Hydroxyalkyl and methoxyalkyltryptamines

Abstract

The present disclosure, in some embodiments, relates to certain psilocin and psilocybin analogs, such as tryptamines containing 4-(2-hydroxyalkyl)-7-alkyl or 4-(2-methoxyalkyl)-7-alkyl substitutions on the indole phenyl ring. In some embodiments, the disclosure relates to pharmaceutical compositions containing the compounds and methods of using such compounds and compositions to modulate neurotransmission (e.g., serotonergic neurotransmission), modulate neuroplasticity, and treat medical conditions, such as inflammatory diseases and conditions. JPEG2026508302000076.jpg4454

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under PCT Article 8(1) and Rule 4.10 to U.S. Provisional Patent Application No. 63 / 448,011, filed February 24, 2023, which is incorporated by reference for all purposes as if fully set forth herein.

[0002] Disclosed are certain psilocin and psilocybin analogs, such as tryptamines containing 4-(2-hydroxyalkyl)-7-alkyl or 4-(2-methoxyalkyl)-7-alkyl substitutions on the indole phenyl ring. In some embodiments, the disclosure further relates to methods for using such compounds, including methods for synthesizing the compounds, compositions containing the compounds, and administering them to subjects. In some embodiments, the characteristics of the compounds include neuromodulatory activity, such as serotonin receptor activation. In some further embodiments, the compounds are useful as therapeutic agents, such as anti-inflammatory agents. [Background technology]

[0003] Psychedelics such as psilocybin and LSD, as well as entactogens such as MDMA, are currently being investigated for various medical uses due to their hallucinogenic, anxiolytic, and antidepressant properties. In particular, psilocybin has received FDA Breakthrough Therapy Designation for its effectiveness in treating depression in conjunction with psychological support. Psilocybin is a naturally occurring tryptamine alkaloid found in fungi, including the Psilocybe genus. Psilocybin is currently being investigated for various medical uses due to its hallucinogenic, anxiolytic, and antidepressant properties. In vivo, psilocybin is rapidly dephosphorylated by endogenous phosphatase enzymes to produce psilocin, the active compound that stimulates serotonin 2 (5-HT2) receptors in the brain and other tissues.

[0004] Beyond mental health, psychedelic drugs may hold promise for 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 psychedelic drugs, including psilocybin and its analogs, remain federally illegal under Schedule I of the Controlled Substances Act in the United States. Novel compounds that minimize side effects, optimize efficacy, and enable wider access would be particularly beneficial. Provided herein are compounds, compositions, methods, uses, and pharmaceutical kits that meet these and other needs and have advantages and improvements that will become readily apparent throughout the following disclosure.

[0005] Incorporation by Reference Each of the cited patents, publications, and non-patent literature is incorporated herein by reference in its entirety as if each were individually incorporated by reference and as if each were fully set forth herein. However, such citation is not an admission that the cited references are from fields analogous or directly applicable to the present invention, nor should any citation be construed as an admission that the documents or underlying information in any jurisdiction are prior art or part of the common general knowledge in the art. Summary of the Invention [Means for solving the problem]

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

[0007] In a first aspect, a compound of formula (1): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, is provided, having the formula: R 1 is -(CH2)2OH, -(CH2)3OH, -CH2OH, -(CH2)3O-C1-C6 alkyl, -(CH2)2O-C1-C6 alkyl, -CH2O-C1-C6 alkyl, -(CH2)3OPO3H2, -(CH2)2OPO3H2, or -CH2OPO3H2; R 2 is C1-C6 alkyl; and R' and R" are both C1-C6 alkyl; or R' is H and R" is C1-C6 alkyl or -CH2-C6-C 12 aryl, and the C6 to C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 optionally substituted with aryl, F, Cl, Br, or I; or R' and R" together form a 4- to 6-membered heterocyclyl, said heterocyclyl being optionally substituted with C1-C6 alkyl.

[0008] In some embodiments, R 1 is —(CH)OH, —(CH)OH, or —CHOH. In some embodiments, R 1 is —(CH)O—C₁-C₆ alkyl, —(CH)O—C₁-C₆ alkyl, or —CHO—C₁-C₆ alkyl. In some embodiments, R 1 is —(CH)OCH, —(CH)OCH, or —CHOCH. In some embodiments, R 1 is —(CH)OCH. In some embodiments, R 1is —(CH)OPOH, —(CH)OPOH, or —CHOPOH. In some embodiments, R 1 is -(CH2)2OPO3H2.

[0009] In some embodiments, R 2 is methyl.

[0010] In some embodiments, the compound has the formula (1A): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

[0011] 3. The compound of formula (1B): [ka] 10. The compound of claim 1, having the structure:

[0012] In some embodiments, R' and R" are both C1-C6 alkyl. In some embodiments, R' and R" are both methyl. In some embodiments, R' and R" are both ethyl. In some embodiments, R' and R" are both isopropyl.

[0013] In some embodiments, R' is H and R" is C1-C6 alkyl. In some embodiments, R" is methyl. In some embodiments, R" is ethyl. In some embodiments, R" is isopropyl.

[0014] In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 In some embodiments, R' is H and R" is -CH2-phenyl, wherein phenyl is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' is H and R" is -CH2-phenyl, wherein the phenyl is unsubstituted. In some embodiments, R' is H and R" is -CH2-phenyl, wherein the phenyl is methyl substituted. In some embodiments, R' is H and R" is -CH2-(2-methylphenyl), -CH2-(3-methylphenyl), or -CH2-(4-methylphenyl).

[0015] In some embodiments, R' and R" are taken together to form a 4-6 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with C1-C6 alkyl. In some embodiments, R' and R" are taken together to form an azetidinyl, which is optionally substituted with C1-C6 alkyl. In some embodiments, the azetidinyl is unsubstituted. In some embodiments, the azetidinyl is C1-C6 alkyl substituted. In some embodiments, R' and R" are taken together to form an azetidinyl, which is optionally substituted with C1-C6 alkyl. [ka] or [ka] Form.

[0016] In some embodiments, the compound is selected from Table 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof.

[0017] In some embodiments, the compound is [ka] or [ka] or [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof.

[0018] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of a compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration. In some embodiments, the composition is provided in a unit dosage form. In some embodiments, the composition comprises the compound in a total amount of about 0.01 to 100 mg.

[0019] In some embodiments, the composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory drugs, analgesics, anti-neuropathic and anti-nociceptive drugs, anti-migraine drugs, anti-anxiety drugs, antidepressants, antipsychotic drugs, anti-PTSD drugs, dissociative drugs, cannabinoids, immunostimulants, anti-cancer drugs, antiemetics, appetite stimulants, antiulcer drugs, antihistamines, antihypertensive drugs, anticonvulsants, anti-epileptic drugs, bronchodilators, neuroprotective agents, nootropics, empathogens, psychedelics, plasticity inducers, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic drugs, NMDA modulators, NMDA antagonists, and vitamins.

[0020] Also provided is a method of modulating neurotransmission in a subject comprising administering to the subject a 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.

[0021] In embodiments, modulating neurotransmission is 5-HT 2A or 5-HT 2C This involves stimulating receptors.

[0022] Also provided is a method of increasing neuroplasticity in a subject, comprising administering to the subject a 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.

[0023] Also provided is a method of treating a medical condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a 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.

[0024] In some embodiments, the medical condition is a disorder associated with dysregulation or insufficient function of serotonergic neurotransmission.

[0025] In embodiments, the medical condition is a psychiatric, behavioral, or neurodevelopmental disorder.

[0026] In some embodiments, the medical condition is a neurodevelopmental disorder, schizophrenia or other primary psychotic disorder, catatonia, a mood disorder, an anxiety- or fear-related disorder, an obsessive-compulsive disorder or related disorder, a stress-related disorder, a dissociative disorder, an eating or purging disorder, a somatic pain disorder or somatic experiencing disorder, a substance use or addictive behavior disorder, an impulse control disorder, a disruptive or antisocial behavior disorder, a personality disorder, a paraphilia, a factitious disorder, a neurocognitive disorder, a mental or behavioral disorder related to pregnancy, childbirth, or the postpartum period, a sleep-wake disorder, or a sexual dysfunction disorder.

[0027] In embodiments, the compound is administered in conjunction with one or more psychotherapy sessions.

[0028] In some embodiments, the medical condition is inflammation or an inflammatory disease, hi some embodiments, the inflammation is skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, cystitis, stomach inflammation, intestinal inflammation, nerve inflammation, eye inflammation, or brain inflammation.

[0029] 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.

[0030] 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.

[0031] In some embodiments, the inflammatory disease is dermatitis, hi some embodiments, the dermatitis is atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic eczema, discoid eczema, varicose eczema, herpetic dermatitis, neurodermatitis, autosensitization dermatitis, stasis dermatitis, suppurative dermatitis, dyshidrotic eczema, follicular eczema, spongiform dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

[0032] In some embodiments, the subject has a weakened immune system. In some embodiments, the subject has an autoimmune disorder. In some embodiments, the subject has a contraindication to corticosteroids.

