Substituted ergoline

Abstract

This disclosure relates, in some embodiments, to substituted ergolines such as 14-monosubstituted and 2,14-disubstituted lysergic amides and their quaternated derivatives. In some embodiments, this disclosure relates to methods for using these compounds, including methods for synthesizing these compounds, compositions containing these compounds, and methods for administering them to subjects. In some embodiments, the characteristics of the compounds include neuromodulatory activity, such as activation of serotonin receptors. In some further embodiments, the compounds are useful as therapeutic agents, such as anti-inflammatory agents. [Formula 1] JPEG2026525309000071.jpg5750

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 526,915, filed on 14 July 2023, pursuant to PCT Section 8(1) and Rule 4.10, which is incorporated by reference for any purpose as fully presented herein.

[0002] Certain substituted ergolines, such as 14-monosubstituted and 2,14-disubstituted lysergic amides, and their quaternated derivatives, are disclosed. In several embodiments, the disclosure relates to methods for using these compounds, including methods for synthesizing these compounds, compositions containing these compounds, and methods for administering them to subjects. In several embodiments, the characteristics of these compounds include neuromodulatory activity, such as activation of serotonin receptors. In some embodiments, these compounds are useful as therapeutic agents, such as anti-inflammatory agents. [Background technology]

[0003] Ergolines are a class of molecules derived from lysergic acid, a semi-synthetic product induced by the hydrolysis of a naturally occurring compound produced by the parasitic rye fungus Claviceps purpurea. One of the most notable ergolines is lysergic acid diethylamide, or LSD, synthesized by Albert Hoffman in 1938. LSD was found to possess unique physiological properties, including the ability to induce intensely altered states of consciousness. Early research suggested that LSD could be used as an adjunct to psychotherapy to improve patient outcomes. Modern research supports these early findings, demonstrating that LSD has clinical potential for a wide range of mental disorders, including depression, anxiety, and addiction.

[0004] Beyond mental health, psychoactive drugs such as LSD may hold promise in the treatment of inflammatory, neurological, and neurodegenerative diseases and disorders. However, there is a continuing need for the development of novel therapeutic compounds that can be used to treat a wide range of disease indications, particularly chronic conditions for which no effective treatments exist. Many psychoactive drugs, including LSD and its analogues, are illegal under federal law in the United States under Schedule I of the Controlled Substances Act. Novel compounds that minimize side effects, optimize efficacy, and are more readily available are particularly beneficial. This specification provides compounds, compositions, methods, uses, and kits that meet these and other needs and have advantages and improvements as will become apparent from the following disclosures.

[0005] Built-in by reference Each cited patent, publication, and non-patent document is incorporated herein by reference in whole, as if each were individually incorporated by reference and as if each were fully described herein. However, such citations do not constitute an admission that the cited references originate from a field similar to or directly applicable to the present invention, and no citation should be construed as an admission that any document or underlying information in any jurisdiction is prior art or part of the common general knowledge in the art. [Overview of the Initiative]

[0006] The following provides a simplified overview of some embodiments of the present invention to give a basic understanding of the invention. This overview is not a comprehensive overview of the invention. It is not intended to identify important or essential elements of the invention or to clarify the scope of the invention. Its sole purpose is to present some embodiments of the invention in a simplified form as a prelude to the more detailed descriptions that will be presented later.

[0007] In the first embodiment, the compound of formula (1): [ka] Or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotope derivative, hydrate or solvate thereof is provided, wherein: R 1 is H or -C(O)-C1-C6 alkyl; R 2 is H, C1-C6 alkyl, or halo; R 6 is C1-C6 alkyl or C2-C6 alkenyl; R 14 is C1-C6 alkyl, C1-C6 alkoxy, or halo; and R’ and R” are both C1-C6 alkyl; or R’ and R” together form an optionally substituted heterocyclyl.

[0008] In some embodiments, R 1 is H or -C(O)-C1-C6 alkyl.

[0009] In some embodiments, R 6 [[ID=三十]] 6 is methyl or ethyl. In some embodiments, R 6 is C2-C6 alkenyl. In some embodiments, R 6 is allyl.

[0010] In some embodiments, R 2 is H or C1-C6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is halo. In some embodiments, R 2 is bromo.

[0011] In some embodiments, R 14 is C1-C6 alkyl, methyl, or halo. In some embodiments, R 14 is Cl. In some embodiments, R​14 R is a C1-C6 alkoxy. In some embodiments, 14 It is methoxy.

[0012] In some embodiments, R' and R'' are both C1-C6 alkyl groups. In some embodiments, R' and R'' are both ethyl or both methyl groups. In some embodiments, R' is methyl and R'' is n-propyl. In some embodiments, R' is methyl and R'' is isopropyl groups.

[0013] In some embodiments, R' and R'' together form an optionally substituted heterocycline. In some embodiments, R' and R'' together form an azetidinyl, which is optionally substituted with a C1-C6 alkyl group. In some embodiments, R' and R'' together form an unsubstituted azetidinyl group. In some embodiments, R' and R'' together form an azetidinyl, which is substituted with a C1-C6 alkyl group. In some embodiments, R' and R'' together [ka] or [ka] The formula forms a connection point to the rest of the compound, and the asterisk (*) in the formula indicates a connection point to the rest of the compound.

[0014] In another embodiment, the compound of formula (2): [ka] Alternatively, a prodrug, hydrate, or solvate thereof is provided, in the formula: R 1 is H or -C(O)-C1~C6 alkyl; R 2is H, C1-C6 alkyl, or halo; R 6 These are C1-C6 alkyl or C2-C6 alkenyl; R 6’ These are C1-C6 alkyl groups; R 14 is a C1-C6 alkyl, C1-C6 alkoxy, or halo; and R' and R'' are both C1-C6 alkyl groups; or R' and R'' together form a heterocycline which may be substituted.

[0015] In some embodiments, R 1 The element is either H or -C(O)-C1~C6 alkyl.

[0016] In some embodiments, R 6 is a C1-C6 alkyl group. In some embodiments, R 6 is methyl or ethyl. In some embodiments, R 6 R is a C2-C6 alkenyl. In some embodiments, R 6 This is an allele.

[0017] In some embodiments, R 2 is H or C1-C6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 It is Bromo.

[0018] In some embodiments, R 14 is a C1-C6 alkyl group. In some embodiments, R 14 is methyl. In some embodiments, R 14 is a halo. In some embodiments, R 14 is Cl. In some embodiments, R 14 R is a C1-C6 alkoxy. In some embodiments, 14It is methoxy.

[0019] In some embodiments, R' and R'' are both C1-C6 alkyl groups. In some embodiments, R' and R'' are both ethyl groups. In some embodiments, R' and R'' are both methyl groups. In some embodiments, R' is methyl and R'' is n-propyl groups. In some embodiments, R' is methyl and R'' is isopropyl groups.

[0020] In some embodiments, R' and R'' together form an optionally substituted heterocycline. In some embodiments, R' and R'' together form an azetidinyl, which is optionally substituted with a C1-C6 alkyl group. In some embodiments, R' and R'' together form an unsubstituted azetidinyl group. In some embodiments, R' and R'' together form an azetidinyl, which is substituted with a C1-C6 alkyl group. In some embodiments, R' and R'' together [ka] or [ka] The formula forms a connection point to the rest of the compound, and the asterisk (*) in the formula indicates a connection point to the rest of the compound.

[0021] In some embodiments, compounds selected from Tables 1 and 2, or pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof are provided.

[0022] In some embodiments, the compound is [ka] That is the case.

[0023] In some embodiments, the compound is [ka] That is the case.

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

[0025] In some embodiments, the composition further comprises a therapeutically effective amount of a further active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the further active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and anti-nociceptive agents, anti-migraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anticancer agents, antiemetics, appetite stimulants, anti-ulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotective agents, nootropics, empathogens, psychotropic agents, plasticity inducers, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, NMDA modulators, NMDA antagonists, and vitamins.

[0026] Also provided are methods for modulating neurotransmission in a subject, comprising administering to the subject any compound of any of the disclosed embodiments or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or a pharmaceutical composition of any of the disclosed embodiments. In the embodiments, the modulation of neurotransmission is 5-HT 2A This includes stimulating receptors.

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

[0028] Furthermore, methods are provided for treating medical conditions in subjects requiring treatment, which include administering a therapeutically effective amount of a compound of any of the disclosed embodiments or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to a subject; or a pharmaceutical composition of any of the disclosed embodiments.

[0029] In some embodiments, the medical condition is a disorder related to dysregulation or insufficient function of serotonergic neurotransmission.

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

[0031] In some embodiments, the medical condition is a neurodevelopmental disorder, schizophrenia or other primary psychotic disorder, catatonia, mood disorder, anxiety or fear-related disorder, obsessive-compulsive disorder or related disorder, stress-related disorder, dissociative disorder, nutritional or eating disorder, excretory disorder, physical pain disorder or physical experience disorder, substance use disorder or addictive behavior disorder, impulse control disorder, disorderly or antisocial behavior disorder, personality disorder, paraphilia, compulsion disorder, neurocognitive disorder, mental or behavioral disorder related to pregnancy, childbirth or puerperium, sleep-wake disorder, or sexual dysfunction.

[0032] In the embodiment, the compound is administered in conjunction with one or more psychotherapy sessions.

[0033] In some embodiments, the medical condition is inflammation or an inflammatory disease. In some embodiments, the inflammation is skin inflammation, myoflammation, tendinitis, ligament inflammation, bone inflammation, chondritis, pneumonia, heart inflammation, hepatitis, pancreatic inflammation, nephritis, cystitis, gastritis, enteritis, neuroinflammation, ocular inflammation, or encephalitis.

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

[0035] In some embodiments, the inflammatory disease 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, sepsis, conjunctivitis, and Alzheimer's disease.

[0036] In some embodiments, the inflammatory disease is dermatitis. In some embodiments, dermatitis is atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic dermatitis, discoid eczema, varicose vein eczema, herpetic dermatitis, neurodermatitis, autosensitization dermatitis, stasis dermatitis, suppurative dermatitis, dyshidrotic eczema, follicular eczema, cavernous dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

[0037] In some embodiments, the subjects have a weakened immune system. In some embodiments, the subjects have an autoimmune disorder. In some embodiments, the subjects have a contraindication to corticosteroids.

[0038] In some embodiments, treatment of inflammation or inflammatory disease involves reducing the level of an inflammatory biomarker by approximately 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, the inflammatory biomarker is an inflammatory response gene product. In some embodiments, the inflammatory response gene product is mRNA. In some embodiments, the mRNA is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β mRNA. In some embodiments, the inflammatory response gene product is a protein. In some embodiments, the protein is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β.

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

[0040] 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 disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia including vascular dementia, Huntington's disease, Ritico Bodig disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson's disease or parkinsonism, prion disease, progressive supranuclear palsy, and traumatic brain injury.

[0041] Compounds of any of the disclosed embodiments, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are also provided for use in the treatment of medical conditions.

[0042] The use of the compounds of the disclosed embodiments, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, for the manufacture of pharmaceuticals for treating medical conditions is also provided.

[0043] Pharmaceutical compositions of any of the disclosed embodiments for use in the treatment of medical conditions are also provided.

[0044] Use of any of the disclosed embodiments of a pharmaceutical composition for manufacturing a pharmaceutical product for treating a medical condition.

[0045] The preceding paragraphs broadly summarize and outline certain relevant features of this disclosure so that the detailed description of the invention below may be better understood, and thus the contribution of the invention to the art may be better understood. Therefore, this summary should be considered a brief and general overview of only some of the purposes and embodiments disclosed herein, and is provided solely for the benefit and convenience of the reader and is not intended to limit in any way the scope of the claims or equivalents to which the claims are lawfully granted. Further features of the invention are described below. It should be understood by those skilled in the art that all specific compositions and methods disclosed are illustrative and can be readily used as a basis for modifying or designing other compositions and methods to accomplish the same purposes. Such equivalent compositions and methods will also be understood to be within the scope and spirit of the invention as described in the claims.

[0046] The headings within this document are used solely to facilitate reader review. They should not be construed as limiting the invention in any way.

[0047] To further clarify the various aspects of the present invention, a more detailed description of the invention is provided by reference to specific exemplary embodiments of the invention shown in the drawings. It will be understood that these drawings only illustrate exemplary embodiments of the invention and should not be considered to limit the scope of the invention. They are provided only as illustrative descriptions of certain concepts of some embodiments of the invention. These figures and the elements shown therein are not necessarily drawn to a consistent or arbitrary scale. Accordingly, specific aspects of the invention are further described and explained in more specific and detail with reference to the accompanying drawings, but are only examples. [Brief explanation of the drawing]

[0048] [Figure 1] Figure 1 shows dose-response curves from cell-based agonist IP-1 assays for 14-Me-LSD against 5-HT2A and 5-HT2B, as described in Example 3.

[0049] [Figure 2] Figure 2 shows dose-response curves from cell-based agonist IP-1 assays for 2-Br-14-Me-LSD against 5-HT2A and 5-HT2B, as described in Example 3. [Modes for carrying out the invention]

[0050] While various aspects and features of specific embodiments are summarized above, the following detailed description further elaborates on several exemplary embodiments to enable those skilled in the art to implement such embodiments and to create and use the full scope of the claimed invention. The examples described are provided for illustrative purposes only and are not intended to limit the scope of the invention or its uses. The scope of the invention includes all embodiments and their formulations, not just those expressly described below, and it will be understood that many modifications, substitutions, changes and variations in the described examples, embodiments, uses and details can be made by those skilled in the art without departing from the spirit of the invention or the scope of the claims. Headings in this document are used solely to facilitate reader review. They should not be construed as limiting the invention in any way.

[0051] A. General definitions and terms Where used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple referents unless the context clearly indicates otherwise. For example, a reference to “activator” includes a reference to a combination of two or more activators, and a reference to “excipient” includes a reference to a combination of two or more excipients. The term “one or more” may also be used, but where it is not used (or replaced by the singular), it does not mean only one, but simply emphasizes that there may be multiple agents or components in a particular embodiment. The terms “comprising,” “including,” “such as,” and “having” are inclusive and non-exclusive (i.e., other elements may be present in addition to the enumerated elements). The term “or” is used herein to mean the terms “and / or” and is used interchangeably unless the context clearly indicates otherwise.

[0052] Unless otherwise specified, all numbers representing properties such as quantities, concentrations, and reaction conditions of components used to describe and claim specific embodiments of this disclosure should be understood to be modified in some cases by the term “about.” Thus, in some embodiments (and similarly, “in the embodiments”), numerical parameters described in the specification and claims are approximations that may vary depending on the desired properties to be obtained by the particular embodiment. In some embodiments, “about” refers to plus or minus 5 percent (±5%) of the described unit of measurement. The term “substantially” is to be read to provide appropriate certainty in the context of this disclosure and in light of the knowledge of the art, for example, by using standards recognized in the art to measure the meaning of “substantially” as a degree, or by confirming the range as understood by those skilled in the art. Where such certainty cannot be established from the context, the term may also be understood to mean “about,” for example, within ±1%, within ±5%, or within ±10%.

[0053] When "approximately" is used to modify one number within a series or range, it is understood that for a range, it modifies all numbers within that series or range, including both the upper and lower bounds of that range. Therefore, the term "approximately 1, 2, or 3" is understood to mean "approximately 1, approximately 2, or approximately 3," and the term "approximately 1 to 10" means "approximately 1 to approximately 10."

[0054] In some embodiments, numerical parameters should be interpreted by applying common rounding techniques in light of the number of significant figures reported. Although the numerical ranges and parameters representing a wide range of some embodiments of this disclosure are approximations, the numerical values ​​shown in specific examples are reported as accurately as possible. The numerical values ​​presented in some embodiments may include certain errors that inevitably arise from the standard deviation observed in each test measurement.

[0055] A comprehensive list of abbreviations used by organic chemists skilled in the art is provided in the first volume of each issue of the Journal of Organic Chemistry; this list is typically presented in a table titled “Standard List of Abbreviations”; the list as of the date of this application is incorporated herein by reference as if it were entirely contained herein.

[0056] Unless otherwise defined, all technical and scientific terms herein have meanings that are generally understood by those skilled in the art to which the invention pertains, and which may be simply abbreviated as “those skilled in the art.” Further definitions that may help the reader understand the disclosed embodiments are given below; however, such definitions are not intended to limit the scope of the invention and should be interpreted and understood appropriately by referring to the full specification (and its obvious meaning known to those skilled in the art), taking into account the language used in the claims. The terms used herein are for the purpose of describing, and not limiting, specific embodiments.

[0057] In general, the nomenclature and procedures used herein are known and commonly used in the fields relating to one or more aspects of the present invention, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or medicinal chemistry. Standard techniques and procedures are commonly carried out according to the prior art.

[0058] "Alkyl" is understood to include linear or branched radicals having any degree or level of saturation, i.e., groups having only a single carbon-carbon bond, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having a mixture of single, double, and triple carbon-carbon bonds. The terms "alkanyl," "alkenyl," and "alkynyl" can also be used when a specific level of saturation is intended. In some embodiments, alkyl groups contain 1 to 10 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. For any alkyl group, the alkyl group may optionally be substituted at one or more positions with deuterium, halogen, alkyl, alkenyl, alkynyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, and -SONH2. In embodiments, the alkyl group is optionally substituted. In embodiments, the alkyl group is substituted at one or more positions. In embodiments, the alkyl group is not substituted at any position.

[0059] "Alkenyl" refers to an unsaturated branched, linear, or cyclic alkyl radical having at least one carbon-carbon double bond, induced by removing one hydrogen atom from a single carbon atom of the parent alkene. This group can be in either a cis or trans conformation with respect to the double bond(s). Typical alkenyl groups include ethenyl;propenyl, e.g., propa-1-en-1-yl, propa-1-en-2-yl, propa-2-en-1-yl(allyl), propa-2-en-2-yl, cyclopropa-1-en-1-yl and cyclopropa-2-en-1-yl;butenyl, e.g., buta-1-en-1-yl, buta-1-en-2-yl, 2-methylpropa-1-en-1-yl, buta-2-en-1-yl, buta-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobuta-1-en-1-yl, cyclobuta-1-en-3-yl and cyclobuta-1,3-dien-1-yl. The alkenyl group may or may not be substituted.

[0060] "Alkynyl" refers to an unsaturated branched, linear, or cyclic alkyl radical having at least one carbon-carbon triple bond, induced by removing one hydrogen atom from a single carbon atom of the parent alkyne. Typical alkynyl groups include ethynyl; propynyl, e.g., propa-1-in-1-yl and propa-2-in-1-yl; and butynyl, e.g., buta-1-in-1-yl, buta-1-in-3-yl and buta-3-in-1-yl. Alkynyl groups may or may not be substituted.

[0061] "Aryl" refers to a monovalent aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom in a symphilitic aromatic ring system. Typical aryl groups include those derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafen, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In some embodiments, the aryl group contains 6 to 20 carbon atoms or 6 to 12 carbon atoms. The aryl group may or may not be substituted.

[0062] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, fused bicyclic, or bridging polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyls include 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, and 9 to 10 carbon atoms. It can contain any number of carbon atoms, such as 1, 3-11, 4-11, 5-11, 6-11, 7-11, 8-11, 9-11, 10-11, 3-12, 4-12, 5-12, 6-12, 7-12, 8-12, 9-12, 10-12, and 11-12. Examples of monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Examples of bicyclic compounds include spirocyclic compounds, condensed bicyclic compounds, and bridged bicyclic compounds. Examples of bicyclic and polycyclic cycloalkyl rings include norbornane, bicyclooctane, decahydronaphthalene, and adamantane. 3-8 When the group is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 If the group is cycloalkyl, exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may or may not be substituted.

[0063] A "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring. However, if two or more double bonds are present, they cannot form a completely delocalized π-electron system across all rings (otherwise, the group is an "aryl" as defined herein). If composed of two or more rings, the rings may be connected to each other in a condensation manner. Cycloalkenyls include 3-6 carbon atoms, 4-6 carbon atoms, 5-6 carbon atoms, 3-8 carbon atoms, 4-8 carbon atoms, 5-8 carbon atoms, 6-8 carbon atoms, 7-8 carbon atoms, 3-9 carbon atoms, 4-9 carbon atoms, 5-9 carbon atoms, 6-9 carbon atoms, 7-9 carbon atoms, 8-9 carbon atoms, 3-10 carbon atoms, 4-10 carbon atoms, 5-10 carbon atoms, 6-10 carbon atoms, 7-10 carbon atoms, 8-10 carbon atoms, 9-1 A cycloalkenyl group can contain any number of carbon atoms, such as 0 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. Typical 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. The cycloalkenyl group may or may not be substituted.

[0064] "Cycloalkylmethyl" refers to a radical having a methylene component and a cycloalkyl component, where the methylene component links to the cycloalkyl component at the bonding site. The cycloalkyl component is as defined above and can have any number of carbon atoms, for example, 3 to 6 carbon atoms (i.e., C3-C6 cycloalkylmethyl), 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 This may include 7-10 carbon atoms, 8-10 carbon atoms, 9-10 carbon atoms, 3-11 carbon atoms, 4-11 carbon atoms, 5-11 carbon atoms, 6-11 carbon atoms, 7-11 carbon atoms, 8-11 carbon atoms, 9-11 carbon atoms, 10-11 carbon atoms, 3-12 carbon atoms, 4-12 carbon atoms, 5-12 carbon atoms, 6-12 carbon atoms, 7-12 carbon atoms, 8-12 carbon atoms, 9-12 carbon atoms, 10-12 carbon atoms, and 11-12 carbon atoms. In some embodiments, the cycloalkylmethyl group is a cyclopropylmethyl group. The cycloalkylmethyl group may or may not be substituted.

[0065] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0066] "Hypercycloalkyl" refers to the cycloalkyl group as defined above, having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Heterocycloalkyl groups include bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, condensed bicyclic compounds, and bridged bicyclic compounds. Heteroatoms can also be oxidized, including but not limited to -S(O)- and -S(O)2-. Heterocycloalkyl groups can contain any number of ring members, 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. Heterocycloalkyl groups may contain any appropriate number of heteroatoms, 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. Examples of heterocycloalkyl groups include 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, thiethane, thiolane (tetrahydrothiophene), thian (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can also condense with aromatic or non-aromatic ring systems to form members containing, but not limited to, indoline. Heterocycloalkyl groups may be substituted or unsubstituted. For example, heterocycloalkyl groups can be substituted with C1-6 alkyl or oxo (=O) groups, among many others.

[0067] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links to the heterocycloalkyl component at a bonding site. The alkyl component is as defined above, except that it is at least a divalent alkylene to bond to the heterocycloalkyl component and the bonding site. The alkyl component can contain any number of carbon atoms, 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 cases, the alkyl component may be absent. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group may or may not be substituted.

[0068] A "heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 ring atoms are heteroatoms such as N, O, or S. A heteroaryl group can contain any number of ring members, such as 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12. Any appropriate number of heteroatoms can be contained in a heteroaryl group, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. Heteroaryl groups can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups include pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomers, 1,2,4-isomers, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also condense with aromatic ring systems such as phenyl rings to form members including, but not limited to, benzopyrroles (e.g., indole and isoindole), benzopyridines (e.g., quinoline and isoquinoline), benzopyrazines (quinoxaline), benzopyrimidines (quinazoline), benzopyridazines (e.g., phthalazine and cinnoline), benzothiophenes, and benzofurans. Other heteroaryl groups include heteroaryl rings linked by bonds such as bipyridine. Heteroaryl groups may or may not be substituted.

[0069] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to a bonding site. The alkyl component is as defined above, except that it is at least a divalent alkylene to bond to the heteroaryl component and the bonding site. The alkyl component can contain any number of carbon atoms, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6, and C5-6. In some cases, the alkyl component may be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may or may not be substituted.

[0070] "Alkoxy" refers to the formula -OR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. A non-restrictive list of alkoxys includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxys may or may not be substituted.

[0071] "Alkylthio" or "thioalkyl" refers to formula -SR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. A non-restrictive list of alkylthios includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio. Alkylthios may or may not be substituted.

[0072] "Acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl atoms bonded via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acrylic. Acyls may or may not be substituted.

[0073] "Haloalkyl" refers to any alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogens (e.g., fluorine, chlorine, bromine, or iodine). If an alkyl group is substituted with two or more halogens, it may be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkyl refers to an alkyl group substituted with two halo groups, which may or may not be the same halogen. Examples of haloalkyl groups include difluoromethyl (-CHF2), bromofluoromethyl (-CHBrF), trifluoromethyl (-CF3), and 2-fluoroethyl (-CH2CH2F). Further examples of haloalkyl groups include -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(CH3)(CF3), -CH(CH3)(CHF2), and -CH(CH3)(CH2F). Haloalkyl groups may or may not be substituted.

[0074] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl groups may or may not be substituted.

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

[0076] "Sulfenyl" refers to an -SR group in which R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. Sulfenyl may or may not be substituted.

[0077] "Sulfinyl" refers to the -S(=O)-R group, where R can be the same as defined for sulfenyl. Sulfinyl may or may not be substituted.

[0078] "Sulfonyl" refers to the -SO2R group, where R may be the same as defined for sulfenyl. Sulfonyl may or may not be substituted.

[0079] "O-carboxy" refers to an -RC(=O)O- group where R may be a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. The O-carboxy may or may not be substituted.

[0080] "Ester" and "C-carboxyl" refer to the -C(=O)OR group, where R may be the same as defined for O-carboxyl. The ester group and C-carboxyl group may or may not be substituted.

[0081] "Thiocaunal" refers to a -C(=S)R group where R may be the same as defined for an O-carboxyl group. Thiocaunal may or may not be substituted.

[0082] "Trihalomethanesulfonyl" refers to an X3CSO2- group where each X is a halogen.

[0083] "Trihalomethanesulfonamide" is X3CS(O)2N(R A )- refers to a group, where each X is a halogen, and R A These are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein.

[0084] "S-sulfonamide" is -SO2N(R A R B ) refers to the base, and in the formula, R A and R B These can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. The S-sulfonamide may or may not be substituted.

[0085] "N-sulfonamide" is RSO2N(R A )- Refers to the base, in the formula, R and R A This can independently be a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. The N-sulfonamide may or may not be substituted.

[0086] "O-carbamyl" is -OC(=O)N(R A R B ) refers to the base, and in the formula, R A and R BO-carbamyl may be independently a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein.

[0087] "N-carbamyl" is ROC(=O)N(R A )- Refers to the base, in the formula, R and R A This can independently be a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-carbamyl may or may not be substituted.

[0088] "O-thiocarbamyl" is -OC(=S)-N(R A R B ) refers to the base, and in the formula, R A and R B These can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. O-thiocarbamyl may or may not be substituted.

[0089] "N-thiocarbamyl" is ROC(=S)N(R A )- Refers to the base, in the formula, R and R A This can independently be a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-thiocarbamyl may or may not be substituted.

[0090] The "C-amide" group is -C(=O)N(R A R B ) refers to the base, and in the formula, R A and R BThese can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. The C-amide may or may not be substituted.

[0091] "N-amide" is RC(=O)N(R A )- Refers to the base, in the formula, R and R A This can independently be a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. The N-amide may or may not be substituted.

[0092] Unless otherwise specified, "optionally substituted" means that the group is either unsubstituted or can be substituted by one or more substituents listed for that group. Similarly, when a group is described as "unsubstituted or substituted," if substituted, one or more substituents may be selected from one or more of the listed substituents. If multiple substituents exist, they 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 yet another embodiment, an optionally substituted group has three substituents. In yet another embodiment, an optionally substituted group has four substituents. If no substituent is indicated for a "optionally substituted" or "substituted" group, it means that the indicated "optionally substituted" or "substituted" group may be substituted with one or more groups 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-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azide, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, amino, monosubstituted amino groups, disubstituted amino groups, and trisubstituted amino groups.

