compound increases total neurite length. In embodiments, a disclosed compound increases maximum neurite length. In embodiments, administration of a disclosed compound increases the number of neurite nodes. In embodiments, administration of a disclosed compound increases the number of neurite extremities. In embodiments, administration of a disclosed compound increases dendritogenesis. In embodiments, administration of a disclosed compound increases spinogenesis. In embodiments, administration of a disclosed compound increases synaptogenesis. In embodiments, administration of a disclosed compound increases the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., number of synapses per neuron), or total dendritic length. These factors can be measured using a Sholl analysis and other techniques known to those of skill in the art (see, e.g., Ly et al. ACS Pharmacol Transl Sci. 2020;4(2):452-460). c. Treatment

[0320]

[0269] In embodiments, a disclosed compound is used to treat a medical condition, such as a disease or disorder. In embodiments, a disclosed compound is used in the manufacture of a medicament to treat a condition, such as a disease or disorder. Also provided are methods of administering a disclosed compound to a subject having a condition, such as a disease or disorder, thereby treating said condition.

[0321]

[0270] In embodiments, a disclosed compound is administered to a subject by one or more routes of administration, including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes. When administered through one or more of such routes, the compound is useful in methods for treating a patient in need of such treatment.

[0322]

[0271] 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. In 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 in view of the disclosure and the knowledge in the art.

[0323]

[0272] In embodiments, a disclosed compound is 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

[0324]

[0273] In embodiments, a disclosed compound is used to treat a mental, behavioral, or neurodevelopmental disorder. In embodiments, a disclosed compound is 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.

[0325]

[0274] 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.

[0326]

[0275] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will 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.

[0327]

[0276] Although the terms “mental disorder” and “mental health disorder,” as well as terms that define specific diseases and disorders, generally refer to the criteria in the ICD-11 , or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are also 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 clinical diagnosis.

[0328]

[0277] In embodiments, a disclosed compound is used to treat a mental health disorder in a subject. In embodiments, a subject has a mental health disorder. In 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 embodiments, a disclosed compound is 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 embodiments, a disclosed compound is 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.

[0329]

[0278] In embodiments, measures of therapeutic efficacy include reports by a subject or an observer. In 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.

[0330]

[0279] In embodiments, a disclosed compound is used to treat a neurodevelopmental disorder in a subject. In embodiments, a subject has a neurodevelopmental disorder. In 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 a disclosed compound, include a disorder of intellectual development, a developmental speech or language disorder, autism, autism spectrum disorder (ASD), social anxiety in autistic subjects, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.

[0331]

[0280] In embodiments, a disclosed compound is used to treat schizophrenia or another primary psychotic disorder. In embodiments, a subject has schizophrenia or another primary psychotic disorder. In 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 a disclosed compound, include schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder.

[0332]

[0281] In embodiments, a disclosed compound is used to treat catatonia. In embodiments, a subject has catatonia. In 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 embodiments, catatonia is associated with another mental disorder. In embodiments, catatonia is induced by substances or medications.

[0333]

[0282] In embodiments, a disclosed compound is used to treat a mood disorder. In embodiments, a subject has a mood disorder. In 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 a disclosed compound, include depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. In 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 embodiments, the mood disorder is a depressive disorder. In embodiments, the depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, seasonal affective disorder, mixed depressive and anxiety disorder, or an unspecified depressive disorder. In embodiments, the depressive disorder is major depressive disorder (MDD) or treatment resistant depression (TRD).

[0334]

[0283] In embodiments, depression is assessed through the Patient Health Questionnaire-9 (PHQ-9) screening tool, Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale, Beck Depression Inventory (BDI-II), Zung Self-Rating Depression Scales (SDS), Major Depression Inventory (MDI), Center for Epidemiologic Studies Depression Scale (CED-D), Rome Depression Inventory (RDI), Hamilton Rating Scale for Depression (HRSD), and Carroll Rating Scale (CRS).

[0335]

[0284] In embodiments, a disclosed compound is used to treat an anxiety or fear-related disorder. In embodiments, a subject has an anxiety or fear-related disorder. In 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 a disclosed compound, include generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or a substance-induced anxiety disorder.

[0336]

[0285] In embodiments, a disclosed compound is used to treat an obsessive-compulsive or related disorder. In embodiments, a subject has an obsessive-compulsive or related disorder. In 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 a disclosed compound, 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.

[0337]

[0286] In embodiments, a disclosed compound is used to treat a disorder associated with stress. In embodiments, a subject has a disorder associated with stress. In 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 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 a disclosed compound, include post-traumatic stress disorder (PTSD), complex PTSD (ePTSD), prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder.

[0338]

[0287] In embodiments, a disclosed compound is used to treat a dissociative disorder. In embodiments, a subject has a dissociative disorder. In 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 a disclosed compound, 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.

[0339]

[0288] In embodiments, a disclosed compound is used to treat a feeding or eating disorder. In embodiments, a subject has a feeding or eating disorder. In 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 a disclosed compound, include anorexia nervosa (including anorexia with significantly low body weight, with dangerously low body weight, and anorexia in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.

[0340]

[0289] In embodiments, a disclosed compound is used to treat an elimination disorder. In embodiments, a subject has an elimination disorder. In 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 a disclosed compound, include enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or encopresis (including both with constipation or overflow incontinence, and without constipation or overflow incontinence).

[0341]

[0290] In embodiments, a disclosed compound is used to treat a disorder of bodily distress or bodily experience. In embodiments, a subject has a disorder of bodily distress or bodily experience. In 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 a disclosed compound, include bodily distress disorder (including mild, moderate, and severe bodily distress disorder) or body integrity dysphoria.

[0291] In embodiments, a disclosed compound is used to treat a disorder due to substance use or addictive behaviors. In embodiments, a subject has a disorder due to substance use or addictive behaviors. In 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 embodiments, a disclosed compound is used to treat disorders due to substance use (i.e., a substance use disorder, or SUD). In 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 compound, 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 embodiments, the substance use disorder is alcohol use disorder. In embodiments, the substance use disorder is cannabis use disorder. In embodiments, the substance use disorder is caffeine use disorder. In embodiments, the substance use disorder is phencyclidine use disorder. In embodiments, the substance use disorder is inhalant use disorder. In embodiments, the substance use disorder is opioids use disorder. In embodiments, the substance use disorder is sedatives use disorder. In embodiments, the substance use disorder is hypnotics use disorder. In embodiments, the substance use disorder is anxiolytics use disorder. In embodiments, the substance use disorder is stimulants use disorder. In embodiments, the substance use disorder is tobacco use disorder. In embodiments, the substance use disorder is alcohol use disorder, wherein said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism. In embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder). In embodiments, 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).

[0342]

[0292] In embodiments, a disclosed compound is used to treat an impulse control disorder. In embodiments, a subject has an impulse control disorder. In 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 embodiments, impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts. Examples of an impulse control disorder, treatable using a disclosed compound, include pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.

[0343]

[0293] In embodiments, a disclosed compound is used to treat a disruptive behavior disorder or a dissocial disorder. In embodiments, a subject has a disruptive behavior disorder or a dissocial disorder. In 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 a disclosed compound, 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).

[0344]

[0294] In embodiments, a disclosed compound is used to treat a personality disorder. In embodiments, a subject has a personality disorder. In 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 embodiments, a disclosed compound is used to treat a mild, moderate, or severe personality disorder. In 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 a disclosed compound, 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.

[0345]

[0295] In embodiments, a disclosed compound is used to treat a paraphilic disorder. In embodiments, a subject has a paraphilic disorder. In 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 a disclosed compound, 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.

[0346]

[0296] In embodiments, a disclosed compound is used to treat a factitious disorder. In embodiments, a subject has a factitious disorder. In 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 a disclosed compound, include a factitious disorder imposed on self or a factitious disorder imposed on another.

[0347]

[0297] In embodiments, a disclosed compound is used to treat a neurocognitive disorder. In embodiments, a subject has a neurocognitive disorder. In 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 a disclosed compound, include delirium, amnestic disorder, dementia, Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, or Lewy body disease. In embodiments, a neurocognitive disorder, treatable using the disclosed compounds, is associated with a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a disclosed compound is used to treat delirium. In embodiments, the delirium is associated with another disease or disorder. In embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a disclosed compound is used to treat mild neurocognitive disorder. In embodiments, a disclosed compound is used to treat an amnestic disorder. In embodiments, the amnestic disorder is associated with another disease or disorder. In embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a disclosed compound is used to treat dementia. In embodiments, the dementia is associated with Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, Lewy body disease, a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a disclosed compound is used to treat a behavioral or psychological disturbance associated with dementia. In embodiments, dementia is assessed using a Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).