[0033] In some embodiments, treating inflammation or an inflammatory disease comprises reducing the level of an inflammatory biomarker by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, the inflammatory biomarker is an inflammatory response gene product. In some embodiments, the inflammatory response gene product is mRNA. In some embodiments, the mRNA is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β mRNA. In some embodiments, the inflammatory response gene product is a protein. In some embodiments, the protein is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β.

[0034] In some embodiments, the medical condition is an ophthalmic disease. In some embodiments, the ophthalmic disease is an inflammatory disease.

[0035] In some embodiments, the medical condition is a neurodegenerative disorder, hi some embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis or Charcot's disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia including vascular dementia, Huntington's disease, Litiko-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.

[0036] Also provided is a compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment of a medical condition.

[0037] Also provided is the use of a compound of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a medicament for treating a medical condition.

[0038] Also provided is a pharmaceutical composition of any of the disclosed embodiments for use in treating a medical condition.

[0039] Use of a pharmaceutical composition of any of the disclosed embodiments for the manufacture of a medicament for treating a medical condition.

[0040] The foregoing has outlined in broad summary form certain pertinent features of the present disclosure so that the detailed description of the present invention that follows may be better understood, and so that the present contribution to the art may be more fully appreciated. This summary, therefore, should be considered a brief, general overview of only some of the objects and embodiments disclosed herein, and is provided solely for the benefit and convenience of the reader. It is not intended to limit in any way the scope or equivalents to which the claims are lawfully entitled. Additional features of the present invention are described below. It should be understood by those skilled in the art that all disclosed specific compositions and methods are merely illustrative and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods also will be understood to be within the scope and spirit of the present disclosure as set forth in the claims.

[0041] Headings within this document are utilized solely to facilitate reader review and should not be construed as limiting the invention in any manner.

[0042] To further clarify various aspects of the present invention, a more particular description of the invention will be provided by reference to specific exemplary embodiments thereof, which are illustrated in the drawings. It will be understood that these drawings depict only exemplary embodiments of the invention and should not be considered as limiting the scope of the invention. They are provided merely as illustrative illustrations of certain concepts of some embodiments of the invention. These figures and the elements shown therein are not necessarily drawn to consistent scale or to any scale. Unless the context suggests otherwise, like elements are designated by like numerals. Accordingly, certain aspects of the invention will be further described and explained with additional specificity and detail, by way of example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0043] [Figure 1]FIG. 1 shows radioligand binding affinity assay data for Compound 1 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as described in Example 5.

[0044] [Figure 2] FIG. 1 shows radioligand binding affinity assay data for Compound 2 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as described in Example 5.

[0045] [Figure 3] FIG. 1 shows radioligand binding affinity assay data for Compound 3 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as described in Example 5.

[0046] [Figure 4] FIG. 1 shows radioligand binding affinity assay data for Compound 4 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as described in Example 5.

[0047] [Figure 5] FIG. 1 shows cell-based agonist IP-One assay data for Compound 1 at the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as described in Example 6.

[0048] [Figure 6] FIG. 1 shows cell-based calcium flux assay data for Compound 1 at the 5-HT2A receptor, as described in Example 6.

[0049] [Figure 7] FIG. 1 shows cell-based agonist IP-One assay data for Compound 2 at the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as described in Example 6.

[0050] [Figure 8]FIG. 1 shows cell-based calcium flux assay data for Compound 2 at the 5-HT2A receptor, as described in Example 6.

[0051] [Figure 9] FIG. 1 shows cell-based agonist IP-One assay data for Compound 3 at the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as described in Example 6.

[0052] [Figure 10] FIG. 1 shows cell-based calcium flux assay data for Compound 3 at the 5-HT2A receptor, as described in Example 6.

[0053] [Figure 11] FIG. 1 shows cell-based agonist IP-One assay data for compound 4 at the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as described in Example 6.

[0054] [Figure 12] FIG. 1 shows cell-based calcium flux assay data for Compound 4 at the 5-HT2A receptor, as described in Example 6. DETAILED DESCRIPTION OF THE INVENTION

[0055] While various aspects and features of certain embodiments have been summarized above, the following detailed description provides further details of several exemplary embodiments to enable those skilled in the art to implement such embodiments and to make and use the full scope of the invention as claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its application. The scope of the invention includes all embodiments and formulations thereof, not just those explicitly described below, and it will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details may be made by those skilled in the art without departing from the spirit of the invention or the scope of the invention as described in the claims. The headings within this document are used solely to facilitate reader review. They should not be construed as limiting the invention in any way.

[0056] A. General Definitions and Terminology As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "active agent" includes a reference to a combination of two or more active agents, and a reference to an "excipient" includes a reference to a combination of two or more excipients. While the term "one or more" is sometimes used, its absence (or substitution for the singular) does not refer to a singular number alone, but merely emphasizes that there may be multiple agents or components present in a particular embodiment. The terms "comprising," "including," "such as," and "having" are inclusive and not exclusive (i.e., other elements may be present in addition to the listed elements). The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless the context clearly dictates otherwise.

[0057] Unless otherwise specified, all numbers expressing properties such as amounts and concentrations of ingredients, reaction conditions, and the like, used to describe and claim particular embodiments of the present disclosure should be understood to be modified, in some cases, by the term "about." Thus, in some embodiments (or, equally briefly, "in embodiments"), the numerical parameters set forth in the specification and claims are approximations that may vary depending on the desired properties sought to be obtained by a particular embodiment. In some embodiments, "about" refers to plus or minus five percent (±5%) of the recited unit of measure. The term "substantially," when applied to modify features or limitations herein, should be read to provide an appropriate degree of certainty in the context of the present disclosure and in light of the knowledge in the art, for example, by using art-recognized standards for measuring the meaning of "substantially" as a term of degree, or by ascertaining a range as would be understood by one of ordinary skill in the art.

[0058] In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as practicable. The numerical values ​​presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0059] A comprehensive list of abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled "Standard List of Abbreviations"; the list as of the date of this application is incorporated herein by reference as if fully set forth herein.

[0060] Unless otherwise defined, all technical and scientific terms in this specification have the meanings commonly understood by those skilled in the art to which this invention belongs, who may simply be referred to as "persons of ordinary skill in the art" as abbreviations. Further definitions that can help readers understand the disclosed embodiments are as follows; however, it will be understood that such definitions are not intended to limit the scope of the present invention, and should be properly interpreted and understood by referring to the complete specification (and the clear meaning known to those skilled in the art) in light of the language used in the claims. The terms used in this specification are intended to describe only specific embodiments and are not intended to be limiting.

[0061] Generally, the nomenclature used and procedures performed herein are those known in the art relevant to one or more aspects of the present invention, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or medicinal chemistry, and are those well known and commonly used in such art. Standard techniques and procedures are generally performed according to conventional methods in the art.

[0062] "Alkyl" is understood to include straight-chain 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 mixtures of single, double, and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions "alkanyl," "alkenyl," and "alkynyl" can also be used. Preferably, alkyl groups contain 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms. For any alkyl, the alkyl may be optionally 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, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH), -OC(O)H, -OSOOH, -OC(O)NH, and -SONH. 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.

[0063] "Alkenyl" refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include ethenyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl, and cycloprop-2-en-1-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, and cyclobuta-1,3-dien-1-yl. The alkenyl group can be substituted or unsubstituted.

[0064] "Alkynyl" refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon triple bond derived by removing one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include ethynyl; propynyl, such as prop-1-yn-1-yl and prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, and but-3-yn-1-yl. Alkynyl groups can be substituted or unsubstituted.

[0065] "Aryl" refers to a monovalent aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include those derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. Preferably, the aryl group contains 6 to 20 carbon atoms, more preferably 6 to 12 carbon atoms. The aryl group may be substituted or unsubstituted.