[0093] Further definitions and abbreviations are provided elsewhere in this specification.

[0094] B. Compound In one embodiment, the compound of formula (1): [ka] Alternatively, a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided, in formula: R 1 R is H or -C(O)-C1~C6 alkyl; 2 R is a halo, H, or C1-C6 alkyl; 6 R is a C1-C6 alkyl or C2-C6 alkenyl; 14 R' and R'' are C1-C6 alkyl, C1-C6 alkoxy, or halo; and R' and R'' are both C1-C6 alkyl; or R' and R'' together form a heterocycline which may be substituted.

[0095] In some embodiments of equation (1), R 1 is H or -C(O)-C1~C6 alkyl. In some embodiments, R 1 H is H. In some embodiments, R 1 is a -C(O)-C1~C6 alkyl group. For example, in some embodiments, R 1 is acetyl. In some embodiments, R 1 is propanoyl. In some embodiments, R 1 is butyryl. In some embodiments, R 1 This is Valeril.

[0096] In some embodiments of equation (1), R 2 is a halo, H, or C1-C6 alkyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 is F, Cl, Br, or I. In some embodiments, R 2 F is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I. In some embodiments, R 2 H is H. In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R 2 is methyl.

[0097] In some embodiments of formula (1), R 6 is C1-C6 alkyl or C2-C6 alkenyl. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is C2-C6 alkenyl. In some embodiments, R 6 is allyl.

[0098] In some embodiments of formula (1), R 14 is C1-C6 alkyl, C1-C6 alkoxy, or halo. In some embodiments, R 14 is C1-C6 alkyl. In some embodiments, R 14 is methyl. In some embodiments, R 14 is ethyl. In some embodiments, R 14 is C1-C6 alkoxy. In some embodiments, R 14 is methoxy. In some embodiments, R 14 is halo. In some embodiments, R 14 is F, Cl, Br or I. In some embodiments, R 14 is F. In some embodiments, R 14 is Cl. In some embodiments, R 14 is Br. In some embodiments, R 14 is I.

[0099] In some embodiments of formula (1), R' and R'' are both C1-C6 alkyl groups. In embodiments where R' and R'' are both C1-C6 alkyl groups, it will be understood that R' and R'' may be the same or different. For example, in an exemplary embodiment where R' and R'' are both C1-C6 alkyl groups, R' and R'' are both ethyl. However, in another exemplary embodiment where R' and R'' are both C1-C6 alkyl groups, R' is methyl and R'' is isopropyl. In some embodiments, R' and R'' are both methyl. In some embodiments, R' and R'' are both ethyl. In some embodiments, R' is methyl and R'' is n-propyl. In some embodiments, R' is methyl and R'' is isopropyl.

[0100] In some embodiments of formula (1), R' and R'' together form a heterocycline, which is optionally substituted with an alkyl group. In some embodiments, R' and R'' together form a 4- to 6-membered heterocycline, which is optionally substituted with an alkyl group. In some embodiments, R' and R'' together form a heterocycline, which is optionally substituted with an alkyl group. In some embodiments, R' and R'' together form a 4- to 6-membered heterocycline, which is optionally substituted with a C1-C6 alkyl group. In some embodiments, R' and R'' together form a 4- to 6-membered heterocycline, which is unsubstituted. For example, in some embodiments, R' and R'' together form a 4-membered heterocycline such as azetidine. In some embodiments, R' and R'' together form a 5-membered heterocycline such as pyrrolidine. In some embodiments, R' and R'' together form a 6-membered heterocycline such as piperidine. In some embodiments, where R' and R'' together form a 4- to 6-membered heterocycline, the 4- to 6-membered heterocycline contains an additional heteroatom. For example, in some embodiments, R' and R'' together form a 6-membered heterocycline containing an additional heteroatom such as oxygen (morpholine), sulfur (thiomorpholine), or nitrogen (piperazine). In some embodiments, R' and R'' together form a 4- to 6-membered heterocycline, and the heterocycline is substituted with a C1- to C6 alkyl group. In certain preferred embodiments, R' and R'' together form a 4- to 6-membered heterocycline, and the heterocycline is substituted with a methyl group. In some embodiments, R' and R'' combine to form 2-methylazetidine. In some embodiments, R' and R'' combine to form a 4- to 6-membered heterocycline, the heterocycline being substituted with ethyl. In some embodiments, R' and R'' combine to form 2-ethylazetidine. In some embodiments, R' and R'' combine to form dimethylazetidine.In some such embodiments, R’ and R” together form 2,4-dimethylazetidine. In some embodiments, R’ and R” together.

Chemical formula

Chemical formula

[0101] In some embodiments, the compound of formula (1) has the structure of formula (1A),

Chemical formula

[0102] In some embodiments, the compound of formula (1) has the structure of formula (1B),

Chemical formula

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

[0104] In some embodiments, the compound of formula (1) is formula (1C), [ka] Having the structure of, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, in the formula, R 14’ is a C1-C6 alkyl group; and R 1 , R 2 , R 6 R' and R'' are defined for equation (1).

[0105] In some embodiments, R 14’ is a C1-C6 alkyl group. In some embodiments, R 14’ It is methyl.

[0106] In another embodiment, the compound of formula (2): [ka] Alternatively, a prodrug, hydrate, or solvate thereof is provided, in formula: R 1 R is H or -C(O)-C1~C6 alkyl; 2 R is H, C1-C6 alkyl, or halo; 6 R is a C1-C6 alkyl or C2-C6 alkenyl; 6’ R is a C1-C6 alkyl group; 14 R' and R'' are C1-C6 alkyl, C1-C6 alkoxy, or halo; and R' and R'' are both C1-C6 alkyl; or R' and R'' together form a heterocycline which may be substituted.

[0107] In some embodiments of equation (2), R 1 is H or -C(O)-C1~C6 alkyl. In some embodiments, R 1 H is H. In some embodiments, R 1 is a -C(O)-C1~C6 alkyl group. For example, in some embodiments, R 1 is acetyl. In some embodiments, R 1 is propanoyl. In some embodiments, R 1 is butyryl. In some embodiments, R 1 This is Valeril.

[0108] In some embodiments of equation (2), R 2 is H, C1-C6 alkyl, or halo. In some embodiments, R 2 H is H. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is methyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 is F, Cl, Br, or I. In some embodiments, R 2 F is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 It is I.

[0109] In some embodiments of equation (2), R 6 is a C1-C6 alkyl or C2-C6 alkenyl. In some embodiments, R 6 is a C1-C6 alkyl group. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 R is a C2-C6 alkenyl. In some embodiments, R 6This is an allele.

[0110] In some embodiments of equation (2), R 6’ is a C1-C6 alkyl group. In some embodiments, R 6’ It is methyl.

[0111] In some embodiments of equation (2), R 14 is a C1-C6 alkyl, a C1-C6 alkoxy, or a halo. In some embodiments, R 14 is a C1-C6 alkyl group. In some embodiments, R 14 is methyl. In some embodiments, R 14 is ethyl. In some embodiments, R 14 R is a C1-C6 alkoxy. In some embodiments, 14 is methoxy. In some embodiments, R 14 is a halo. In some embodiments, R 14 is F, Cl, Br, or I. In some embodiments, R 14 F is F. In some embodiments, R 14 is Cl. In some embodiments, R 14 is Br. In some embodiments, R 14 It is I.

[0112] In some embodiments of formula (2), R' and R'' are both C1-C6 alkyl groups. In embodiments where R' and R'' are both C1-C6 alkyl groups, it will be understood that R' and R'' may be the same or different. For example, in an exemplary embodiment where R' and R'' are both C1-C6 alkyl groups, R' and R'' are both ethyl. However, in another exemplary embodiment where R' and R'' are both C1-C6 alkyl groups, R' is methyl and R'' is isopropyl. In some embodiments, R' and R'' are both methyl. In some embodiments, R' and R'' are both ethyl. In some embodiments, R' is methyl and R'' is n-propyl. In some embodiments, R' is methyl and R'' is isopropyl.

[0113] In some embodiments of formula (2), R' and R'' together form a heterocycline, which is optionally substituted with an alkyl group. In some embodiments, R' and R'' together form a 4- to 6-membered heterocycline, which is optionally substituted with an alkyl group. In some embodiments, R' and R'' together form a heterocycline, which is optionally substituted with an alkyl group. In some embodiments, R' and R'' together form a 4- to 6-membered heterocycline, which is optionally substituted with a C1- to C6 alkyl group. In some embodiments, R' and R'' together form a 4- to 6-membered heterocycline, which is unsubstituted. For example, in some embodiments, R' and R'' together form a 4-membered heterocycline such as azetidine. In some embodiments, R' and R'' together form a 5-membered heterocycline such as pyrrolidine. In some embodiments, R' and R'' together form a 6-membered heterocycline such as piperidine. In some embodiments, where R' and R'' together form a 4- to 6-membered heterocycline, the 4- to 6-membered heterocycline contains an additional heteroatom. For example, in some embodiments, R' and R'' together form a 6-membered heterocycline containing an additional heteroatom such as oxygen (morpholine), sulfur (thiomorpholine), or nitrogen (piperazine). In some embodiments, R' and R'' together form a 4- to 6-membered heterocycline, and the heterocycline is substituted with a C1- to C6 alkyl group. In certain preferred embodiments, R' and R'' together form a 4- to 6-membered heterocycline, and the heterocycline is substituted with a methyl group. In some embodiments, R' and R'' combine to form 2-methylazetidine. In some embodiments, R' and R'' combine to form a 4- to 6-membered heterocycline, the heterocycline being substituted with ethyl. In some embodiments, R' and R'' combine to form 2-ethylazetidine. In some embodiments, R' and R'' combine to form dimethylazetidine.In some such embodiments, R' and R'' combine to form 2,4-dimethylazetidine. In some embodiments, R' and R'' combine. [ka] or [ka] R' and R'' form a connection point to the rest of the compound, where the asterisk (*) indicates a connection point to the rest of the compound. In some embodiments, R' and R'' together form tetramethylazetidine.

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

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

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

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

Table 2-1

Table 2-2

Table 2-3

Table 2-4

[0117] This disclosure is understood to also encompass pharmaceutically acceptable salts of the disclosed compounds. The term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base and which can be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of these agents with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or in a mixture thereof. Generally, non-aqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, the salt of the compound is one in which the counterion is pharmaceutically acceptable. Those skilled in the art can select a pharmaceutically acceptable counterion from a wide variety of available counterions. In particular applications, the selection of a given anion or cation for the preparation of the salt may result in an increase or decrease in the solubility of that salt. Examples of salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-naphthylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidebenzoate, acefyllinate, acetate, aceturate, adipine, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besilate, Bicarbonate, bisulfate, tartrate, borate, butyrate, calcium edetate, calcium, camphor carbonate, camphorate, camphor sulfonate, cansilate, carbonate, cholate, citrate, clavulanate, cyclopentanepropionate, cypionate, d-aspartate, d-cansilate, d-lactate, decanoate, dichloroacetate, digluconate, dodecyl sulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethylSulfates, fumarates, furates, fusidicates, galactarates (mucates), galacturonic acid, gallates, gentisic acid, gluceptic acid, glucoheptanates, gluconates, glucuronates, glutamic acid, glutarates, glycerophosphates, glycolates, glycolyl arsanilates, hemisulfates, heptaneates (enanthates), heptaneates, hexafluorophosphates, hexanoates, hexylresorcinate, horse Urate, hibenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-cansylate, l-lactate, lactobionate, laurate, laurylsulfonate, lithium, magnesium, malate, maleate, malonate, mandelate, mesotartarate, mesylate, methanesulfonate, odor Methyl nitrate, methyl sulfate, mucinate, myristicate, N-methylglucamine ammonium salt, napadisylate, naphthylate, napsilate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitic acid, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, diphosphate, picrinate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharinate, Examples include salicylates, salicyl sulfates, sodium, stearates, acetates, succinates, sulfates, sulfosaliculates, sulfosalicylates, suramate, tannates, tartrates, theoclates, terephthalates, thiocyanates, thiosalicylates, tosylates, tribrophenates, triethiodides, undecanoates, undecylenates, valersates, valproates, xinafoates, and other salts. (See Berge et al., J. Pharm. Sci. 1997, 66, 1-19).

[0118] Certain compounds disclosed herein may comprise one or more ionizable groups (groups from which protons can be removed (e.g., -COOH), added (e.g., amine), or quaternized (e.g., amine)). All possible ionic forms of such molecules and their salts are included in this disclosure.

[0119] The disclosed compounds may exist in solid or liquid form. In the solid state, the compounds may exist in crystalline or amorphous form, or as mixtures thereof. Those skilled in the art will understand that pharmaceutically acceptable solvates may be formed for crystalline or amorphous compounds. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may contain, but are not limited to, non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may contain water as the solvent incorporated into the crystal lattice. Solvates in which water is the solvent incorporated into the crystal lattice are typically called “hydrates.” Hydrates include stoichiometric hydrates, as well as compositions containing a variable amount of water. The subject matter described herein includes such solvates.

[0120] Those skilled in the art will further understand that certain compounds described herein, existing in crystalline forms including their various solvates, may exhibit polymorphism (i.e., the ability to exist in different crystalline structures). These different crystalline forms are typically known as “polymorphs.” The subject matter disclosed herein includes such polymorphs. Polymorphs include different crystalline packing arrangements of compounds with the same elemental composition. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of their crystalline solid state. Thus, polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and solubility. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will understand, for example, that different polymorphs can be produced by changing or adjusting the reaction conditions or reagents used in the production of the compound. For example, changes in temperature, pressure, or solvent may result in polymorphism. A single crystalline form may be dominant due to various factors such as the recrystallization solvent, crystallization rate, and storage temperature. Furthermore, one polymorph may spontaneously transform into another polymorph under certain conditions.

[0121] The compounds described herein may contain one or more chiral centers, resulting in enantiomatous, diastereomatous, and other stereoisomeric forms. Each chiral center may be defined as (R)- or (S)- with respect to absolute stereochemistry. This disclosure includes all such possible isomers, as well as mixtures thereof, including racemates 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 may be divided using prior art. Various methods for preparing optically active forms and determining their activity are known in the art. Such methods include the standard tests described herein and other similar tests well known in the art. Examples of methods that can be used to obtain optical isomers of the compounds described herein 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). Where the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Similarly, tautomers are included.

[0122] This disclosure also includes compounds having a desired isotopic substitution of at least one atom in an amount exceeding the natural abundance of the isotope, i.e., isotope-enriched. An isotope is an atom with the same atomic number but a different mass number, i.e., an atom with the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into the disclosed compounds are isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, for example, respectively. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O and 36 Cl is one example. In one non-limiting embodiment, isotope-labeled compounds are used in metabolic studies.14 Using C), reaction kinetic studies (for example) 2 H or 3 It can be used in 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 radiation therapy for patients. 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Furthermore, deuterium, i.e. 2 Substitution with heavier isotopes, such as 1H, can lead to therapeutic benefits due to improved metabolic stability, such as an extended in vivo half-life or a reduction in the required dose, and may therefore be preferable in some situations. The isotope-labeled compounds of this disclosure can generally be prepared by performing the procedures disclosed in the following schemes or examples and preparations, by using readily available isotope-labeling reagents instead of non-isotope-labeling reagents.

[0123] This disclosure also includes prodrugs of the disclosed compounds. A “prodrug” is a precursor to a biologically active drug that can be converted into a biologically active drug through chemical or metabolic transformation. Prodrugs can be converted into biologically active drugs in vitro through chemical transformation processes. In vivo, prodrugs are converted into biologically active drugs through metabolic, enzymatic, or degradation processes that remove the prodrug portion to form a biologically active drug. Typical examples of prodrugs include compounds that have a biologically unstable or cleavable (protecting) group in the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce an active compound. Commonly used functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides. These functional groups can be attached to drug molecules via linkers designed to be cleaved under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage. The selection of functional groups depends on factors such as stability, ease of synthesis, enzyme activity, and the desired prodrug conversion rate.

[0124] Generally, the individual compounds disclosed are administered as part of a pharmaceutical composition or formulation, and are prepared for inclusion in such composition or formulation as isolated or purified compounds. As used herein, the terms “isolated,” “purified,” or “substantially pure” refer to a material that is substantially or essentially free of components that would normally accompany the material if the material were produced by synthesis, manufacture, or other means. Accordingly, an “isolated,” “purified,” or “substantially pure” preparation of a compound is defined as a preparation having a chromatographic purity (of the desired compound) 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 the HPLC profile or other similar detection methods.

[0125] Preferably, the substantially pure compounds used in this disclosure substantially contain no other active compounds that are not intended to be administered to the subject. In this context, “substantially contain” can be interpreted to mean that active compounds other than the active compound intended to be administered to the subject are not detectable by HPLC or other similar detection methods, or are below the desired detection threshold as defined above.

[0126] In some embodiments, the characteristics of the disclosed compound offer various advantages. Such advantages may relate to the modulation of neurotransmission, pharmacokinetics such as properties related to the absorption, distribution, metabolism, and excretion of the disclosed compound, as well as subjective effects such as those upon administration to a subject. In embodiments, such advantages are determined relative to a control drug.

[0127] In some embodiments, the control drug is a lysergic amide lacking substituents at the 2-position and / or 14-position. For example, in some embodiments, the control drug is LSD. In some embodiments, the control drug is 2-Br-LSD. In some embodiments, the control drug is LSZ.

[0128] C. Method for preparing the disclosed compound In some embodiments, methods for preparing disclosed compounds, such as compounds of formula (1), formula (2), and any subformulas thereof, are provided herein.

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

[0130] In one example, R 14 A compound of formula (1) in which is methyl is prepared according to the following reaction sequence. [ka]

[0131] The disclosed compound contains a 2-halo substituent (i.e., R 2 However, in some embodiments, the compound is a compound of formula (1) or (2) which is F, Cl, Br or I. In some embodiments, the compound is a corresponding compound that contains hydrogen at the 2 position (i.e., R 2 It can be prepared by halogenation of a compound in which H is present. 2 The following exemplary reaction scheme is shown for the preparation of the compound of formula (1) where is F, Cl, Br or I. [ka]

[0132] Halogenation can be carried out according to methods known to those skilled in the art. (See, for example, Troxler and Hofmann, Helvetica Chimica Acta, 1957, 40(7), 2160-2170.)

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

[0134] Lysergic acid precursors can be prepared according to known methods, particularly the method disclosed in Knight et al., J.Org.Chem.2023,88,4,2158-2165.

[0135] The disclosed compound contains an N(1) substituent (i.e., R 1 However, in some embodiments, the compound is a compound of formula (1) or (2) which is a -C(O)-C1~C6 alkyl compound, and the compound is a corresponding compound containing hydrogen at the N(1) position (i.e., R 1 It can be prepared by halogenation of a compound in which H is present. 1 The following exemplary reaction scheme is shown for the preparation of the compound of formula (1) in which is -C(O)-C1~C6 alkyl. [ka]

[0136] Although an acid anhydride is illustrated above as an exemplary acyling agent, those skilled in the art will understand that any suitable acyling agent can be substituted (e.g., an acid chloride). Suitable acyling methods are known to those skilled in the art.

[0137] The compounds disclosed in formula (2) can be prepared by quaternization of the corresponding compounds in formula (1). [ka]

[0138] Suitable precursors and reaction conditions for quaternization are known in the art. In this reaction sequence, R 6’ -X represents a suitable alkylating agent containing the alkyl moiety and the leaving group (X). For example, in some embodiments, the alkylating agent is methyl iodide.

[0139] For disclosed compounds in which R' and R'' combine to form azetidines such as unsubstituted azetidine or alkyl-substituted azetidine, the intermediates azetidine, alkylyl azetidine, or dialkyl azetidine can be prepared according to procedures known in the art (see, for example, Dall'Asta & Pedrazzoli, Experientia, 1970, 26, 1188-1189; Marinetetti et al., Eur. J. Org. Chem., 2000, 1815-1920).

[0140] Further synthetic methods that may be useful for synthesizing the disclosed compounds and any necessary starting materials can be found in Nichols et al., J. Med. Chem. 2002, 45, 4344-4349; and in general references well known in the art (e.g., Green et al., "Protective Groups in Organic Chemistry" (Wiley, 2nd edition, 1991); Harrison et al., "Compendium of Synthetic Organic Methods" Vols. 1-8 (John Wiley & Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry," Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., "Reagents for Organic Synthesis" Vols. 1-17, Wiley Interscience; Trost et al., "Comprehensive Organic Synthesis," Pergamon Press, 1991; "Theilheimer's Synthetic Methods of Organic See also: "Chemistry," Vols. 1-45, Karger, 1991; March, "Advanced Organic Chemistry," Wiley Interscience, 1991; Larock, "Comprehensive Organic Transformations," VCH Publishers, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis," John Wiley & Sons, 1995.

[0141] D. Pharmaceutical Compositions In some embodiments, compositions comprising the disclosed compounds, such as pharmaceutical compositions, are provided herein. A "pharmaceutical composition" is a composition comprising the disclosed compound in a certain amount (e.g., in a unit dosage form) together with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments include multiple carriers, diluents, and / or excipients, rather than having a single carrier, diluent, or excipient alone. The compositions can be prepared by standard pharmaceutical formulation techniques, such as those disclosed in Remington: The Science & Practice of Pharmacy (2020) 23rd ed., Acad Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, NJ; 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.; and Poznansky et al., Drug Delivery Sys. (1980), RL Juliano, ed., Oxford, NY, pp. 253-315).

[0142] As used in relation to excipients, carriers, diluents, or other components, “pharmaceutically acceptable” means that the component is generally safe and suitable for use in contact with human and animal cells within the bounds of sound medical judgment, in proportion to a reasonable risk-benefit ratio, without excessive toxicity, irritation, allergic reactions, or complications.

[0143] In some embodiments, pharmaceutical compositions containing the disclosed compounds can be administered by various routes, including oral, mucosal (e.g., oral cavity, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal. In some embodiments, the compounds used in the methods of the present disclosure are effective as oral, mucosal (e.g., oral cavity, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal compositions. Such compositions are prepared by methods well known in the pharmaceutical field and contain at least one active compound. (See, for example, Remington, 2020.)

[0144] The disclosed compositions are preferably formulated into unit dosage forms, each dose containing a therapeutically effective amount of the active ingredient, for example, in the doses disclosed below. The term “unit dosage form” refers to a physically distinct unit suitable as a unit dose for the subject being treated, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are often used for ease of administration and dose uniformity. Unit dosage forms may include a single or individual dose or unit, subdose, or an appropriate proportion thereof of the pharmaceutical composition being administered (for example, half of a “full” dose for a “booster” dose, as described below).

[0145] Unit dosage forms include capsules, lozenges, cachets, tablets, ampoules, and vials, which may contain compositions in a freeze-dried or lyophilized state; for example, a sterile liquid carrier may be added before in vivo administration or delivery. Unit dosage forms also include ampoules and vials in which the liquid composition is contained. Unit dosage forms further include compounds for transdermal administration, such as "patches" that come into contact with the epidermis (including mucous membranes) for a prolonged or short period of time.

[0146] In embodiments, the disclosed compositions are formulated into pharmaceutically acceptable oral dosage forms. Oral dosage forms include oral liquid dosage forms (e.g., tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions) as well as oral solid dosage forms. The disclosed pharmaceutical compositions may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, liposomes, and sterile powders for reconstitution into sterile injection solutions or dispersions.

[0147] In embodiments, the disclosed pharmaceutical compositions may be formulated into topical formulations (e.g., topical dosage forms). Topical formulations include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, plasters, gels, pastes, lotions, liniments, oils, and creams, and may contain pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients for topical formulations include penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and co-solvents, viscosity modifiers (e.g., thickeners), adhesion modifiers (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizers, colorants, binders, humectants, surfactants, gelling agents, and other such components commonly known to those skilled in the art.

[0148] In some embodiments, topical formulations include penetration enhancers. While not theoretically bound, penetration enhancers are generally characterized by their ability to increase permeability through biological barriers such as the scalp. In some embodiments, including a penetration enhancer in the formulation improves the ability of the active ingredient to diffuse into skin tissue and increases the bioavailability of the active ingredient. Penetration enhancers include, for example, fatty acids and oils such as castor oil, coconut oil, medium-chain triglycerides (MCTs), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, 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, cetyltrimethylammonium, 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 the group comprising low-chain alcohols having 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, physophosphatidylcholine, phosphatidylcholine, azon, cyclodextrin, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, benzalkonium chloride, cetylpyridinium chloride, vitamin E TPGS, caprylocaproyl polyoxylglyceride, stearoyl macrogol glyceride, propylene glycol dicaprylocaprate, or mixtures thereof.

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

[0150] In some embodiments, the topical formulation includes a carrier. The carrier can be designed to provide a controlled release profile, improved circulation time, and better penetration across the epithelium. In some embodiments, the carrier is a hydrophobic drug carrier. Hydrophobic drug carriers have the advantage of exhibiting sustained release and may have good adhesion to biological surfaces. Hydrophobic drug carriers may have slow (i.e., long-acting) release kinetics, but may be constructed to have a rapid or immediate release profile. Novel techniques include the development of hydrophilic coatings on hydrophobic nanoparticles to improve transport across tissue surfaces while maintaining a sustained-release profile. These include polyethylene glycol and chitosan coatings (see, e.g., de la Fuente et al., Nanomedicine 2008;3:845-857). A wide variety of pharmaceutically acceptable carriers may be used, including, but are not limited to, aqueous media such as water, saline, glycine, and hyaluronic acid; solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talc, cellulose, glucose, sucrose, lactose, trehalose, and magnesium carbonate; solvents; dispersions; coatings; antimicrobial and antifungal agents; isotonic and absorption retardants; and other inert components. The choice of pharmacologically acceptable carrier may depend on the mode of administration.Non-limiting specific examples of the use of such drug carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (edited by Howard C. Ansel et al., Lippincott Williams & Wilkins Publishers, 7th ed., 1999); Remington: The Science and Practice of Pharmacy (edited by Alfonso R. Gennaro, Lippincott, Williams & Wilkins, 20th ed., 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (edited by Joel G. Hardman et al., McGraw-Hill Professional, 10th ed., 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th ed., 2003).

[0151] In embodiments, the topical formulation includes an emulsifier. The emulsifier may be anionic, cationic, or neutral. In certain embodiments, the emulsifier is an anionic emulsifier selected from the group consisting of alkyl sulfates, aralkyl sulfates, alkyl ethoxyether sulfates, alkali sulfonates, alkyl succinates, alkyl sulfosuccinates, N-alcoyl sarconsinate, isethionate, N-acyl taurate, sodium lauryl sulfate, sodium laureth sulfate, sodium oleyl succinate, sodium dodecylbenzenesulfonate, and sodium lauryl sarconsinate. Exemplary nonionic or neutral emulsifiers include sorbitan esters, ethoxylated sorbitan esters, ethoxylated alkyl ethers, ethoxylated fatty acid ethers, fatty alcohols, ethoxylated fatty alcohols, and esters of glycerin and fatty acids. In certain embodiments, the emulsifier is a synthetic or natural polymer. In certain embodiments, the emulsifier includes silicon. In certain embodiments, the emulsifier is a silicone (e.g., dimethicone, phenyl trimethicone, PEG dimethicone, PPG dimethicone, etc.).