[0348]

[0298] In embodiments, a disclosed compound is used to treat a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. In embodiments, a subject has a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. In 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 embodiments, the disorder includes psychotic symptoms. In embodiments, a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, with psychotic symptoms. In embodiments, a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, without psychotic symptoms.

[0349]

[0299] In embodiments, a disclosed compound is used to treat a sleep-wake disorder. In embodiments, a subject has a sleep-wake disorder. In 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 a disclosed compound, include an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder.

[0300] In embodiments, a disclosed compound is used to treat sexual dysfunction. In embodiments, a subject has sexual dysfunction. In 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 compound, include hypoactive sexual desire dysfunction, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse.

[0350]

[0301] In embodiments, a disclosed compound 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).

[0351]

[0302] In embodiments, a disclosed compound 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 disclosed compounds. 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.

[0352]

[0303] In embodiments, “psychotherapy” is specifically “psychedelic-assisted psychotherapy” (“PAT”) or “psychedelic-assisted therapy” (“PAT”). PAP and PAT, broadly, include a range of related approaches that involve at least one session where a patient ingests a psychedelic and is monitored, supported, or otherwise engaged by one or more trained (generally, 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., described in Mithoefer 2017).

[0353]

[0304] In 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 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 the disclosed compound.

[0354]

[0305] In embodiments, a disclosed compound is administered together with standardized psychological treatment or support, such as any accepted modality of standard psychotherapy or counseling, whether once a week, twice a week, or as needed; whether in person or virtual (e.g., over telemedicine or by means of a web program or mobile app); and whether with a human therapist or a virtual or Al “therapist.” Herein, “therapist” refers to a person who treats a patient using a disclosed compound or method, whether the person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, although it will be understood that certain requirements are appropriate to certain aspects of the drug-assisted therapy (e.g., prescribing, dispensing, or administering a drug, offering psychotherapeutic support). In embodiments, a “person” may also include an Al.

[0355]

[0306] In embodiments, a subject will participate in a disclosed treatment protocol or method, or be administered a disclosed compound as part of a method, if the subject meets certain inclusion criteria, does not meet certain exclusion criteria, and / or does not meet any withdrawal criteria during such treatment.

[0356]

[0307] In embodiments, a personalized or precision medicine approach may be used, based on individual characteristics, including drug metabolism (e.g., CYP2D6 or CYP3A4) or individual genetic variation. The term “genetic variation” refers to a change in a gene sequence relative to a reference sequence (e.g., a commonly-found and / or wild-type sequence). Genetic variation may be recombination events or mutations such as substitution / deletion / insertion events like point and splice site mutations.

[0357]

[0308] In embodiments, the genetic variation is a variation in one or more cytochrome P450 (CYP or CYP450) enzymes that affects drug metabolism, e.g., CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5. In embodiments, also including 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, CYP11 B1 , CYP11 B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1 , CYP27B1 , CYP39, CYP46, and CYP51.

[0358]

[0309] In embodiments, a disclosed compound is taken together with a compound that is metabolized by the same CYP enzyme(s) as a disclosed compound, so as to permit a lower dose to be taken, increase the effective bioavailability of one or both, or otherwise affect drug metabolism or PK. In embodiments, the dose of a disclosed compound is adjusted, such as reduced, when administered to a subject known to be a poor metabolizer of a disclosed compound, or increased when administered to a subject known to be a rapid metabolizer of a disclosed compound. In embodiments, a patient is tested using means known to in the art to determine if the patient is a poor or rapid metabolizer.

[0359]

[0310] In 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.

[0360]

[0311] In embodiments, a genetic variation is an inclusion criteria for the administration of a disclosed compound. In embodiments, a genetic variation is an exclusion criteria for the administration of a disclosed compound. In 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

[0361]

[0312] In embodiments, a disclosed compound is used to treat a neurodegenerative disorder. In embodiments, a disclosed compound is administered, such as in a therapeutically effective amount, to a subject having a neurodegenerative disorder. In some methods herein, a disclosed compound, when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a neurodegenerative disorder. 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 or peripheral nervous systems, and which may involve the degeneration, impairment, or death of neuronal cells, leading to a decline in cognitive, motor, and / or sensory abilities. 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. Pathol Neurodegen Diseases. Cold Spring Harbor Perspectives Biol. 2017:9(7); a028035). Neurodegenerative 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).

[0362]

[0313] In embodiments, the neurodegenerative disorder is any of Alzheimer’s disease, amyotrophic lateral sclerosis, Charcot’s disease, chronic traumatic encephalopathy (CTE), corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease, Parkinsonisms, prion disease, progressive supranuclear palsy, and traumatic brain injury (TBI), including mild traumatic brain injury (mTBI). iii. Pain Disorders

[0363]

[0314] In embodiments, a disclosed compound is used to treat a pain disorder. In embodiments, a disclosed compound is administered, such as in a therapeutically effective amount, to a subject having a pain disorder. In some methods herein, a disclosed compound, when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a pain disorder.

[0364]

[0315] 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 disclosed compound is used to treat neuropathic pain. In embodiments, a disclosed compound is used to treat psychogenic pain. In embodiments, a disclosed compound is used to treat idiopathic pain. In embodiments, a disclosed compound is used to treat radicular pain.

[0365]

[0316] Pain disorders may manifest as acute or chronic pain, and can affect different parts of the body, such as musculoskeletal, neurological, gastrointestinal, or visceral systems. Pain can be expressed as, e.g., postherpetic 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.

[0366]

[0317] 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

[0367]

[0318] 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. Inflammatory agents may act directly to remove harmful stimuli and initiate various signaling responses to return damaged tissue to a state of homeostasis. Although the response is often self-terminating, resolution of inflammation may fail for multiple reasons, extending the inflammation response into a chronic stage (Ahmed. Front Biol. 2011 ;6(4): 274-281). Chronic inflammation is associated with or underlies a variety of pathological conditions, including major cardiovascular and neuropsychiatric disorders (Nichols. Cardiovasc Psychiatry Neurol 2009:475108).

[0368]

[0319] 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, S-HT^ receptors 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. 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, et al. Brain Behav Immun. 2000 Sep; 14(3):219-24; Cloez-Tayarani, 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).

[0369]

[0320] Due to their significant action on 5-HT^ receptors 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-a 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.”

[0370]

[0321] This work, and subsequent in vitro and in vivo studies have demonstrated that (R)-DOI inhibits TNF-a induced expression of genes encoding intracellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), and inflammatory cytokines IL-6 and IL-10, and chemokines monocyte chemotactic protein-1 (MCP1). (R)-DOI also blocks activation and nuclear translocation of NF-KB, 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.).

[0371]

[0322] 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-HT^ receptor, 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 pharmacophore 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.

[0372]

[0323] 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 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.

[0373]

[0324] 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.

[0374]

[0325] 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, IL1 b, 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.

[0375]

[0326] 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 TNFo, Arg-1, IL-4, IL-5, IL-6, IL-8, IL-9, IL-lfi, ll-IA, IL-12, IL-13, IFNa, IFNb, IFNg, TGF- / 3, IL-15, IL-17, IL-20, IL-22, LTA, IL-23, IL-18, VCM / 11, 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-1 , TNFa, IL-15, IL-17, Arg-1, and IL-18. In some embodiments, the inflammation response gene encodes an anti-inflammatory agent. An anti-inflammatory agent is a protein that reduces an inflammatory response. Anti-inflammatory agents include, for example, the proteins IL-1 , IL-4, IL-10, IL-11, and IL-13. In some embodiments, the inflammation response gene encodes an agent that may be inflammatory or anti-inflammatory. For example, leukemia inhibitory factor, interferon-alpha, IL-6, and transforming growth factor (TGF-0) 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).

[0376]

[0327] 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.

[0377]

[0328] 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-1 ft. In some embodiments, the biomarker of inflammation response is a IL-1 ft gene product. In some embodiments, the biomarker is IL-1 ft mRNA. In some embodiments, the biomarker is the IL-1 protein. In some embodiments, the inflammation response gene is Arg-1. In some embodiments, the biomarker of inflammation response is an Arg-1 gene product. In some embodiments, the biomarker is Arg-1 mRNA. In some embodiments, the biomarker is the Arg-1 protein.

[0378]

[0329] 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-p. In some embodiments, the biomarker of inflammation response is a TGF-ft gene product. In some embodiments, the biomarker is TGF-ft mRNA. In some embodiments, the biomarker is the TGF-p protein.

[0379]

[0330] 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-y, TNFa, TNFP, GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17, IL-25, IL-33, or TGF-0. 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 CX3CLI . 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).

[0380]

[0331] 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).

[0381]

[0332] 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.