[0066] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl includes 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 10 to 12 carbon atoms, 12 to 12 carbon atoms, 14 to 14 carbon atoms, 16 to 16 carbon atoms, 17 to 17 carbon atoms, 18 to 18 carbon atoms, 19 to 20 carbon atoms, 21 to 22 carbon atoms, 22 to 24 carbon atoms, 23 to 25 carbon atoms, 24 to 26 carbon atoms, 25 to 26 carbon atoms, 26 to 27 carbon atoms, 27 to 28 carbon atoms, 28 to 29 carbon atoms, 29 to 30 carbon atoms, 30 to 31 carbon atoms, 31 to 32 carbon atoms, 32 to 33 carbon atoms, 33 to 34 carbon atoms, 34 to 35 carbon atoms, 35 to 36 carbon atoms, 36 to 37 carbon atoms, 37 to 38 carbon atoms, 38 to 39 carbon atoms, 39 to 40 carbon atoms, 40 to 41 carbon atoms, 41 to 42 carbon atoms, 42 to 43 The cycloalkyl rings can contain any number of carbon atoms, such as 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decahydronaphthalene, and adamantane. When the cycloalkyl is a monocyclic C 3-8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When it is cycloalkyl, exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0067] "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, the double bonds cannot form a completely delocalized π-electron system across all rings (otherwise the group is an "aryl" as defined herein). When composed of two or more rings, the rings can be connected to each other in a fused fashion. Cycloalkenyl can be any of the following: 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, 9-10 carbon atoms, 10-11 carbon atoms, 11-12 carbon atoms, 12-13 carbon atoms, 13-14 carbon atoms, 14-15 carbon atoms, 15-16 carbon atoms, 16-17 carbon atoms, 17-18 carbon atoms, 18-19 carbon atoms, 19-20 carbon atoms, 20-21 carbon atoms, 21-22 carbon atoms, 22-23 carbon atoms, 23-24 carbon atoms, 24-25 carbon atoms, 25-26 carbon atoms, 26-27 carbon atoms, 27-28 carbon atoms, 28-29 carbon atoms, 29-30 carbon atoms, 30-31 carbon atoms, 31-32 carbon atoms, 32-33 carbon atoms, 33-34 carbon atoms, 34-35 carbon atoms, 35-36 carbon atoms, 36-37 carbon atoms, 3 The cycloalkenyl group can contain any number of carbons, such as 0 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. Representative cycloalkenyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. A cycloalkenyl group can be unsubstituted or substituted.

[0068] "Cycloalkylmethyl" refers to a radical having a methylene moiety and a cycloalkyl moiety, where the methylene moiety connects the cycloalkyl moiety to the point of attachment. The cycloalkyl moiety is as defined above and can have any number of carbons, e.g., 3-6 carbon atoms (i.e., C3-C6 cycloalkylmethyl), 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. The cycloalkylmethyl group can include, for example, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. In some preferred embodiments, the cycloalkylmethyl group is a cyclopropylmethyl group. The cycloalkylmethyl group can be substituted or unsubstituted.

[0069] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0070] "Heterocycloalkyl" refers to a cycloalkyl, as defined above, having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Heterocycloalkyl includes bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. The heteroatoms may also be oxidized, including, but not limited to, -S(O)- and -S(O)-. Heterocycloalkyl groups can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Heterocycloalkyl groups can contain 1, 2, 3, or 4, or any suitable number of heteroatoms, such as 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl groups can include groups such as aziridine, azetidinyl, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C alkyl or oxo (=O), among others.

[0071] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component connects the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent alkylene to connect to the heterocycloalkyl component and the point of attachment. The alkyl component can contain any number of carbons, such as C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, and C. In some cases, the alkyl component may be absent. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group may be substituted or unsubstituted.

[0072] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, wherein 1 to 5 ring atoms are heteroatoms such as N, O, or S. A heteroaryl group can contain any number of ring atoms, such as 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in a heteroaryl group, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have 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 includes groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused to an aromatic ring system, such as a phenyl ring, to form members including, but not limited to, benzopyrroles, such as indole and isoindole, benzopyridines, such as quinoline and isoquinoline, benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), benzopyridazines, such as phthalazine and cinnoline, benzothiophenes, and benzofurans. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridines. Heteroaryl groups can be substituted or unsubstituted.

[0073] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component connects the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent alkylene to connect to the heteroaryl component and the point of attachment. The alkyl component can contain any number of carbons, such as C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, and C. In some cases, the alkyl component may be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0074] "Alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxy can be substituted or unsubstituted.

[0075] "Alkylthio" or "thioalkyl" refers to a group of formula -SR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. A non-limiting list of alkylthio groups is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio. Alkylthio groups can be substituted or unsubstituted.

[0076] "Acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl bonded as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl may be substituted or unsubstituted.

[0077] "Haloalkyl" refers to any alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with a halogen (e.g., fluorine, chlorine, bromine, or iodine). When an alkyl group is substituted with more than one halogen, it can be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkyl refers to an alkyl substituted with two halo groups, which may, but need not, be the same halogen. Examples of haloalkyl groups include difluoromethyl (-CHF), bromofluoromethyl (-CHBrF), trifluoromethyl (-CF), and 2-fluoroethyl (-CHCHF). Further examples of haloalkyl groups include -CHF, -CHF, -CHCF, -CHCHF, -CH(CH)(CF), -CH(CH)(CHF), and -CH(CH)(CHF). Haloalkyls can be substituted or unsubstituted.

[0078] "Hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced with a hydroxy group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl can be substituted or unsubstituted.

[0079] "Haloalkoxy" refers to an -O-alkyl group in which one or more of the hydrogen atoms has been replaced with a halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). The halogens may be the same or different in each occurrence. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. The haloalkoxy may be substituted or unsubstituted.

[0080] "Sulfenyl" refers to the group -SR, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. Sulfenyl can be substituted or unsubstituted.

[0081] "Sulfinyl" refers to the group -S(=O)-R, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0082] "Sulfonyl" refers to the group -SO2R, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0083] "O-carboxy" refers to the group -RC(=O)O-, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. The O-carboxy can be substituted or unsubstituted.

[0084] "Ester" and "C-carboxy" refer to the -C(=O)OR group, where R can be the same as defined for O-carboxy. The ester and C-carboxy groups can be substituted or unsubstituted.

[0085] "Thiocarbonyl" refers to the group -C(=S)R, where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted.

[0086] "Trihalomethanesulfonyl" refers to a X3CSO2- group where each X is a halogen.

[0087] "Trihalomethanesulfonamide" is X3CS(O)2N(R A )-group, where each X is a halogen and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein.

[0088] "S-sulfonamide" is -SO2N(R A R B ) group, wherein R A and R B may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. S-sulfonamides may be substituted or unsubstituted.

[0089] "N-sulfonamide" is RSO2N(R A )-group, wherein R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-sulfonamides may be substituted or unsubstituted.

[0090] "O-carbamyl" is -OC(=O)N(R A R B ) group, wherein R A and R Bmay be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. O-carbamyl may be substituted or unsubstituted.

[0091] "N-carbamyl" is ROC(=O)N(R A )-group, wherein R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-carbamyl may be substituted or unsubstituted.

[0092] "O-thiocarbamyl" is -OC(=S)-N(R A R B ) group, wherein R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. O-thiocarbamyl may be substituted or unsubstituted.

[0093] "N-thiocarbamyl" is ROC(=S)N(R A )-group, wherein R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-thiocarbamyl may be substituted or unsubstituted.

[0094] A "C-amido" group is a -C(=O)N(R A R B ) group, wherein R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. C-amides may be substituted or unsubstituted.

[0095] "N-amide" is RC(=O)N(R A )-group, wherein R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. N-amidos may be substituted or unsubstituted.

[0096] Unless otherwise specified, "optionally substituted" means that a group can be unsubstituted or substituted with one or more of the substituents listed for that group. Similarly, when a group is described as "unsubstituted or substituted," if substituted, the one or more substituents can be selected from one or more of the listed substituents. When multiple substituents are present, the substituents can be the same or different. In some embodiments, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. If no substituents are indicated for an "optionally substituted" or "substituted" group, it means that the indicated "optionally substituted" or "substituted" group can 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-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amino groups, disubstituted amino groups, and trisubstituted amino groups.

[0097] Still further definitions and abbreviations are provided elsewhere herein.

[0098] B. Compound In one embodiment, a compound of formula (1): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R 1 is -(CH2) n OH, -(CH2) n OCH3, -(CH2) n O-C1-C6 alkyl, or -(CH2) n OPO3H2; n is 1, 2, or 3; R 2 is C1-C6 alkyl; or R' is H and R" is C1-C6 alkyl or -CH2-C6-C 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 optionally substituted with aryl, F, Cl, Br, or I; or R' and R" together are C1-C6 alkyl; or R' and R" together form a 4- to 6-membered heterocyclyl, which is optionally substituted with C1-C6 alkyl.

[0099] In some embodiments, R 1 is -(CH2) n OH, -(CH2) n OCH3, -(CH2) n O-C1-C6 alkyl, or -(CH2) n OPO3H2. In some embodiments, R 1 is -(CH2) n OH or -(CH2) n OCH3. In some embodiments, R 1 Ha-(CH2) n OH. In some embodiments, R 1 Ha-(CH2) n OCH3. In some embodiments, R 1 is -(CH2) n In some embodiments, R 1is -(CH2) n It is OPO3H2.

[0100] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0101] In some embodiments, R 1 is —(CH2)2OH, —(CH2)3OH, —CH2OH, —(CH2)3O—C1-C6 alkyl, —(CH2)2O—C1-C6 alkyl, —CH2O—C1-C6 alkyl, —(CH2)3OPO3H2, —(CH2)2OPO3H2, or —CH2OPO3H2.

[0102] In some embodiments, R 1 is —(CH)OH, —(CH)OH, or —CHOH. In some embodiments, R 1 is —(CH)OH. In some embodiments, R 1 is —(CH)OH. In some embodiments, R 1 is -CHOH.