[0152] In embodiments, the topical formulation includes an antioxidant. The antioxidant is an amino acid (e.g., glycine, histidine, tyrosine, tryptophan) and its derivatives, an imidazole (e.g., urocanic acid) and its derivative peptides (e.g., D,L-carnosine, D-carnosine, L-carnosine and its derivatives (e.g., anserine)), a carotenoid, a carotene (e.g., β-carotene, lycopene) and its derivatives, a chlorogenic acid and its derivatives, a liponic acid and its derivatives (e.g., dihydrolipoic acid), aurothioglucose, propylthiouracil, and other thiols (e.g., thiorhodokyl Cysine, glutathione, cysteine, cystine, cystamine, and their glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, and lauryl, palmitoyl, oleyl, γ-linoleyl, cholesteryl, and glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts), and sulfoximine compounds (e.g., butionine sulfoximine, homocytine). The very low tolerable dose (e.g., pmol~μmol / kg) of stain sulfoximine, butionine sulfone, penta, hexa, and heptathionine sulfoximine may also be used, as well as (metal) chelating agents (e.g., α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, gallic acid, bile extract, bilirubin, biliverdin, EDTA and its derivatives, unsaturated fatty acids and their derivatives (e.g., γ-linolenic acid, linoleic acid, oleic acid), leaves Acids and their derivatives, ubiquinone and ubiquinol and their derivatives, vitamin C and its derivatives (e.g., sodium ascorbate, ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and its derivatives (e.g., vitamin E acetate, tocotrienol), vitamin A and its derivatives (vitamin A palmitate), and benzoic acid resin coniferyl benzoate, rutic acid and its derivatives, α-glycosylrutin, ferulic acid, furfrillidene glucitol, carnosine,It may also be butylhydroxytoluene, butylhydroxyanisole, nordihydroguaiarecate, nordihydroguaiaretinic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (e.g., ZnO, ZnSO4), selenium and its derivatives (e.g., seleniummethionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide).

[0153] In the embodiment, the topical formulation includes a thickening agent. The thickening agent may be cross-linked polyacrylic acid and its derivatives, polysaccharides and their derivatives, such as xanthan gum, agar, alginate or tyrose, cellulose derivatives (e.g., carboxymethylcellulose or hydroxycarboxymethylcellulose), fatty alcohols, monoglycerides and fatty acids, polyvinyl alcohol and PVP.

[0154] In the embodiments, the topical formulation contains a substance that is active as a cosmetic and / or skin cosmetic. The substance that is active as a cosmetic and / or skin cosmetic may be a color-imparting active substance, a skin or hair coloring composition, a coloring composition, a tanning composition, a bleaching agent, a keratin curing agent, an antibacterial active substance, a light-filtering active substance, a repellent active substance, a substance having hyperemia activity, a substance having keratolytic or keratoproliferative activity, an anti-inflammatory agent, a substance having keratinizing activity, an antioxidant active substance or a substance that is active as a free radical scavenger, a skin moisturizing substance or skin moisturizer, a fat-replenishing (refatting) active substance, a substance having anti-erythema activity or anti-allergic activity, a branched fatty acid, and any mixture thereof.

[0155] In embodiments, topical formulations contain fragrance oils. Natural fragrances are extracts of flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, caraway, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), woods (pine, sandalwood, guaiac, cedar, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Typical synthetic fragrance compounds are products of the type consisting of esters, ethers, aldehydes, ketones, alcohols, and hydrocarbons. Low-volatility essential oils commonly used as fragrance components, such as sage oil, chamomile oil, clove oil, palm oil, mint oil, cinnamon leaf oil, lime tree flower oil, juniper oil, vetiver oil, oliban oil, galbanum oil, labolanum oil, and lavandin oil, are also suitable as fragrance oils. Bergamot oil, dihydromyrcenolate, lilial, liral, citronellol, phenylethyl alcohol, α-hexyl cinnamaldehyde, geraniol, benzylacetone, cyclamenaldehyde, linalool, Boisambrene® Forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclobertal, lavandin oil, muscatel sage oil, G39 damascone, bourbon geranium oil, cyclohexyl salicylate, Vertofix® Coeur, iso-E-Super®, Fixolide® NP, ebemyl, iraldine gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romylate, ilotyl and floramat.

[0156] In embodiments, topical formulations include a solvent and, optionally, a co-solvent. The solvent and co-solvent are sometimes collectively referred to as the “solvent system.” While not theoretically bound, the chosen solvent system may affect the stability, bioavailability, and overall efficacy of the formulation. In some embodiments, the solvent system should be able to dissolve or solubilize one or more activators and included excipients at one or more desired concentrations and should be stable and compatible with one or more activators and any other excipients in the formulation. In some embodiments, where the solvent system includes two or more solvents, the ratio of the co-solvent is optimized, for example, to enhance the penetration or bioavailability of the activator. Preferred solvent systems are also safe and non-toxic to human consumption. In some embodiments, potential adverse effects, such as irritation or allergic reactions, are considered and minimized during the selection of solvents to be included in the solvent system of this disclosure. The solvents that may be included in a topical formulation are, but are not limited to, water, ethanol, polyhydric alcohols (e.g., glycerin), 1,3-butylene glycol, propylene glycol, hexylene glycol, propanediol, ethylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, other sugars that are liquid at room temperature, water-soluble alkoxylated nonionic polymers such as polyethylene glycol, and combinations thereof. The solvent may be present in the formulation individually or in total (if two or more solvents are included) in an amount ranging from about 0.1% by weight to about 95% by weight (calculated by dividing the total weight of the solvent in the formulation by the total weight of the formulation).

[0157] In some embodiments, the topical formulation includes a viscosity modifier. In some embodiments, the viscosity modifier is a thickener. Common thickeners include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenan, 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, rosin, resins, paraffin, and petrolatum. In some embodiments, the viscosity modifier is a carbohydrate. Exemplary carbohydrates include monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Exemplary polysaccharides include cellulose, methylcellulose, hydroxypropyl methylcellulose, chitin, galactoarabinan, polygalactose, and polyarabinose. Exemplary glycerides include hydroxystearate monoglyceride, hydroxystearate diglyceride, isostearate monoglyceride, isostearate diglyceride, oleate monoglyceride, oleate diglyceride, ricinoleate monoglyceride, ricinoleate diglyceride, linoleate monoglyceride, linoleate diglyceride, linolenic acid monoglyceride, linolenic acid diglyceride, erucate monoglyceride, erucate diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citrate monoglyceride, citrate diglyceride, malic acid monoglyceride, malic acid monoglyceride, malic acid diglyceride, and mixtures thereof. In some embodiments, the viscosity modifier is a polymer. The polymer may be natural or synthetic. Natural polymers include polysaccharides, nucleic acids, and proteins. Examples of synthetic polymers include polyesters, polyureas, polycarbonates, polyvinyl alcohols, polyamides, polyethers, polyesters, polyamines, polytyrosine, polyanhydrides, polyphosphazenes, polyacrylamides, polyacrylates, polymethacrylates, and polyvinylpyrrolidone (PVP). Exemplary thickeners include alginate derivatives, pre-neutralized carbomer 430, hydrophilic silica, polysaccharides, xanthan gum, guar, agar, carboxymethylcellulose, hydroxyethylcellulose, polyacrylates, polyacrylamides, PVP, and salts.

[0158] In some embodiments, the topical formulation includes an adhesion modifier. In some embodiments, the topical formulation includes an adhesive polymer. The adhesive polymer has physicochemical properties that allow for long-term adhesion to the tissue surface. In some embodiments, including an adhesive polymer in the formulation increases the amount of time the activator can contact and diffuse across a barrier (e.g., skin). In some embodiments, the adhesive polymer is chitosan, gelatinous gum, lectin, sodium alginate, soluble starch, tragacanth, xanthan gum deacetylated gum, polyacrylic acid, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, a type of thiomer, polycarbophil, hyaluronic acid, dermatan sulfate, or a combination thereof. In some embodiments, the adhesion modifier is a tackifier. Common tackifiers include, but are not limited to, gums, resins (natural or modified), carbomers, or other natural or synthetic polymers.

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

[0160] In embodiments, the topical formulation contains an antioxidant. While not theoretically bound, antioxidants can generally delay or inhibit the oxidative degradation of the components of the topical formulation, thereby improving the stability of the topical formulation and extending its shelf life. In embodiments, the antioxidant is α-tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, methionine, citric acid, ascorbic acid, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metasulfite, ascorbyl palmitate, thioglycerol, propyl gallate, cysteine, or a combination thereof. In some embodiments, the antioxidant is cyclodextrin, D-α-tocopherol, rosmarinic acid, or a combination thereof.

[0161] In some embodiments, the topical formulation includes a solubilizer. While not theoretically bound, the solubilizer generally forms a complex with the active ingredient that may have different physicochemical properties than the active ingredient alone. The properties of the complex can increase the solubility of the active ingredient in the formulation. In some embodiments, the solubilizer is a water-soluble organic solvent, a nonionic surfactant, a water-insoluble lipid, an organic liquid, a cyclodextrin, or a phospholipid. In some embodiments, the solubilizer is a water-soluble enhancer. In some embodiments, the water-soluble enhancer is polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, xanthan gum, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, or a combination thereof. In some embodiments, the solubilizer is propylene glycol. In some embodiments, the solubilizer is xanthan gum. In some embodiments, the solubilizer is a nonionic surfactant. In some embodiments, the nonionic surfactant is Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, mono and di fatty acid esters of PEG 300, 400, or 1750, or a combination thereof. In some embodiments, the solubilizer is an organic liquid. In some embodiments, the organic liquid is beeswax, d-alpha-tocopherol, oleic acid, or a medium-chain mono- or diglyceride. In some embodiments, the solubilizer is cyclodextrin. In some embodiments, the solubilizer is a phospholipid. In some embodiments, the phospholipid is hydrogenated soybean phosphatidylcholine, distearoyl phosphatidylglycerol, L-alpha-dimryristoyl phosphatidylcholine, or L-alpha-dimryristoyl phosphatidylglycerol. In some embodiments, the solubilizer is lecithin.

[0162] In embodiments, the topical formulation includes a colorant. Suitable colorants and / or dyes and / or pigments include, for example, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, brown, and combinations thereof, and pigments such as Timica Extra Large Sparkles, titanium dioxide and chromium oxide green, ultramarine blue and pink, and iron oxide. The colorants and / or dyes and / or pigments may be present in the disclosed formulation individually or in total (if two or more colorants and / or dyes and / or pigments are included) in an amount ranging from about 0.01% by weight to about 5% by weight (calculated as the total weight of the colorants and / or dyes and / or pigments in the formulation divided by the total weight of the formulation). The colorants may be present in the disclosed formulation individually or in total (if two or more colorants are included) in an amount ranging from about 0.01% by weight to about 5% by weight (calculated as the total weight of the colorants in the formulation divided by the total weight of the formulation).

[0163] In embodiments, the topical formulation includes a binder. Suitable binders include, but are not limited to, polyvinylpyrrolidone (PVP), marine colloids, carboxyvinyl polymers, starch, cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (carmellose), hydroxypropylmethylcellulose, hydroxyethylpropylcellulose, hydroxybutylmethylcellulose and their salts (e.g., carmellose sodium), natural gums such as karaya, xanthan gum, carrageenan, gellan gum, locust bean gum, gum arabic, and tragacanth gum, chitosan, colloidal magnesium aluminum silicate, and colloidal silica. The binder may be present in the disclosed formulation individually or collectively (if two or more binders are included) in an amount ranging from about 0.01% to about 5% by weight (calculated as the total weight of the binder in the formulation divided by the total weight of the formulation).

[0164] In embodiments, the topical formulation includes a humectant. The humectant, such as low molecular weight polyethylene glycol (e.g., PEG6-PEG12), may be present individually or collectively (if two or more humectants are included) in the formulation in amounts up to about 10% by weight, up to about 5% by weight, up to about 3% by weight, up to about 1% by weight, or up to about 0.1% by weight (calculated by dividing the total weight of the humectants in the formulation by the total weight of the formulation).

[0165] In embodiments, the topical formulation includes a surfactant. The surfactant that may be included in the formulation may be anionic, nonionic, or amphoteric compound. Suitable examples of anionic surfactants are one or more higher alkyl sulfates such as potassium lauryl sulfate or sodium lauryl sulfate, higher fatty acid monoglyceride monosulfates such as monosulfated monoglycerides of hydrogenated coconut oil fatty acids, alkyl sulfonates such as sodium dodecylbenzenesulfonate, higher fatty acid sulfoacetates, and higher fatty acid esters of 1,2-dihydroxypropanesulfonate. Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various hydrogen-containing compounds that are reactive therewith and have long hydrophobic chains (e.g., aliphatic chains of about 12 of 20 carbon atoms), the condensation products of hydrophilic polyoxyethylene moieties, e.g., poly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides and other fatty moieties, as well as condensation products with propylene oxide and polypropylene oxide, e.g., Pluronic materials such as Pluronic F127. Suitable example alkyl polyglycoside (APG) surfactants that may be used in formulations may include APG C8-C10, APG C10-C16, decyl glucoside, coco glucoside, anionic APG carboxylate, sodium lauryl glucose carboxylate, lauryl glucoside, D-glucopyranose (oligomeric type, CIO-16 glycoside, carboxymethyl ether, sodium salt), C12-C16 fatty alcohol glycosides, and combinations thereof. Exemplary APG surfactants that may be used may have industry names such as Plantaren® 2000 N UP / MB, Plantapon® LGC Sorb, Plantaren® 1200 N UP / MB, and Plantaren® 818 UP / MB. Surfactants may be present in the formulation, individually or collectively (if two or more surfactants are present), in amounts ranging from approximately 0.01% by weight to approximately 10% by weight (calculated by dividing the total weight of surfactants in the formulation by the total weight of the formulation).

[0166] In embodiments, the topical formulation includes a gelling agent. Exemplary gelling agents used in the disclosed formulation may include pectin, starch, and gelatin forms derived from animal or plant (e.g., porcine gelatin). Pectin in the formulation may include, for example, high-methoxyl pectin, low-methoxyl pectin, or a combination thereof. In some embodiments, the pectin is amidated pectin. In other embodiments, the pectin is unamidated pectin. In certain embodiments, the pectin is a combination of amidated and unamidated pectin. Gelatin in the formulation may include type A gelatin, type B gelatin, skin gelatin (e.g., calf skin, porcine skin), and / or bone gelatin (e.g., calf bone, porcine bone), used alone or in combination. One or more gelling agents may be present in the formulation individually or collectively (if multiple gelling agents are included) in an amount ranging from about 0.1% by weight to about 20% by weight (calculated as the total weight of gelling agents in the formulation divided by the total weight of the formulation).

[0167] In some embodiments, the disclosed compositions are formulated as oral solid dosage forms. Oral solid dosage forms may include, but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multi-particle formulations, beads, spheres, and / or any combination thereof. Oral solid dosage forms may be formulated as immediate-release, controlled-release, sustained-release formulations, sustained-release, or modified-release formulations. Thus, in some embodiments, the disclosed oral solid dosage forms may be in the form of tablets (including suspension tablets, fast-disintegrating tablets, chewable tablets, rapid-disintegrating tablets, effervescent tablets, or caplets), pills, powders (including sterile-packaged powders, dispensable powders, or effervescent powders), capsules (including both soft capsules and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersions, solid solutions, bioerosive dosage forms, controlled-release formulations, pulse-release formulations, multi-particle dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet another embodiment, the pharmaceutical formulation is in the form of a tablet, including a fast-dissolving tablet. Furthermore, the pharmaceutical formulation may be administered as a single capsule or in the form of multiple capsules. In some embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.

[0168] Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, flow enhancers, binders, dispersants, suspending agents, disintegrants, thickeners, film-forming agents, granulation aids, flavoring agents, sweeteners, coating agents, solubilizers, and combinations thereof. Oral solid dosage forms may also contain, alone or in combination, one or more pharmaceutically acceptable additives such as compatible carriers, complexing agents, ionic dispersion regulators, disintegrants, surfactants, lubricants, colorants, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, and defoaming agents, and one or more auxiliary active compounds.

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

[0170] In some embodiments, the disclosed compositions are formulated as oral liquid dosage forms. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions. These oral liquid dosage forms may be formulated using any pharmaceutically acceptable excipients known to those skilled in the art for preparing liquid dosage forms, as well as solvents, diluents, carriers, and other excipients selected to be appropriate for the solubility and other properties of the activator and other components. Solvents may be, for example, water, glycerin, monosyrups, alcohols, medium-chain triglycerides (MCTs), and combinations thereof.

[0171] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and liquids, which may contain inert diluents such as water. Pharmaceutical formulations may be prepared as liquid suspensions or liquids using sterile liquids such as oils, water, and alcohols, and combinations of pharmaceutically appropriate surfactants, suspending agents, and emulsifiers may be added for oral or parenteral administration. Liquid formulations may also be prepared as single-dose or multi-dose beverages. Suspensions may contain oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include carrier oils such as MCT oil and long-chain triglyceride (LCT) oil. Suspension formulations may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycers, and acetylated fatty acid glycers. The suspension formulation may contain alcohol (such as ethanol, isopropyl alcohol, or 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 the suspension formulation. Therefore, the suspension may contain aqueous or non-aqueous liquids, oil-in-water liquid emulsions, or water-in-oil emulsions.

[0172] In some embodiments, formulations are provided for oral administration to a subject, comprising the disclosed composition and at least one dispersant or suspending agent. The formulation may be a powder and / or granules for suspension, which, when mixed with water, yield a substantially homogeneous suspension. The aqueous dispersion may contain amorphous and non-amorphous particles of multiple effective particle sizes so that the drug is absorbed in a controlled manner over time.

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

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

[0175] In some embodiments, the disclosed pharmaceutical compositions can be formulated into ophthalmic formulations. The ophthalmic formulations of this disclosure include topical formulations such as eye drops, gels, and ointments, and may include excipients suitable for topical formulations, such as penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and co-solvents, viscosity modifiers (e.g., thickeners), adhesion modifiers (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizers, colorants, binders, humectants, surfactants, gelling agents, and other such components described herein and commonly known to those skilled in the art.

[0176] The disclosed ophthalmic formulations may contain one or more viscosity modifiers and have a viscosity that is comfortable to the eye and does not cause blurring of vision. For example, the ophthalmic formulations may have a viscosity of 1.0 to 100,000 cP (e.g., about 2.0 to 90,000 cP or about 2.5 to 75,000 cP). Viscosity modifiers are substances that have the ability to cause thickening (increase in viscosity) of ophthalmic formulations. Examples of viscosity modifiers include xanthan gum, EDTA, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyethylene glycol, propylene glycol alginate, chitosan, and tragacanth. Hydrogels may also be used as thickening excipients, particularly in artificial tears. Suitable viscosity modifiers can be used in all formulations referred to herein. The concentration of viscosity modifiers in the ophthalmic formulations of this disclosure may range from about 0.1% to about 10% by weight (e.g., 1% to 5% by weight). Sorbitol can be used as a composite excipient of an isotonic agent and a viscosity modifier. Sorbitol may be used in the ophthalmic formulations of this disclosure in a concentration range of about 0.1% to about 10% by weight (e.g., 2% to 5% by weight).

[0177] Ophthalmic formulations may include, for example, penetration enhancers to aid the penetration of one or more active compounds into and across the skin or eyelid skin. Examples of penetration enhancers for ophthalmic formulations include, for example, aliphatic alcohols, fatty acids (including their salts), 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. In some embodiments, the penetration enhancer is ethanol, glycerol, diethylene glycol, propylene glycol, polyethylene glycol and higher aliphatic alcohols (e.g., saturated or unsaturated higher aliphatic alcohols 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 their salts); 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, Esters of fatty acids such as pimelic acid, crotonic acid, sorbic acid, maleic acid, fumaric acid, and sebacic acid with lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, heptanol, and octanol; isopropyl myristate, isopropyl palmitate, diisopropyl adipate, and diethyl sebacate; ethers of polyhydric alcohols 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, oligosaccharides, and reduced oligosaccharides with alkyl alcohols;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., monoglycerides, diglycerides, triglycerides and mixtures thereof), glyceryl monolaurate, glyceryl monomyristate, glyceryl monostearate, glyceryl monooleate, glyceryl dilaurate, glyceryl dimyristate, glyceryl distearate, glyceryl trilaurate, glyceryl trimyristate and glyceryl tristearate, ethyl monocaprylate These include propylene glycol, propylene glycol monocaprylate, glyceryl monocaprylate, mono-2-ethylene glycol ethylhexanoate, mono-2-propylene glycol ethylhexanoate, di(2-propylene glycol) ethylhexanoate, propylene glycol, dicaprylate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate, methyl lactate, ethyl lactate, methyl 2-methoxypropionate, ethyl 2-methoxypropionate, monoethanolamine, triethanolamine, creatinine, and meglumine. In some embodiments, the ophthalmic formulation includes a wettable powder. The wettable powder can also facilitate the penetration of active compounds through cells or junctions of barriers, including mucous membranes, cutaneous mucous membranes, and the stratum corneum. Examples of wettable powders include, for example, hyaluronic acid (or its salts, e.g., sodium hyaluronate), water, physiological saline, and PVP, propylene glycol, glycerol, sorbitol, polyethylene glycol, despanthenol, pantothenic acid, ectoin, carboxyvinyl polymer, carmellose sodium, and povidone.

[0178] In some embodiments, the ophthalmic formulation includes a surfactant. The surfactant can promote the dissolution and / or absorption of the formulation components and includes, for example, any of anionic surfactants, cationic surfactants, nonionic surfactants, and amphoteric surfactants. Exemplary surfactants include, for example, any of fatty acid salts, alkyl sulfates, polyoxyethylene alkyl sulfates, alkyl sulfocarboxylates, alkyl ether carboxylates, amine salts, quaternary ammonium salts, polysorbate 80, poloxamer, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, alkyl betaines, dimethylalkylglycine, and lecithin.

[0179] In some embodiments, the ophthalmic formulation is a gum and / or resin, for example, sodium polyacrylate, cellulose ether, calcium alginate, carboxyvinyl polymer, ethylene-acrylic acid copolymer, vinylpyrrolidone polymer, vinyl alcohol-vinylpyrrolidone copolymer, nitrogen-substituted acrylamide polymer, polyacrylamide, cationic polymers such as cationic guar gum, dimethylacrylammonium polymer, acrylic acid-methacrylic acid copolymer, polyoxyethylene-polypropylene copolymer, polyvinyl alcohol, It contains any of the following: lulan, agar, gelatin, chitosan, polysaccharides derived from tamarind seeds, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, gum arabic, microcrystalline cellulose, arabinogalactan, karaya gum, tragacanth gum, alginate, albumin, casein, curdlan, gellan gum, dextran, cellulose, polyethyleneimine, high polymer polyethylene glycol, cationic silicone polymer, synthetic latex, acrylic silicone, trimethylsiloxysilicate, and fluorinated silicone resin.

[0180] In some embodiments, the ophthalmic formulation includes a pH adjuster. The pH adjuster can be used to adjust the pH of the formulation to a desired range, for example, pH 4 to 10, pH 5 to 8, or any range that maximizes the penetration of one or more compounds in the composition into the skin. In some embodiments, the pH adjuster is one of the following: hydrochloric acid, citric acid, sodium citrate, acetic acid, sodium acetate, ammonium acetate, succinic acid, tartaric acid, sodium L-tartrate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, lactic acid, calcium lactate, sodium lactate, sodium fumarate, sodium propionate, boric acid, ammonium borate, maleic acid, phosphoric acid, sodium hydrogen phosphate, malic acid, adipic acid, triethanolamine, diisopropanolamine, meglumine, monoethanolamine, sulfuric acid, and potassium aluminum sulfate.

[0181] In some embodiments, the ophthalmic formulation includes a stabilizer. Exemplary stabilizers include, for example, 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 dihydrate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbic acid, and / or succinic acid.

[0182] Further ophthalmic formulations of this disclosure include contact lenses. In some embodiments, the disclosed compounds or pharmaceutical compositions are incorporated into contact lenses for drug delivery to the eye. The contact lenses may be hydrogel contact lenses or molecularly imprinted contact lenses. Another exemplary contact lens drug delivery system known to those skilled in the art is the experimental SIGHT (Sustained Innovative Glaucoma and Ocular Hypertension Treatment) therapy, which aims 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 a contact lens formulated for controlled drug release. The SIGHT lens includes a drug layer and a barrier layer on the lens surface to control the diffusion release rate of the drug. Ophthalmic formulations of this disclosure include those with material designs similar to the SIGHT lens, as well as others commonly known to those skilled in the art (e.g., Franco et al., Polymers, 2021, 13, 1102).

[0183] The disclosed pharmaceutical compositions contain any excipients (e.g., surfactants, carriers, antioxidants, etc.) in amounts of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, and about 1% of the formulation by weight or volume. It may be contained in concentrations of 4%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 75%, approximately 75%, or approximately 80%.

[0184] E. Combinations of medications It should be readily apparent that the disclosed compositions are not limited to a single combination of compounds, or (when formulated as a pharmaceutical composition) to a single carrier, diluent, and / or excipient, but may also include multiple compounds (including further active compounds), and / or combinations of multiple carriers, diluents, and excipients. Accordingly, the pharmaceutical compositions of this disclosure may include the compound of formula (1) in combination with one or more other active agents (or their derivatives and analogues), together with one or more pharmaceutically acceptable carriers, diluents, and / or excipients, and together with one or more other active compounds.

[0185] In some embodiments, the formulations of the present disclosure are prepared to enhance existing therapeutic effects, provide further therapeutic effects, increase desired properties such as stability or shelf life, reduce undesirable effects or properties, alter properties in a desired manner (e.g., pharmacokinetic or pharmacodynamic), modulate desired systems or pathways (e.g., neurotransmission systems), or provide synergistic effects.

[0186] The “therapeutic effects” that may be increased or added in embodiments of this disclosure include, but are not limited to, antioxidant, anti-inflammatory, analgesic, antineuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anticancer, antiemetic, appetite-stimulating, anti-ulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilating, neuroprotective, empathogenic, psychoactive, sedative, and stimulating effects.

[0187] "Synergistic effect" should be understood as an increase in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect that is greater than the additive contribution of the components acting individually. There are numerous methods known to those skilled in the art for determining whether there is a synergistic effect with respect to a particular effect, that is, whether the effect of mixing two or more components together is greater than the sum of the effects of the individual components applied individually, thereby resulting in "1+1>2". Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol., 2019;10:1222) or Loewe's additiveity equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326). Synergistic effects can also 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 mentioned above are the concentration-effect curve and the combination exponential curve, respectively. Applying each of the equations mentioned above to experimental data to create the corresponding graphs can help evaluate the effects of drug combinations.

[0188] In some embodiments, the disclosed pharmaceutical composition comprises further active compounds. In some embodiments, the further active compounds are selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and anti-nociceptive agents, anti-migraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociative agents, cannabinoids, immunostimulants, anticancer agents, antiemetics, appetite stimulants, anti-ulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotective agents, nootropics, empathogens, psychoactive agents, plasticity inducers (e.g., psychoplasticizers), monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins. In some embodiments, further active compounds act to increase therapeutic effects, provide further therapeutic effects, reduce undesirable effects, increase stability or shelf life, improve bioavailability, induce synergistic effects, increase plasticity (e.g., neuroplasticity), or alter pharmacokinetics or pharmacodynamics. In some embodiments, further therapeutic effects include antioxidant, anti-inflammatory, analgesic, antineuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anticancer, antiemetic, appetite-stimulating, anti-ulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilating, neuroprotective, empathy-generating, psychoactive, sedative, or stimulating effects.