[0382]

[0333] 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.

[0383]

[0334] 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.

[0384]

[0335] 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.

[0385]

[0336] 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.

[0386]

[0337] 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.

[0387]

[0338] 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.

[0388]

[0339] 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.

[0389]

[0340] 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.

[0390]

[0341] In some embodiments, a disclosed compound is useful for treating neuroinflammation. In some embodiments, treating neuroinflammation comprises reducing an inflammatory response to a CNS insult (from, e.g., a pathogen, tissue damage, abnormal stimulation, a neurotoxin, an infection, an injury, and the like). As will be known to those of skill, multiple pathways are involved in neuroinflammation, which can involve numerous CNS cell types (e.g., neurons, microglia, astrocytes, etc.).

[0391]

[0342] 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).

[0392]

[0343] 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-KB-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.

[0393]

[0344] 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): 1174-119O.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).

[0394]

[0345] 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.

[0395]

[0346] 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.

[0396]

[0347] 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-Schonlein 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.

[0397]

[0348] 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 (e.g., Germolec et al. Methods Mol Biol. 2018;1803:57-79; Luo et al. Clin Lab. 2019 1 ;65(3)). v. Ophthalmic Diseases and Disorders

[0398]

[0349] 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).

[0399]

[0350] 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.

[0400]

[0351] 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.

[0401] Ill

[0352] 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.

[0402]

[0353] 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).

[0403]

[0354] In some embodiments, a disclosed compound is used to treat allergic conjunctivitis, including vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC); dry eye syndrome; 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.

[0404]

[0355] In some embodiments, the ophthalmic disease or disorder is an inflammatory disorder. In some embodiments, the ophthalmic disease or disorder is macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis, conjunctivitis, keratitis, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber's disease, retinal detachment, retinal pigment epithelial detachment, rubeosis iridis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinochoroidal neovascularization, or a combination thereof.

[0405]

[0356] 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.

[0406] I. Examples

[0407]

[0357] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0408] EXAMPLE 1 : Synthesis of N-[2-[5-(2-amino-2-oxo-ethyl)-4-bromo-2-methoxy-phenyl]ethyl]carbamate (HCI salt) (2CB-5CAM)

[0409] Target Step 1: Methyl 2-(2-bromo-4-methoxyphenyl)acetate

[0410]

[0358] A solution of 2-(2-bromo-4-methoxyphenyl)acetic acid (10 g, 40.8 mmol, 1 eq) in HCI / MeOH (4 M, 102 mL, 10 eq) was stirred at 60 °C for 2 hours. TLC (petroleum ether: ethyl acetate = 1 :1) showed 2-(2-bromo-4-methoxy-phenyl)acetic acid remained and a new spot was detected. The reaction was poured in water (50 mL) and extracted with MTBE (2 x 50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give methyl 2-(2-bromo-4-methoxyphenyl)acetate (10.5 g, crude) as a colorless oil.

[0411] Step 2: Methyl 2-(2-bromo-5-iodo-4-methoxyphenyl)acetate

[0412]

[0359] To a solution of methyl 2-(2-bromo-4-methoxyphenyl)acetate (5 g, 19.3 mmol, 1 eq) in DCM (40 mL) was added AgOTf (5.45 g, 21.23 mmol, 1.1 eq) and the solution was stirred at 20 °C for 0.5 hour. I2(5.39 g, 21.2 mmol, 4.28 mL, 1.1 eq) was added into the solution and the solution was stirred at 20 °C for 11.5 hours. TLC (petroleum ether: ethyl acetate = 5:1) showed methyl 2-(2-bromo-4-methoxyphenyl)acetate was consumed completely and a new spot with lower polarity was detected. The reaction was filtered and the filtrate was washed with saturated Na2SO3solution (50 mL) and extracted with MTBE (2 x 50 mL). The combined organics were concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give methyl 2-(2-bromo-5-iodo-4-methoxyphenyl)acetate (7.14 g, crude) as a yellow oil.

[0413] Step 3: 2-(2-bromo-5-iodo-4-methoxyphenyl)acetamide

[0414]

[0360] A solution of methyl 2-(2-bromo-5-iodo-4-methoxyphenyl)acetate (2.9 g, 7.53 mmol, 1 eq) in NH3 / MeOH (7 M, 30 mL, 28.0 eq) was stirred at 60 °C for 12 hours. LCMS showed ethyl 2-(2-bromo-5-iodo-4-methoxy-phenyl)acetate remained and desired mass was detected. The reaction was filtered and the cake was washed with MeOH (5 mL). The cake was concentrated to give 2-(2-bromo-5-iodo-4-methoxyphenyl)acetamide (1.37 g, 3.70 mmol, 49.2% yield) as a white solid. Alternatively, after Step 2, the ester can be treated directly under conditions that would install the aminoethyl side chain; for example, according to the reaction described in Step 4.

[0415] Sfep 4: Tert-butyl(5-(2-amino-2-oxoethyl)-4-bromo-2-methoxyphenethyl)carbamate

[0416]

[0361] Ten reactions were carried out in parallel. To a solution of 2-(2-bromo-5- iodo-4-methoxyphenyl)acetamide (100 mg, 270 pmol, 1 eq), potassium 2-(tert-butoxy- carbonylamino)ethyl-trifluoroboranuide (67.9 mg, 270 pmol, 1 eq) and Cs2CO3(264 mg, 810 pmol, 3 eq) in toluene (3 mL) and H2O (1 mL) was added Pd(dppf)CI2.DCM (22.1 mg, 27.0 pmol, 0.1 eq). The mixture was degassed and purged with N2for 3 times. The mixture was stirred at 85 °C for 12 hours under N2. LCMS showed 2-(2-bromo-5-iodo-4-methoxyphenyl)acetamide was consumed completely and desired mass was detected. The ten reactions were combined and the mixture was concentrated to get a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 pm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 20%-55% B over 8.0 min) to give desired tert-butyl N-[2-[5-(2-amino-2-oxo-ethyl)-4-bromo-2-methoxy-phenyl]ethyl] carbamate (105 mg, 271.13 pmol, 10.03% yield) as an off-white solid.

[0417] Sfep 5: [5-(2-Aminoethyl)-2-bromo-4-methoxyphenyl]acetamide (2CB-5CAM)

[0418]

[0362] To a solution of tert-butyl N-[2-[5-(2-amino-2-oxo-ethyl)-4-bromo-2- methoxyphenyl]ethyl]carbamate (130 mg, 335 pmol, 1 eq) in dioxane (3 mL) was added HCI / dioxane (3 M, 448 pL, 4 eq) at 20 °C and the solution was stirred at 20 °C for 1 hour. LCMS showed tert-butyl N-[2-[5-(2-amino-2-oxo-ethyl)-4-bromo- 2-methoxy-phenyl]ethyl] carbamate was consumed completely and desired mass was detected. The reaction was concentrated to give [5-(2-Aminoethyl)-2-bromo-4-methoxyphenyl]acetamide (2CB-5CAM) (105 mg, 315 pmol, 94.03% yield, 97.28% purity, HCI salt) as a white solid.1H NMR (DMSO-d6) 5: 7.89 (br s, 3H), 7.26-7.35 (m, 1 H), 7.19 (s, 1 H), 7.15 (s, 1 H), 6.94 (br s, 1 H), 3.81 (s, 3H), 2.89-2.99 (m, 2H), 2.75-2.85 (m, 2H).

[0419] EXAMPLE 2: Synthesis of 5-(2-aminoethyl)-2-bromo-4-methoxybenzamide (HCI Salt) (2CB-5CA)

[0420] Step 1: 2-Bromo-4-methoxybenzoyl chloride

[0421]

[0363] To a solution of 2-bromo-4-methoxybenzoic acid (12 g, 51.9 mmol, 1 eq) in DMF (1 mL) and DCM (120 mL) was added oxalyl dichloride (19.8 g, 156 mmol, 3 eq) dropwise at 0 °C and the solution was stirred at 20 °C for 2 hours. Thin Layer Chromatography (TLC) showed 2-bromo-4-methoxybenzoic acid was consumed completely and a new spot was detected. The reaction was concentrated under reduced pressure to give crude 2-bromo-4-methoxybenzoyl chloride (12 g, crude) as a yellow solid.

[0422] Sfep 2: 2-Bromo-4-methoxybenzamide

[0423]

[0364] A solution of 2-bromo-4-methoxy-benzoyl chloride (12 g, 48.1 mmol, 1 eq) in DCM (20 mL) was added into NH3.H2O (91.0 g, 649 mmol, 100 mL, 25% purity, 13.5 eq) at O °C and the solution was stirred at 20 °C for 1 hour. Many solids precipitated out. TLC showed 2-bromo-4-methoxybenzoyl chloride was consumed completely and a new spot was detected. The reaction mixture was filtered and the cake was washed with H2O (2 x 50 mL). The filtered cake was dried in vacuum to get the desired product to give 2-bromo-4-methoxybenzamide (10 g, crude) as a white solid.