[0103] In some embodiments, R 1 is —(CH)O—C₁-C₆ alkyl, —(CH)O—C₁-C₆ alkyl, or —CHO—C₁-C₆ alkyl. In some embodiments, R 1 is —(CH)O—C-C alkyl. In some embodiments, R 1 is —(CH)OCH. In some embodiments, R 1 is —(CH)O—C-C alkyl. In some embodiments, R 1 is —(CH)OCH. In some embodiments, R 1 is —CH2O—C1-C6 alkyl. In some embodiments, R 1 is -CH2OCH3.

[0104] In some embodiments, R 1 is —(CH)OPOH, —(CH)OPOH, or —CHOPOH. In some embodiments, R 1 is —(CH)OPOH. In some embodiments, R 1 is —(CH)OPOH. In some embodiments, R 1 is -CH2OPO3H2.

[0105] In some embodiments, R 2 is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl.

[0106] In some embodiments, R' is H and R" is C1-C6 alkyl; or R' and R" are both C1-C6 alkyl. In some embodiments, R' is H and R" is C1-C6 alkyl. In some embodiments, R' is H and R" is C1-C6 alkyl or -CH2-C6-C6 alkyl. 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' and R" are both C1-C6 alkyl. It is understood that in embodiments where R' and R" are both C1-C6 alkyl, R' and R" can be the same or different. For example, in an exemplary embodiment where R' and R" are both C1-C6 alkyl, R' and R" are both methyl. However, in another exemplary embodiment where R' and R" are both C1-C6 alkyl, R' is methyl and R" is ethyl. In some embodiments, R' is C1-C6 alkyl and R" is C1-C6 alkyl or -CH2-C6-C6 alkyl. 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' and R" are both methyl. In some embodiments, R' and R" are both ethyl. In some embodiments, R' and R" are both isopropyl.

[0107] In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12 The aryl is unsubstituted. In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 In some embodiments, R' is H and R" is -CH2-phenyl, wherein phenyl is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 In some embodiments, R' is H and R" is -CH2-phenyl, and phenyl is unsubstituted. In some embodiments, R' is H and R" is -CH2-phenyl, and phenyl is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C6 alkylthio, C6-C6 alkyl ... 12 In some embodiments, R" is substituted with aryl, F, Cl, Br, or I. In some embodiments, R' is H and R" is -CH2-phenyl, wherein said phenyl is methyl substituted. In some embodiments, R' is H and R" is -CH2-(2-methylphenyl), -CH2-(3-methylphenyl), or -CH2-(4-methylphenyl). In some embodiments, R" is -CH2-methylenedioxyphenyl. In some embodiments, R" is -CH2-dihydrofuranylphenyl.

[0108] In some embodiments, R' and R" are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with C1-C6 alkyl. In some embodiments, R' and R" are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is unsubstituted. For example, in some embodiments, R' and R" are taken together to form a 4-membered heterocyclyl such as azetidinyl. In some embodiments, R' and R" are taken together to form a 5-membered heterocyclyl such as pyrrolidine. In some embodiments, R' and R" are taken together to form a 6-membered heterocyclyl such as piperidine. In some embodiments, where R' and R" are taken together to form a 4- to 6-membered heterocyclyl, the 4- to 6-membered heterocyclyl contains an additional heteroatom. For example, in some embodiments, R' and R" together form a 6-membered heterocyclyl 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 heterocyclyl, wherein the heterocyclyl is C1-C6 alkyl substituted. In certain preferred embodiments, R' and R" together form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is methyl substituted. In some embodiments, R' and R" together form dimethylazetidinyl. In some such embodiments, R' and R" together form 2,4-dimethylazetidinyl. In some embodiments, R' and R" together form [ka] or [ka] where the asterisk (*) indicates the point of attachment to the rest of the compound. In some embodiments, R′ and R″ together form tetramethylazetidinyl.

[0109] In another embodiment, the compound of formula (1A): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' is H and R" is C1-C6 alkyl or -CH2-C6-C6 alkyl. 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 optionally substituted with aryl, F, Cl, Br, or I; or R' and R" are both C1-C6 alkyl; or R' and R" together form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with C1-C6 alkyl.

[0110] In some embodiments of Formula (1A), R' is H and R" is C1-C6 alkyl; or R' and R" are both C1-C6 alkyl. In some embodiments, R' is H and R" is C1-C6 alkyl. In some embodiments, R' is H and R" is C1-C6 alkyl or -CH2-C6-C6 alkyl. 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' and R" are both C1-C6 alkyl. It is understood that in embodiments where R' and R" are both C1-C6 alkyl, R' and R" can be the same or different. For example, in an exemplary embodiment where R' and R" are both C1-C6 alkyl, R' and R" are both methyl. However, in another exemplary embodiment where R' and R" are both C1-C6 alkyl, R' is methyl and R" is ethyl. In some embodiments, R' is C1-C6 alkyl and R" is C1-C6 alkyl or -CH2-C6-C6 alkyl. 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' and R" are both methyl. In some embodiments, R' and R" are both ethyl. In some embodiments, R' and R" are both isopropyl.

[0111] In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12 The aryl is unsubstituted. In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 In some embodiments, R' is H and R" is -CH2-phenyl, wherein phenyl is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 In some embodiments, R' is H and R" is -CH2-phenyl, and phenyl is unsubstituted. In some embodiments, R' is H and R" is -CH2-phenyl, and phenyl is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C6 alkylthio, C6-C6 alkyl ... 12 In some embodiments, R" is substituted with aryl, F, Cl, Br, or I. In some embodiments, R' is H and R" is -CH2-phenyl, wherein said phenyl is methyl substituted. In some embodiments, R' is H and R" is -CH2-(2-methylphenyl), -CH2-(3-methylphenyl), or -CH2-(4-methylphenyl). In some embodiments, R" is -CH2-methylenedioxyphenyl. In some embodiments, R" is -CH2-dihydrofuranylphenyl.

[0112] In some embodiments of Formula (1A), R' and R" are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with C1-C6 alkyl. In some embodiments, R' and R" are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is unsubstituted. For example, in some embodiments, R' and R" are taken together to form a 4-membered heterocyclyl, such as azetidinyl. In some embodiments, R' and R" are taken together to form a 5-membered heterocyclyl, such as pyrrolidine. In some embodiments, R' and R" are taken together to form a 6-membered heterocyclyl, such as piperidine. In some embodiments, where R' and R" are taken together to form a 4- to 6-membered heterocyclyl, the 4- to 6-membered heterocyclyl contains an additional heteroatom. For example, in some embodiments, R' and R" together form a 6-membered heterocyclyl 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 heterocyclyl, wherein the heterocyclyl is C1-C6 alkyl substituted. In certain preferred embodiments, R' and R" together form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is methyl substituted. In some embodiments, R' and R" together form dimethylazetidinyl. In some such embodiments, R' and R" together form 2,4-dimethylazetidinyl. In some embodiments, R' and R" together form [ka] or [ka] where the asterisk (*) indicates the point of attachment to the rest of the compound. In some embodiments, R′ and R″ together form tetramethylazetidinyl.

[0113] In another embodiment, the compound of formula (1B): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' is H and R" is C1-C6 alkyl or -CH2-C6-C6 alkyl. 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 optionally substituted with aryl, F, Cl, Br, or I; or R' and R" are both C1-C6 alkyl; or R' and R" together form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with C1-C6 alkyl.

[0114] In some embodiments of Formula (1A), R' is H and R" is C1-C6 alkyl; or R' and R" are both C1-C6 alkyl. In some embodiments, R' is H and R" is C1-C6 alkyl. In some embodiments, R' is H and R" is C1-C6 alkyl or -CH2-C6-C6 alkyl. 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' and R" are both C1-C6 alkyl. It is understood that in embodiments where R' and R" are both C1-C6 alkyl, R' and R" can be the same or different. For example, in an exemplary embodiment where R' and R" are both C1-C6 alkyl, R' and R" are both methyl. However, in another exemplary embodiment where R' and R" are both C1-C6 alkyl, R' is methyl and R" is ethyl. In some embodiments, R' is C1-C6 alkyl and R" is C1-C6 alkyl or -CH2-C6-C6 alkyl. 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 optionally substituted with aryl, F, Cl, Br, or I; or R' and R" are both C1-C6 alkyl. In some embodiments, R' and R" are both methyl. In some embodiments, R' and R" are both ethyl. In some embodiments, R' and R" are both isopropyl.

[0115] In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12 Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 Optionally substituted with aryl, F, Cl, Br, or I. In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12 The aryl is unsubstituted. In some embodiments, R' is H and R" is -CH2-C6-C 12 Aryl, C6-C 12Aryl is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 In some embodiments, R' is H and R" is -CH2-phenyl, wherein phenyl is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C 12 In some embodiments, R' is H and R" is -CH2-phenyl, and phenyl is unsubstituted. In some embodiments, R' is H and R" is -CH2-phenyl, and phenyl is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C6-C6 alkylthio, C6-C6 alkyl ... 12 In some embodiments, R" is substituted with aryl, F, Cl, Br, or I. In some embodiments, R' is H and R" is -CH2-phenyl, wherein said phenyl is methyl substituted. In some embodiments, R' is H and R" is -CH2-(2-methylphenyl), -CH2-(3-methylphenyl), or -CH2-(4-methylphenyl). In some embodiments, R" is -CH2-methylenedioxyphenyl. In some embodiments, R" is -CH2-dihydrofuranylphenyl.