[0189] In some embodiments, the further active compound is tryptamine. As will be understood by those skilled in the art, tryptamine is a compound having the following general structure, where R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 This is defined herein and as commonly understood in the art: [ka]

[0190] In some embodiments, R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 Each of these is independently hydrogen, deuterium, halogen (F, Cl, Br or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Furthermore, R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 Any two of these and an intervening atom can combine to form optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In embodiments, tryptamine is R N1 and R N2 Further R to the nitrogen to which it is bonded N3 It is a quaternary salt that is connected; R N3 This is optionally a substituted alkyl, optionally a substituted alkoxy, optionally a substituted alkyl, optionally a substituted alkenyl, optionally a substituted alkynyl, optionally a substituted cycloalkyl, optionally a substituted cycloalkenyl, optionally a substituted aryl, or optionally a substituted heterocyclyl.

[0191] In some embodiments, further active compounds include O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 6-allyl-N,N-diethyl-norlycergamide (AL-LAD), N,N-dibutyltryptamine (DBT), N,N-diethyltryptamine (DET), N,N-diisopropyltryptamine (DiPT), 5-methoxy-α-methyltryptamine (α,O-DMS), N,N-dimethyltryptamine (DMT), 2,α-dimethyltryptamine (2,α-DMT), and α,N-dimethyltryptamine (α N,N-DMT), N,N-dipropyltryptamine (DPT), N-ethyl-N-isopropyltryptamine (EiPT), α-ethyltryptamine (AET), 6,N,N-triethylnorlycergamide (ETH-LAD), 3,4-dihydro-7-methoxy-1-methylcarboline (Harmarin), 7-methoxy-1-methylcarboline (Harmine), N,N-dibutyl-4-hydroxytryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl-4-hydroxytryptamine Tamin (4-HO-DiPT), 4-hydroxy-N,N,N-trimethyltryptamine (4-HO-TMT), N,N-dimethyl-4-hydroxytryptamine (4-HO-DMT), N,N-dimethyl-5-hydroxytryptamine (5-HO-DMT, buhotenine), N,N-dipropyl-4-hydroxytryptamine (4-HO-DPT), N-ethyl-4-hydroxy-N-methyltryptamine (4-HO-MET), 4-hydroxy-N-isopropyl-N-methyltryptamine (4-HO-MiPT), 4-hydroxy-N-methyl- N-propyl-tryptamine (4-HO-MPT), 4-hydroxy-N,N-tetramethylenetryptamine (4-HO-pyr-T), 12-methoxyibogamine (ibogaine), N-butyl-N-methyltryptamine (MBT), N,N-diisopropyl-4,5-methylenedioxytryptamine (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylenedioxytryptamine (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxytryptamine (4,5-MDO-DMT), N,N-dimethyl-5,6-Methylenedioxytryptamine (5,6-MDO-DMT), N-Isopropyl-N-methyl-5,6-methylenedioxytryptamine (5,6-MDO-MiPT), N,N-Diethyl-2-methyltryptamine (2-Me-DET), 2,N,N-Trimethyltryptamine (2-Me-DMT), N-Acetyl-5-methoxytryptamine (Melatonin), N,N-Diethyl-5-methoxytryptamine (5-MeO-DET), N,N-Diisopropyl-5-methoxytryptamine (5-Me O-DiPT), N,N,diallyl-5-methoxytryptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-isopropyl-4-methoxy-N-methyltryptamine (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyltryptamine (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyltryptamine (5,6-MeO-MiPT), 5-methoxy-N-methyltryptamine (5-MeO-N MT), 5-Methoxy-N,N-tetramethylenetryptamine (5-MeO-pyr-T), 6-Methoxy-1-methyl-1,2,3,4-tetrahydrocarborin (6-MeO-THH), 5-Methoxy-2,N,N-trimethyltryptamine (5-MeO-TMT), N,N-dimethyl-5-methylthiotryptamine (5-MeS-DMT), N-isopropyl-N-methyltryptamine (MiPT), α-methyltryptamine (α-MT), N-ethyltryptamine (NET), N-methyltryptamine The tryptamine is selected from the group consisting of α,N-dimethyl-5-methoxytryptamine (α,N,O-TMS), α-methyl-1,2,3,4-tetrahydrocarboline (tetrahydroharmin), or α,N-dimethyl-5-methoxytryptamine (α,N,O-TMS), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, or a combination thereof.

[0192] In some embodiments, the further tryptamine is a “complex tryptamine” or other indoleamine, including ibogaine and other iboga alkaloids, as well as their analogs, metabolites and derivatives, and examples such as β-carbolin.

[0193] In some embodiments, the further active compound is phenethylamine. As will be understood by those skilled in the art, phenethylamine is a compound having the following general structure, where R N1 , R N2 , R α , R β , and R 2 ~R 6 Each of these is as taught herein and as is commonly understood in the art: [ka]

[0194] In some embodiments, R N1 , R N2 , R α , R β , and R 2~6 Each of these is independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In some embodiments, R 3 and R 4 These combine to form heterocyclines, which may be substituted, such as dioxol (similar to MDMA), furan, tetrahydrofuran, thiophene, pyrrole, pyridine, pyrrolidine, ethylene oxide, ethyleneimine, trimethylene oxide, pyran, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine. In some embodiments, R 3 and R 4These combine to form an aryl that is more substituted in some cases, such as phenyl. In some embodiments, phenethylamine is R N1 , R N2 , and further R N3 Each of the substituents is independently an alkyl or aryl group, and the quaternary ammonium cation comprises the same substituents as above. In some embodiments, phenethylamine is R N1 and R N2 Further R to the nitrogen to which it is bonded N3 It is a quaternary salt that is connected; R N3 This is optionally a substituted alkyl, optionally a substituted alkoxy, optionally a substituted alkyl, optionally a substituted alkenyl, optionally a substituted alkynyl, optionally a substituted cycloalkyl, optionally a substituted cycloalkenyl, optionally a substituted aryl, or optionally a substituted heterocyclyl.

[0195] In some embodiments, further active compounds include α-ethyl-3,4,5-trimethoxyphenethylamine (AEM), 4-allyloxy-3,5-dimethoxyphenethylamine (AL), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH), 2,5-dimethoxy-4-ethylthioamphetamine (ALEPH-2), 2,5-dimethoxy-4-isopropylthioamphetamine (ALEPH-4), 2,5-dimethoxy-4-phenylthioamphetamine (ALEPH-6), and 2,5-dimethoxy-4-propylthioamphetamine. Tamin (ALEPH-7), 2,5-dimethoxy-α-ethyl-4-methylphenethylamine (ARIADNE), 3,4-diethoxy-5-methoxyphenethylamine (ASB), 4-butoxy-3,5-dimethoxyphenethylamine (B), 2,5-dimethoxy-4,N-dimethylamphetamine (BEATRICE), 2,5-bismethylthio-4-methylamphetamine (BIS-TOM), 4-bromo-2,5,β-trimethoxyphenethylamine (BOB), 2,5,β-trimethoxy-4-methylphenethylamine (BOD), β-meth Xy-3,4-methylenedioxyphenethylamine (BOH), 2,5-dimethoxy-β-hydroxy-4-methylphenethylamine (BOHD), 3,4,5,β-tetramethoxyphenethylamine (BOM), 4-bromo-3,5-dimethoxyamphetamine (4-Br-3,5-DMA), 2-bromo-4,5-methylenedioxyamphetamine (2-Br-4,5-MDA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-benzyloxy-3,5 -Dimethoxy-amphetamine (3C-BZ), 4-chloro-2,5-dimethoxyphenethylamine (2C-C), 2,5-dimethoxy-4-methylphenethylamine (2C-D), 2,5-dimethoxy-4-ethylphenethylamine (2C-E), 3,5-dimethoxy-4-ethoxyamphetamine (3C-E), 2,5-dimethoxy-4-fluorophenethylamine (2C-F), 2,5-dimethoxy-3,4-dimethylphenethylamine (2C-G), 2,5-dimethoxy-3,4-trimethylenephenethylamine (2C-G-3), 2,5-Dimethoxy-3,4-tetramethylenephenethylamine (2C-G-4), 3,4-norbornyl-2,5-dimethoxyphenethylamine (2C-G-5), 1,4-dimethoxynaphthyl-2-ethylamine (2C-GN), 2,5-dimethoxyphenethylamine (2C-H), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), 2,5-dimethoxy-4-nitrophenethylamine (2C-N), 2,5-dimethoxy-4-isopropoxyphenethylamine (2C-O-4), 2,5-dimethoxy-4-propylphenethylamine Luamine (2C-P), 4-cyclopropylmethoxy-3,5-dimethoxyphenethylamine (CPM), 2,5-dimethoxy-4-methylselenophenethylamine (2C-SE), 2,5-dimethoxy-4-methylthiophenethylamine (2C-T), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,6-dimethoxy-4-isopropylthiophenethylamine (psi-2C-T-4), 2,5-dimethoxy-4-propylthio Phenethylamine (2C-T-7), 4-Cyclopropylmethylthio-2,5-dimethoxyphenethylamine (2C-T-8), 4-(t)-butylthio-2,5-dimethoxyphenethylamine (2C-T-9), 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine (2C-T-13), 4-Cyclopropylthio-2,5-dimethoxyphenethylamine (2C-T-15), 4-(s)-butylthio-2,5-dimethoxyphenethylamine (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio) Phenethylamine (2C-T-21), 3,5-dimethoxy-4-triduteromethylphenethylamine (4-D), β,β-didutero-3,4,5-trimethoxyphenethylamine (β-D), 3,5-dimethoxy-4-methylphenethylamine (DESOXY), 2,4-dimethoxyamphetamine (2,4-DMA), 2,5-dimethoxyamphetamine (2,5-DMA), 3,4-dimethoxyamphetamine (3,4-DMA), 2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine (DMCPA), 3,4-Dimethoxy-β-hydroxyphenethylamine (DME), 2,5-Dimethoxy-3,4-methylenedioxyamphetamine (DMMDA), 2,3-Dimethoxy-4,5-methylenedioxyamphetamine (DMMDA-2), 3,4-Dimethoxyphenethylamine (DMPEA), 4-Amyl-2,5-Dimethoxyamphetamine (DOAM), 4-Bromo-2,5-Dimethoxyamphetamine (DOB), 4-Butyl-2,5-Dimethoxyamphetamine (DOBU), 4-Chloro-2,5-Dimethoxyamphetamine (DOC ), 2,5-dimethoxy-4-(2-fluoroethyl)amphetamine (DOEF), 2,5-dimethoxy-4-ethylamphetamine (DOET), 4-iodo-2,5-dimethoxyamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM(STP)), 2,6-dimethoxy-4-methylamphetamine (psi-DOM), 2,5-dimethoxy-4-nitroamphetamine (DON), 2,5-dimethoxy-4-propylamphetamine (DOPR), 3,5-dimethoxy-4-ethoxyphenethylamine (E), 2,4,5-triethoxyamphetamine (EEE), 2,4-diethoxy-5-methoxyamphetamine (EEM), 2,5-diethoxy-4-methoxyamphetamine (EME), 4,5-dimethoxy-2-ethoxyamphetamine (EMM), 2-ethylamino-1-(3,4-methylenedioxyphenyl)butane (ETHYL-J), 2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane (ETHYL-K), 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran ( F-2), 6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran (F-22), N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine (FLEA), 2,5-dimethoxy-3,4-(trimethylene)amphetamine (G-3), 2,5-dimethoxy-3,4-(tetramethylene)amphetamine (G-4), 3,6-dimethoxy-4-(2-aminopropyl)benzonorbornane (G-5), 2,5-dimethoxy-3,4-dimethylamphetamine (GANESHA), 1,4-Dimethoxynaphthyl-2-isopropylamine (GN), 2,5-Dimethoxy-4-ethylthio-N-hydroxyphenethylamine (HOT-2), 2,5-Dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine (HOT-7), 4-(s)-Butylthio-2,5-Dimethoxy-N-hydroxyphenethylamine (HOT-17), 2,5-Dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA), 2,3,4-Trimethoxyphenethylamine (IM), 3,5-Dimethoxy-4-isopropoxyph Ethoxyamine (IP), 5-ethoxy-2-methoxy-4-methylamphetamine (IRIS), 2-amino-1-(3,4-methylenedioxyphenyl)butane (J,BDB), 3-methoxy-4,5-methylenedioxyphenethylamine (LOPHOPHINE), 3,4,5-trimethoxyphenethylamine (M), 4-methoxyamphetamine (4-MA,PMA), 2,N-dimethyl-4,5-methylenedioxyamphetamine (MADAM-6), 3,5-dimethoxy-4-methallyloxyphenethylamine (MAL), 3,4- Methylenedioxyamphetamine (MDA), N-allyl-3,4-methylenedioxyamphetamine (MDAL), N-butyl-3,4-methylenedioxyamphetamine (MDBU), N-benzyl-3,4-methylenedioxyamphetamine (MDBZ), N-cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM), N,N-dimethyl-3,4-methylenedioxyamphetamine (MDDM), N-ethyl-3,4-methylenedioxyamphetamine (MDE), N-(2-hydroxyethyl)-3,4-methylene N-dioxyamphetamine (MDHOET), N-isopropyl-3,4-methylenedioxyamphetamine (MDIP), N-methyl-3,4-methylenedioxyamphetamine (MDMA), 3,4-ethylenedioxy-N-methylamphetamine (MDMC), N-methoxy-3,4-methylenedioxyamphetamine (MDMEO), N-(2-methoxyethyl)-3,4-methylenedioxyamphetamine (MDMEOET), 3,4-methylenedioxy-α,α,N-trimethylphenethylamine (MDMP), N-hydroxy-3,4-Methylenedioxyamphetamine (MDOH), 3,4-Methylenedioxyphenethylamine (MDPEA), α,α-Dimethyl-3,4-Methylenedioxyphenethylamine (MDPH), 3,4-Methylenedioxy-N-propargyl-amphetamine (MDPL), 3,4-Methylenedioxy-N-propyl-amphetamine (MDPR), 3,4-Dimethoxy-5-ethoxyphenethylamine (ME), 4,5-Ethylenedioxy-3-methoxyamphetamine (MEDA), 4,5-Diethoxy-2-methoxyamphetamine ( MEE), 2,5-dimethoxy-4-ethoxyamphetamine (MEM), 4-ethoxy-3-methoxyphenethylamine (MEPEA), 5-bromo-2,4-dimethoxyamphetamine (META-DOB), 2,4-dimethoxy-5-methylthioamphetamine (META-DOT), 2,5-dimethoxy-N-methylamphetamine (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methylamphetamine (METHYL-DOB), 2-methylamino-1-(3,4-methylenedioxyphenyl)butane (METHY L-J, MBDB), 2-methylamino-1-(3,4-methylenedioxyphenyl)pentane (METHYL-K), 4-methoxy-N-methyl-amphetamine (METHYL-MA, PMMA), 2-methoxy-N-methyl-4,5-methylenedioxyamphetamine (METHYL-MMDA-2), 3-methoxy-4,5-methylenedioxyamphetamine (MMDA), 2-methoxy-4,5-methylenedioxyamphetamine (MMDA-2), 2-methoxy-3,4-methylenedioxyamphetamine (MMDA-3a), 4- Methoxy-2,3-methylenedioxyamphetamine (MMDA-3b), 2,4-dimethoxy-5-ethoxyamphetamine (MME), 3,4-dimethoxy-5-(n)-propoxyphenethylamine (MP), 2,5-dimethoxy-4-(n)-propoxyamphetamine (MPM), 4,5-dimethoxy-2-methylthioamphetamine (ORTHO-DOT), 3,5-dimethoxy-4-propoxyphenethylamine (P), 3,5-dimethoxy-4-phenethyloxyphenethylamine (PE), phenethylamine (PEA), 3,5-Dimethoxy-4-(2-propynyloxy)phenethylamine (PROPYNYL), 3,5-Diethoxy-4-methoxyphenethylamine (SB), 2,3,4,5-Tetramethoxyamphetamine (TA), 4-Ethoxy-3-ethylthio-5-methoxyphenethylamine (3-TASB), 3-Ethoxy-4-ethylthio-5-methoxyphenethylamine (4-TASB), 3,4-Diethoxy-5-methylthio-phenethylamine (5-TASB), 4-(, n)-Butylthio-3,5-dimethoxyphenethylamine (TB), 4-ethoxy-5-methoxy-3-methylthiophenethylamine (3-TE), 3,5-dimethoxy-4-ethylthiophenethylamine (TE, 4-TE), 3,4-dimethoxy-2-methylthiophenethylamine (2-TIM), 2,4-dimethoxy-3-methylthiophenethylamine (3-TIM), 2,3-dimethoxy-4-methylthiophenethylamine (4-TIM), 3,4-dimethoxy-5-methylthiophenethylamine (3-TM), 3,5-dimethoxy-4-methylthiophenethylamine Thirthiophenethylamine (4-TM), 3,4,5-trimethoxyamphetamine (TMA), 2,4,5-trimethoxyamphetamine (TMA-2), 2,3,4-trimethoxyamphetamine (TMA-3), 2,3,5-trimethoxyamphetamine (TMA-4), 2,3,6-trimethoxyamphetamine (TMA-5), 2,4,6-trimethoxyamphetamine (TMA-6), 4,5-dimethoxy-3-ethylthiophenethylamine (3-TME), 3-ethoxy-5-methoxy-4-methylthiophenethylamine (4-TME ), 3-ethoxy-4-methoxy-5-methylthiophenethylamine (5-TME), 3,4-methylenedioxy-2-methylthioamphetamine (2T-MMDA-3a), 2-methoxy-4,5-methylene-thiooxyamphetamine (4T-MMDA-2), 2,4,5-trimethoxyphenethylamine (TMPEA), 4-ethyl-5-methoxy-2-methylthioamphetamine (2-TOET), 4-ethyl-2-methoxy-5-methylthioamphetamine (5-TOET), 5-methoxy-4-methyl-2-methylthioamphetamine (2 -TOM), 2-methoxy-4-methyl-5-methylthioamphetamine (5-TOM), 2-methoxy-4-methyl-5-methyl-sulfinylamphetamine (TOMSO), 3,5-dimethoxy-4-propylthiophenethylamine (TP), 3,4,5-triethoxyphenethylamine (TRIS), 3-ethoxy-5-ethylthio-4-methoxyphenethylamine (3-TSB), 3,5-diethoxy-4-methylthiophenethylamine (4-TSB), 3,4-diethoxy-5-ethylthiophenethylamine (3-T-TRIS), 3,A phenethylamine selected from the group consisting of 5-diethoxy-4-ethylthiophenethylamine (4-T-TRIS) and (R)-2,5-dimethoxy-4-iodoamphetamine (R-DOI), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer or tautomer, or a combination thereof.

[0196] In the embodiment, the further active compound is ergoline. In the embodiment, the further active compound is ergot alkaloid. In the embodiment, the further active compound is lysergic acid amide. As will be understood by those skilled in the art, lysergic acid amide is a compound having the following general structure, where R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 This is defined herein and as commonly understood in the art: [ka]

[0197] In some embodiments, R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14Each of these is independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Furthermore, R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 Any two of these and the intervening atom together can form optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In some embodiments, the lysergic acid amide further R 6A However, R 6 It is a quaternary salt that is bonded to the nitrogen; R 6A This is optionally a substituted alkyl, optionally a substituted alkoxy, optionally a substituted alkyl, optionally a substituted alkenyl, optionally a substituted alkynyl, optionally a substituted cycloalkyl, optionally a substituted cycloalkenyl, optionally a substituted aryl, or optionally a substituted heterocyclyl.

[0198] In some embodiments, further active compounds include lysergic acid diethylamide (i.e., LSD, LSD-25, LAD, Delysid), 6-ethyl-6-nor-lysergic acid diethylamide (ETH-LAD), 6-propynyl-6-nor-lysergic acid diethylamide (PARGY-LAD), 6-allyl-6-nor-lysergic acid diethylamide (AL-LAD), 6-propyl-6-nor-lysergic acid diethylamide (PRO-LAD), 6-Isopropyl-6-nor-lysergic acid diethylamide (IP-LAD), 6-Cyclopropyl-6-nor-lysergic acid diethylamide (CIP-LAD), 6-Butyl-6-nor-lysergic acid diethylamide (BU-LAD), 6-(2-fluoroethyl)-6-nor-lysergic acid diethylamide (FLUOROETH-LAD), 1-Acetyl-lysergic acid diethylamide (i.e., ALD, ALD-52, N-acetyl-LSD), 1-Propionyl- Lysergic acid diethylamide (1P-LSD), 1-butyryl-lysergic acid diethylamide (1B-LSD), 1-valeryl-lysergic acid diethylamide (1V-LSD), 1-(cyclopropylmethanoyl)-lysergic acid diethylamide (1cP-LSD), 1-(1,2-dimethylcyclobutane-1-carbonyl)-lysergic acid diethylamide (1D-LSD), 1-propionyl-6-allyl-6-nor-lysergic acid diethylamide (1P-AL-LAD) The lysergic acid amide is selected from the group consisting of 1-(cyclopropylmethanoyl)-6-allyl-6-nor-lysergic acid diethylamide (1cP-AL-LAD), 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), 2,4-dimethylazetidide lysergic acid (i.e., LA-SS-Az, LSZ), piperidide lysergic acid (LSD-Pip), and methylisopropyl lysergic acid amide (MIPLA).

[0199] Other tryptamines, phenethylamines, and lysergic acid amides that are useful as further active compounds for the purposes of the present invention and are therefore intended to be included herein are generally known in the art (see, for example, Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997); Grob & Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi & Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacological Reviews, 2016; 68(2), 264-355; Glennon, Pharmacology Biochemistry and Behavior, 1999; 64, 251-256; each of these is incorporated by reference as if fully described herein).

[0200] F. Dosage and Administration In some embodiments, the pharmaceutical composition comprises a therapeutically effective dose or an effective dose of the disclosed compound for administration to a subject. Administration of a “therapeutically effective dose” or “effective dose” of the pharmaceutical composition to a subject means the administration of a sufficient amount of the composition to achieve the desired effect. If “effective dose” means an amount effective in treating the disorder or symptom described in the subject, then “therapeutic effect” is understood to mean one or more post-treatment responses in the mammal that are deemed desirable and beneficial. Thus, depending on the mental health disorder being treated, or the desired improvement in mental health or function, and depending on one or more specific components in the disclosed composition under consideration, these responses will differ, but will be readily apparent to those skilled in the art through an understanding of the disclosures herein and general knowledge in the art (for example, by referring to the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for the disorders described).

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

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

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

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

[0205] In some embodiments, if the pharmaceutical composition contains the disclosed compound, the disclosed compound is present in a single dose (in milligrams calculated based on the patient's kilogram body weight) of, for example, 0.25 mg / kg or less (including doses 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, and at least 1.0 mg / kg It may exist in amounts such as kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, as well as amounts within these ranges.

[0206] In some embodiments, if the pharmaceutical composition contains the disclosed compound, the disclosed compound may be present in such an amount that a single dose (in milligrams calculated based on the patient's kilogram body weight) is about 0.001 mg / kg to 1.0 mg / kg, about 0.005 mg / kg to 0.5 mg / kg, or about 0.01 mg / kg to 0.1 mg / kg, for example, 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 a range between these values. In some embodiments, the single dose is approximately 0.1 mg / kg to 1.0 mg / kg, for example, approximately 0.1 mg / kg, approximately 0.2 mg / kg, approximately 0.3 mg / kg, approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 0.6 mg / kg, approximately 0.7 mg / kg, approximately 0.8 mg / kg, approximately 0.9 mg / kg, and approximately 1.0 mg / kg, as well as amounts and ranges between these values.

[0207] In some embodiments, if the pharmaceutical composition contains the disclosed compound, the disclosed compound is present in a single dose (in milligrams calculated based on the patient's kilogram body weight) of, for example, 0.25 mg / kg or less (including doses of 0.10 mg / kg or less, 0.09 mg / kg or less, 0.08 mg / kg or less, 0.07 mg / kg or less, 0.06 mg / kg or less, 0.05 mg / kg or less, 0.04 mg / kg or less, 0.03 mg / kg or less, 0.02 mg / kg or less, 0.01 mg / kg or less, 0.005 mg / kg or less, and 0.001 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg It may exist in amounts such as kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, and at least 2.0 mg / kg, as well as amounts within these ranges.

[0208] In some embodiments, if the pharmaceutical composition contains the disclosed compound, the disclosed compound may be present in an amount such that the single dose is about 0.1 mg to 1.0 mg (whether such a dose is present in the unit dosage form or not), for example, 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, and a range between these values. In some embodiments, the single dose is about 1 mg to 10 mg, for example, 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, and a range between these values. In some embodiments, the single dose is about 10 mg to 100 mg.

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

[0210] In some embodiments, if the pharmaceutical composition contains a further active compound, for example, if the further active compound is phenethylamine or another tryptamine, the further active compound may be present in a single dose (in milligrams calculated based on the patient's kilogram body weight) of, for example, 0.25 mg / kg or less (including doses 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 It may be present in amounts of 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, as well as amounts within these ranges.

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

[0212] It will be understood that the dosage may vary depending on whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability or susceptibility of the symptoms targeted by the treatment, the desired clinical endpoint, previous, concurrent, or subsequent treatments, the subject's general health, age, sex and race, bioavailability, the possibility of systemic, local or local adverse reactions, the presence of other disorders or diseases in the subject, and other factors understood by those skilled in the art (e.g., medical history or family history).

[0213] The dose, frequency, or duration may be increased or decreased as indicated by the desired clinical outcome, the state of the disease or symptoms, any adverse side effects of the treatment or procedure, or concomitant medications. Those skilled in the art will understand, together with the teachings of this disclosure, the factors that may influence the dose, frequency, and timing necessary to provide a sufficient or effective amount to deliver a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0214] In some embodiments, the actual dose administered will be determined by a physician in light of the disorder being treated, the chosen route of administration, the actual composition or formulation being administered, the individual patient's age, weight and response, and the severity of the patient's symptoms. Therefore, it will be understood that no dose range disclosed herein is intended to limit the scope of this disclosure. In some cases, a dose below the lower limit of the disclosed range may be sufficient, while doses above the range may be used without causing adverse side effects. For example, such a high dose may be divided into several lower doses for administration, and may be administered together or separately.

[0215] In some embodiments, particularly when the formulation is prepared in a single unit dosage form such as a capsule, tablet, or lozenge, the recommended dosage can be determined by referring to the form of the formulation itself. In embodiments where the formulation is prepared in multiple dosage forms, such as liquid suspensions and topical formulations, the recommended dosage can be determined by referring to the means of administration, or by referring to the packaging and labeling, package inserts, marketing materials, training materials, or other information and knowledge available to those skilled in the art or the public.

[0216] Accordingly, another aspect of the present disclosure provides a pharmaceutical kit comprising a pharmaceutical composition or formulation of the present disclosure, recommended dosing guidelines or prescription information therefor, and a suitable container. Individual unit dosage forms may be included in multi-dose kits or containers. Pharmaceutical formulations may also be packaged in one or more unit dosage forms for uniformity of dosage and ease of administration.

[0217] G. Kitt Another aspect of this disclosure provides a pharmaceutical kit comprising a pharmaceutical composition or formulation of the disclosure, recommended dosing guidelines or prescription information therefor, and a suitable container. Individual unit dosage forms may be included in multi-dose kits or containers. Pharmaceutical formulations may also be packaged in one or more unit dosage forms for uniformity of dosage and ease of administration.