[0424] Sfep 3: 2-Bromo-5-iodo-4-methoxybenzamide

[0425]

[0365] To a solution of 2-bromo-4-methoxybenzamide (4.6 g, 20.0 mmol, 1 eq) in H2SO4(50 mL) was added NIS (4.27 g, 19.0 mmol, 0.95 eq) at 0 °C. The solution was stirred at 20 °C for 12 hours. LCMS showed 2-bromo-4-methoxybenzamide was consumed completely and one main peak with desired mass was detected. The reaction mixture was poured into ice water (120 mL), containing sodium sulfite (3.8 g, 30 mmol) and the mixture was stirred for 1 hour. The mixture was extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to get a residue. The residue was triturated with DCM (30 mL) for 0.5 hour and filtered. The cake was dried in vacuum to give 2-bromo-5-iodo-4-methoxybenzamide (6.2 g, 17.4 mmol, 87.1% yield) as a white solid. LCMS (ESI) [M+H-56]+m / z: 335.9.

[0426] Sfep 4: Tert-butyl (4-bromo-5-carbamoyl-2-methoxyphenethyl)carbamate

[0427]

[0366] To a reaction mixture of 2-bromo-5-iodo-4-methoxybenzamide (0.5 g, 1.40 mmol, 1 eq), potassium 2-(tertbutoxycarbonylamino) ethyl-trifluoro-boranuide (423 mg, 1.69 mmol, 1.2 eq) and K3PO4(895 mg, 4.21 mmol, 3 eq) in toluene (10 mL) and water (2.5 mL) was added Pd(dppf)CI2.CH2CI2(115 mg, 140 pmol, 0.1 eq) under N2. The reaction mixture was degassed and purged with N2for 3 times. The solution was stirred at 100 °C for 12 hours. LCMS showed 2-bromo-5-iodo-4-methoxybenzamide was consumed completely and desired mass was detected. The reaction was concentrated under reduced pressure to give tert-butyl N-[2-(4-bromo-5-carbamoyl-2-methoxy-phenyl)ethyl]carbamate (500 mg, crude) as a yellow oil. LCMS (ESI) [M+H-56]+m / z: 317.0.

[0428] Sfep 5: 5-(2-Aminoethyl)-2-bromo-4-methoxybenzamide

[0429]

[0367] A solution of tert-butyl N-[2-(4-bromo-5-carbamoyl-2-methoxyphenyl)ethyl]carbamate (0.5 g, 1.34 mmol, 1 eq) in HCI / EtOAc (4 M, 6.70 mL, 20 eq) was stirred at 20 °C for 0.5 hour. LCMS showed tert-butyl N-[2-(4-bromo-5-carbamoyl-2-methoxy-phenyl)ethyl]carbamate was consumed completely and desired mass was detected. The reaction was concentrated to get a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40mm * 5pm; mobile phase: [H20(0.04% HCI)-ACN]; gradient: 1 %-20% B over 8.0 min) to give 5-(2-aminoethyl)-2-bromo-4-methoxybenzamide (68 mg, 216 pmol, 16.1 % yield, 98.3% purity, HCI salt) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 = 2.77 - 2.87 (m, 2 H) 2.91 - 3.03 (m, 2 H) 3.84 (s, 3 H) 7.21 (s, 1 H) 7.28 (s, 1 H) 7.47 (br s, 1 H) 7.72 (br s, 1 H) 7.95 (br s, 3 H) LCMS (ESI) [M+H]+m / z: 273.0.

[0430] EXAMPLE 3: Synthesis of 2-[5-(2-aminoethyl)-2-bromo-4-hydroxy-phenyl]acetamide (HCI salt) (2CB-2OH-5CAM)

[0431]

[0432] 5 Target

[0433] Step 1: 2-(2-Bromo-4-methoxyphenyl)acetyl chloride

[0434]

[0368] To a solution of 2-(2-bromo-4-methoxyphenyl)acetic acid (21 g, 85.7 mmol, 1 eq) in DCM (50 mL) was added SOCI2(20.4 g, 171 mmol, 2 eq). The mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 2-(2-bromo-4-methoxyphenyl)acetyl chloride (21 g, 79.7 mmol, 93.0% yield) was obtained as yellow oil.

[0435] Step 2: 2-(2-Bromo-4-methoxy-phenyl)acetamide

[0436]

[0369] To a solution of NH3.H2O (91.00 g, 649 mmol, 25% purity, 8.15 eq) in DCM (100 mL) was added 2-(2-bromo-4-methoxyphenyl)acetyl chloride (21 g, 79.7 mmol, 1 eq). The mixture was stirred at 40 °C for 2 hours. The reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give 2-(2-bromo-4-methoxyphenyl) acetamide (18 g, 73.74 mmol, 92.54% yield) as a white solid.

[0437] Step 3: 2-(2-Bromo-5-iodo-4-methoxy-phenyl)acetamide

[0438]

[0370] To a solution of 2-(2-bromo-4-methoxy-phenyl)acetamide (10 g, 41.0 mmol, 1 eq) in EtOH (300 mL) was added l2(10.4 g, 41.0 mmol, 1 eq) and AgOTf (10.5 g, 41.0 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / Ethyl acetate=10 / 1 to 1 / 3) to give 2-(2-bromo-5-iodo-4-methoxyphenyl)acetamide (6 g, 16.2 mmol, 39.58% yield) as a white solid.1H NMR (400MHz, DMSO-d6): 5 7.74 (s, 1 H), 7.17 (s, 1 H), 3.83 (s, 3H), 3.48 (s, 2H).

[0439] Step 4: Tert-butyl N-[2-[5-(2-amino-2-oxo-ethyl)-4-bromo-2-methoxy-phenyl]ethyl]carbamate

[0440]

[0371] A mixture of 2-(2-bromo-5-iodo-4-methoxyphenyl)acetamide (5 g, 13.5 mmol, 1 eq), 2-(tert-butoxycarbonylamino)ethyl-trifluoro-boron potassium hydride (3.39 g, 13.5 mmol, 1 eq), Cs2CO3(13.2 g, 40.5 mmol, 3 eq) and Pd(dppf)CI2.CH2CI2(1.10 g, 1.35 mmol, 0.1 eq) in toluene (240 mL) and H2O (60 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 85 °C for 12 hours under N2atmosphere. The reaction mixture was concentrated under reduced pressure to remove toluene, diluted with EtOAc (600 mL) and H2O (300 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 0 / 1) to give tert-butyl N-[2-[5-(2-amino-2-oxoethyl)-4-bromo-2-methoxyphenyl]ethyl]carbamate (1.6 g, 1.01 mmol, 7.47% yield, 24.4% purity) was obtained as a light yellow solid.

[0441] Sfep 5: 2-[5-(2-Aminoethyl)-2-bromo-4-hydroxy-phenyl]acetamide

[0442]

[0372] To a solution of tert-butyl N-[2-[5-(2-amino-2-oxo-ethyl)-4-bromo-2-methoxyphenyl] ethylcarbamate

[0443] (1.1 g, 2.84 mmol, 1 eq) in DCM (12 mL) was added BBr3(2 M, 12 mL, 8.45 eq) at -78 °C. The mixture was stirred at -78 °C for 4 hours. The reaction mixture was quenched with water at 0 °C and pH was adjusted to

[0444] 6-8 with sodium bicarbonate solution. And then extracted with EtOAc (12 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 3 pm; mobile phase: [H20(0.05%HCI)-ACN]; gradient: 0%-15% B over 15.0 min) to give 2-[5-(2-aminoethyl)-2-bromo- 4-hydroxy-phenyl]acetamide (0.1 g, 322 pmol, 11.3% yield, 99.8% purity, HCI salt) as a white solid.1H NMR (400MHz, DMSO-d6): 5 10.17 (s, 1 H), 8.01 (br s, 3H), 7.32 (br s, 1 H), 7.14 (s, 2H), 6.98 (br s, 1 H), 3.48 (s, 2H), 3.09 - 2.97 (m, 2H), 2.89 - 2.78 (m, 2H).