[0116] In some embodiments of Formula (1A), R' and R" are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with C1-C6 alkyl. In some embodiments, R' and R" are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is unsubstituted. For example, in some embodiments, R' and R" are taken together to form a 4-membered heterocyclyl, such as azetidinyl. In some embodiments, R' and R" are taken together to form a 5-membered heterocyclyl, such as pyrrolidine. In some embodiments, R' and R" are taken together to form a 6-membered heterocyclyl, such as piperidine. In some embodiments, where R' and R" are taken together to form a 4- to 6-membered heterocyclyl, the 4- to 6-membered heterocyclyl contains an additional heteroatom. For example, in some embodiments, R' and R" together form a 6-membered heterocyclyl 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 heterocyclyl, wherein the heterocyclyl is C1-C6 alkyl substituted. In certain preferred embodiments, R' and R" together form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is methyl substituted. In some embodiments, R' and R" together form dimethylazetidinyl. In some such embodiments, R' and R" together form 2,4-dimethylazetidinyl. In some embodiments, R' and R" together form [ka] or [ka] where the asterisk (*) indicates the point of attachment to the rest of the compound. In some embodiments, R′ and R″ together form tetramethylazetidinyl.

[0117] In some embodiments, provided herein is a compound selected from Table 1 below, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0118] In some embodiments, the compound is [ka] or [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof. In some embodiments, the compound is selected from the group consisting of: [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate or solvate thereof.

[0119] The present disclosure is understood to encompass pharmaceutically acceptable salts of the disclosed compounds. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases and can be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of these drugs with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of compounds are those in which the counterion is pharmaceutically acceptable. One skilled in the art can select a pharmaceutically acceptable counterion from a wide variety of available counterions. In certain applications, the selection of a given anion or cation for the preparation of a salt may result in increased or decreased solubility of the salt. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-naphsylate, 3-hydroxy-2-naphthoate, 3-phenyl-propionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphor carbonate, camphorate, camphorsulfonate, camcyl acid salt, carbonate, cholate, citrate, clavulanate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecyl sulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisic acid, gluceptic acid, glucoheptanoate, gluconate, glucuronate, glutamic acid, glutarate, glycerophosphate, glycolate,Glycolylarsanilic acid, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulfonate, lithium, magnesium, malate, maleate, malonate, mandelate, mesotartarate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisylate, naphthylate, napsylar Examples of suitable salts include acetone, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, diphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, acetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, and zinc salts. (See Berge et al., J. Pharm. Sci. 1997, 66, 1-19).

[0120] Certain compounds disclosed herein may contain one or more ionizable groups (groups that can remove (e.g., —COOH) or add (e.g., amine) a proton, or can be quaternized (e.g., amine)). All possible ionic forms of such molecules and salts thereof are included in the present disclosure.

[0121] The disclosed compounds can exist in solid or liquid form. In the solid state, the compounds can exist in crystalline or amorphous form, or as a mixture thereof. Those skilled in the art will understand that pharmaceutically acceptable solvates can be formed for crystalline or amorphous compounds. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may contain non-aqueous solvents, such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or 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 referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The subject matter described herein includes such solvates.

[0122] Those skilled in the art will further understand that certain compounds described herein that exist in crystalline forms, including various solvates thereof, 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 of the same elemental composition. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have different physical properties, such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will understand that different polymorphs can be produced, for example, by changing or adjusting the reaction conditions or reagents used to prepare the compound. For example, changes in temperature, pressure, or solvents can result in polymorphism. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, can cause a single crystalline form to predominate. Additionally, one polymorph may spontaneously convert to another polymorph under certain conditions.

[0123] The compounds described herein may contain one or more asymmetric centers and may give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present disclosure includes all such possible isomers and 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 resolved using conventional techniques. Various methods for preparing optically active forms and determining activity are known in the art. Such methods include standard assays described herein and other similar assays known in the art. Examples of methods that can be used to obtain optical isomers of compounds according to the present disclosure include selective crystallization, enzymatic resolution, asymmetric synthesis (including asymmetric chemical synthesis and asymmetric enzymatic synthesis), kinetic resolution, and chiral chromatography (including chiral liquid chromatography, gas chromatography, and high-performance liquid chromatography). When the compounds described herein contain an olefinic double bond or other center of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as tautomeric forms.

[0124] The present disclosure also includes compounds with desired isotopic substitution of at least one atom at an amount greater than the natural abundance of the isotope, i.e., isotopically enriched. Isotopes are atoms with the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, such as 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O and 36In one non-limiting embodiment, the isotope-labeled compound is used for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), 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 for radiation treatment of patients. 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Additionally, deuterium, i.e. 2 Substitution with heavier isotopes, such as H, can confer therapeutic advantages due to increased metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0125] The present disclosure also includes prodrugs of the disclosed compounds. A "prodrug" is a precursor of a biologically active drug that can undergo chemical or metabolic conversion to become a biologically active agent. A prodrug can be converted to a biologically active drug in vitro by a chemical conversion process. In vivo, a prodrug is converted to a biologically active drug by the action of metabolic, enzymatic, or degradative processes that remove the prodrug moiety and form the biologically active drug. Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on functional moieties 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 generate the 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 cleave under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage. The choice of functional group depends on factors such as stability, ease of synthesis, enzymatic activity, and the desired rate of prodrug conversion.

[0126] Generally, the disclosed individual compounds are administered as part of pharmaceutical compositions or formulations and are prepared for inclusion in such compositions or formulations 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 from components that normally accompany the material when it is synthesized, manufactured, or otherwise produced. Thus, an "isolated," "purified," or "substantially pure" preparation of a compound is defined as one that has a chromatographic purity (of the desired compound) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method.

[0127] Preferably, the substantially pure compound used in the present disclosure is substantially free of any other active compounds that are not intended to be administered to a subject. In this context, "substantially free" can be interpreted to mean that no active compounds other than the active compounds intended to be administered to a subject are detectable by HPLC or other similar detection methods, or are below the desired detection threshold as defined above.

[0128] In some aspects, the characteristics of the disclosed compounds provide various advantages. Such advantages may relate to modulation of neurotransmission, pharmacokinetics, such as properties related to absorption, distribution, metabolism, and excretion of the disclosed compounds, and subjective effects upon administration to a subject. In embodiments, such advantages are determined relative to a control drug.

[0129] In some embodiments, the control agent is a tryptamine having a 7-alkyl substituent but lacking a 4-(2-hydroxyalkyl) or 4-(2-methoxyalkyl) substituent. For example, in some embodiments, the control agent is a 7-alkyl (e.g., 7-methyl) analog of psilocybin, psilocin, or an N,N-dialkyltryptamine (e.g., DMT, DET, DiPT). In some embodiments, the control agent is a tryptamine having a 4-(2-hydroxyalkyl) or 4-(2-methoxyalkyl) substituent but lacking a 7-alkyl group. For example, in some embodiments, the control agent is a 4-(2-hydroxyalkyl)- or 4-(2-methoxyalkyl)-substituted N,N-dialkyltryptamine (e.g., 4-(2-hydroxymethyl)-DMT, 4-(2-methoxymethyl)-DiPT, etc.).

[0130] C. Methods for Preparing the Disclosed Compounds In some aspects, provided herein are methods for preparing the disclosed 4-(2-hydroxyalkyl)-7-alkyl or 4-(2-methoxyalkyl)-7-alkyltryptamine compounds, such as compounds of Formula (1), Formula (1A), Formula (1B), or any subformula thereof.

[0131] In some embodiments, the disclosed 4-(2-hydroxyalkyl)-7-alkyltryptamine compounds, e.g., compounds of formula (1A), and 4-(2-methoxyalkyl)-7-alkyltryptamine compounds, e.g., compounds of formula (1B), are prepared according to the following exemplary reaction sequence: [ka] (i) potassium vinyltrifluoroborate, Pd(OAc)2, SPhos, K2CO3 in dioxane / H2O; (ii) BH3-THF, H2O2, NaOH, then PivCl, Et3N, THF; (iii) (COCl)2, Et2O, then HNR'R', then LiAlH4; (iv) BH3-THF, H2O2, NaOH, then MsCl, Et3N, NaOMe.

[0132] Alternatively, in some embodiments, precursor (A) can be directly converted to intermediate (D), for example, by Pd-catalyzed cross-coupling with potassium (2-methoxyethyl)trifluoroborate in the presence of a suitable base, such as cesium carbonate.

[0133] In other embodiments, the disclosed 4-(2-hydroxyalkyl)-7-alkyl compounds of formula (1A) can be prepared according to the following exemplary reaction scheme: [ka]

[0134] Additional procedures known in the art that are useful for preparing the disclosed compounds can be found in WO 2023 / 010000.