[0218] A kit generally includes appropriate packaging. A kit may include one or more containers containing any of the compounds described herein. Each component (if there are two or more components) may be packaged in a separate container, or several components may be combined in one container, where cross-reactivity and shelf life permit. A kit may be a unit dosage form, a bulk package (e.g., a multi-dose package), or a sub-unit dose. For example, a kit may be provided containing sufficient doses of the compounds disclosed herein and / or further pharmaceutically active compounds useful for diseases detailed herein, to provide effective treatment of an individual over any of the following long periods: one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or longer. A kit may also include multiple unit doses of the compounds and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0219] Preferably, information regarding drug administration and appropriate dosing (if necessary) is printed directly on the multi-dose kit (e.g., on the blister pack or other internal packaging holding the compositions or formulations of the Disclosure); however, the kits of the Disclosure may further include a package insert and other printed instructions (e.g., on the outer packaging) for administering the disclosed compositions and for their appropriate therapeutic use.

[0220] H.How to use In some embodiments, methods for using the disclosed compounds are provided herein. In some embodiments, the disclosed compounds are used to modulate neurotransmission. In some embodiments, the disclosed compounds are used to treat conditions such as diseases or disorders. In some embodiments, the disclosed compounds are used in the manufacture of pharmaceuticals for therapeutic and / or prophylactic treatment of conditions such as diseases or disorders. In some embodiments, the disclosed compounds are administered as part of a treatment. In some embodiments, the disclosed compounds are administered in conjunction with psychotherapy, psychological support, or patient monitoring. In some embodiments, the disclosed compounds are administered in therapeutically effective doses to subjects having a condition such as a disease or disorder. In some embodiments, this condition is a mental health disorder. In some embodiments, this condition is a neurodegenerative disorder. In some embodiments, this condition is a pain disorder. In some embodiments, the disclosed compounds are administered to healthy subjects.

[0221] In this specification, the terms “subject,” “user,” “patient,” and “individual” are used interchangeably and refer to any mammal, including mice, monkeys, domestic mammals, sports animals, and pet mammals such as dogs and cats, but preferably to humans. Such terms are understood to include persons who have indications for which the compounds, compositions, or methods described herein may be effective, or who otherwise can benefit from the invention. The disclosed therapeutic methods may be modified to treat multiple patients at once, including couples or families. Thus, these terms are also understood to mean two or more individuals. In general, all disclosed compounds, compositions, and methods will be understood to be effective in all individuals, although individual differences are to be expected.

[0222] In some embodiments, the disclosed compounds or compositions thereof are administered to a subject orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation, or transdermally. In some embodiments, when administered via one or more such routes, the disclosed compounds and the disclosed compositions and formulations containing them are useful in methods of treating patients requiring such treatment.

[0223] a. Regulation of neurotransmission In some embodiments, the disclosed compounds modulate neurotransmission in a subject, such as after administering a therapeutically effective dose to the subject. In embodiments, the modulation of neurotransmission by administering the disclosed compounds to a subject treats the disease or disorder of the subject. In embodiments, the modulation of neurotransmission includes, for example, regulating monoamine levels in the CNS and peripheral tissues. In embodiments, the modulation of neurotransmission by administering the disclosed compounds to a subject treats the disease or disorder of the subject.

[0224] In some embodiments, modulation of neurotransmission contributes to the therapeutic effect of the disclosed compound in the subject. In some embodiments, modulation of neurotransmission by administration of the disclosed compound to the subject treats the disease or disorder of the subject.

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

[0226] In some embodiments, the disclosed compound modulates the spike rate, which is the number of action potentials per second. In some embodiments, the disclosed compound modulates the burst rate, which is a series of action potentials known as bursts that occur rapidly and continuously. The burst rate is the number of bursts per second. In some embodiments, the disclosed compound modulates the spike contrast, a measure of the variability of neuronal activity, measured as the difference in the number of spikes occurring in the first and second halves of a recording period (i.e., 700 milliseconds). In some embodiments, the disclosed compound modulates the burst spike count, which is the number of spikes per burst. In some embodiments, the disclosed compound modulates the burst duration, which is the average duration of detected bursts. In some embodiments, neurotransmission is measured as burst amplitude. To obtain the burst amplitude, an integral function with decay is calculated over the burst timestamps. The burst amplitude is the peak value of the integral, which increases with the occurrence of high-frequency and numerous spikes.

[0227] In some embodiments, the disclosed compounds modulate oscillatory behavior, a measure of parameter variability measured as the standard deviation of the parameter over time within an experimental episode. In some embodiments, the disclosed compounds modulate the synchronicity of activity in a neuronal population, a measure of the relative variability of activity across a neuronal population. In some embodiments, the disclosed compounds modulate synchronicity share, the average number of units involved in a population burst, with higher values ​​reflecting a higher degree of synchronization of bursts occurring between neuronal populations. In some embodiments, the disclosed compounds modulate the sync distance, defined as the average distance from the center of a population burst to the start of the burst within the population burst, with lower values ​​reflecting stronger network synchronicity. In some embodiments, the disclosed compounds modulate the spike simplex, a measure of connectivity and complexity in a neuronal network, with higher values ​​reflecting higher synchronicity between neurons.

[0228] In some embodiments, the disclosed compounds activate serotonin receptors. In some embodiments, the disclosed compounds stimulate and / or antagonize serotonin receptors (5-HT receptors, e.g., 5-HT2 receptors). The 5-HT2 receptor family consists of three distinct receptor subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C It consists of 5-HT. 2A and 5-HT 2C The receptor is 5-HT 2B It is more highly expressed in the brain than in other subtypes. Psilosine and other related psychotropic tryptamines are primarily 5-HT 2A They exert their psychoactive effects by acting as receptor agonists. However, many of these tryptamines (including psilocine) also exert their psychoactive effects due to the high sequence homology between the three 5-HT2 receptor subtypes. 2B and 5-HT 2CIt is also a receptor agonist (Nichols, Pharmacol. Rev. 2016, 68, 264-355). Activation of all 5-HT2 receptor subtypes can lead to decreased efficacy or adverse side effects. For example, 5-HT 2C Receptor activation is 5-HT 2A It has been shown to functionally antagonize the effects of receptor activation (ibid.), but in myocardial tissue, 5-HT 2B Receptor activation is associated with cardiac valve disease (Hutcheson et al., Pharmacol.Ther. 2011, 132(2):146-157). In embodiments, compounds, particularly those that may be used regularly or over a relatively long period of time, are 5-HT 2B It may be desirable that the activity (e.g., agonism) of the receptor be reduced. In some embodiments, the disclosed compounds are 5-HT receptors, e.g., 5-HT 1A and 5-HT 1B 5-HT1 receptors such as 5-HT1 receptors, 5-HT 2A , 5-HT 2B and 5-HT 2C It stimulates, or partially stimulates, one or more of the 5-HT2 receptors, as well as 5-HT6 receptors.

[0229] In some embodiments, the disclosed compound is 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2C In vitro EC against one or more of the following: , and 5-HT6 50 The (agonist mode) is less than 10 μM, less than 5 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In the embodiment, the disclosed compound is 5-HT 2A In vitro EC 50 The (agonist mode) is less than 1 μM, less than 0.5 μM, less than 0.1 μM, less than 0.05 μM, less than 0.01 μM, less than 0.005 μM, or less than 0.001 μM. In the embodiment, the disclosed compound is 5-HT 2C In vitro EC 50The (agonist mode) is less than 1 μM, less than 0.5 μM, less than 0.1 μM, less than 0.05 μM, less than 0.01 μM, less than 0.005 μM, or less than 0.001 μM.

[0230] In some embodiments, the disclosed compound is compared to another 5-HT receptor with respect to 5-HT receptors. 2A It exhibits greater efficacy in the following embodiments. In some embodiments, the disclosed compound is used with respect to a 5-HT1 receptor, another 5-HT2 receptor, for example, a 5-HT2 receptor. 2B and 5-HT 2C For example, compared to one or more of the 5-HT5 receptor, 5-HT6 receptor, and 5-HT7 receptor, 5-HT 2A It exhibits greater effectiveness.

[0231] Determine the agonism and antagonistism, EC 50 and IC 50 The measurement of each can be determined according to methods available to those skilled in the art. For example, the measurement of Gq-mediated calcium flux is a widely recognized target of psychoactive compounds such as 5-HT 2A This is a known method for evaluating the regulation, e.g., activation. See, for example, 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 those skilled in the art will recognize, partial agonists are different from full agonists (E MAX Compared to =100%), the maximum effect (E) was reduced. MAX This indicates that, for example, serotonin is an example of a 5-HT receptor.

[0232] The specific effects of the disclosed compounds are at least in part due to serotonin receptors (e.g., 5-HT). 2A , 5-HT2C Since it can be obtained from the selective activation of another serotonin receptor (e.g., 5-HT), one possible approach for next-generation compounds that can lead to improved therapeutic efficacy, a better safety profile, and reduced side effects may be to optimize selective serotonin receptor activation. Therefore, in some embodiments, the disclosed compounds may be obtained from the selective activation of another serotonin receptor (e.g., 5-HT). 2B Receptor, or 5-HT 2C 5-HT receptor 2A It has high selectivity for the receptor. In some embodiments, the disclosed compound is 5-HT 2B 5-HT receptor 2A It has high selectivity for the receptor. In some embodiments, the disclosed compound is 5-HT 2C 5-HT receptor 2A It exhibits high selectivity for receptors. In some embodiments, selectivity is achieved by targeting other receptors (e.g., 5-HT). 2B Receptor or 5-HT 2C A single receptor (e.g., 5-HT receptor) compared to a serotonin receptor (such as a receptor like 5-HT receptor). 2A The maximum half-effective concentration (EC) of the disclosed compound against the receptor. 50 It is defined as functional selectivity calculated by the ratio of 5-HT of a hypothetical compound. 2A EC 50 The concentration is 0.2 μM, and 5-HT 2B EC 50 If the concentration is 1.0 μM, the compound is 5-HT 2B 5-HT receptor 2A It can be said that it has a five-fold functional activity selectivity for the receptor. In some embodiments, the selectivity is such that it has a five-fold functional activity selectivity for one receptor (e.g., 5-HT). 2A (receptor) and another receptor (e.g., 5-HT) 2B Serotonin receptors such as receptors, or 5-HT 2C Binding affinity to receptors (e.g., K i Affinity selectivity can be defined as the ratio of (evaluated by) the 5-HT of a hypothetical compound. 2A K i The concentration is 0.1 μM, and 5-HT 2BEC 50 If the concentration is 1.0 μM, the compound is 5-HT 2B 5-HT receptor 2A It can be said that it has 10 times the affinity selectivity for the receptor.

[0233] In some embodiments, the disclosed compound is 5-HT 2B 5-HT receptor 2A The compounds exhibit affinity selectivity of approximately 1.1 times, 1.5 times, 1.6 times, 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 150 times, or at least 150 times, relative to the receptor. In embodiments, the disclosed compounds exhibit affinity selectivity of approximately 1.1 times, 1.5 times, 1.6 times, 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 150 times, or at least 150 times, relative to the receptor. 2B 5-HT receptor 2A Affinity selectivity for the receptor has been improved.

[0234] In the embodiment, the disclosed compound is 5-HT 2B 5-HT receptor 2A The compounds exhibit functional activity selectivity of approximately 1.1 times, 1.5 times, 1.6 times, 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 150 times, or at least 150 times, relative to the receptor. In the embodiments, the disclosed compounds exhibit functional activity selectivity of approximately 1.1 times, 1.5 times, 1.6 times, 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 150 times, or at least 150 times, relative to the receptor. 2B 5-HT receptor 2A Affinity selectivity for the receptor has been improved.

[0235] In some embodiments, the disclosed compound is 5-HT 2B 5-HT receptor 2C The compounds exhibit affinity selectivity of approximately 1.1 times, 1.5 times, 1.6 times, 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 150 times, or at least 150 times, relative to the receptor. In embodiments, the disclosed compounds exhibit affinity selectivity of approximately 1.1 times, 1.5 times, 1.6 times, 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 150 times, or at least 150 times, relative to the receptor. 2B 5-HT receptor 2C Affinity selectivity for the receptor has been improved.

[0236] In the embodiment, the disclosed compound is 5-HT2B 5-HT receptor 2C The compounds exhibit functional activity selectivity of approximately 1.1 times, 1.5 times, 1.6 times, 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 150 times, or at least 150 times, relative to the receptor. In the embodiments, the disclosed compounds exhibit functional activity selectivity of approximately 1.1 times, 1.5 times, 1.6 times, 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 150 times, or at least 150 times, relative to the receptor. 2B 5-HT receptor 2C Affinity selectivity for the receptor has been improved.

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

[0238] Neuroplasticity can be defined in relation to neurite generation, spine formation, and synapse formation in neurons. Neurite generation refers to the process by which neurons generate and extend their neurites (i.e., form axons and dendrites). Neurite generation is a crucial step in neurogenesis and the formation of neural circuits. Spine formation refers to the formation of dendritic spines, which are small projections on the dendrites of neurons. Dendritic spines are essential for synaptic connections and play a vital role in synaptic transmission and plasticity. Synapse formation refers to the formation of synapses, which are essential for the establishment and improvement of neural circuits and are a fundamental process that underlies learning, memory, and information processing in the brain.

[0239] In some embodiments, the disclosed compound increases neurite formation. Neurite formation can be measured with respect to total neurite length, maximum neurite length, number of neurite segments, and / or number of neurite terminals. In some embodiments, the disclosed compound increases total neurite length. In some embodiments, the disclosed compound increases maximum neurite length. In some embodiments, the disclosed compound increases the number of neurite segments. In some embodiments, the disclosed compound increases the number of neurite terminals.

[0240] In some embodiments, administration of the disclosed compounds to subjects increases the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., the number of synapses per neuron), or the total length of dendritic tissue. These factors can be measured using Scholl analysis and other techniques known to those skilled in the art (Ly et al., ACS Pharmacol Transl Sci. 2020;4(2):452-460).

[0241] c.Treatment In some embodiments, the disclosed compounds are used to treat medical conditions such as diseases or disorders. In embodiments, the disclosed compounds are used to manufacture pharmaceuticals for treating conditions such as diseases or disorders. Methods are also provided for administering the disclosed compounds to subjects having a condition such as a disease or disorder, thereby treating the condition.

[0242] In some embodiments, the disclosed compounds, or pharmaceutical compositions containing the disclosed compounds, are administered to a target by one or more routes of administration, including, for example, oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhalation, ocular, intraocular, topical, and transdermal routes. When administered via one or more such routes, one or more of the disclosed compounds, as well as the disclosed compositions and formulations containing them, are useful in methods of treating patients requiring such treatment.

[0243] In some embodiments, methods are provided for treating and / or preventing a mammalian condition, comprising administering a therapeutically effective amount of a disclosed compound or pharmaceutical composition to the mammal. In some embodiments, “treat” or “cure” means treating a disease or disorder in a mammal, preferably a human, and causing a desired biological or pharmacological effect, for example: (a) preventing the onset of the disorder in a subject that may be predisposed to the disorder but has not yet been diagnosed with the disorder; (b) inhibiting the disorder, i.e., stopping its progression; (c) mitigating the disorder, i.e., causing its regression; (d) protecting against or reducing symptoms or conditions caused by or associated with the disorder; (e) reducing, decreasing, inhibiting, improving or preventing the onset, severity, duration, progression, frequency or likelihood of one or more symptoms or conditions associated with the disorder; and (f) preventing or inhibiting the exacerbation or progression of symptoms or conditions associated with or coexisting with the disorder. In some embodiments, treatment includes prevention. In other embodiments, treatment does not include prevention. Other such measurements, benefits, and surrogate or clinical endpoints, either alone or in combination, will be understood by those skilled in the art in consideration of the teachings herein and the knowledge of those skilled in the art.

[0244] In embodiments, the disclosed compounds are used to treat central nervous system (CNS) disorders. Generally, CNS disorders include diseases of the nervous system (e.g., motor disorders, neurodegenerative disorders), as well as psychiatric, behavioral, and neurodevelopmental disorders, such as those described in DSM-5, Merck Manual, ICD-11, or other such diagnostic resources known to those skilled in the art.

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

[0246] ICD-11, which is incorporated herein in its entirety by reference, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant impairments in an individual’s cognition, affect regulation, or behavior, reflecting an underlying psychological, biological, or developmental impairment of 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, stress-specific disorders, dissociative disorders, nutritional (or feeding) disorders, urinary disorders, disorders of physical pain or physical experience, disorders of substance use or addictive behavior, impulse control disorders, disorderly or antisocial behavior disorders, personality disorders (and associated traits), paraphilias, compulsory disorders, neurocognitive disorders, mental or behavioral disorders related to pregnancy, childbirth or puerperium, sleep-wake disorders, sexual dysfunction, and gender dysphoria.

[0247] Other mental, behavioral, or neurodevelopmental disorders not defined elsewhere are understood to refer to disorders as defined in ICD-11. Within the categories of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or “mental health disorder”) generally refers to a disordered state involving negative changes in affect, mood, thought, and / or behavior. Generally, a mental health disorder is characterized by a clinically significant impairment of an individual’s cognition, affect, behavior, or combination thereof, resulting in functional impairment, distress, or increased risk of morbidity. The terms “mental disorder” and “mental health disorder,” as well as the terms defining specific diseases and disorders, generally refer to patients with ICD-11 criteria or a diagnosis based thereon, but the methods disclosed will be understood to be equally applicable to patients with comparable underlying disorders, regardless of whether the disorder is diagnosed based on ICD-11, ICD-10, DSM-5, or DSM-IV criteria (each incorporated herein in whole by reference), whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet received a formal clinical diagnosis.

[0248] In some embodiments, the disclosed compounds are used to treat mental health disorders in a subject. In some embodiments, the subject has a mental health disorder. In some embodiments, the subject is at risk of a mental health disorder. Diagnosing mental health disorders and determining whether a subject is at risk of neurodevelopmental disorders will be known to those skilled in the art. In some embodiments, the disclosed compounds are administered, for example, in a therapeutically effective dose to a subject having a mental health disorder, thereby treating the mental health disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective dose, provide beneficial therapeutic effects for the treatment of mental health disorders. In some embodiments, the compounds and compositions of this disclosure are used to alleviate the symptoms of mental health disorders. The symptoms of the mental health disorder to be treated can be determined by those skilled in the art by referring to the general understanding of the disorder in the art.

[0249] In some embodiments, measures of treatment effectiveness include reports from subjects or observers. In some embodiments, measures of treatment effectiveness include responses to questionnaires. Non-restrictive representative examples of applicable scales for symptom improvement include: 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 (MINI5), 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), and Self-Compassion Scale. These include the Scale (SCS), the Trauma History Questionnaire (THQ), the Beck Depression Index (BDI), and scales reported by the relevant subject or observer.

[0250] In some embodiments, the disclosed compounds are used to treat neurodevelopmental disorders in subjects. In some embodiments, subjects have neurodevelopmental disorders. In some embodiments, subjects are at risk of neurodevelopmental disorders. Diagnosing neurodevelopmental disorders and determining whether a subject is at risk of neurodevelopmental disorders will be known to those skilled in the art. Examples of neurodevelopmental disorders that can be treated with the disclosed compounds include intellectual disability, developmental speech or language disorders, autism spectrum disorder, developmental learning disability, developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorders.

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

[0252] In some embodiments, the disclosed compounds are used to treat catatonia. In some embodiments, the subject has catatonia. In some embodiments, the subject is at risk of catatonia. Diagnosing catatonia and determining whether a subject is at risk of catatonia will be known to those skilled in the art. In some embodiments, catatonia is associated with another mental disorder. In some embodiments, catatonia is induced by a substance or drug.

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

[0254] In some embodiments, the disclosed compounds are used to treat anxiety or fear-related disorders. In some embodiments, the subject has an anxiety or fear-related disorder. In some embodiments, the subject is at risk of developing an anxiety or fear-related disorder. Diagnosing anxiety or fear-related disorders and determining whether a subject is at risk of developing an anxiety or fear-related disorder will be known to those skilled in the art. Examples of anxiety or fear-related disorders that can be treated with the disclosed compounds include generalized anxiety disorder, panic disorder, agoraphobia, specific phobias, social anxiety disorder, separation anxiety disorder, selective mutism, or substance-induced anxiety disorder.

[0255] In some embodiments, the disclosed compounds are used to treat obsessive-compulsive or related disorders. In some embodiments, the subject has an obsessive-compulsive or related disorder. In some embodiments, the subject is at risk of developing an obsessive-compulsive or related disorder. Diagnosing an obsessive-compulsive or related disorder and determining whether a subject is at risk of developing an obsessive-compulsive or related disorder will be known to those skilled in the art. Examples of obsessive-compulsive or related disorders that can be treated with the disclosed compounds include obsessive-compulsive disorder, body dysmorphic disorder, olfactory association disorder, hypochondriasis, hoarding disorder, repetitive physical concentration disorder, or substance-induced obsessive-compulsive disorder.

[0256] In some embodiments, the disclosed compounds are used to treat stress-related disorders. In some embodiments, the subject has a stress-related disorder. In some embodiments, the subject is at risk of stress-related disorder. Diagnosing stress-related disorders and determining whether a subject is at risk of stress-related disorder will be known to those skilled in the art. In some embodiments, stress-related disorders have identifiable stressors that are causative factors, such as a stressful or traumatic event, or exposure to a series of such events or harmful experiences. Stressors may be within the range of normal life experiences (e.g., divorce, socioeconomic problems) or may result from threatening or traumatic experiences. Generally, the nature and duration of symptoms that arise in response to a stressor can distinguish this disorder from everyday stress. Examples of stress-related disorders that can be treated with the disclosed compounds include post-traumatic stress disorder, complex post-traumatic stress disorder, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social interaction disorder.

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

[0258] In some embodiments, the disclosed compounds are used to treat nutritional supplementation or eating disorders. In some embodiments, subjects have nutritional supplementation or eating disorders. In some embodiments, subjects are at risk of nutritional supplementation or eating disorders. Diagnosing nutritional supplementation or eating disorders and determining whether a subject is at risk of nutritional supplementation or eating disorders will be known to those skilled in the art. Examples of nutritional supplementation or eating disorders that can be treated with the disclosed compounds include anorexia nervosa (including severely underweight anorexia, dangerously underweight anorexia, or anorexia in recovery at normal weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.

[0259] In some embodiments, the disclosed compounds are used to treat excretory disorders. In some embodiments, the subject has an excretory disorder. In some embodiments, the subject is at risk of an excretory disorder. Diagnosing an excretory disorder and determining whether a subject is at risk of an excretory disorder will be known to those skilled in the art. Examples of excretory disorders that can be treated with the disclosed compounds include enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or encopresis (including both encopresis with constipation or overflow incontinence and encopresis without constipation or overflow incontinence).

[0260] In some embodiments, the disclosed compounds are used to treat physical pain or disorders of physical experience. In some embodiments, the subject has physical pain or disorders of physical experience. In some embodiments, the subject is at risk of physical pain or disorders of physical experience. Diagnosing physical pain or disorders of physical experience and determining whether a subject is at risk of physical pain or disorders of physical experience will be known to those skilled in the art. Examples of physical pain or disorders of physical experience that can be treated with the disclosed compounds include physical pain disorders (including mild, moderate, and severe physical pain disorders) or bodily integrity dysphoria.

[0261] In some embodiments, the disclosed compounds are used to treat substance use or addictive behavior disorders. In some embodiments, the subject has a substance use or addictive behavior disorder. In some embodiments, the subject is at risk of substance use or addictive behavior disorder. Diagnosing substance use or addictive behavior disorder and determining whether a subject is at risk of substance use or addictive behavior disorder will be known to those skilled in the art. In some embodiments, the disclosed compounds are used to treat substance use disorders (i.e., substance use disorders, or SUDs). In some embodiments, the substance use disorder is related to alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics or anxiolytics, cocaine, stimulants (e.g., amphetamine, methamphetamine, methcathinone, synthetic cathinone, caffeine), hallucinogens, nicotine, volatile inhalants, MDMA or MDA, dissociative agents such as ketamine and phencyclidine, or other substances (including drugs and non-psychoactive substances). Examples of substance use disorders treatable with the disclosed compounds include alcohol use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalant use disorder, opioid use disorder, sedative use disorder, hypnotic use disorder, anxiolytic use disorder, stimulant use disorder, and tobacco use disorder. In some embodiments, the substance use disorder is alcohol use disorder. In some embodiments, the substance use disorder is cannabis use disorder. In some embodiments, the substance use disorder is caffeine use disorder. In some embodiments, the substance use disorder is phencyclidine use disorder. In some embodiments, the substance use disorder is inhalant use disorder. In some embodiments, the substance use disorder is opioid use disorder. In some embodiments, the substance use disorder is sedative use disorder. In some embodiments, the substance use disorder is hypnotic use disorder. In some embodiments, the substance use disorder is anxiolytic use disorder. In some embodiments, the substance use disorder is stimulant use disorder. In some embodiments, the substance use disorder is tobacco use disorder.In some embodiments, the substance use disorder is alcohol use disorder, which is selected from alcohol abuse, alcohol dependence, and alcoholism. In some embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorder, gaming disorder). In some embodiments, the substance use disorder can be screened using the Short Intervention Screening (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Short Screener for Alcohol, Tobacco, and Other Drugs (BSTAD), Tobacco, Alcohol, Prescription Drugs, and Other Substance Use (TAPS), Opioid Risk Tool-OUD (ORT-OUD) Chart, Drug Abuse Screening Test (DAST-10), and Tobacco, Alcohol, Prescription Drugs, and Other Substance Use (TAPS).

[0262] In some embodiments, the disclosed compounds are used to treat impulse control disorders. In some embodiments, the subject has an impulse control disorder. In some embodiments, the subject is at risk of impulse control disorder. Diagnosing impulse control disorders and determining whether a subject is at risk of impulse control disorder will be known to those skilled in the art. In some embodiments, impulse control behaviors include arson, theft, inappropriate sexual behavior, and violent emotional outbursts. Examples of impulse control disorders treatable with the disclosed compounds include pyromania, kleptomania, obsessive-compulsive sexual behavior disorder, or intermittent explosive disorder.

[0263] In some embodiments, the disclosed compounds are used to treat disorderly behavioral disorders or antisocial behavioral disorders. In some embodiments, the subjects have disorderly behavioral disorders or antisocial behavioral disorders. In some embodiments, the subjects are at risk of disorderly behavioral disorders or antisocial behavioral disorders. The diagnosis of disorderly behavioral disorders or antisocial behavioral disorders and the determination of whether a subject is at risk of disorderly behavioral disorders or antisocial behavioral disorders will be known to those skilled in the art. Examples of disorderly behavioral disorders or antisocial behavioral disorders treatable with the disclosed compounds include oppositional defiant disorder (including oppositional defiant disorder with chronic irritability and anger, and oppositional defiant disorder without chronic irritability and anger) or conduct and antisocial behavioral disorders (including childhood-onset conduct and antisocial behavioral disorders and adolescent-onset conduct and antisocial behavioral disorders).

[0264] In some embodiments, the disclosed compounds are used to treat personality disorders. In some embodiments, the subject has a personality disorder. In some embodiments, the subject is at risk of developing a personality disorder. Diagnosing a personality disorder and determining whether a subject is at risk of developing a personality disorder will be known to those skilled in the art. In some embodiments, the disclosed compounds are used to treat mild, moderate, or severe personality disorders. In some embodiments, the disclosed compounds are used to treat prominent personality traits or patterns (e.g., negative affect, detachment, antisociality, disinhibition, restrictiveness, borderline patterns). Examples of personality disorders that can be treated with the disclosed compounds include antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, masochistic or sadistic behavior, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, psychopathy, sociopathy, schizoid personality disorder, or schizotypal personality disorder.