[0445] EXAMPLE 4: Synthesis of 2-[5-(2-aminoethyl)-4-hydroxy-2-isobutyl-phenyl]acetamide (HCI Salt) (2CIB-2OH-5CAM)

[0446] Step 1: 2-[4-Methoxy-2-(2-methylprop-1-enyl)phenyl]acetamide

[0447]

[0373] A mixture of 2-(2-bromo-4-methoxyphenyl)acetamide (6 g, 24.6 mmol, 1 eq), 2- methylprop-1-enylboronic acid (4.91 g, 49.2 mmol, 2 eq), Pd(dppf)CI2 (1.80 g, 2.46 mmol, 0.1 eq) and K2CO3(5.10 g, 36.9 mmol, 1.5 eq) in dioxane (60 mL) and H2O (15 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 12 hours under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 3) to give 2-[4-methoxy-2-(2-methylprop-

[0448] 1-enyl)phenyl]acetamide (5.2 g, 23.7 mmol, 96.47% yield) as a brown solid.

[0449] Step 2: 2-(2-lsobutyl-4-methoxy-phenyl)acetamide

[0450]

[0374] To a solution of 2-[4-methoxy-2-(2-methylprop-1-enyl)phenyl]acetamide (3.5 g, 16.0 mmol, 1 eq) in MeOH (100 mL) was added Pd / C (1.70 g, 1.60 mmol, 10% purity, 0.1 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(50 psi) at 50 °C for 12 hours. The reaction mixture was filtered. The filter liquor was concentrated to give

[0451] 2-(2-isobutyl-4-methoxy-phenyl)acetamide (3.2 g, 14.46 mmol, 90.60% yield) as a white solid.

[0452] Step 3: 2-(5-lodo-2-isobutyl-4-methoxy-phenyl)acetamide

[0453]

[0375] To a solution of 2-(2-isobutyl-4-methoxy-phenyl)acetamide (3.2 g, 14.5 mmol, 1 eq) in EtOH (50 mL) was added l2(3.67 g, 14.5 mmol, 1 eq) and AgOTf (3.72 g, 14.5 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 3) to give 2-(5-iodo-2-isobutyl-4-methoxy-phenyl)acetamide (2.2 g, 6.34 mmol, 43.8% yield) as a white solid.

[0454] Step 4: Tert-butyl N-[2-[5-(2-amino-2-oxo-ethyl)-4-isobutyl-2-methoxyphenyl]ethyl]carbamate

[0455]

[0376] A mixture of 2-(5-iodo-2-isobutyl-4-methoxy-phenyl)acetamide (0.3 g, 864 pmol, 1 eq), 2-(tert-butoxycarbonylamino)ethylpotassium trifluoroborane (260 mg, 1.04 mmol, 1.2 eq) , Cs2CO3(845 mg, 2.59 mmol, 3 eq) and Pd(dppf)CI2.CH2CI2(70.6 mg, 86.4 pmol, 0.1 eq) in toluene (16 mL) and H2O (4 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 85 °C for 12 hours under N2atmosphere. The reaction mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 3) to give tert-butyl N-[2-[5-(2-amino-2-oxo-ethyl)-4-isobutyl-2-methoxy-phenyl]ethyl]carbamate (2 g, 5.49 mmol, 48.9% yield) was obtained as yellow oil.

[0456] Sfep 5: 2-[5-(2-Aminoethyl)-4-hydroxy-2-isobutyl-phenyl]acetamide

[0457]

[0377] To a solution of tert-butyl N-[2-[5-(2-amino-2-oxo-ethyl)-4-isobutyl-2-methoxyphenyl] ethylcarbamate (2 g, 5.49 mmol, 1 eq) in DCM (20 mL) was added BBr3(2 M, 20 mL, 7.29 eq) at -78 °C. The mixture was stirred at -78 °C for 2 hours. The reaction mixture was quenched with water at 0 °C and pH was adjusted to 6-8 with sodium bicarbonate aqueous solution. And then extracted with H2O (20 mL x 3). The aqueous phase was concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: CD18-Welch Ultimate C18 150 * 40mm * 7pm; mobile phase: [H20(0.05%HCI)-ACN]; gradient: 0%-23% B over 10.0 min) to give 2-[5-(2-aminoethyl)-4-hydroxy-2-isobutylphenyl]acetamide (0.1 g, 348 pmol, 6.34% yield, 99.71% purity, HCI salt) as a white solid.1H NMR (400MHz, DMSO-d6): 5 8.10 (br s, 3H), 7.25 (br s, 1 H), 6.95 - 6.75 (m, 2H), 6.63 (s, 1 H), 3.28 (s, 2H), 3.00 - 2.88 (m, 2H), 2.84 - 2.72 (m, 2H), 2.34 (br d, J = 7.1 Hz, 2H), 1.81 - 1.67 (m, 1 H), 0.87 (d, J = 6.5 Hz, 6H). EXAMPLE 5: In Vitro Receptor Binding and Functional Activity (IP-One)

[0458]

[0378] Membrane was extracted from 5-HT2A / HEK293, 5-HT2B / HEK293 and 5-HT2C / HEK293 cells. The reference compounds and screening compound were 4-fold serially diluted in 100% DMSO for 8 points. Transferred 1 pL of serial diluted references and screening compound to the assay plates. Then added 100 pL / well of membrane and 100 pL / well of radioligand3H-LSD. Incubated at room temperature for 1 hour. Filtered the reaction mixture through the GF / C plate using PerkinElmer Filtermate Harvester and washed the plates. Dried the filter plate for 1 hour at 50 °C. Sealed the bottom of the filter plate using Perkin Elmer Unifilter-96 backing seal tape. Added 50 pL of Perkin Elmer Microscint 20 cocktail to each well of assay plate and counted3H trapped on filter plate using Perkin Elmer MicroBeta2 Reader.

[0459] 5-HT2R IP-One Assay:

[0460]

[0379] Intracellular accumulation of IP1 was measured using an IP-One HTRF) assay kit (Cat.# 62IPAPEJ, Cisbio) at WuXi AppTec Co. Ltd. (Hong Kong) Discovery Biology Unit according to their standard protocols. Briefly, 5-HT2B / HEK293 were plated in a 384-well plate and incubated at 37 °C and 5% CO2 overnight. The reference compounds and screening compound were 3.16-fold serially diluted in 100% DMSO for 10 points using Bravo. 70 nL of compounds was added to the cell plate using Echo555. Incubated for 60 minutes at 37 °C. Added 3 pL of IP1 d2 Reagent working solution and 3 pL of IP1 Tb Cryptate Antibody working solution to all wells. The plates were incubated for 1 hour at room temperature and read on for fluorescence at 620 nm and 665 nm on an EnVision Multimode Plate Reader (PerkinElmer). The ratio of the acceptor and donor emission signals (665 / 620) were calculated for each individual well and substituted into the standard curve to obtain the log concentration of IP level. After converting to the antilog base IP-1 , the average background control signal was subtracted from each well and values were normalized to the maximal response of 5-HT at 3 pM (100%). % MAX was calculated by taking the average normalized maximal response at the highest concentration tested. The data were then analyzed using the four-parameter nonlinear regression curve-fitting function in GraphPad Prism 5 (GraphPad Software, San Diego, CA) to generate potency (EC50) values. Parameter constraint "Top=100" was used in the analysis of 5-HT2B IP1.

[0461]

[0380] Intracellular accumulation of IP1 was measured using an IP-One HTRF assay kit (Cat.# 62IPAPEJ, Cisbio) at WuXi AppTec Co. Ltd. (Hong Kong) Discovery Biology Unit according to their standard protocols. Briefly, the reference compounds and screening compound were 3.16-fold serially diluted in 100% DMSO for 10 points using Bravo. 70 nL of compounds were added to the assay plate using Echo555. Added 14 pL / 7500 cells / well of 5-HT2A-expressing HEK293 or 5-HT2C-expressing HEK293 to the assay plate and incubated for 60 min at 37°C. Added 3 pL of IP1 d2 Reagent working solution and 3 pL of IP1 Tb Cryptate Antibody working solution to all wells. The plates were incubated for 1 hour at room temperature and read for fluorescence at 620 nm and 665 nm on an EnVision Multimode Plate Reader (PerkinElmer).

[0381] The ratio of the acceptor and donor emission signals (665 / 620) were calculated for each individual well and substituted into the standard curve to obtain the log concentration of IP level. After converting to the antilog base IP-1, the average background control signal was subtracted from each well and values were normalized to the maximal response of 5-HT at 3 pM (100%). % MAX was calculated by taking the average normalized maximal response for each compound at the highest concentration tested. The data were then analyzed using the four-parameter nonlinear regression curve-fitting function in GraphPad Prism 5 (GraphPad Software, San Diego, CA) to generate potency (EC50) values.

[0462] Results:

[0463]

[0382] 2CB-5CAM exhibits selective binding affinity for 5-HT2Cover 5-HT2A and 5-HT2B. The affinity selectivity for 5-HT2Cover 5-HT2Awas >100-fold.