[0135] Those skilled in the art will understand that while the reaction schemes show exemplary reagents and / or solvents, alternatives are also encompassed by the present disclosure. For example, while pyridine is used as an exemplary base, those skilled in the art will understand that other inorganic or organic bases (e.g., triethylamine) may be suitable for use in the same reaction steps. Similarly, while THF is shown as an exemplary solvent, those skilled in the art will understand that other solvents (e.g., polar aprotic solvents) may be used for the same purpose.

[0136] Specific examples of the synthesis of the disclosed compounds are provided in Examples 1-4.

[0137] Additional methods for synthesizing the compounds described herein, and any necessary starting materials, are described in the art or can be found in general references known in the art (e.g., Green et al., "Protective Groups in Organic Chemistry" (Wiley, 2nd ed., 1991); Harrison et al., "Compendium of Synthetic Organic Methods," Vols. 1-8 (John Wiley & Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry," Beilstein Institute Organic Chem., Frankfurt, Germany; Feiser et al., "Reagents for Organic Synthesis," Vols. 1-17, Wiley Interscience; Trost et al., "Comprehensive Organic Synthesis," Pergamon Press, 1991; "Theilheimer's Synthetic Methods of Organic Chemistry," Vols. 1-45, Karger, 1991; March, "Advanced Organic Chemistry," Wiley Interscience, 1991; Larock, "Comprehensive Organic Synthesis," It will be readily apparent to one of ordinary skill in the art that consideration of these and other related compounds (see, for example, "Transformations," VCH Publishers, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis," John Wiley & Sons, 1995) can be used to synthesize the disclosed compounds.

[0138] D. Pharmaceutical Compositions In some aspects, compositions, such as pharmaceutical compositions, comprising the disclosed compounds are provided herein. A "pharmaceutical composition" is a composition comprising a disclosed compound in an amount (e.g., in unit dosage form) together with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments include multiple carriers, diluents, and / or excipients rather than a single carrier, diluent, or excipient alone. The compositions can be prepared by standard pharmaceutical formulation techniques, e.g., as 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), R.L. Juliano, ed., Oxford, NY, pp. 253-315).

[0139] "Pharmaceutically acceptable" as used with reference to an excipient, carrier, diluent, or other ingredient means that the ingredient is generally safe and suitable for use in contact with human and animal cells without undue toxicity, irritation, allergic response, or complications, within the scope of sound medical judgment, commensurate with a reasonable risk / benefit ratio.

[0140] In some embodiments, pharmaceutical compositions containing the disclosed compounds can be administered by various routes, including oral, mucosal (e.g., buccal, 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., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal compositions. Such compositions are prepared by methods well known in the pharmaceutical arts and contain at least one active compound. (See, e.g., Remington, 2020.)

[0141] The disclosed compositions are preferably formulated into unit dosage forms, each dosage containing a therapeutically effective amount of the active ingredient, for example, in the dosage amounts disclosed below. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for a subject to be treated, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in combination with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are often used for ease of administration and uniformity of dosage. A unit dosage form can contain a single or individual dose or unit, sub-dose, or an appropriate fraction thereof (e.g., half of a "full" dose for a "booster" dose as described below) of the pharmaceutical composition to be administered.

[0142] The unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampoules and vials, which may contain the composition in a freeze-dried or lyophilized state; for example, a sterile liquid carrier can be added before administration or delivery in vivo. The unit dosage forms also include ampoules and vials into which a liquid composition is placed. The unit dosage forms also include compounds for transdermal administration, such as "patches" that contact the epidermis (including mucous membranes) for long or short periods of time.

[0143] In embodiments, the disclosed compositions are formulated into pharmaceutically acceptable oral dosage forms. Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions) and oral solid dosage forms. The disclosed pharmaceutical compositions can be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, including physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0144] In embodiments, the disclosed pharmaceutical compositions can be formulated into topical preparations (e.g., topical dosage forms). Topical preparations include transmucosal and transdermal preparations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams, and may contain pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients for topical preparations include, for example, penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifiers (e.g., thickeners), adhesion modifiers (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizers, colorants, binders, humectants, surfactants, gelling agents, and other such ingredients commonly known to those skilled in the art.

[0145] In some embodiments, the topical formulation includes a penetration enhancer. Without being bound by theory, penetration enhancers are generally characterized by their ability to increase the permeability of biological barriers, such as the scalp. In some embodiments, the inclusion of a penetration enhancer in the formulation improves the ability of the active agent to diffuse into skin tissues, increasing the bioavailability of the active agent. Penetration enhancers include, for example, fatty acids and oils such as castor oil, coconut oil, medium-chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, 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, propylene laurate, 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, azone, cyclodextrin, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, benzalkonium chloride, cetylpyridinium chloride, vitamin E TPGS, caprylocaproyl polyoxylglyceride, stearoyl macrogolglyceride, propylene glycol dicaprylocaprate, or mixtures thereof.

[0146] In some embodiments, the topical formulations comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, The composition may contain a penetration enhancer at a concentration of 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%.

[0147] 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 epithelia. 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 can have slow (i.e., prolonged) release kinetics, but may also be constructed to have a rapid or immediate release profile. New technologies 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). Any of a variety of pharmaceutically acceptable carriers may be used, including, but not limited to, aqueous media such as water, saline, glycine, hyaluronic acid, etc.; solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talc, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, etc.; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or other inactive ingredients. The choice of a pharmacologically acceptable carrier may depend on the mode of administration.Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (eds. Howard C. Ansel et al., Lippincott Williams & Wilkins Publishers, 7th ed., 1999); Remington: The Science and Practice of Pharmacy (ed. Alfonso R. Gennaro, Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapics (eds. 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).

[0148] In embodiments, topical formulations contain an emulsifier.The emulsifier can be anionic, cationic or neutral emulsifier.In certain embodiments, the emulsifier is an anionic emulsifier selected from the group consisting of alkyl sulfate, aralkyl sulfate, alkyl ethoxy ether sulfate, alkaryl sulfonate, alkyl succinate, alkyl sulfosuccinate, N-alcohol sarconsinate, isethionate, N-acyltaurate, 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 comprises silicon. In certain embodiments, the emulsifier is a silicone (e.g., dimethicone, phenyl trimethicone, PEG dimethicone, PPG dimethicone, etc.).

[0149] In embodiments, the topical formulation comprises an antioxidant, such as amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g., urocanic acid) and derivatives thereof, peptides such as D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g., anserine), carotenoids, carotenes (e.g., β-carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, liponic acid and derivatives thereof (e.g., dihydrolipoic acid), aurothioglucose, propylthiouracil, and other thiols (e.g., thiorodoxine, thiol ... thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (e.g., buthionine sulfoximine, homocysteine, glutathione, cysteine, cystine, cystamine, and their glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, and lauryl, palmitoyl, oleyl, gamma-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., buthionine sulfoximine, homocysteine, These may be very low tolerated doses (e.g., pmol to μmol / kg) of compounds such as thionine sulfoximine, buthionine sulfone, penta-, hexa-, and heptathionine sulfoximine, 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, etc. acid and its derivatives, ubiquinone and ubiquinol and its derivatives, vitamin C and its derivatives (e.g., sodium ascorbate, ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and derivatives (e.g., vitamin E acetate, tocotrienol), vitamin A and derivatives (vitamin A palmitate), and coniferyl benzoate of benzoic acid resin, rutinic acid and its derivatives, α-glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine,The compound may be butylhydroxytoluene, butylhydroxyanisole, nordihydroguaiac resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (e.g., ZnO, ZnSO), selenium and its derivatives (e.g., selenium methionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide).

[0150] In embodiments, the topical formulation comprises a thickening agent, which may be cross-linked polyacrylic acid and its derivatives, polysaccharides and their derivatives, such as xanthan gum, agar agar, alginate or tylose, cellulose derivatives (e.g., carboxymethylcellulose or hydroxycarboxymethylcellulose), fatty alcohols, monoglycerides and fatty acids, polyvinyl alcohol and PVP.

[0151] In embodiments, the topical formulation comprises a cosmetic and / or dermocosmetic active agent, which may be a color-imparting active agent, a skin or hair coloring composition, a coloring composition, a tanning composition, a bleaching agent, a keratin-hardening agent, an antibacterial active agent, a light filter active agent, a repellent active agent, a substance with hyperemic activity, a substance with keratolytic or prokeratotic activity, an anti-inflammatory agent, a substance with keratinizing activity, an antioxidant active agent or a substance active as a free radical scavenger, a skin moisturizing substance or skin moisturizer, a refatting active agent, a substance with anti-erythema or anti-allergic activity, a branched fatty acid, and any mixture thereof.