[0265] In some embodiments, the disclosed compounds are used to treat paraphilias. In some embodiments, the subject has a paraphilia. In some embodiments, the subject is at risk of having a paraphilia. The diagnosis of a paraphilia and determining whether a subject is at risk of having a paraphilia will be known to those skilled in the art. Examples of paraphilias that can be treated with the disclosed compounds include exhibitionism, voyeurism, pedophilia, compulsive sexual sadism, voyeurism, other paraphilias involving non-consensual individuals, or paraphilias involving solitary or consensual individuals.

[0266] In some embodiments, the disclosed compounds are used to treat dysentery. In some embodiments, the subject has dysentery. In some embodiments, the subject is at risk of dysentery. Diagnosing dysentery and determining whether a subject is at risk of dysentery will be known to those skilled in the art. A subject with dysentery may seek treatment or otherwise present themselves or others as being in a diseased, injured or disabled state. Examples of dysentery that can be treated with the disclosed compounds include dysentery imposed on oneself or on others.

[0267] In some embodiments, the disclosed compounds are used to treat neurocognitive disorders. In some embodiments, the subject has a neurocognitive disorder. In some embodiments, the subject is at risk of neurocognitive disorder. Diagnosing neurocognitive disorders and determining whether a subject is at risk of neurocognitive disorder will be known to those skilled in the art. Examples of neurocognitive disorders treatable with the disclosed compounds include delirium, amnesia, dementia, Alzheimer's disease, Parkinson's disease, cerebrovascular disease, or Lewy body dementia. In some embodiments, the neurocognitive disorders treatable with the disclosed compounds are related to psychotropic substances (including drugs and illegal or unlawful substances). In some embodiments, the disclosed compounds are used to treat delirium. In some embodiments, delirium is related to another disease or disorder. In some embodiments, delirium is related to psychotropic substances (including drugs and illegal or unlawful substances). In some embodiments, the disclosed compounds are used to treat mild neurocognitive disorders. In some embodiments, the disclosed compounds are used to treat amnesia. In some embodiments, amnesia is related to another disease or disorder. In some embodiments, delirium is associated with psychotropic substances (including drugs and illegal or unlawful substances). In some embodiments, the disclosed compounds are used to treat dementia. In some embodiments, dementia is associated with Alzheimer's disease, Parkinson's disease, cerebrovascular disease, Lewy body dementia, and psychotropic substances (including drugs and illegal or unlawful substances). In some embodiments, the disclosed compounds are used to treat behavioral or psychological disorders associated with dementia. In some embodiments, dementia is assessed using the Functional Assessment Questionnaire (FAQ), the Dementia Assessment 8 (AD8), Mini-Cog, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).

[0268] In some embodiments, the disclosed compounds are used to treat mental or behavioral disorders associated with pregnancy, childbirth, or the postpartum period. In some embodiments, the subject has a mental or behavioral disorder associated with pregnancy, childbirth, or the postpartum period. In some embodiments, the subject is at risk of developing a mental or behavioral disorder associated with pregnancy, childbirth, or the postpartum period. Diagnosing mental or behavioral disorders associated with pregnancy, childbirth, or the postpartum period and determining whether a subject is at risk of developing a mental or behavioral disorder associated with pregnancy, childbirth, or the postpartum period is known to those skilled in the art. In some embodiments, the disorder includes psychotic symptoms. In some embodiments, the disclosed compounds are used to treat mental or behavioral disorders associated with pregnancy, childbirth, or the postpartum period accompanied by psychotic symptoms. In embodiments, the disclosed compounds are used to treat mental or behavioral disorders associated with pregnancy, childbirth, or the postpartum period without psychotic symptoms.

[0269] In some embodiments, the disclosed compounds are used to treat sleep-wake disorders. In some embodiments, the subject has a sleep-wake disorder. In some embodiments, the subject is at risk of sleep-wake disorders. The diagnosis of sleep-wake disorders and determining whether a subject is at risk of sleep-wake disorders will be known to those skilled in the art. Examples of sleep-wake disorders that can be treated with the disclosed compounds include insomnia, hypersomnia, sleep-related breathing disorders, circadian rhythm sleep-wake disorders, or parasomnias.

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

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

[0272] In some embodiments, the disclosed compounds and compositions may be administered in combination with or as an adjunct to psychotherapy. In other embodiments, psychotherapy may not be necessary or desirable, or a particular type of psychotherapy may not be necessary or desirable, but any of the disclosed methods may be used in combination with one or more psychotherapy sessions. The flexibility to participate in a particular therapy, as well as to choose between any such therapies (or to decide to discontinue any particular therapy), while still receiving clinically significant therapeutic effects, is one of the advantages of the present invention. Furthermore, patients may participate in a number of other therapeutically beneficial activities. Such participation may take place after or in conjunction with the administration of the compositions and may include breathing exercises, meditation and concentration exercises, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, writing meditation, grounding techniques, positive self-dialogue, or interaction with a pet or animal. It should be understood that such participation may take place with or without the participation or guidance of a therapist.

[0273] In some embodiments, “psychotherapy” specifically refers to “psychotherapy-assisted psychotherapy.” Psychotherapy-assisted psychotherapy, in a broad sense, includes a variety of related approaches involving at least one session in which the patient is monitored, supported, or otherwise involved by one or more trained mental health professionals while the patient is taking a psychoactive drug and under its influence (see, e.g., Schenberg 2018). Protocols have been developed to standardize procedures that emphasize a higher level of care, such as the therapeutic approach used by MAPS to treat patients with PTSD using MDMA (see, e.g., Mithoefer 2017) (see, e.g., Johnson 2008).

[0274] In some embodiments, psychotherapy using the disclosed compound is conducted in sessions spaced far apart. These sessions can be held as frequently as weekly, but are usually held about once a month or less. In most cases, a small number of sessions, about one to three, are needed for the patient to experience significant clinical progress, such as indicated by a reduction in the symptoms of the mental health disorder being treated. In some embodiments, the psychotherapy comprises multiple sessions, during which the disclosed compound is administered ("pharmacotherapy-assisted psychotherapy"); in other embodiments, the patient participates in psychosocial therapy or behavioral therapy without co-administration of the drug or without administration of the disclosed compound.

[0275] In some embodiments, the disclosed compounds or compositions are administered once, twice, or as needed, in conjunction with standardized psychological treatment or support, referring to any accepted modality of standard psychotherapy or counseling sessions, by a human therapist or a virtual or AI “therapist,” either in person or virtually (e.g., via telemedicine or using a web program or mobile application). In this specification, “therapist” refers to a person treating a patient using the disclosed compositions and methods, regardless of whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, but it will be understood that certain requirements are suited to certain aspects of adjunctive pharmacotherapy (e.g., prescription, dispensing, or administration of drugs, provision of psychotherapeutic support). In some embodiments, “person” may also include AI.

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

[0277] Preferably, when the disclosed pharmaceutical composition is administered, such administration is carried out without or with reduced risk of adverse effects requiring physician supervision, and thus enables treatment at home or otherwise outside a clinic without requiring such supervision and / or additionally without requiring supplemental psychotherapy (although this may also be provided in specific embodiments herein).

[0278] In some embodiments, the disclosed compositions may be administered in combination with or as an adjunct to psychotherapy. In other embodiments, psychotherapy may not be necessary or desirable, or a particular type of psychotherapy may not be necessary or desirable, but any of the disclosed methods may be used in combination with one or more psychotherapy sessions. The flexibility to participate in a particular therapy, as well as to choose between any such therapies (or to decide to discontinue any particular therapy), while still receiving clinically significant therapeutic effects, is one of the advantages of the present invention. Furthermore, patients may participate in a number of other therapeutically beneficial activities. Such participation may take place after or in conjunction with the administration of the compositions and may include breathing exercises, meditation and concentration exercises, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, writing meditation, grounding techniques, positive self-dialogue, or interaction with a pet or animal. It should be understood that such participation may take place with or without the participation or guidance of a therapist.

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

[0280] In some embodiments, the genetic mutations affect drug metabolism, including the metabolism of the disclosed compositions, and are genetic mutations in one or more cytochrome P450 (CYP or CYP450) enzymes, including CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP3A5. Other examples of CYP enzymes include CYP1A1, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, and CY Examples include P4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0281] In some embodiments, the disclosed composition is administered together with compounds metabolized by the same one or more CYP enzymes as the disclosed composition to enable lower dose intake, increase the effective bioavailability of one or both, or affect drug metabolism or pharmacokinetics. In some embodiments, the dose of the disclosed composition is adjusted, such as decreasing it when administered to subjects known to be low metabolites of the active compounds in the composition (e.g., those with genetic mutations in CYP2D6 and / or CYP3A4), or increasing it when administered to subjects known to be rapidly metabolites. In some embodiments, the patient is tested using conventional means known to those skilled in the art to determine whether the patient is low metabolite or rapidly metabolite for one or more such CYP enzymes.

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

[0283] In some embodiments, the treated mammals exhibit altered epigenetic regulation of genes whose expression is associated with mental health status or susceptibility to mental health treatment, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.

[0284] ii. Neurodegenerative disorders In some embodiments, the disclosed compounds are used to treat neurodegenerative disorders. In some embodiments, the disclosed compounds are administered to subjects having neurodegenerative disorders, for example, in a therapeutically effective dose. In some methods described herein, the disclosed compositions, when administered in a therapeutically effective dose, produce beneficial therapeutic effects for the treatment of neurodegenerative disorders.

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

[0286] Neurodegenerative disorders can be classified according to their major clinical features, such as dementia, parkinsonism, or motor neuron disease; the anatomical distribution of neurodegeneration, such as frontotemporal degeneration, extrapyramidal disorders, or spinocerebellar degeneration; or according to major molecular abnormalities (Dugger B, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology. 2017:9(7);a028035). These disorders may involve a variety of etiologies, including, but not limited to, the presence of pathogenic proteins, age, environmental stressors, and genetic predisposition (Armstrong R. Folia Neuropathologica. 2020:58(2);93-112).

[0287] In some embodiments, neurodegenerative disorders are selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis or Charcot disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia including vascular dementia, Huntington's disease, Ritico Bodig disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson's disease or parkinsonism, prion disease, progressive supranuclear palsy, and traumatic brain injury.

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

[0289] "Pain disorders" refer to a class of medical conditions characterized by the experience of localized or widespread, persistent or recurrent physical or psychological pain that significantly impairs an individual's daily functioning and quality of life. These disorders may involve a variety of etiologies, including, but are not limited to, nociceptive, neuropathic, psychogenic, idiopathic, or radicular origin. In embodiments, the compound is used to treat neuropathic pain. In embodiments, the compound is used to treat psychogenic pain. In embodiments, the compound is used to treat idiopathic pain. In embodiments, the compound is used to treat radicular pain.

[0290] Pain disorders can manifest as acute or chronic pain and may affect various parts of the body, including the musculoskeletal, nervous, gastrointestinal, or visceral systems. Pain may manifest as, but is not limited to, postherpetic neuralgia, trigeminal neuralgia, occipital headache, or genital pain. In embodiments, the disclosed compounds are used to treat pain associated with chemotherapy (e.g., chemotherapy-related neuropathy). In embodiments, the disclosed compounds are used to treat arthritis, low back pain, central pain, chronic fatigue syndrome, cluster headache, migraine, phantom limb pain, complex regional pain syndrome, compressive mononeuropathy, diabetic neuropathy, fibromyalgia, focal neuropathy, herniated disc pain, or sciatica.

[0291] In some embodiments, pain is assessed using the Pain, Pleasure, and General Activity Scale (PEG), Numerical Rating Scale (NRS), Visual Analog Scale (VAS), Behavioral Pain Scale (BPS), and Facial Pain Scale-R (FPS-R).

[0292] iv. Inflammatory diseases Inflammation is a critical immune response to tissue damage, such as microbial infection, acute injury, chemical irritants, or other dysregulation of normal tissue function. The inflammatory process is characteristic of the innate immune system, which recognizes molecular patterns of tissue damage and responds with various inflammatory substances, including cytokines and chemokines. These inflammatory substances directly act to initiate various signaling responses to remove harmful stimuli and restore damaged tissue to a homeostatic state. While this response often self-terminates, inflammation can fail to resolve for several reasons, potentially extending the inflammatory response to a chronic stage (Ahmed AU. Front Biol. 2011:6(4):274-281). Chronic inflammation is often associated with or underlying a variety of pathological conditions, including major cardiovascular and neuropsychiatric disorders (Nichols CD. Cardiovasc Psychiatry Neurol 2009:475108).

[0293] Recent evidence suggests that 5-HT mediates the termination of inflammatory responses.2A This suggests a significant role for serotonin receptor subtypes. 5-HT 2A Receptors are found throughout the body, including in both the central nervous system and peripheral tissues (Flanagan & Nichols. In'l Rev of Psychiatry. 2018;30(4):363-375). In the brain, 5-HT 2A The receptor is involved in cognitive function and working memory, mediates the effects of psychoactive compounds, and is related to the underlying mechanisms of neuropsychiatric disorders such as schizophrenia (Nichols CD.Cardiovasc Psychiatry Neurol.2009;475108). Peripherally, 5-HT 2A Receptors are found in multiple immune-related tissues, including the spleen, thymus, and circulating lymphocytes, as well as in components of both the innate and adaptive immune systems (Stefulj J et al., Brain Behav Immun. 2000 Sep;14(3):219-24; Cloez-Tayarani I et al., Int Immunol. 2003 Feb;15(2):233-40). 5-HT receptors are also found in these tissues. 2A Research on receptors has revealed their roles in regulating the immune response (Flanagan TW, Nichols CD. Int Rev Psychiatry. 2018 Aug;30(4):363-375).

[0294] 5-HT in the brain 2A Due to its important effect on receptors, the psychoactive compound 5-HT 2ASeveral studies have been conducted to evaluate the effects of receptors on the inflammatory modulating effects. One such study found that (R)-2,4-dimethoxy-4-iodoamphetamine ((R)-DOI) can potently suppress TNF-α-induced inflammation. This study found that the same effect could be induced, albeit with slightly weaker potency, by the psychoactive 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 the anti-inflammatory effects of some psychoactive compounds is at the low picomolar concentration range, which is approximately 500 times more potent than conventional corticosteroids at their target. Anti-inflammatory doses of psychoactive drugs may also be below the threshold for producing subjective or behavioral effects, meaning they can exhibit anti-inflammatory effects without causing a psychoactive "trip."

[0295] This study, as well as subsequent in vitro and in vivo studies, demonstrated that (R)-DOI inhibits TNF-α-induced expression of genes encoding intracellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), inflammatory cytokines IL-6 and IL-1β, and chemokine monocyte chemotactic protein-1 (MCP1). (R)-DOI also blocks NF-κB activation and nuclear translocation, nitric oxide synthase activity, and downregulates asthma-related protein arginase-1 (NauF 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). Furthermore, some psychoactive compounds potently suppress selected key pro-inflammatory biomarkers while remaining unaffected by others. In the case of biomarkers where suppression is evident, the suppression is potent, and even relatively high doses of the drug do not suppress levels below baseline, but rather restore them to baseline levels (Nichols CD. Neuropharmacol. 2022;219:109232). Therefore, some psychoactive agents can reduce the expression of specific key inflammatory components with minimal impairment of the immune response. This is a unique mechanism of action among known anti-inflammatory and immunomodulatory agents and may be advantageous because it is predicted to result in fewer side effects, such as opportunistic infections, associated with broad-spectrum immunosuppressants like corticosteroids (ibid.).

[0296] Psychotropic drugs have high therapeutic potential as anti-inflammatory agents, but there is considerable variability in the effectiveness of different psychotropic drugs. Due to the diversity of chemical structures among psychotropic drugs, 5-HT 2AIt is hypothesized that functional selectivity may occur at the receptor, allowing a specific ligand to engage with a particular subset of amino acid residues within the receptor's binding pocket, inducing a stable conformation that binds to different anti-inflammatory signaling effectors. This hypothesis is supported by the different peripheral effects of (R)-DOI and (R)-DOTFM, the former inducing anti-inflammatory effects in a mouse asthma model, while the latter does not (Flanagan et al., ACS Pharmacol Transl Sci. 2024). This finding relates to anti-inflammatory phenethylamine 5-HT 2A This supports previous research that determined the primary pharmacophore of the receptor agonist to be 2,5-dimethoxyphenethylamine (2C-H) (Flanagan TW et al., ACS Pharmacol Transl Sci. 2020 Aug 13;4(2):488-502). However, 5-HT 2A The structure-activity relationship between anti-inflammatory agents with receptor agonist properties remains unclear.

[0297] In some embodiments, the disclosed compounds are potent anti-inflammatory agents that act on specific inflammatory mediators, thereby restoring chronically inflammatory tissue to a healthy state. In some embodiments, the anti-inflammatory effect is exerted without extensive suppression of the immune system, and therefore may be beneficial for treating inflammatory diseases in which steroids are contraindicated or the condition is steroid-resistant.

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

[0299] In some embodiments, the disclosed compounds exhibit potent anti-inflammatory properties. In some embodiments, administration of the disclosed compounds suppresses several pro-inflammatory markers (e.g., mRNA encoding IL6, IL1b, GMCSF, Arg1, and IL5). In some embodiments, administration of the disclosed compounds suppresses pro-inflammatory markers to baseline levels. While not bound by theory, the disclosed compounds are 5-HT 2A Due to its functional selectivity at the receptor, the compound may exert its anti-inflammatory effect by engaging with specific amino acid residues within the receptor and stabilizing it in a conformation that triggers anti-inflammatory signaling pathway effectors.

[0300] In some embodiments, the biomarker for inflammatory response gene expression is mRNA. In some embodiments, the biomarker for inflammatory response gene expression is a protein. In some embodiments, the inflammatory response gene is TNFα, Arg-1, IL-4, IL-5, IL-6, IL-8, IL-9, IL-1β, IL-1A, IL-12, IL-13, IFNα, IFNb, IFNg, TGF-β, IL-15, IL-17, IL-20, IL-22, LTA, IL-23, IL-18, VCAM1, ICAM1, MCP1, MMP-9, Muc5ac, Gm-csf, CCL2, CCL5, CCL3, CCL4, CCL11, CD11a, CD3, CD4, CD8, or CRP. In some embodiments, the inflammatory response gene encodes an inflammatory substance. The inflammatory substance is a protein that activates the inflammatory response. Examples of inflammatory substances include the proteins IL-1β, TNFα, IL-15, IL-17, Arg-1, and IL-18. In some embodiments, the inflammatory response gene encodes an anti-inflammatory agent. An anti-inflammatory agent is a protein that reduces the inflammatory response. Examples of anti-inflammatory agents include the proteins IL-1, IL-4, IL-10, IL-11, and IL-13. In some embodiments, the inflammatory response gene encodes a substance that can be inflammatory or anti-inflammatory. For example, leukemia inhibitors, interferon-α, IL-6, and transforming growth factor (TGF-β) can act as either inflammatory or anti-inflammatory cytokines under various circumstances (Zhang JM, An J. Int Anesthesiol Clin. 2007 Spring; 45(2): 27-37).

[0301] In some embodiments, the inflammatory response gene is ICAM1. In some embodiments, the biomarker for the inflammatory response is the ICAM1 gene product. In some embodiments, the biomarker is ICAM1 mRNA. In some embodiments, the biomarker is ICAM1 protein. In some embodiments, the inflammatory response gene is VCAM1. In some embodiments, the biomarker for the inflammatory response is the VCAM1 gene product. In some embodiments, the biomarker is VCAM1 mRNA. In some embodiments, the biomarker is VCAM1 protein. In some embodiments, the inflammatory response gene is MCP1. In some embodiments, the biomarker for the inflammatory response is the MCP1 gene product. In some embodiments, the biomarker is MCP1 mRNA. In some embodiments, the biomarker is MCP1 protein. In some embodiments, the inflammatory response gene is IL-5. In some embodiments, the biomarker for the inflammatory response is the IL-5 gene product. In some embodiments, the biomarker is IL-5 mRNA. In some embodiments, the biomarker is IL-5 protein. In some embodiments, the inflammatory response gene is IL-6. In some embodiments, the biomarker for the inflammatory response is the IL-6 gene product. In some embodiments, the biomarker is IL-6 mRNA. In other embodiments, the biomarker is IL-6 protein.

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

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

[0304] In some embodiments, the inflammatory response biomarker is a cytokine. Cytokines are small signaling proteins that regulate the interactions of various cell types involved in the amplification and regulation of the inflammatory response. In some embodiments, the cytokine biomarker is IL-2, IFN-γ, TNFα, TNFβ, GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17, IL-25, IL-33, or TGF-β. In some embodiments, the inflammatory response biomarker is a chemokine. Chemokines are small signaling proteins that induce the migration of other cell types, such as migration to the site of tissue injury. In some embodiments, the chemokine biomarker is CCL-1~CCL-28, CXCL-1~CXCL-16, IL-8, MCP1, RANTES, XCL1, XCL2, or CX3CL1. In some embodiments, the inflammatory response biomarker is an enzyme. In some embodiments, the enzyme biomarker is Arg-1. In some embodiments, inflammatory biomarkers for specific inflammatory diseases, comorbidities, or patient attributes will be known to those skilled in the art (see Sreedhar R, et al., General Mechanisms of Immunity and Inflammation. In: Watanabe K & Arumugam S. eds. Japanese Kampo medicines for the treatment of common diseases: Focus on inflammation. Academic Press; 2017: Chapter 3; Germolec DR et al., Markers of Inflammation. Methods Mol Biol. 2018; 1803: 57-79; Calder PC et al., Br J Nutr. 2013 Jan; 109 Suppl 1: S1-34).

[0305] In some embodiments, the disclosed compounds bring the levels of inflammatory response biomarkers in a subject closer to baseline levels. “Baseline levels” refer to the levels of biomarkers observed in a healthy population that has not experienced inflammation. Baseline levels vary depending on the biomarker and can be known to those skilled in the art or measured by standard techniques (Calder PC et al., Br J Nutr. 2013 Jan;109 Suppl 1:S1-34).

[0306] In some embodiments, the disclosed compounds reduce the levels of inflammatory biomarkers. In some embodiments, the disclosed compounds do not reduce the levels of inflammatory biomarkers below baseline. In some embodiments, the disclosed compounds reduce the levels of inflammatory biomarkers (e.g., mRNA biomarkers, cytokine biomarkers, chemokine biomarkers) by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, the disclosed compounds reduce the levels of inflammatory biomarkers (e.g., mRNA biomarkers, cytokine biomarkers, chemokine biomarkers) to within about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of their baseline level. In some embodiments, the disclosed compounds reduce 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, 40 pg / 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, this is a plasma sample.

[0307] In some embodiments, the disclosed compounds increase the levels of anti-inflammatory biomarkers. In some embodiments, the disclosed compounds do not raise the levels of pro-inflammatory biomarkers above baseline. In some embodiments, the disclosed compounds increase the levels of pro-inflammatory biomarkers (e.g., mRNA biomarkers, cytokine biomarkers, chemokine biomarkers) by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, the disclosed compounds increase 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, 40 pg / 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, this is a plasma sample.

[0308] In some embodiments, the dosage of the disclosed compound used to elicit an anti-inflammatory effect is sub-behavioral. In some embodiments, the disclosed compound is used in dosages of approximately 0.001–0.01 mg / kg, approximately 0.01–0.05 mg / kg, approximately 0.05 mg / kg–0.1 mg / kg, approximately 0.1 mg / kg–0.2 mg / kg, approximately 0.4 mg / kg–0.3 mg / kg, approximately 0.3 mg / kg–0.4 mg / kg, or approximately 0.4 mg / kg–0.5 mg / kg to elicit an anti-inflammatory effect.

[0309] In embodiments, the disclosed compounds are used to treat inflammatory diseases. In embodiments, the disclosed compounds are used to reduce inflammation. In embodiments, the disclosed compounds are used to manufacture pharmaceuticals for treating inflammatory diseases or reducing inflammation.

[0310] In some embodiments, the disease is an acute inflammatory disease. In some embodiments, the disease is a chronic inflammatory disease. In some embodiments, the inflammatory disease is asthma, chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn's disease, multiple sclerosis, sepsis, conjunctivitis, Alzheimer's disease, or another inflammatory condition described herein.

[0311] In some embodiments, the disclosed compounds are useful for treating inflammatory conditions in patients with autoimmune disorders or other weakened immune systems. For example, the disclosed compounds are 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's disease, celiac disease, autoimmune encephalitis, gout, vasculitis, mixed connective tissue disease, undifferentiated connective tissue disease, myositis, scleroderma, Sjögren's syndrome, uveitis, inflammatory bowel disease (IBD), Guillain-Barré syndrome, psoriasis, Graves' disease, scleroderma (systemic sclerosis), dermatomyositis, Hashimoto's thyroiditis, pernicious anemia, Alzheimer's disease, heart disease, cardiovascular disease, chronic liver and kidney disease, fibromyalgia, allergies, or chronic obstructive pulmonary disease (COPD). In some embodiments, the disclosed compounds are useful for treating chronic inflammation in immunocompromised chemotherapy patients.

[0312] In some embodiments, the disclosed compounds are useful for treating inflammatory conditions in patients with steroid-resistant diseases or disorders. In some embodiments, the steroid-resistant diseases or disorders are 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 leukemia, steroid-resistant rheumatoid arthritis, or steroid-resistant idiopathic nephropathy.

[0313] In some embodiments, the disclosed compounds are useful for treating inflammatory conditions in patients with contraindications to corticosteroids. Contraindications to corticosteroids may occur, for example, due to hypersensitivity to any component of corticosteroid preparations, co-administration of live vaccines or attenuated live vaccines (e.g., when using immunosuppressive doses), systemic fungal infections, osteoporosis, uncontrolled hyperglycemia, adrenal suppression, Cushing's syndrome, diabetes mellitus, glaucoma, cataracts, joint infections, uncontrolled hypertension, herpes simplex keratitis, myopathy, certain mental disturbances and / or psychiatric disorders, as well as varicella infection. Further exemplary contraindications include peptic ulcer disease, congestive heart failure, and viral or bacterial infections that are not controlled with anti-infective or antibacterial agents.

[0314] In the embodiments, the disclosed compounds are useful for treating skin inflammation, myoinflammation, tendinitis, ligament inflammation, osteitis, chondritis, pneumonia, cardiac inflammation, hepatitis, pancreatic inflammation, nephritis, cystitis, gastritis, enteritis, neuroinflammation, ocular inflammation, and encephalitis.

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

[0316] In some embodiments, the inflammatory disease is any of the following: long-term COVID syndrome, food allergy, Lyme disease post-treatment syndrome, and ulcers. In some embodiments, the inflammatory disease is asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchitis, bronchiolitis, bullous pemphigoid, burns, bursitis, cancer including NF-κB-induced inflammatory cancer; cardiovascular diseases including hypertension, endocarditis, myocarditis, valvular insufficiency, congestive heart failure, myocardial infarction, diabetic cardiac abnormalities, vasculitis (including arteritis, phlebitis, and vasculitis); arterial occlusion including arteriosclerosis and stenosis. Obstructive diseases; inflammatory cardiomegaly, peripheral artery disease, aneurysm, embolism, incision, pseudoaneurysm, vascular malformations, vascular nevi, 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, dacryoadenitis, and dementia.