[0464]

[0383] 2CB-5CAM also exhibits functional selectivity for 5-HT2Bover 5-HT2Aand 5-HT2C.

[0465] EXAMPLE 6: In Vitro Receptor Functional Activity (Ca Flux)

[0466]

[0384] Purpose: The agonist activity of test compounds at 5-HT2Aand 5-HT2Breceptors was determined using a calcium flux assay.

[0467]

[0385] Methods: Briefly, Human Embryonic Kidney (293T) cells transiently expressing human 5-HT2Areceptors or human 5-HT2Breceptors were seeded in 200 pL DMEM supplemented with 1% (v / v) dialyzed fetal bovine serum (Gibco, Cat. #A33820-01) onto black 96-well poly-D-lysine coated plates with clear bottoms (40 000 cells / well) and maintained overnight in a humidified atmosphere at 37 °C and 5% CO2. The following day, media was aspirated and replaced with 100 pL HBSS supplemented with 20 mM HEPES (pH 7.4), loaded with 5 pM Fluo-2 AM HA (ION Biosciences, San Marcos, TX) and 2.5 mM water-soluble probenecid (Thermo Fisher Scientific, Waltham, MA). Plates were incubated for 1 hour at 37 °C, washed once with 100 pL HBSS-HEPES, and maintained in 100 pL HBSS-HEPES supplemented with 2.5 mM water-soluble probenecid. The plates of dye-loaded cells were placed into a FlexStation 3 microplate reader (Molecular Devices, Sunnyvale, CA) set at 37 °C to monitor fluorescence (excitation, 485 nm; emission, 525 nm; cutoff, 515 nm). Plates were read for 30 s (2 s interval) to establish baseline fluorescence and then administered 50 pL of 2,7-dimethyl-4-hydroxy-DET and read for an additional 120 s. After obtaining a calcium flux trace, the mean baseline fluorescence (F) was subtracted from peak fluorescence (AF) in each well and the product normalized by F (AF / F). The data were analyzed using the four-parameter nonlinear regression curve-fitting function in GraphPad Prism 10.2.3 (GraphPad Software, San Diego, CA), to generate potency (EC50) and maximal response values. Maximal response values were normalized to the maximum 5-HT response (100%) and minimum 5-HT response (0%) on the same plate. Each concentration point was tested in triplicate.

[0468]

[0386] Results: FIGS. 1-4 show the dose-response curves for 2CB-5CAM (FIG. 1), 2CB-5CA (FIG. 2), 2CIB-2OH-5CAM (FIG. 3), and 2CB-2OH-5CAM (FIG. 4). EXAMPLE 7: Anti-Inflammatory Properties

[0469]

[0387] 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 Pharmacology & Translational Science 2020, 4(2), 488-502.

[0470]

[0388] Procedure: The respiratory pathogen-free Brown Norway (RijHsd-BN) rats used in this Example were housed singly in a pathogen-free animal facility with free access to food and water on a 12h / 12h light / dark cycle. Animal protocols were 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 were allowed to acclimate at least 1 week prior to initiation of sensitization with chicken ovalbumin grade V (OVA).

[0471]

[0389] For sensitization, Brown Norway rats (7-9 weeks old) were i.p. injected with (500 pL) of 2.0 mg of chicken OVA emulsified in 2.0 mL of Inject Alum [AI(OH)3 / Mg(OH)2] on days 0 and 7, as described in Elwood et al. J Allergy Clin Immunol. 1991, 88(6), 951 -60. OVA exposure methods were 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).

[0472]

[0390] OVA-alone treated rats were exposed to 3 times weekly exposure of 10.0 mg of OVA slowly dissolved in 10.0 mL of 0.9% sterile saline solution in a 15 L (38.00 x 19.05 x 19.7 cm) acrylic induction chamber. No more than 6 animals were 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.

[0473]

[0391] For drug exposures, rats were exposed in groups of 3-4 rats / group to the appropriate concentration of test compound (2CB-5CAM) 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 was aerosolized using a nebulizer in conjunction with a Pari Proneb pump. Exposures lasted 15 min. All respiratory parameters were measured 48 h after the final OVA exposure.

[0474]

[0392] To minimize the impact of circadian influences, all respiratory recordings were 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 was used in spontaneously breathing, unrestrained rodents. The plethysmograph was ventilated by a continuous flow of 2.5 L / min. A differential pressure transducer was connected on one pole to the main chamber and on the second pole to a reference chamber. The transducer measured pressure differences between both chambers as caused by the respiratory cycle, mainly inhalation and exhalation. Computer software provided a breath-by-breath analysis of pressure signals and transformed pressure differences via computerized calculations to a dimensionless empirically established value, enhanced pause or PenH.

[0393] 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).

[0475]

[0394] For the assay, the chamber pressure signal was calibrated by dynamic injection of 5 mL of room air via syringe. Rats were then placed in the chamber, where baseline data was recorded for 5 min following a 10 min habituation period in the plethysmograph. After measurement of baseline PenH, either aerosolized saline (0.9% NaCI Solution) or an aqueous solution of MeCh in increasing concentrations (4, 8, 16, 32 mg / mL) was nebulized through an inlet of the plethysmography chamber for 3 min, followed by measurements of PenH values for 3 min. A vibrating-mesh nebulizer was used to generate aerosol. Following recordings, to prevent a MeCh gradient there was a wash-out period of 7 min in which the rat was provided with fresh air. Data are expressed as the mean SEM of maximal PenH values per group.

[0476]

[0395] Results: FIG. 5 shows that 2CB-5CAM administration was found to reduce PenH Max values and reduce pulmonary inflammation at a concentration of 0.5 mg / kg.

[0477] EXAMPLE 8: In Vivo Assessment of Behavioral Effects Using HTR

[0478]

[0396] 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-HT2A receptor agonists ( / ol).

[0479]

[0397] Methods: An HTR assay was 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 were performed using adult (2-4 months old) male C57BL / 6 J mice weighing 20-30 g. Mice were 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).

[0480]

[0398] 2CB-5CAM was dissolved in a sterile 0.9% aqueous saline vehicle at concentrations ranging from 0.03 mg / kg to 30 mg / kg, and administered subcutaneously immediately prior to testing. Mice were injected with drug or vehicle, and HTR activity is recorded as follows.

[0481]

[0399] On the day of an experiment, mice in their home cages were transported from the vivarium to the experimental test room and were given 1 h for acclimation. For the experimental sessions, mice received 2CB-5CAM or vehicle injections and were placed into cylindrical acrylic arenas (7.5 in diameter) housed inside of mouse locomotor boxes. The arenas had transparent floor panels with white bench paper underneath to provide a light background for contrast. Video cameras were used to record high frame rate (120 frames per sec) overhead videos (960p resolution) of mice that receive injections of 2CB-5CAM or their saline vehicle. Video cameras were mounted ca. 10 inches above the arena floor, and experimental test sessions were recorded for 30 min post-injection. All experiments occurred during the light phase of the light-dark cycle between 0900 and 1700 h local time.

[0482]

[0400] Mice were randomized to treatment conditions and were repeat-tested once per 1-2 weeks to avoid potential tolerance to the effects of 2CB-5CAM on HTR. After videos of each experiment were recorded, the video files were transferred to an external hard drive for storage until subsequent computer analysis as described below.

[0483]

[0401] A commercially available software package (TopScan, Clever Sys Inc.) was adapted for use in measuring HTR. A custom feature of the TopScan software package monitored the ears of the mice to detect head movements that are classified as HTRs. All videos were analyzed for HTRs according to the developer’s instructions. Briefly, experimental details (mouse ID, treatment, date, experiment #, etc.) were entered into the software and the following three procedures were carried out for each video: (1) a background image file was generated to distinguish the arena and its background from the mouse, (2) an arena file was generated that was customized to the shape and area of any arena contained in each video, and (3) an animal color model file was 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 was dynamic and could be adapted for different lighting conditions or to detect different color contrasts.

[0484]

[0402] 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 was conducted. After videos were scored, all HTRs identified for each video were quickly reviewed in the software as a list of short video segments that were viewed and used to remove any potential non-HTR events or false positives as well as confirm HTRs. Finally, the data were exported in several different formats for further processing and statistical analyses.

[0485]

[0403] Two trained observers watched the videos and visually scored 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 was tallied. The visual scoring was carried out blind to treatment conditions, and HTRs from the two trained observers were averaged to determine the total number of HTRs per video as well as to assess the relationship to the software- based scoring method.