[0152] In some 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), peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, carmus), 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 ingredients, such as sage oil, chamomile oil, clove oil, balm oil, mint oil, cinnamon leaf oil, lime tree flower oil, juniper oil, vetiver oil, olivan oil, galbanum oil, labolanum oil and lavandin oil, are also suitable as perfume oils. Bergamot Oil, Dihydromyrcenol, Lilial, Lyral, Citronellol, Phenylethyl Alcohol, α-Hexyl Cinnamaldehyde, Geraniol, Benzyl Acetone, Cyclamen Aldehyde, Linalool, Boisambrene® Forte, Ambroxan, Indole, Hedione, Sandelice, Lemon Oil, Mandarin Oil, Orange Oil, Allyl Amyl Glycolate, Cyclobutal, Lavandin Oil, Muscatel Sage Oil, G39 Damascone, Bourbon Geranium Oil, Cyclohexyl Salicylate, Vertofix® Coeur, iso-E-Super®, Fixolide® NP, Ebemil, Iraldein Gamma, Phenylacetic Acid, Geranyl Acetate, Benzyl Acetate, Rose Oxide, Romilate, Irotyl, and Floramat.

[0153] In embodiments, the topical formulation comprises a solvent and, optionally, a co-solvent. The solvent and co-solvent may be collectively referred to as a "solvent system." Without being bound by theory, the selected solvent system may affect the stability, bioavailability, and overall efficacy of the formulation. In some embodiments, the solvent system should be capable of dissolving or solubilizing one or more active agents and included excipients at the desired concentration or concentrations, and should be stable and compatible with the one or more active agents and any other excipients in the formulation. In some embodiments, the solvent system comprises two or more solvents, the ratio of the co-solvents is optimized to, for example, enhance the penetration or bioavailability of the active agent. Preferred solvent systems are also safe and non-toxic for human consumption. In some embodiments, potential adverse effects, such as irritation or allergic reactions, are considered and minimized during the selection of solvents to be included in the solvent systems of the present disclosure. Solvents that may be included in topical formulations include, 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. Solvents may be present in the formulation, individually or in total (when two or more solvents are included), in amounts ranging from about 0.1% to about 95% by weight (calculated as the total weight of solvents in the formulation divided by the total weight of the formulation).

[0154] In 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, carrageenans, gums, resins, polysaccharides, and high-melting waxes and oils, such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed oil, 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, hydroxypropylmethylcellulose, chitin, galactoarabinan, polygalactose, and polyarabinose. Exemplary glycerides include hydroxystearic acid monoglyceride, hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid monoglyceride, linolenic acid diglyceride, erucic acid monoglyceride, erucic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglyceride, malic acid monoglyceride, malic acid monoglyceride, malic acid diglyceride, and mixtures thereof. In some embodiments, the viscosity modifier is a polymer. The polymer may be a natural or synthetic polymer. Natural polymers include polysaccharides, nucleic acids, and proteins. Synthetic polymers include polyesters, polyureas, polycarbonates, polyvinyl alcohols, polyamides, polyethers, polyesters, polyamines, polytyrosines, polyanhydrides, polyphosphazenes, polyacrylamides, polyacrylates, polymethacrylates, polyvinylpyrrolidone (PVP), etc. Exemplary thickeners include alginate derivatives, pre-neutralized carbomer 430, hydrophilic silica, polysaccharides, xanthan gum, guar guar, agar agar, carboxymethylcellulose, hydroxyethylcellulose, polyacrylates, polyacrylamides, PVP, and salts.

[0155] In embodiments, the topical formulation includes an adhesion modifier. In embodiments, the topical formulation includes an adhesive polymer. The adhesive polymer has physicochemical properties that allow it to bond to the tissue surface for a long period of time. In some embodiments, the inclusion of an adhesive polymer in the formulation increases the amount of time the active agent can contact a barrier (e.g., skin) and diffuse across the barrier. In some embodiments, the adhesive polymer is chitosan, gelatin gum, lectin, sodium alginate, soluble starch, tragacanth, deacetylated xanthan gum, polyacrylic acid, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, a 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.

[0156] In embodiments, topical preparations contain preservatives.Preservatives can be used to inhibit microbial growth or improve the stability of preparations, thereby extending the shelf life of preparations.Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates (for example, sodium benzoate), vitamin A, vitamin C (ascorbic acid), citric acid, vitamin E and tocopherol.

[0157] In some embodiments, the topical formulation contains an antioxidant. Without being bound by theory, antioxidants can generally delay or inhibit the oxidative decomposition of the ingredients of topical formulations, thereby improving the stability of topical formulations and extending their shelf life. In some embodiments, the antioxidant is α-tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, methionine, citric acid, ascorbic acid, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, propyl gallate, cysteine, or a combination thereof. In some embodiments, the antioxidant is cyclodextrin, D-α-tocopherol, rosmarinic acid, or a combination thereof.

[0158] In embodiments, the topical formulation includes a solubilizing agent. Without being bound by theory, the solubilizing agent generally forms a complex with the active ingredient, which may have different physicochemical properties than the active ingredient alone. The properties of the complex can enhance the solubility of the active agent in the formulation. In some embodiments, the solubilizing agent is a water-soluble organic solvent, a non-ionic surfactant, a water-insoluble lipid, an organic liquid, a cyclodextrin, or a phospholipid. In some embodiments, the solubilizing agent is a water-solubility enhancer. In some embodiments, the water-solubility 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 solubilizing agent is propylene glycol. In some embodiments, the solubilizing agent is xanthan gum. In some embodiments, the solubilizing agent is a non-ionic surfactant. In some embodiments, the 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 solubilizing agent is an organic liquid. In some embodiments, the organic liquid is beeswax, d-alpha-tocopherol, oleic acid, or a medium-chain mono- or diglyceride. In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the solubilizing agent is a phospholipid. In embodiments, the phospholipid is hydrogenated soy phosphatidylcholine, distearoyl-phosphatidylglycerol, L-alpha-dimyristoyl-phosphatidylcholine or L-alpha-dimyristoyl-phosphatidylglycerol. In some embodiments, the solubilizing agent is lecithin.

[0159] 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, such as 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 formulations, individually or in total (when two or more colorants and / or dyes and / or pigments are included), in amounts ranging from about 0.01% 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 formulations, individually or in total (when two or more colorants are included), in amounts ranging from about 0.01% to about 5% by weight (calculated as the total weight of the colorants in the formulation divided by the total weight of the formulation).

[0160] In embodiments, the topical formulation includes a binder. Suitable binders include, but are not limited to, polyvinylpyrrolidone (PVP), marine colloids, carboxyvinyl polymers, starch, cellulose-based polymers such as hydroxyethyl cellulose, carboxymethyl cellulose (carmellose), hydroxypropyl methylcellulose, hydroxyethyl propyl cellulose, hydroxybutyl methylcellulose, and salts thereof (e.g., carmellose sodium), natural gums such as karaya, xanthan, carrageenan, gellan gum, locust bean gum, gum arabic, and tragacanth gum, chitosan, colloidal magnesium aluminum silicate, and colloidal silica. Binders may be present in the disclosed formulations individually or in total (when two or more binders are included) in amounts ranging from about 0.01% to about 5% by weight (calculated as the total weight of binders in the formulation divided by the total weight of the formulation).

[0161] In embodiments, the topical formulation comprises a humectant, such as a low molecular weight polyethylene glycol (e.g., PEG6-PEG12), which may be present individually or collectively (when more than one humectant is included) in the formulation in an amount of 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 as the total weight of humectants in the formulation divided by the total weight of the formulation).

[0162] In embodiments, the topical formulation contains a surfactant. The surfactant that can be included in the formulation can be anionic, nonionic, or amphoteric compounds. Suitable examples of anionic surfactants include higher alkyl sulfates such as potassium lauryl sulfate or sodium lauryl sulfate, higher fatty acid monoglyceride monosulfates such as salts of monosulfated monoglycerides of hydrogenated coconut oil fatty acids, alkyl sulfonates such as sodium dodecylbenzenesulfonate, higher fatty acid sulfoacetates, and higher fatty acid esters of 1,2-dihydroxypropanesulfonate. Examples of water-soluble nonionic surfactants are the condensation products of ethylene oxide with various hydrogen-containing compounds that are reactive with it and have long hydrophobic chains (e.g., aliphatic chains of about 12 of 20 carbon atoms), including hydrophilic polyoxyethylene moieties, such as poly(ethylene oxide), with fatty acids, fatty alcohols, fatty amides, and other fatty moieties, and the condensation products of propylene oxide and polypropylene oxide, such as Pluronic materials such as Pluronic F127. Exemplary suitable alkyl polyglycoside (APG) surfactants that can be used in the formulations include APG C8-C10, APG C10-C16, decyl glucoside, coco glucoside, anionic APG carboxylate, sodium lauryl glucose carboxylate, lauryl glucoside, D-glucopyranose (oligomeric, C10-16 glycoside, carboxymethyl ether, sodium salt), C12-C16 fatty alcohol glycoside, and combinations thereof. Exemplary APG surfactants that can be used can have the trade names Plantaren® 2000 N UP / MB, Plantapon® LGC Sorb, Plantaren® 1200 N UP / MB, and Plantaren® 818 UP / MB. The surfactants may be present in the formulation, individually or collectively (if two or more surfactants are included), in amounts ranging from about 0.01% to about 10% by weight (calculated as the total weight of surfactants in the formulation divided by the total weight of the formulation).