[0317] In some embodiments, inflammatory diseases are dermatitis disorders. While not bound by theory, dermatitis refers to chronic inflammation of the skin that can occur due to impaired skin barrier function, abnormal inflammatory responses, and persistent itching (Nakahara T et al., J Dermatol. 2021;48(2):130-139; Beck LA et al., JID Innov. 2022;2(5):100131). Common features among dermatitis disorders include redness, persistent itching, and dry skin, but the further clinical phenotypes of dermatitis disorders are highly heterogeneous, reflecting the diversity and complexity of the underlying mechanisms that lead to the disorders (Renert-Yuval Y et al., J Allergy Clin Immunol. 2021;147(4):1174-1190.e1). Many inflammatory substances involved in chronic inflammation are also involved in the inflammatory response to dermatitis, and these include, but are 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 treatment of dermatitis disorders often targets the inflammatory pathway, thereby modulating the inflammatory response and improving the symptoms of the dermatitis disorder (Wollenberg A et al., Br J Dermatol. 2014;170 Suppl 1:7-11).

[0318] In some embodiments, inflammatory diseases include dermatitis disorders such as atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact dermatitis, dry eczema, seborrheic dermatitis, discoid eczema, varicose vein eczema, herpetic dermatitis, neurodermatitis, autosensitization dermatitis, stasis dermatitis, suppurative dermatitis, dyshidrotic eczema, follicular eczema, cavernous dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

[0319] In some embodiments, the dermatitis is atopic dermatitis. In some embodiments, the dermatitis is chronic photosensitive dermatitis. In some embodiments, the dermatitis is eczema. In some embodiments, the dermatitis is atopic eczema. In some embodiments, the dermatitis is contact eczema. In some embodiments, the dermatitis is dry eczema. In some embodiments, the dermatitis is seborrheic dermatitis. In some embodiments, the dermatitis is nummular eczema. In some embodiments, the dermatitis is varicose vein eczema. In some embodiments, the dermatitis is herpetic dermatitis. In some embodiments, the dermatitis is neurodermatitis. In some embodiments, the dermatitis is herpetic dermatitis. In some embodiments, the dermatitis is autosensitization dermatitis. In some embodiments, the dermatitis is stasis dermatitis. In some embodiments, the dermatitis is suppurative dermatitis. In some embodiments, the dermatitis is dyshidrotic eczema. In some embodiments, the dermatitis is follicular eczema. In some embodiments, the dermatitis is cavernous dermatitis. In some embodiments, the dermatitis is hand dermatitis. In some embodiments, the dermatitis is diaper dermatitis. In some embodiments, the dermatitis is occupational contact dermatitis. In some embodiments, the dermatitis is lichen planus-like atopic dermatitis.

[0320] In some embodiments, inflammatory diseases include dermatitis including psoriasis, which includes atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic dermatitis, dyshidrosis, nummular eczema, venous eczema, herpetic dermatitis, neurodermatitis and autosensitization dermatitis, stasis dermatitis, purulent sweat, lichen planus, psoriasis vulgaris, onychopsoriasis, pruritic psoriasis, scalp psoriasis, reverse psoriasis, pustular psoriasis, erythrodermic psoriasis and psoriatic arthritis; rosacea, scleroderma (including Morphea); pharmacologically induced inflammation (including from legal or illegal drugs and chemicals); primary and chronic neurogenic inflammation including secondary neuroinflammation; dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcers, gastrointestinal diseases, emphysema, encephalitis, endocarditis, endometritis, enteritis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, connectitis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, valvular heart failure, hepatitis, pyogenic spondylitis, Huntington's disease, hyperlipidemia, hypertension, ileitis, lymphangitis, lymphadenitis, bacterial cystitis, bacterial encephalitis, pandemic influenza, viral encephalitis , and infections including viral hepatitis (types A, B, and C); inflammatory bowel disease including Crohn's disease; inflammatory cardiomegaly, 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 fatty liver disease, obesity, omphalitis, ovitis, orchitis, chondritis, osteopenia, osteomyelitis, osteoporosis, osteomyelitis, otitis, pancreatitis, parkin Son's disease, mumps, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, interstitial pneumonia, polycystic glomerulonephritis, polymyositis, proctitis, prostatitis, psoriasis, meningitis, portal phlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever rhinitis, salpingitis, sarcoidosis, sialadenitis, sepsis (including bacteremia and viremia); sinusitis, spastic colon, stenosis, stomatitis, stroke, inflammation associated with surgical complications, synovitis, tendinitis, tendinitis, tendinitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection (including graft-versus-host disease (GVHD));Th1-mediated inflammatory diseases, cystic trigoneitis, tuberculosis, tumors, urethritis, bursitis, uveitis, vaginitis; Buerger's disease, cerebrovascular disease, Churg-Strauss arteritis, cryoglobulinemia, essential cryoglobulinic vasculitis, giant cell arteritis, Golfer's vasculitis, Henoch-Schönlein purpura, hypersensitivity vasculitis, Kawasaki disease, microscopic polyarteritis / polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatic vasculitis, Takayasu's arteritis, Wegener's granulomatosis, systemic lupus erythematosus (SLE), relapsing polychondritis, vasculitis including Behçet's disease; ulcerative colitis, including ulcerative proctitis, left-sided colitis, pancolitis and fulminant colitis; and vulvitis.

[0321] The reduction of inflammation, such as chronic systemic inflammation, can be measured according to various methods available to those skilled in the art. Inflammatory biomarkers may be detected from biological specimens, such as the 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 blood tests. CRP can also be detected in saliva samples. Salivary CRP is not synthesized locally in the oral cavity and may reflect inflammation at a more systemic level compared to other inflammatory biomarkers such as cytokines (Szabo & Slavish, Psychoneuroendocrin. 202;124:105069). Furthermore, clinicopathological data, such as hematological data regarding red blood cell parameters, platelet count, total white blood cell count, and white blood cell differentiation and morphology, coagulation data regarding clotting time and fibrinogen, and clinicochemical data regarding total protein, albumin and globulin, liver enzymes, kidney parameters, electrolytes, and bilirubin, can provide initial indicators of the presence and potential location of inflammation when specific immunohistochemical data are unavailable. See, for example, Germolec et al., Methods Mol Biol. 2018;1803:57-79 and Luo et al., Clin Lab. 2019 1;65(3).

[0322] v. Ophthalmic diseases and disorders In some embodiments, the disclosed compounds are used to treat ophthalmic diseases or disorders. Ophthalmic diseases and disorders are often caused by infection and / or inflammation of ocular tissues and are the leading causes of corneal blindness and visual impairment worldwide (Bourne RR et al., Lancet Glob Health. 2013;1(6):e339-49). Repeated episodes of infection or inflammation can trigger a chronic inflammatory disease process, which may result in neovascularization and subsequent corneal scarring that threatens vision (Vaidyanathan U et al., Med Hypothesis Discov Innov Ophthalmol. 2019;8(3):163-176). Corticosteroids are often used to control ocular inflammatory responses, but this treatment is immunosuppressive and can lead to uncontrolled pathogen replication, loss of the intact corneal epithelial barrier, elevated intraocular pressure, and ultimately, decreased vision (Fung AT et al., Clin Exp Ophthalmol. 2020;48(3):366-401). In contrast, modulation with 5-HT receptor agonists has been shown to possess anti-inflammatory and anti-angiogenic properties, as well as the ability to lower intraocular pressure (Foster T et al., Invest Ophthalmol Vis Sci. 2020;61(7):429).

[0323] In some embodiments, the disclosed compounds can be used to alleviate, improve, or prevent ophthalmic diseases or disorders, non-limiting examples of which are described herein.

[0324] In some embodiments, administration of the disclosed compound lowers the intraocular pressure of the subject. In some embodiments, the disclosed compound is used to treat ocular hypertension.

[0325] Normal intraocular pressure (IOP) is generally considered to be between 10 mmHg and 21 mmHg. This pressure is primarily determined by the balance between the amount of aqueous humor produced and drained within the eye. Factors such as corneal thickness and stiffness also play a role in influencing this pressure. Typically, IOP averages around 15–16 mmHg, with a potential variation of up to 6 mmHg. For example, at night, this pressure often decreases due to reduced aqueous humor production. Furthermore, IOP can change in response to several physiological factors, including exercise, heart rate, respiration, fluid intake, and the use of certain systemic or topical medications. Elevated IOP can lead to optic nerve damage, a condition known as glaucoma. When optic nerve damage is absent, the term ocular hypertension is used. Various factors, including conditions such as orbital swelling, traumatic anterior chamber hemorrhage, pupillary occlusion, residual surgical material, intraocular inflammation, or corticosteroid use, can contribute to increased IOP. High intraocular pressure is a significant risk factor for glaucoma, and conversely, glaucoma is often associated with increased intraocular pressure. Symptoms that may arise from elevated intraocular pressure or from a combination of glaucoma and increased pressure include optic nerve damage, optic disc hemorrhage, loss of nerve fiber layers, notch formation, vertically elongated cupping, uneven or progressive enlargement of optic disc cupping, visual field loss, halos, blurred vision, and eye discomfort.

[0326] In some embodiments, the disclosed compounds are used to treat glaucoma. In some embodiments, the glaucoma is open-angle glaucoma, normal-tension glaucoma, closed-angle glaucoma, congenital glaucoma, neovascular glaucoma, pigmentary glaucoma, exfoliation glaucoma, uveitis glaucoma, or glaucoma caused by another factor (e.g., cataract, tumor, eye injury).

[0327] In some embodiments, the disclosed compounds are used to treat allergic conjunctivitis, including vernal keratoconjunctivitis and atopic keratoconjunctivitis; dry eye syndrome and meibomian gland dysfunction; cataracts; keratoconus; bullous keratopathy and other keratopathy; Fuchs' corneal endothelial degeneration; ocular scarring pemphigoid; conditions associated with photoreactive keratotomy (PRK) healing and other corneal healing; conditions associated with tear lipid degradation or lacrimal gland dysfunction; uveitis, including anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, non-infectious uveitis, and infectious uveitis; keratitis; scleritis; iritis; cyclitis; ocular graft-versus-host disease (GVHD); optic neuritis; ocular Stevens-Johnson syndrome; blepharitis; ocular rosacea with or without meibomian gland dysfunction; post-cataract; persistent corneal erosion; and inflammation associated with corneal trauma, corneal transplantation, and refractive surgery.

[0328] In some embodiments, the ophthalmic disease or disorder is an inflammatory disease. 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, polypoid 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 iris, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinal choroidal neovascularization, or a combination thereof.

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

[0330] I. Example The following examples are included for illustrative purposes only and are not intended to limit the scope of the present invention.

[0331] Example 1: Synthesis of 14-methyl-LSD (14-Me-LSD) Indole (2) [ka]

[0332] To a solution of commercially available indole 1 (573 mg, 2.73 mmol) in pyridine (1.59 mL), ICl (1 M in DCM, 2.73 mL, 2.73 mmol) was added at 0°C. After stirring the mixture at 0°C for 1 hour, Boc2O (1.32 mL, 5.73 mmol) and DMAP (33.3 mg, 0.273 mL) were added. 1 After completion of 1H NMR analysis, the mixture was quenched with ice water (10 mL) and extracted with toluene (3 × 30 mL). The combined organic layer was washed with saturated Na₂S₂O₃ solution (15 mL) and brine (15 mL), dried over MgSO₄, and concentrated under reduced pressure. Purification of the crude mixture by flash column chromatography (19:1 hexane:toluene eluent, silica) yielded 1.05 g (87% yield) of indole 2.

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

[0334] HRMS m / z:[M+H] + C 14 H 16 BrINO2 calculated value: 435.9409; measured value: 435.9368

[0335] Alcohol (3) [ka]

[0336] A solution of indole-2 (970.4 mg, 2.225 mmol) in THF (12.30 mL), cooled in an acetone / dry ice bath (-78°C), was added dropwise to a solution of i-PrMgCl·LiCl (2.00 mL, 1.11 M, 2.225 mmol). The mixture was stirred in a cooling bath for 1 hour. 1When 2 was consumed as determined by 1H NMR, a solution of methyl 6-formylnicotinate (735.0 mg, 4.451 mmol) in THF (10.00 mL) was added dropwise to the reaction via intubation. After adding methyl 6-formylnicotinate, the bath was replaced with an ice bath, and the reaction mixture was gradually warmed to room temperature. The reaction was then quenched with a saturated aqueous solution of NH4Cl (10 mL), diluted with water (10 mL), and extracted with toluene (3 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (3:1 hexane:toluene eluent, silica) to obtain 1.057 g (61% yield) of alcohol 3.

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

[0338] HRMS m / z:[M+H] + C 22 H 24 Calculated value of BrN2O5: 475.0868; Measured value: 475.0820

[0339] Pyridine (4) [ka]

[0340] While venting the generated gas, TFA (2.83 mL) was carefully added to a suspension of NaBH4 pellets (175.1 mg, 4.63 mmol) in DCE (11.57 mL) at room temperature. The mixture was stirred until the complete dissolution of the NaBH4 pellets could be visually observed and a fine, grayish-white, cloudy solution was obtained. After dissolution, alcohol 3 (550 mg, 1.157 mmol) was added dropwise as a solution in DCE (11.57 mL). The reaction was stirred at room temperature for 1 hour, and then heated overnight at 60°C. 1 After determination by 1H NMR analysis, the reaction was cooled to room temperature, diluted with H2O (20 mL), neutralized with K2CO3, and extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (3:2 hexane:siRNA eluent, silica) to obtain 326 mg (78% yield) of pyridine 4.

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

[0342] HRMS m / z:[M+H] + C 17 H 16 Calculated value of BrN2O2: 359.0395; measured value: 359.0374

[0343] Tetrahydropyridine (5) [ka]

[0344] To a stirred solution of compound 4 (325.0 mg, 0.904 mmol) in CH2Cl2 (9.05 mL), MeOTf (0.113 mL, 0.995 mmol) was added at 0°C. After 2 hours, the reaction was completed as determined by TLC and concentrated under reduced pressure. The crude residue was redissolved in MeOH (9.05 mL), and solid NaBH4 (136.9 mg, 3.619 mmol) was added gradually at 0°C, causing the solution to turn canary yellow. This combined mixture was stirred overnight at 0°C and finally warmed to room temperature. 1 The reaction was determined to be complete by 1H NMR analysis. The reaction was quenched with a 1:1 mixture of saturated aqueous NaHCO3 and acetone (3 mL). The mixture was extracted with toluene (3 × 15 mL), the combined organic layer was washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (1:1 hexane:toluene, followed by 19:1 DCM:MeOH eluent, silica) to obtain 310 mg (91% yield) of tetrahydropyridine 5.

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

[0346] HRMS m / z:[M+H] + C 18 H 22 Calculated value of BrN2O2: 377.0864; measured value: 377.0861

[0347] Calvamart (6) [ka]

[0348] To a solution of tetrahydropyridine 5 (1.18 g, 3.13 mmol) in DCM (31.2 mL), DMAP (38.2 mg, 0.313 mmol) was added, followed by the addition of Boc2O (0.862 mL, 3.75 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours, 1 The reaction was determined to be complete by 1H NMR analysis. The reaction was quenched by adding H2O (30 mL), extracted with toluene (3 × 30 mL), washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (toluene eluent, silica) to obtain 1.08 g (72% yield) of carbamate 6.

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

[0350] HRMS m / z:[M+H] + C 23 H 30 Calculated value of BrN2O4: 477.1388; measured value: 477.1375

[0351] Tetrahydropyridine (7a and 7b) [ka]

[0352] The following procedure is representative of two parallel reactions that were post-processed and purified together. In a glove box, LiTMP (320.6 mg, 2.179 mmol) was weighed into a flame-dried screw-cap reaction vial containing a septum, and then removed from the glove box. Under a stream of N2, THF (2.20 mL) was added to this vial to obtain an amber-colored solution. To this solution, a solution of carbamate 6 (208 mg, 0.4357 mL) in THF (2.20 mL) was added dropwise at -78°C. The mixture was stirred at -78°C for 1 hour, and then determined to be complete by TLC analysis. The reaction was quenched at -78°C with a saturated aqueous solution of NH4Cl (2.0 mL) and warmed to room temperature. The mixture was diluted with water (10 mL) and extracted with toluene (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (1:1 hexane:toluene eluent, silica) to obtain a mixture of tetrahydropyridine diastereomers 7a and 7b in a ratio of 1.5:1, yielding 335 mg (average yield 79%).

[0353] 1 1H NMR (7a) (600 MHz, CDCl3): δ 7.42(s,1H),7.30(dd,J=7.9,1.1Hz,1H),6.92(dd,J=7.9,1.1Hz,1H),5.91-5 .85(m,1H),5.70(dt,J=10.2,2.5Hz,1H),3.71(s,3H),3.59(ddd,J=14.8,4.4 ,1.2Hz,1H),3.42(ddt,J=8.4,5.5,2.8Hz,1H),3.28-3.15(m,2H),2.87-2.76 (m,1H),2.67(dd,J=11.6,9.6Hz,1H),2.55(s,3H),2.50(s,3H),1.63(s,9H).

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

[0355] HRMS m / z:[M+H] + C 23 H 30 Calculated value of BrN2O4 is 477.1388; measured value is 477.1366

[0356] Erukin (8, 9a, および9b)

change

[0357] In a glove box, Pd(tBu3P)2 (360 mg, 0.7038 mmol) was weighed into a flame-dried screw-cap reaction vial containing a septum, and then removed from the glove box. Dioxane (5.0 mL) was added to this reaction vial under a stream of N2. In a separate RBF, tetrahydropyridine 7a and 7b (336 mg, 0.7038 mmol) were dissolved in dioxane (30.2 mL), and the previously prepared Pd(tBu3P) solution, followed by Cy2NMe (0.452 mL, 2.111 mmol), was added. N2 was then injected into this mixture for 5 minutes, and then heated to 100°C in an oil bath. After 2 hours, TLC analysis determined that the reaction was complete. Once the reaction had cooled to room temperature, the mixture was diluted with water (30 mL) and extracted with RINKAN (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography with silica neutralized with Et3N (4:1 hexane:Ã eluent, silica) to obtain 220 mg (79% yield) of ergoline compound 8 containing trace amounts of isomers presumed to be 9a and 9b. This mixture was used in subsequent steps without affecting the results.

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

[0359] HRMS m / z:[M+H] + C 23 H 29 Calculated value of N2O4: 397.2127; measured value: 397.2109

[0360] Carboxylic acid (10) [ka]

[0361] A stirred solution of tetracyclic compound 8:9a:9b (220 mg, 0.555 mmol) in ethanol (6.94 mL) was mixed with 1 M KOH (6.94 mL), and the mixture was heated in an oil bath at 70 °C for 12 hours. Upon completion, as determined by HRMS, the mixture was cooled to room temperature and acidified to pH 6.0 using 1 M HCl. The resulting solution was concentrated, and the residue was suspended in pyridine (10 mL). This suspension was then filtered, and the filtrate was evaporated to obtain crude carboxylic acid 10 as a brown oily substance.

[0362] 14-Me-LSD(11) [ka]

[0363] Diethylamine (0.128 mL, 1.234 mmol) was added at 0°C to a solution of crude carboxylic acid 10 (268 mg, 0.949 mmol) in DCM (9.5 mL) and pyridine (0.245 mL, 3.047 mmol). The reaction was stirred at 0°C for 30 minutes, then T3P (0.735 mL, 1.234 mmol, 50% in pharmaceutically acceptable ammonium compounds) was added, the mixture was stirred overnight, and finally warmed to room temperature. The reaction was quenched by adding DI H2O (10 mL), stirred for 30 minutes, then the layers were separated and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified using centrifugation thin-layer chromatography (SiO, followed by 19:1 DCM:MeOH eluent and silica) to obtain 51 mg (27% across two steps) of 14-Me-LSD11 as a brown oil.

[0364] 1H NMR(11)(600MHz,CDCl3):δ 8.11(s,1H),7.12(d,J=7.4Hz,1H),6.93(d,J=1.0Hz,1H),6.89(s,1H),6.30(s,1H) ),4.01-3.95(m,1H),3.52(dd,J=14.5,5.5Hz,1H),3.49-3.40(m,4H),3.30(dddd, J=9.1,7.6,4.5,2.6Hz,1H),3.16(ddd,J=11.1,4.9,1.4Hz,1H),2.94(t,J=10.9Hz ,1H),2.76(ddd,J=13.7,11.6,1.7Hz,1H),2.63(s,3H),2.45(s,3H),1.24(t,J=7.2 3H),1.17(t,J=7.1Hz,3H).

[0365] HRMS m / z:[M+H] + C 21 H 28 Calculated value of N3O: 338.2232; measured value: 338.2227

[0366] Preparation of maleate of 11: To a solution of 11 (37.5 mg, 0.111 mmol) in ¼ (0.9 mL) and MeOH (0.1 mL), a solution of maleic acid (12.9 mg, 0.111 mmol) in ¼ (1 mL) was added at room temperature. After cooling the solution to -20°C overnight in a freezer, it was evaporated to dryness and triturated with Et₂O (3 × 3 mL) to obtain 35 mg (69% yield) of 11 as its corresponding maleate.

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

[0368] To a solution of 14-Me-LSD 11 (18.7 mg, 0.0554 mmol) in dioxane (1.11 mL), solid Br2-dioxane (13.7 mg, 0.0554 mmol) was gradually added at approximately 15°C. After the addition of Br2-dioxane, the reaction mixture was warmed to room temperature and stirred for 30 minutes, after which completion was determined by TLC. The reaction was diluted with DCM (5 mL), quenched by the addition of saturated aqueous solution of NaHCO3 (5 mL), then the layers were separated and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (siRNA eluent, silica) to obtain 14.0 mg (60% yield) of 2-Br-14-Me-LSD 12 as a brown oily substance.

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

[0370] HRMS m / z:[M+H] + C 21 H 27 BrN3O calculated value: 416.1337; measured value: 416.1323

[0371] Preparation of maleate of 12: To a solution of 12 (37.2 mg, 0.089 mmol) in Depositphotos (0.9 mL) and MeOH (0.1 mL), a solution of maleic acid (10.4 mg, 0.089 mmol) in Depositphotos (1 mL) was added at room temperature. After cooling the solution to -20°C overnight in a freezer, it was evaporated to dryness and triturated with Et2O (3 × 3 mL) to obtain 33 mg (69% yield) of 12 as its corresponding maleate.

[0372] 1 H NMR (12 Maleate) (600MHz, CDCl3): δ8.91(s,1H), 7.01(d,J=7.4Hz,1H), 6.87(d,J=7.4Hz,1H), 6.31(s,1H), 4.46-4.43(m,1H), 3.92-3.89(m,1H), 3. 74-3.69(m,1H), 3.58(t,J=11.4Hz,1H), 3.50-3.36(m,4H), 3.12(s,3H), 3 .10-2.98(m,2H), 2.40(s,3H), 1.25(t,J=6.4Hz,3H), 1.18(t,J=7.0Hz,3H)

[0373] Example 3: In vitro receptor activity assay Objective: To identify human 5-HT expressed in transfected HEK-293 cells. 2A Human 5HT expressed in receptors and CHO-K1 cells 2B The agonist activity of the disclosed compounds at the receptor was determined by measuring their effect on IP1 production using HTRF detection.

[0374] Method: Cells were suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCl, 146 mM NaCl, 1 mM CaCl2, 0.5 mM MgCl2, 5.5 mM glucose, and 50 mM LiCl, and then 1.5 × 10⁶ 4 Distribute the cells into a microplate at the specified cell / well density and incubate at 37°C for 30 minutes in the presence of buffer (basic control), test compound, or reference agonist.

[0375] For the measurement of the stimulated control, a separate assay well contains 10 μM 5-HT. After incubation, the cells are lysed and a fluorescent acceptor (D2-labeled IP1) and a fluorescent donor (europium cryptotate-labeled anti-IP1 antibody) are added.

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

[0377] The results are expressed as a percentage of the control response to 10 μM 5-HT. The standard reference agonist is 5-HT, and 5-HT has its EC 50 Several concentrations are tested in each experiment to create a concentration-response curve from which values ​​can be calculated.

[0378] Results: Table 3 shows the 5-HT of 14-Me-LSD and 2-Br-14-Me-LSD. 2ASummarize the agonist activity data. [Table 3]

[0379] The dose-response curves for 14-Me-LSD and 2-Br-14-Me-LSD are shown in Figures 1 and 2, respectively. These data correspond to the following tabular data. [Table 4] [Table 5]

[0380] The results showed that both 14-Me-LSD and 2-Br-14-Me-LSD were 5-HT 2A It was shown to be a potent agonist of the receptor. Furthermore, all of the exemplary compounds were shown to be 5-HT 2B Compared to receptor activation, 5-HT 2A It exhibits excellent selectivity for receptor activation, and 5-HT 2B E max The value is low.

[0381] Example 4: In vitro receptor binding assay Method: The membrane is 5-HT 2A / HEK293 cells, 5-HT 2B / CHO-K1 cells and 5-HT 2C Extracted from HEK293 cells. The reference compound and screening compound were serially diluted 4-fold in 100% DMSO in 8 steps. 1 μL of the serially diluted reference compound and screening compound were transferred to an assay plate. Then, 100 μL / well of membrane and 100 μL / well of radioligand were added. 3 HLSD or 125Add I-DOI. Incubate at room temperature for 1 hour. Filter the reaction mixture through a GF / C plate using a PerkinElmer Filtermate Harvester and wash the plate. Dry the filter plate at 50°C for 1 hour. Seal the bottom of the filter plate using Perkin Elmer Unifilter-96 backing seal tape. Add 50 μL of Perkin Elmer Microscint 20 cocktail to each well of the assay plate and capture the reaction mixture on the filter plate using a Perkin Elmer MicroBeta2 Reader. 3 Count H.

[0382] Results: The results showed that the disclosed compound was 5-HT 2A It strongly binds to another receptor (e.g., 5-HT). 2B Receptor or 5-HT 2C Compared to other 5-HT receptors such as receptors, 5-HT 2A This is expected to demonstrate improved selectivity in terms of receptor binding.

[0383] Example 5: Anti-inflammatory properties of compounds The anti-inflammatory properties of the disclosed compounds will be evaluated in a mouse model of allergic asthma according to the method described by Flanagan et al., ACS Pharmacol Trans Sci. 2020, 4(2), 488-502.

[0384] Procedure: The respiratory pathogen-free brown Norway (RijHsd-BN) rats used in this example are housed alone in a pathogen-free animal facility with free access to food and water in a 12-hour / 12-hour light-dark cycle. The animal protocol is 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, D.C. (2011)). The rats are acclimatized for at least one week before initiating sensitization with ovalbumin grade V (OVA).

[0385] For sensitization, as described by Elwood et al., J Allergy Clin Immunol. 1991, 88(6), 951-60, 2.0 mg of chicken OVA (500 μL) emulsified in 2.0 mL of Imject Alum [Al(OH)3 / Mg(OH)2] is intraperitoneally injected into Brown Norwegian rats (7-9 weeks old) on days 0 and 7. The OVA exposure method is 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). Rats treated with OVA alone are exposed three times a week to 10.0 mg of OVA slowly dissolved in 10.0 mL of 0.9% sterile saline in a 15 L (38.00 × 19.05 × 19.7 cm) acrylic induction chamber. No more than six animals are exposed in the chamber per load. As described by Palmans et al., Am J. Respir Crit Care Med. 2000, 161, 627-635, OVA aerosol was generated at a 1.0% OVA concentration for a total of 30 minutes using an ultrasonic nebulizer in combination with a Pari Proneb pump.