[0486]

[0404] Visual scores from the trained observers and computer scores from the software analyses were compared by two-way ANOVA (scoring method x treatment) with Tukey’s post-hoc multiple comparisons test to assess differences between scoring methods and effects of 2CB-5CAM treatment. Pearson r correlations were computed to assess relationships between visual scores from trained observers and computer software scores. Potency (ED50) values were determined from dose-response studies using nonlinear regression of the rising phase of the curve. Analyzes were conducted using GraphPad Prism software.

[0487]

[0405] FIG. 6 shows the HTR count as a function of 2CB-5CAM dose. At all doses, 2CB-5CAM administration resulted in <10 HTR counts over the 30 minute time course of the experiments. As shown in FIG. 7, which depicts HTR counts as a function of time, 2CB-5CAM administration resulted in HTR counts that were not significantly higher than the saline vehicle at the majority of doses and time points.

[0488] EXAMPLE 9: Assessment of Ocular Inflammation Following Application of Compounds

[0489]

[0406] 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.

[0490]

[0407] 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.

[0491]

[0408] 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.

[0492] EXAMPLE 10: In Vitro Metabolic Stability

[0493]

[0409] 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).

[0494]

[0410] 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 MgCI2). 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 pL) are taken out at times 0, 15, 30, 45, and 60 min, and diluted with ice cold acetonitrile (200 pL) to stop the reactions. Samples are centrifuged at 12,000 RPM for 10 min to precipitate proteins. Supernatants are transferred to microcentrifuge tubes and stored for HPLC or LC / MS / MS analysis of the degradation half-life of the test compounds.

[0495]

[0411] Results & Significance: Results show a measurement of the in vitro intrinsic clearance of disclosed compounds. Such data provides a prediction of the metabolic stability and clearance of the compounds.

[0496] EXAMPLE 11 : Carboxylesterase Reaction Phenotyping Assay

[0497]

[0412] Purpose: The purpose of this experiment is to determine whether disclosed compounds are susceptible to metabolism (e.g., hydrolysis) by human carboxylesterase enzymes. Human carboxylesterases (CE) are Phase I drug-metabolizing enzymes of the serine hydrolase superfamily, which may hydrolyze a variety of ester-containing compounds. hCE1 and hCE2 are the most extensively studied of the human CEs. They differ in their substrate specificity and tissue distribution. hCE 1 is expressed in many organs especially in the liver, with low expression in the gastrointestinal tract. hCE2 protein is also expressed in many extrahepatic tissues, especially in the gastrointestinal tract and at lower levels in the liver (Fukami and Yokoi. Drug Metab Pharmacokinet. 2012;27(5):466-477; Imai T. Drug Metab Pharmacokinet. 2006;21 (3):173-185).

[0498]

[0413] Methods: Test systems for this assay include hCE1-b, hCE1-c, hCE2 expressed enzymes, and / or human liver / intestinal microsomes incubated with and without CE inhibitor. The concentration of test compound is 1 pM. A positive control substrate (trandolapril for hCE1; irinotecan for hCE2, monitoring for the formation of 7-ethyl-10-hydroxycamptothecin) is also included. Test compounds are introduced as 100 L of a 10 mM DMSO stock solution. Analysis is conducted by LC-MS / MS to determine the amount of test compound remaining at each time point for each isoform, half life, and standard error of half life.

[0499]

[0414] Results: Results may show that certain disclosed compounds (e.g., those having a 5-carboxyalkyl substituent) are substrates for hCE1 and / or hCE2 and are susceptible to hydrolysis in vivo.

[0500] EXAMPLE 12: Optic Nerve Crush Assay

[0501]

[0415] The purpose of this study is to test disclosed compounds and for potential neuroprotective effects in an optic nerve crush (ONC) model in rats. Animals will receive prophylactic dosing of a disclosed compound (and optionally any comparator compounds) 3 days prior to injury induction. Animals will undergo optical coherence tomography (OCT) exams starting at baseline, and again 7, 14, and 21 days after injury. OCT will be used to measure the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL), and total retinal thickness using a 9x9 spider plot. Animals will also undergo pupillary light reflex testing daily for up to 5 days post procedure and prior to anesthesia for OCT. At the conclusion of the study, whole eye samples will be collected and will undergo immunofluorescent staining using Brn3a and RBPMS to stain for retinal ganglion cells (RGCs) and counter stained with DAPI. From these, RGC loss will be calculated.

[0502]

[0416] The rats will be 12-14 week old Brown Norway rats, and the study will proceed according to the following research pla...

Claims

CLAIMSThe invention claimed is:

1. A compound of Formula (1):wherein:R is — NH2, — NH-CrC6alkyl, or — O-CrC6alkyl;R2is H or CrC6alkyl;R4is Br, F, Cl, I, H, CN, NO2, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, CrC6haloalkyl, CrC6alkoxy, C^Cg haloalkylthio, C^Cg alkylthio, C3-C6cycloalkylmethyl, or — (CH2)0.3-C(O)-O-C1-C6alkyl; n is 1 , 2, 3, or 0; andRais H or CrC6alkyl;Rbis H; andRNis H or — CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12aryl optionally substituted by F, Cl, Br, I, OH, C^Cg alkoxy, or phenyl; orRaand Rbtogether with the intervening atoms form a 3- to 6-membered cycloalkyl; and RNis H or — CH2-Ar; wherein Ar is 6- to 12-membered heterocyclyl or C6-C12aryl optionally substituted by F, Cl, Br, I, OH, CrCg alkoxy, or phenyl; orRais H or CrCg alkyl; andRNand Rbtogether with the intervening atoms form a 4- to 8-membered heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

2. The compound of claim 1 , wherein R is -NH2.

3. The compound of claim 1 , wherein R is -NH-CH3.

4. The compound of claim 1 , wherein R is -O-CpCg alkyl.

5. The compound of claim 4, wherein R is -OCH3.

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

7. The compound of claim 1 , wherein Rais CpCg alkyl.

8. The compound of claim 7, wherein Rais -CH3.

9. The compound of claim 7, wherein Rais -CH2CH3.

10. The compound of claim 1 , wherein Rbis H.

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

12. The compound of claim 1 , wherein RNis -CH2-Ar.

13. The compound of claim 11 , wherein Ar is phenyl substituted by -OH.

14. The compound of claim 11 , wherein Ar is phenyl substituted by -OCH3.

15. The compound of claim 11 , wherein Ar is , , , or ; wherein the * indicates the point of attachment to the remainder of RN.

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

17. The compound of claim 1 , wherein R2is methyl.

18. The compound of claim 1 , wherein n is 1 .

19. The compound of claim 1 , wherein n is 0.

20. The compound of claim 1 , wherein n is 2.21 . The compound of claim 1 , wherein n is 3.

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

23. The compound of claim 1 , wherein R4is C^Cg alkyl.

24. The compound of claim 23, wherein R4is isobutyl.

25. The compound of claim 23, wherein R4is ethyl.

26. The compound of claim 1 , wherein R4is C2-C6alkenyl.

27. The compound of claim 26, wherein R4is allyl.

28. The compound of claim 1 , wherein R4is C3-C6cycloalkylmethyl.

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

30. The compound of claim 1 , having the structure of Formula (2):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.31 . The compound of claim 30, wherein R4is Br, F, Cl, or I.

32. The compound of claim 30, wherein R4is C^Cg alkyl.

33. The compound of claim 32, wherein R4is isobutyl.

34. The compound of claim 32, wherein R4is ethyl.

35. The compound of claim 30, wherein R4is C2-C6alkenyl.

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

37. The compound of claim 30, wherein R4is C3-C6cycloalkylmethyl.

38. The compound of claim 37, wherein R4is cyclopropylmethyl.

39. The compound of claim 1 , having the structure of Formula (3):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof, wherein R' is CrC6alkyl.