[0386] For drug exposure, rats were exposed in groups of 3-4 rats / group to an appropriate concentration of drug dissolved in 4.5 mL of sterile saline using the inExpose nasal inhalation system 30 minutes prior to each OVA load. Each 4.5 mL sample was aerosolized using a nebulizer in combination with a Pari Proneb pump. Exposure continued for 15 minutes. All respiratory parameters were measured 48 hours after the final OVA exposure. To minimize the influence of circadian rhythms, all respiratory recordings were made between 10:00 AM and 3:00 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). To measure airway responsiveness to MeCh, a non-invasive bias-flow ventilation whole-body plethysmography system is used in spontaneously breathing, unrestrained rodents. The plethysmograph is ventilated at a continuous flow rate of 2.5 L / min. A differential pressure transducer is connected to the main chamber at one pole and to the reference chamber at the second pole. The transducer measures the pressure difference between the two chambers caused by the respiratory cycle (primarily inspiration and expiration). Computer software provides analysis of the pressure signal for each breath, and computer calculations convert the pressure difference into a dimensionless, empirically established value, enhanced pause, or PenH.

[0387] 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 According to Med.1997,156,766-775; Djuric et al., Brain, Behav.Immun.1998,12(4),272-84), PenH is a highly reliable and sensitive measure of bronchoconstriction, and has been shown to be a superior measure for assessing the degree of bronchoconstriction compared to other derivation parameters such as box pressure or box flow (Djuric et al., Brain, Behav.Immun.1998,12(4),272-84). Furthermore, PenH faithfully reproduces the results of forced breathing 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).

[0388] In the assay, the chamber pressure signal is calibrated by dynamically injecting 5 mL of room air via syringe. Rats are then placed in the chamber, and baseline data is recorded for 5 minutes using a plethysmograph after a 10-minute acclimatization period. After baseline PenH measurement, either aerosolized saline (0.9% NaCl solution) or progressively increasing concentrations of MeCh aqueous solution (4, 8, 16, 32 mg / mL) are sprayed through the inlet of the plethysmography chamber for 3 minutes, followed by 3 minutes of PenH measurement. Aerosols are generated using a vibrating mesh nebulizer. After recording, a 7-minute washout period is provided, supplying fresh air to the rats to prevent MeCh gradients. Data are presented as the mean SEM of the maximum PenH values ​​per group.

[0389] Results: The results suggest that certain disclosed compounds may possess potent anti-inflammatory properties, more specifically, that they may reduce PenH maximums and suppress pneumonia.

[0390] Example 6: Evaluation of ocular inflammation after application of the compound Objective: Ocular inflammation and uveitis encompass vision-threatening conditions with local and systemic etiologies. Cytokines, such as 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), as well as neuropeptides, such as substance P (Bignami et al., Curr Drug Targets. 2016;17(11):1265-74), can be contributing factors to ocular inflammation.

[0391] Methods: Ocular inflammation is evaluated according to a modified known method. For example, ocular inflammation can be evaluated using an induced uveitis model (see International Publication No. 2015074137, e.g., the endotoxin-induced model in Example 1 and the LPS-induced model in Example 2), a chemical cauterization model of corneal inflammation (see Example 4 in International Publication No. 2015074137, e.g.), or in human subjects at risk of or currently experiencing such inflammation.

[0392] Results and Significance: The application of the disclosed compounds, e.g., topical application, can prevent and / or reduce ocular inflammation. The reduction of ocular inflammation may result in improvement of overall symptoms associated with ocular inflammation, including, but not limited to, redness, pain, and changes in vision (e.g., blurred vision).

[0393] Example 7: In vivo model for evaluating atopic dermatitis after application of a compound Objective: Atopic dermatitis or eczema is characterized by chronic inflammation and can cause inflammatory symptoms such as skin irritation. In some embodiments, the disclosed compounds and compositions may be useful for treating atopic dermatitis. The objective of this experiment is to evaluate the therapeutic effects of the disclosed compounds and compositions (e.g., inhibiting and / or reducing various endpoints associated with atopic dermatitis) in a mouse in vivo model of atopic dermatitis. The model used in this study is a flake-tail mouse strain with a mutation in the gene for the epidermal protein filaggrin, which is comparable to the mutation underlying human atopic dermatitis or eczema (Fallon et al., Nat Genetics, 2009, 41:602-608). Topically applying ovalbumin to these mice induces symptoms similar to atopic dermatitis. Mice typically develop eczema and elevated levels of inflammatory biomarkers in the skin after ovalbumin application. Exemplary measures of effectiveness include skin flake condition, and levels of skin type 2 helper T cells (Th2) and cytokines (such as IL-4, IL-5, and IL-10).

[0394] Methods: A protocol for the application of ovalbumin to the skin of flaketail mice is described in the literature (ibid.). Briefly, the abdomen of 3-5 week old mice is shaved 24 hours before skin application of ovalbumin suspension (50 μg in 50 μL PBS), and the ovalbumin suspension is applied to the abdomen as described above (ibid.).

[0395] There are two experimental groups: In the first group, mice are pre-treated with the disclosed compounds before and during ovalbumin application to investigate their effects in preventing and inhibiting the development of atopic dermatitis. In the second group, mice are treated with the disclosed compounds after 4-5 weeks of ovalbumin treatment (after the appearance of atopic dermatitis symptoms) to investigate the effects of the compounds in treating symptoms. For each compound tested, the compound is administered in several doses (e.g., intravenously, intramuscularly, or orally) to investigate dose-dependent effects. After each experiment, the mice are euthanized, and skin punch biopsy specimens are taken from each abdomen, rapidly frozen in liquid nitrogen, and homogenized with HTAB buffer. The samples are centrifuged, and the supernatant is subjected to cytokine profiling by ELISA for the levels of biomarkers (e.g., Th2, IL4, IL5, and IL10) using protein standards for quantification.

[0396] Results: The results are expected to indicate that administration of the disclosed compound or composition prevents, inhibits, and / or treats the symptoms of atopic dermatitis.

[0397] Example 8: In vitro metabolic stability of compounds The objective of this experiment is to evaluate the metabolic stability of the disclosed compound in an in vitro assay. The liver is a major site of drug metabolism in the body, and the in vitro intrinsic clearance of a compound can be determined using liver microsomes, hepatocytes, and the liver S9 fraction. See, for example, 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).

[0398] Method: The liver microsome stability assay is performed according to available methods, for example, with modifications to the method described in U.S. Patent Application Publication No. 2008 / 0045588. Briefly, this assay is performed with 1 mg / mL of liver microsomal protein using an NADPH-producing system in 2% NaHCO3 (2.2 mM NADPH, 25.6 mM glucose-6-phosphate, 6 units / mL glucose-6-phosphate dehydrogenase, and 3.3 mM MgCl2). The test compound is prepared as a 20% aqueous acetonitrile solution and added to the assay mixture (final assay concentration 5 micrograms / mL), and incubated at 37°C. The final concentration of acetonitrile in the assay should be less than 1%. Aliquots (50 μL) are taken at 0, 15, 30, 45, and 60 minutes and diluted with ice-cold acetonitrile (200 μL) to stop the reaction. The sample is centrifuged at 12,000 RPM for 10 minutes to precipitate the protein. Transfer the supernatant to a microcentrifuge tube and store it for LC / MS / MS analysis of the degradation half-life of the test compound.

[0399] Results and Significance: The results provide measurements of the in vitro intrinsic clearance of the disclosed compounds and predict the metabolic stability and clearance of the compounds.

[0400] Example 9: In vivo model for evaluating intraocular pressure after application Objective: High intraocular pressure (IOP) is a significant risk factor and / or symptom of various eye diseases and disorders (e.g., glaucoma) and other eye conditions. The objective of this protocol is to evaluate the effect of administering the disclosed compounds on intraocular pressure in an in vivo rat model.

[0401] Methods: To evaluate IOP after single or repeated doses of the test compound via topical ocular administration in male Brown Norway rats, the test compound is directly administered to the surface of both eyes using a calibrated forced-displacement pipette. Baseline and subsequent IOP measurements are completed using a TonoLab Rebound Tonometer. IOP measurements are completed while the animals are fully awake. Six IOP measurements are recorded in three sets and averaged for each eye. The animals receive three doses over 10 minutes (10 μL of test compound solution per dose), i.e., a "loading dose" series of 10 μL every 2-3 minutes.

[0402] Results: The results may indicate that administration of the disclosed compound may result in a decrease in IOP, which may demonstrate its usefulness in treating eye diseases and disorders associated with elevated IOP.

[0403] Example 10: In vivo evaluation of the behavioral effects of compounds using HTR. Mouse head-shaking response (HTR) is 5-HT 2A This behavioral test reflects receptor activation and can predict the psychic development effect in humans (Halberstadt et al., J Psychopharmacol. 2011; 25(11): 1548-1561; Glatfelter et al., ACS Pharmacol. Transl. Sci. 2022, 5, 321-330). HTR stands for psychic development 5-HT 2A Receptor agonists are non-psychoactive 5-HT 2A Due to its ability to reliably distinguish it from receptor agonists, it is widely used as an alternative behavior for the human psychic development effect (ibid.).

[0404] Methods: The effects of the disclosed compounds were evaluated in mice by performing an HTR assay according to the method described in Glatfelter et al., ACS Pharmacol.Transl.Sci.2022,5,321-330. All experiments were performed using adult (2-4 month old) male C57BL / 6J mice weighing 20-30 g. Mice were housed individually in an animal housing facility with free access to food and water under standard 12-hour light-dark conditions (lights on from 07:00 to 19:00).

[0405] Dissolve the test compound in a suitable solvent, e.g., water containing 5% Tween 80, and administer a volume of 0.01 mL / g body weight intraperitoneally or subcutaneously immediately before testing. Test different doses to create a dose-response curve. Inject the drug or vehicle into mice and record the HTR amount as follows:

[0406] On the day of the experiment, mice in their home cages are transported from the animal housing facility to the experimental laboratory and given one hour for acclimatization. For the experimental session, the mice receive an injection of the test compound or vehicle and are placed inside a cylindrical acrylic arena (7.5 inches in diameter) housed within a mouse motility measurement box. The arena has a transparent floor panel with white bench paper underneath to provide a bright background for contrast. A video camera is used to record overhead video (960p resolution) at a high frame rate (120 frames / second) of the mice after injection of the test compound or their saline vehicle. The video camera is mounted approximately 10 inches above the arena floor, and the experimental test session is recorded for 30 minutes after injection. All experiments are conducted between 09:00 and 17:00 local time, during the light phase of the light-dark cycle.

[0407] Mice are randomized to one of the treatment conditions, and repeated tests are performed every 1-2 weeks to avoid potential resistance to the disclosed compound's effect on HTR. After each experiment is videotaped, the video files are transferred to an external hard drive for storage until subsequent computer analysis as described below.

[0408] A commercially available software package (TopScan, Clever Sys Inc.) can be adapted for use in HTR measurement. A unique feature of the TopScan software package is that it monitors the mouse's ears to detect head movements classified as HTR. All videos are analyzed for HTR according to the developer's instructions. Briefly, experimental details (mouse ID, procedure, date, experiment number, etc.) are entered into the software, and the following three steps are performed for each video: (1) a background image file is generated to distinguish the arena and its background from the mouse; (2) an arena file is generated that can be customized to match any arena shape and area contained within each video; and (3) an animal color model file is used to track the ears and is checked to ensure that a clear visualization of the ears exists for each set of videos. The animal color model is dynamic and can be adapted to different lighting conditions or to detect different color contrasts.

[0409] Automated software scoring of experimental videos is performed using all three of the aforementioned parameters created for each video within the software, as well as the experimental information entered into the software database. After the videos are scored, all HTRs identified for each video can be quickly reviewed within the software as a list of short video segments that can be viewed and used to eliminate any potential non-HTR events or false positives and to confirm HTRs. Finally, the data can be exported in several different formats for further processing and statistical analysis.

[0410] Two trained observers watch the videos and visually score the number of HTRs in the 5-minute bins for each 30-minute experimental session. The total number of HTRs observed for each 30-minute video is tallied. The visual scoring is blinded to the treatment condition, and the total number of HTRs per video is determined by averaging the HTRs from the two trained observers, and its relationship to a software-based scoring method is evaluated.

[0411] To evaluate the difference between the scoring method and the effect of the drug treatment, a two-way ANOVA (scoring method × treatment) with Tukey's post-hoc multiple comparison test is used to compare visual scores from trained observers with computer-generated scores from software analysis. Pearson r correlations are calculated to assess the relationship between visual scores from trained observers and computer-generated software scores. Nonlinear regression of the rising phase of the curve is used to determine the potency (ED) from dose-response studies. 50 The value is determined. The analysis is performed using GraphPad Prism software.

[0412] The result was ED 50 It can be expressed as (mg / kg). The difference in mouse HTR between the disclosed compound and a preferred comparative compound can be determined according to the method described herein. The result is obtained for the compound in which the 2-position is not substituted (i.e., in formula R 2 =H; for example, administration of certain exemplary disclosed compounds such as 14-Me-LSD may result in HTR; compounds having a 2-substituted substituent other than H (i.e., in formula R 2 The element is anything other than H; for example, other disclosed compounds such as 2-Br-14-Me-LSD may not yield HTR.

[0413] J. Exemplary aspects and embodiments Among the various exemplary and non-limiting aspects and embodiments described herein are the following:

[0414] In one exemplary embodiment, the compound of formula (1): [ka] Alternatively, a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided, in formula: R 1 R is H or -C(O)-C1~C6 alkyl; 2 R is H, C1-C6 alkyl, or halo; 6 R is a C1-C6 alkyl or C2-C6 alkenyl; 14 R' and R'' are C1-C6 alkyl, C1-C6 alkoxy, or halo; and R' and R'' are C1-C6 alkyl; or R' and R'' together form a heterocycline which may be substituted.

[0415] In this embodiment, R 1 H is H. In this embodiment, R 1 is a -C(O)-C1~C6 alkyl group. In the embodiment, R 6 is methyl. In this embodiment, R 6 is ethyl. In the embodiment, R 6 is an allele. In this embodiment, R 2 H is H. In this embodiment, R 2 is a C1-C6 alkyl group. In this embodiment, R 2 is methyl. In this embodiment, R 2 This is a halo. In the embodiment, R 2 This is bromo. In this embodiment, R 14 is a C1-C6 alkyl group. In this embodiment, R 14 is methyl. In this embodiment, R 14 This is a halo. In the embodiment, R 14 is chloro. In this embodiment, R 14 is a C1-C6 alkoxy. In the embodiment, R 14R' is methoxy. In the embodiment, R' and R'' are both C1-C6 alkyl. In the embodiment, R' and R'' are both methyl. In the embodiment, R' and R'' are both ethyl. In the embodiment, R' is methyl and R'' is n-propyl. In the embodiment, R' is methyl and R'' is isopropyl. In the embodiment, R' and R'' together form an azetidinyl, which is optionally substituted with a C1-C6 alkyl. In the embodiment, R' and R'' together form an unsubstituted azetidinyl. In the embodiment, R' and R'' together form an azetidinyl, which is substituted with a C1-C6 alkyl. 【0...

Claims

1. Compound of formula (1): 【Chemistry 1】 or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, in the formula: R １ is H or -C(O)-C １ ~C ６ It is alkyl; R ２ is Halo, H, or C １ ~C ６ It is alkyl; R ６ is C １ to C ６ alkyl or C ２ to C ６ alkenyl; R １４ C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or halo; and R' and R'' are both C １ ~C ６ They are alkyl; or R' and R'' together form a heterocycline which may be substituted.

2. R １ The compound according to claim 1, wherein is H.

3. R １ ga-C(O)-C １ ~C ６ The compound according to claim 1, wherein it is alkyl.

4. R ６ C １ ~C ６ The compound according to claim 1, wherein it is alkyl.

5. R ６ The compound according to claim 4, wherein is methyl.

6. R ６ The compound according to claim 4, wherein is ethyl.

7. R ６ C ２ ~C ６ The compound according to claim 1, wherein the compound is an alkenyl.

8. R ６ The compound according to claim 7, wherein is allyl.

9. R ２ The compound according to claim 1, wherein the compound is a halo.

10. R ２ The compound according to claim 9, wherein is bromo.

11. R ２ The compound according to claim 1, wherein is H.

12. R ２ C １ ~C ６ The compound according to claim 1, wherein it is alkyl.

13. R ２ The compound according to claim 12, wherein is methyl.

14. R １４ C １ ~C ６ The compound according to claim 1, wherein it is alkyl.

15. R １４ The compound according to claim 1, wherein is methyl.

16. R １４ The compound according to claim 1, wherein the compound is a halo.

17. R １４ The compound according to claim 16, wherein is Cl.

18. R １４ C １ ~C ６ The compound according to claim 1, wherein it is an alkoxy.

19. R １４ The compound according to claim 18, wherein is methoxy.

20. Both R' and R'' are C １ ~C ６ The compound according to claim 1, wherein it is alkyl.

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

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

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

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

25. The compound according to claim 1, wherein R' and R'' together form an optionally substituted heterocycline.

26. R' and R'' together form azetidinyl, and the azetidinyl is C １ ~C ６ The compound according to claim 25, which is optionally substituted with an alkyl group.

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

28. R' and R'' together form azetidinyl, and the azetidinyl is C １ ~C ６ The compound according to claim 25, which is substituted with an alkyl group.

29. R' and R'' together, 【Chemistry 2】 or 【Transformation 3】 The compound according to claim 28, wherein it forms a compound, and the asterisk (*) in the formula indicates a connection point to the rest of the compound.

30. Compounds selected from Table 1, or their pharmaceutically acceptable salts, prodrugs, hydrates, or solvates.

31. The aforementioned compound, 【Chemistry 4】 The compound according to claim 30.

32. The aforementioned compound, 【Transformation 5】 The compound according to claim 30.

33. Compound of formula (2): 【Transformation 6】 or its prodrug, hydrate, or solvate, in the formula: R １ is H or -C(O)-C １ ~C ６ It is alkyl; R ２ H, C １ ~C ６ Alkyl or halo; R ６ C １ ~C ６ Alkyl or C ２ ~C ６ It is an alkenil; R ６’ C １ ~C ６ It is alkyl; R １４ C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or halo; and R' and R'' are both C １ ~C ６ They are alkyl; or R' and R'' together form a heterocycline which may be substituted.

34. R １ The compound according to claim 33, wherein is H.

35. R １ ga-C(O)-C １ ~C ６ The compound according to claim 33, wherein it is alkyl.

36. R ６ C １ ~C ６ The compound according to claim 33, wherein it is alkyl.

37. R ６ The compound according to claim 36, wherein is methyl.

38. R ６ The compound according to claim 36, wherein is ethyl.

39. R ６ C ２ ~C ６ The compound according to claim 33, which is an alkenyl.

40. R ６ The compound according to claim 39, wherein is allyl.

41. R ２ The compound according to claim 33, wherein is H.

42. R ２ is C １ -C ６ alkyl, the compound according to claim 33.

43. R ２ The compound according to claim 42, wherein is methyl.

44. R ２ The compound according to claim 33, wherein the compound is a halo.

45. R ２ The compound according to claim 44, wherein is bromo.

46. R １４ is C １ -C ６ alkyl, the compound according to claim 33.

47. R １４ The compound according to claim 46, wherein is methyl.

48. R １４ The compound according to claim 33, wherein the compound is a halo.

49. R １４ The compound according to claim 48, wherein is Cl.

50. R １４ C １ ~C ６ The compound according to claim 33, which is an alkoxy.

51. R １４ The compound according to claim 50, wherein is methoxy.

52. Both R' and R'' are C １ ~C ６ The compound according to claim 33, wherein it is alkyl.

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

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

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

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

57. The compound according to claim 33, wherein R' and R'' together form an optionally substituted heterocycline.

58. R' and R'' together form azetidinyl, and the azetidinyl is C １ ~C ６ The compound according to claim 57, which is optionally substituted with an alkyl group.

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

60. R' and R'' together form azetidinyl, and the azetidinyl is C １ ~C ６ The compound according to claim 57, which is substituted with an alkyl group.

61. R' and R'' together, 【Transformation 7】 or 【Transformation 8】 The compound according to claim 60, wherein it forms a compound, and the asterisk (*) in the formula indicates a connection point to the rest of the compound.

62. Compounds selected from Table 2, or their pharmaceutically acceptable salts, prodrugs, hydrates, or solvates.

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

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

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

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

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

68. The pharmaceutical composition according to claim 67, wherein the further active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory drugs, analgesics, antineuropathic and anti-nociceptive drugs, anti-migraine drugs, anxiolytics, antidepressants, antipsychotics, anti-PTSD drugs, dissociative drugs, cannabinoids, immunostimulants, anticancer drugs, antiemetics, appetite stimulants, anti-ulcer drugs, antihistamines, antihypertensive drugs, anticonvulsants, antiepileptic drugs, bronchodilators, neuroprotective agents, nootropics, empathogens, psychoactive agents, plasticity inducers, monoamine oxidase inhibitors, tryptamine, terpenes, phenethylamine, sedatives, stimulants, serotonin agonists, NMDA modulators, NMDA antagonists, and vitamins.

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

70. The regulation of neurotransmission is the 5-HT ２Ａ The method according to claim 69, comprising stimulating a receptor.

71. A method for enhancing neural plasticity in a subject, comprising administering to the subject a compound described in any one of claims 1 to 62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

73. The method according to claim 72, wherein the medical condition is a disorder related to dysregulation or insufficient function of serotonergic neurotransmission.

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

75. The method according to claim 73, wherein the medical condition is a neurodevelopmental disorder, schizophrenia or other primary psychotic disorder, catatonia, mood disorder, anxiety or phobia-related disorder, obsessive-compulsive disorder or related disorder, stress-related disorder, dissociative disorder, nutritional disorder or eating disorder, excretory disorder, physical pain disorder or physical experience disorder, substance use disorder or addictive behavior disorder, impulse control disorder, disorderly behavior or antisocial behavior disorder, personality disorder, paraphilia, compulsion disorder, neurocognitive disorder, mental or behavioral disorder related to pregnancy, childbirth or puerperium, sleep-wake disorder, or sexual dysfunction.

76. The method according to claim 73, wherein the compound is administered in conjunction with one or more psychotherapy sessions.

77. The method according to claim 72, wherein the medical condition is inflammation or an inflammatory disease.

78. The method according to claim 77, wherein the inflammation is skin inflammation, muscle inflammation, tendinitis, ligament inflammation, bone inflammation, chondritis, pneumonia, heart inflammation, liver inflammation, pancreatic inflammation, nephritis, cystitis, gastritis, enteritis, neuroinflammation, ocular inflammation, or encephalitis.

79. The method according to claim 77, wherein the inflammatory disease is an acute inflammatory disease.

80. The method according to claim 77, wherein the inflammatory disease is a chronic inflammatory disease.

81. The method according to claim 77, wherein the inflammatory disease is a steroid-resistant disease.

82. The method according to claim 77, wherein the inflammatory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes mellitus, inflammatory bowel disease, Crohn's disease, multiple sclerosis, sepsis, conjunctivitis, and Alzheimer's disease.

83. The method according to claim 77, wherein the inflammatory disease is dermatitis.

84. The method according to claim 83, wherein the dermatitis is atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic dermatitis, nummular eczema, varicose vein eczema, herpetic dermatitis, neurodermatitis, autosensitization dermatitis, stasis dermatitis, suppurative dermatitis, dyshidrotic eczema, follicular eczema, cavernous dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

85. The method according to claim 77, wherein the subject has a weakened immune system.

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

87. The method according to claim 77, wherein the subject has a contraindication to corticosteroids.

88. The method according to claim 77, wherein treating inflammation or an inflammatory disease reduces the level of an inflammatory biomarker by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.

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

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

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

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

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

94. The method according to claim 77, wherein the medical condition is an ophthalmic disease.

95. The method according to claim 94, wherein the ophthalmic disease is an inflammatory disease.

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

97. The method according to claim 96, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis or Charcot disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia including vascular dementia, Huntington's disease, Ritico Bodig disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson's disease or parkinsonism, prion disease, progressive supranuclear palsy, and traumatic brain injury.

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

99. Use of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a pharmaceutical product for treating a medical condition.

100. A method for regulating neurotransmission in a subject, comprising administering the pharmaceutical composition described in claim 63 to the subject.

101. The regulation of neurotransmission is the 5-HT ２Ａ The method according to claim 100, comprising stimulating a receptor.

102. A method for enhancing neural plasticity in a subject, comprising administering the pharmaceutical composition described in claim 63 to the subject.

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

104. The method according to claim 103, wherein the medical condition is a disorder related to dysregulation or insufficient function of serotonergic neurotransmission.

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

106. The method according to claim 105, wherein the medical condition is a neurodevelopmental disorder, schizophrenia or other primary psychotic disorder, catatonia, mood disorder, anxiety or fear-related disorder, obsessive-compulsive disorder or related disorder, stress-related disorder, dissociative disorder, nutritional disorder or eating disorder, excretory disorder, physical pain disorder or physical experience disorder, substance use disorder or addictive behavior disorder, impulse control disorder, disorderly behavior or antisocial behavior disorder, personality disorder, paraphilia, compulsion disorder, neurocognitive disorder, mental or behavioral disorder related to pregnancy, childbirth or puerperium, sleep-wake disorder, or sexual dysfunction.

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

108. The method according to claim 103, wherein the medical condition is inflammation or an inflammatory disease.

109. The method according to claim 108, wherein the inflammation is skin inflammation, muscle inflammation, tendinitis, ligament inflammation, bone inflammation, chondritis, pneumonia, heart inflammation, liver inflammation, pancreatic inflammation, nephritis, cystitis, gastritis, enteritis, neuroinflammation, ocular inflammation, or encephalitis.

110. The method according to claim 108, wherein the inflammatory disease is an acute inflammatory disease.

111. The method according to claim 108, wherein the inflammatory disease is a chronic inflammatory disease.

112. The method according to claim 108, wherein the inflammatory disease is a steroid-resistant disease.

113. The method according to claim 108, wherein the inflammatory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes mellitus, inflammatory bowel disease, Crohn's disease, multiple sclerosis, sepsis, conjunctivitis, and Alzheimer's disease.

114. The method according to claim 108, wherein the inflammatory disease is dermatitis.

115. The method according to claim 114, wherein the dermatitis is atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic dermatitis, nummular eczema, varicose vein eczema, herpetic dermatitis, neurodermatitis, autosensitization dermatitis, stasis dermatitis, suppurative dermatitis, dyshidrotic eczema, follicular eczema, cavernous dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

116. The method according to claim 108, wherein the subject has a weakened immune system.

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

118. The method according to claim 108, wherein the subject has a contraindication to corticosteroids.

119. The method according to claim 108, wherein treating inflammation or an inflammatory disease reduces the level of an inflammatory biomarker by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.

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

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

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

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

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

125. The method according to claim 108, wherein the medical condition is an ophthalmic disease.

126. The method according to claim 125, wherein the ophthalmic disease is an inflammatory disease.

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

128. The method according to claim 127, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis or Charcot disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia including vascular dementia, Huntington's disease, Ritico Bodig disease, mild cognitive impairment, multiple sclerosis, motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson's disease or parkinsonism, prion disease, progressive supranuclear palsy, and traumatic brain injury.

129. A pharmaceutical composition according to any one of claims 63 to 68, for use in the treatment of a medical condition.

130. Use of the pharmaceutical composition according to any one of claims 63 to 68 for manufacturing a pharmaceutical for treating a medical condition.

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