40. The compound of claim 39, wherein R' is -CH3.41 . The compound of claim 39, wherein R4is Br, F, Cl, or I.

42. The compound of claim 39, wherein R4is CrC6alkyl.

43. The compound of claim 42, wherein R4is isobutyl.

44. The compound of claim 42, wherein R4is ethyl.

45. The compound of claim 39, wherein R4is C2-C6alkenyl.

46. The compound of claim 45, wherein R4is allyl.

47. The compound of claim 39, wherein R4is C3-C3cycloalkylmethyl.

48. The compound of claim 48, wherein R4is cyclopropylmethyl.

49. The compound of claim 1 , having the structure of Formula (4):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

50. The compound of claim 49, wherein Rais H.51 . The compound of claim 49, wherein Rais CrC6alkyl.

52. The compound of claim 51 , wherein Rais -CH3.

53. The compound of claim 51 , wherein Rais -CH2CH3.

54. The compound of claim 49, wherein Rbis H.

55. The compound of claim 49, wherein n is 1 .

56. The compound of claim 49, wherein n is 0.

57. The compound of claim 49, wherein n is 2.

58. The compound of claim 49, wherein n is 3.

59. The compound of claim 49, wherein R4is Br, F, Cl, or I.

60. The compound of claim 49, wherein R4is C^Cg alkyl.61 . The compound of claim 60, wherein R4is isobutyl.

62. The compound of claim 60, wherein R4is ethyl.

63. The compound of claim 49, wherein R4is C2-C6alkenyl.

64. The compound of claim 63, wherein R4is allyl.

65. The compound of claim 49, wherein R4is C3-C6cycloalkylmethyl.

66. The compound of claim 65, wherein R4is cyclopropylmethyl.

67. The compound of claim 1 , having the structure of Formula (5):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

68. The compound of claim 67, wherein n is 1 .

69. The compound of claim 67, wherein n is 0.

70. The compound of claim 67, wherein n is 2.71 . The compound of claim 67, wherein n is 3.

72. The compound of claim 67, wherein R4is Br, F, Cl, or I.

73. The compound of claim 67, wherein R4is CpCg alkyl.

74. The compound of claim 73, wherein R4is isobutyl.

75. The compound of claim 73, wherein R4is ethyl.

76. The compound of claim 67, wherein R4is C2-C6alkenyl.

77. The compound of claim 76, wherein R4is allyl.

78. The compound of claim 67, wherein R4is C3-C6cycloalkylmethyl.

79. The compound of claim 78, wherein R4is cyclopropylmethyl.

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

81. A compound selected from the group consisting of:or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

82. A compound selected from the group consisting of:or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.

84. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

85. The pharmaceutical composition of claim 84, wherein the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

86. The pharmaceutical composition of claim 85, formulated for topical administration.

87. The pharmaceutical composition of claim 86, formulated as an aerosol, emulsion, spray, ointment, salve, gel, paste, lotion, liniment, oil, or cream88. The pharmaceutical composition of claim 86, comprising one or more pharmaceutically acceptable excipients selected from the group consisting of penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, and gelling agents.

89. The pharmaceutical composition of claim 84, wherein the composition is provided in unit dosage form.

90. The pharmaceutical composition of claim 89, comprising the compound in a total amount of between about 0.01 and 100 mg.91 . The pharmaceutical composition of claim 84, further comprising a therapeutically effective amount ofan additional active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

92. The pharmaceutical composition of claim 91, 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, anti hypertensives, 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.

93. A method of modulating neurotransmission in a subject, comprising administering to the subject the compound of any one of claims 1-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

94. The method of claim 93, wherein modulating neurotransmission comprises agonizing the 5-HT2Areceptor.

95. A method of increasing neuroplasticity or neurogenesis in a subject, comprising administering to the subject the compound of any one of claims 1 -83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

96. The method of claim 95, wherein increasing neuroplasticity or neurogenesis comprises increasing neuritogenesis, spinogenesis, or synaptogenesis.

97. 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 -83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

98. The method of claim 97, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission.

99. The method of claim 97, wherein the medical condition is a mental, behavioral, or neurodevelopmental disorder.

100. The method of claim 99, 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.

101. The method of claim 97, wherein the compound is administered together with one or more sessions of psychotherapy.

102. The method of claim 97, wherein the medical condition is inflammation or an inflammatory disorder.

103. The method of claim 102, 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.

104. The method of claim 102, wherein the inflammatory disorder is an acute inflammatory disorder.

105. The method of claim 102, wherein the inflammatory disorder is a chronic inflammatory disorder.

106. The method of claim 102, wherein the inflammatory disorder is a steroid-resistant disorder.

107. The method of claim 102, 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.

108. The method of claim 102, wherein the inflammatory disorder is dermatitis.

109. The method of claim 108, wherein the 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.

110. The method of claim 102, wherein the subject has a compromised immune system.

111. The method of claim 102, wherein the subject has an autoimmune disorder.

112. The method of claim 102, wherein the subject has a contraindication to a corticosteroid.

113. The method of claim 102, 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% compared to the level of the biomarker before treatment.

114. The method of claim 113, wherein the inflammatory biomarker is an inflammatory response gene product.

115. The method of claim 114, wherein the inflammatory response gene product is mRNA.

116. The method of claim 115, wherein the mRNA is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1 ft, Gm-csf,IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF- / 3 mRNA.

117. The method of claim 113, wherein the inflammatory response gene product is a protein.

118. The method of claim 117, wherein the protein is Arg-1 , ICAM1, VCAM1, MCP1, IL-6, IL-1 , Gm-csf,IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-0.

119. The method of claim 117, wherein the medical condition is an ophthalmic disorder.

120. The method of claim 119, wherein the ophthalmic disorder is an inflammatory disorder.

121. The method of claim 117, wherein the medical condition is a neurodegenerative disorder.

122. The method of claim 121, 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.

123. A compound of any one of claims 1 -83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment of a medical condition.

124. Use of the compound of any one of claims 1 -83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a medicament for the treatment of a medical condition.

125. A method of modulating neurotransmission in a subject, comprising administering to the subject the pharmaceutical composition of claim 84.

126. The method of claim 125, wherein modulating neurotransmission comprises agonizing the 5-HT2Areceptor.

127. A method of increasing neuroplasticity or neurogenesis in a subject in a subject, comprising administering to the subject the pharmaceutical composition of claim 84.

128. The method of claim 127, wherein increasing neuroplasticity or neurogenesis comprises increasing any of dendritogenesis, spinogenesis, and synaptogenesis.

129. 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 84.

130. The method of claim 129, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission.

131. The method of claim 129, wherein the medical condition is a mental, behavioral, or neurodevelopmental disorder.

132. The method of claim 131, 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 associatedwith pregnancy, childbirth or the puerperium, a sleep-wake disorder, or a sexual dysfunction.

133. The method of claim 129, wherein the composition is administered together with one or more sessions of psychotherapy.

134. The method of claim 129, wherein the medical condition is inflammation or an inflammatory disorder.

135. The method of claim 134, 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.

136. The method of claim 134, wherein the inflammatory disorder is an acute inflammatory disorder.

137. The method of claim 134, wherein the inflammatory disorder is a chronic inflammatory disorder.

138. The method of claim 134, wherein the inflammatory disorder is a steroid-resistant disorder.

139. The method of claim 134, 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.

140. The method of claim 134, wherein the inflammatory disorder is dermatitis.141 . The method of claim 140, 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.

142. The method of claim 134, wherein the subject has a compromised immune system.

143. The method of claim 134, wherein the subject has an autoimmune disorder.

144. The method of claim 134, wherein the subject has a contraindication to a corticosteroid.

145. The method of claim 134, 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% compared to the level of the biomarker before treatment.

146. The method of claim 145, wherein the inflammatory biomarker is an inflammatory response gene product.

147. The method of claim 146, wherein the inflammatory response gene product is mRNA.

148. The method of claim 147, wherein the mRNA is ICAM1, VCAM1, MCP1, IL-6, IL-1 ft, Gm-csf, IL-5,IL-9, IL-15, Muc5ac, mmp9, or TGF- / 3 mRNA.

149. The method of claim 145, wherein the inflammatory response gene product is a protein.

150. The method of claim 149, wherein the protein is ICAM1, VCAM1, MCP1, IL-6, IL-1 p, Gm-csf, IL-5,IL-9, IL-15, Muc5ac, mmp9, or TGF-p.

151. The method of claim 129, wherein the medical condition is an ophthalmic disorder.

152. The method of claim 151, wherein the ophthalmic disorder is an inflammatory disorder.

153. The method of claim 129, wherein the medical condition is a neurodegenerative disorder.

154. The method of claim 153, 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.

155. The pharmaceutical composition of any one of claims 84-92 for use in the treatment of a medical condition.

156. Use of the pharmaceutical composition of any one of claims 84-92 for the manufacture of a medicament for the treatment of a medical condition.

157. A method of preparing a compound having the structure of Formula (1):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof, comprising: iv. reacting a compound of Formula (1 A):with a compound of Formula (1 B),in the presence of a catalyst, to form a compound of Formula (1 C),v. subjecting the compound of Formula (1 C) to acidic conditions to form a compound of Formula (1) wherein RNis H; vi. and optionally subjecting the compound of Formula (1) wherein RNis H to reductive amination conditions to form a compound of Formula (1) wherein RNis — CH2-Ar; or according to such further steps disclosed herein, to provide a compound of Formula (1) having such substituents as otherwise defined.

158. The method of claim 157, wherein — BY3is — BF3.

159. The method of claim 157, wherein the catalyst is a palladium catalyst.

160. The method of claim 159, wherein the catalyst is a palladium(ll) catalyst.

Images