[0163] In embodiments, the topical formulation includes a gelling agent. Exemplary gelling agents for use in the disclosed formulations may include pectin, starch, and gelatin forms derived from animals or plants (e.g., porcine gelatin). The 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 nonamidated pectin. In certain embodiments, the pectin is a combination of amidated and nonamidated pectin. The gelatin in the formulation may include type A gelatin, type B gelatin, hide gelatin (e.g., calf hide, pig hide), and / or bone gelatin (e.g., calf bone, pork bone), used alone or in combination. One or more gelling agents may be present in the formulation, individually or in total (when multiple gelling agents are included), in an amount ranging from about 0.1% to about 20% by weight (calculated as the total weight of the gelling agents in the formulation divided by the total weight of the formulation).

[0164] 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, multiparticulates, beads, spheres, and / or any combination thereof. Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended 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-dissolving tablets, chewable tablets, fast-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, for example, capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulsed release dosage forms, multiparticulate dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-dissolving tablet. Furthermore, the pharmaceutical formulation can be administered as a single capsule or in multiple capsule dosage forms. In some embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.

[0165] Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, 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 one or more pharmaceutically acceptable additives, such as compatible carriers, complexing agents, ionic dispersion modifiers, disintegrants, surfactants, lubricants, colorants, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, and one or more auxiliary active compounds, either alone or in combination.

[0166] Auxiliary 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 benzoic acid or benzoates such as sodium benzoate. Antioxidants include compounds such as vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherol, other vitamins or provitamins, and alpha-lipoic acid.

[0167] 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 can be formulated using any pharmaceutically acceptable excipient known to those skilled in the art for preparing liquid dosage forms, as well as solvents, diluents, carriers, excipients, and the like selected to suit the solubility and other properties of the active agent and other ingredients. Solvents can be, for example, water, glycerin, simple syrup, alcohol, medium-chain triglycerides (MCTs), and combinations thereof.

[0168] Liquid dosage forms for oral administration can be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain inert diluents such as water. Pharmaceutical formulations can be prepared as liquid suspensions or solutions using sterile liquids such as, but not limited to, oils, water, and alcohol, and pharmaceutically suitable surfactants, suspending agents, and emulsifiers can be added for oral or parenteral administration. Liquid formulations can also be prepared as single- or multi-dose drinks. Suspensions can contain oils, such as 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 can also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations can contain alcohols (such as ethanol, isopropyl alcohol, hexadecyl alcohol), glycerol, and propylene glycol. Ethers such as polyethylene glycol, petroleum hydrocarbons such as mineral oil and petrolatum, and water can also be used in suspension formulations. Thus, suspensions can contain aqueous or non-aqueous liquids, oil-in-water liquid emulsions, or water-in-oil emulsions.

[0169] In some embodiments, a formulation is provided for oral administration to a subject, comprising the disclosed composition and at least one dispersing or suspending agent. The formulation may be a powder and / or granules for suspension, which, when mixed with water, forms a substantially uniform suspension. The aqueous dispersion may comprise amorphous and non-amorphous particles of multiple effective particle sizes, allowing the drug to be absorbed in a controlled manner over time.

[0170] The dosage form for oral administration can be selected from the group comprising pharmaceutically acceptable aqueous oral dispersion, emulsion, liquid and syrup.See, for example, Singh et al., Encyclopedia of Pharm.Tech., 2nd Ed., 754-757 (2002).In addition to the disclosed compounds, liquid dosage form can comprise one or more additives such as (a) disintegrant, (b) dispersant, (c) wetting agent, (d) preservative, (e) viscosity enhancer, (f) sweetener, or (g) flavoring agent.

[0171] The disclosed compositions can also be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, including physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0172] In some embodiments, the disclosed pharmaceutical compositions can be formulated into ophthalmic preparations. The ophthalmic preparations of the present disclosure include topical preparations such as eye drops, gels, and ointments, and can include excipients suitable for topical preparations, such as penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifiers (e.g., thickeners), adhesion modifiers (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizers, colorants, binders, humectants, surfactants, gelling agents, and other such ingredients described herein and commonly known to those skilled in the art.

[0173] The disclosed ophthalmic formulations may contain one or more viscosity modifiers to provide a viscosity that is comfortable to the eye and does not blur 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 capable of thickening (increasing the viscosity) of ophthalmic formulations. Viscosity modifiers include xanthan gum, edetate, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyethylene glycol, propylene glycol alginate, chitosan, and tragacanth. Hydrogels may also be used as thickening excipients, particularly in artificial tears. Compatible viscosity modifiers may be used in all formulations mentioned herein. The concentration of the viscosity modifier in the ophthalmic formulations of the present disclosure may range from about 0.1% to about 10% by weight (e.g., 1% to 5% by weight). Sorbitol may be used as a combined excipient for tonicity and viscosity adjustment in the ophthalmic formulations of the present disclosure at a concentration ranging from about 0.1% to about 10% by weight (e.g., 2% to 5% by weight).

[0174] Ophthalmic formulations may include, for example, a penetration enhancer to aid in the penetration of one or more active compounds into and across the skin or eyelid skin. Exemplary penetration enhancers for ophthalmic formulations include, for example, any of aliphatic alcohols, fatty acids (including salts thereof), fatty acid esters, polyalcohol alkyl ethers, polyoxyethylene alkyl ethers, glycerides, polyalcohol medium-chain fatty acid esters, polyoxyethylene sorbitan fatty acid esters, alkyl lactate esters, terpenes, and organic amines. In some embodiments, the penetration enhancer is selected from the group consisting of 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 salts thereof); 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 monomyrithlate, glyceryl monostearate, glyceryl monooleate, glyceryl dilaurate, glyceryl dimyrithlate, glyceryl distearate, glyceryl trilaurate, glyceryl trimyristate, glyceryl tristearate, ethylene glycol monocalcium phosphate, glyceryl acrylate, glyceryl acrylate copolymer ... In some embodiments, the ophthalmic formulation comprises a hydrating agent. The hydrating agent can also promote the penetration of the active compound through the cells or junctions of barriers, including the mucous membrane, the mucocutaneous layer, and the stratum corneum. Exemplary hydrating agents include, for example, hyaluronic acid (or its salts, such as sodium hyaluronate), water, saline, and PVP, propylene glycol, glycerol, sorbitol, polyethylene glycol, despanthenol, pantothenic acid, ectoine, carboxyvinyl polymer, carmellose sodium, and povidone;

[0175] In some embodiments, the ophthalmic formulation contains a surfactant. The surfactant can promote 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, 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, dimethyl alkyl glycines, and lecithins.

[0176] In some embodiments, the ophthalmic formulation comprises a gum and / or resin, such as sodium polyacrylate, cellulose ether, calcium alginate, carboxyvinyl polymer, ethylene-acrylic acid copolymer, vinylpyrrolidone polymer, vinyl alcohol-vinylpyrrolidone copolymer, nitrogen-substituted acrylamide polymer, polyacrylamide, cationic polymer such as cationic guar gum, dimethylacrylammonium polymer, acrylic acid-methacrylic acid copolymer, polyoxyethylene-polypropylene copolymer, polyvinyl alcohol, pullulan, agar, gelatin, chitosan, polysaccharides derived from marinad 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, highly polymerized polyethylene glycol, cationic silicone polymer, synthetic latex, acrylic silicone, trimethylsiloxysilicate, and fluorinated silicone resin.

[0177] 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, such as pH 4-10, pH 5-8, or any range that maximizes skin penetration of one or more compounds in the composition. In some embodiments, the pH adjuster is any of hydrochloric acid, citric acid, sodium citrate, acetic acid, sodium acetate, ammonium acetate, succinic acid, tartaric acid, 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 aluminum potassium sulfate.

[0178] In some embodiments, the ophthalmic formulation comprises a stabilizer. Exemplary stabilizers include, for example, sodium bisulfite, sodium sulfite, sodium metabisulfite, 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, edetate disodium, edetate tetrasodium dihydrate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbic acid, and / or succinic acid.

[0179] Further ophthalmic formulations of the present 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) treatment, which seeks to treat mild to moderate glaucoma and ocular hypertension (see Clinical Trial NCT04747808). SIGHT drug-eluting lenses for glaucoma treatment incorporate the FDA-approved drug bimatoprost into contact lenses formulated for controlled drug release. SIGHT lenses contain a drug layer and a barrier layer on the lens surface to control the rate of diffusional drug release. Ophthalmic formulations of the present disclosure include those with similar material designs to SIGHT lenses, as well as others commonly known to those skilled in the art (e.g., Franco et al., Polymers, 2021, 13, 1102).

[0180] The disclosed pharmaceutical compositions may contain any excipients (e.g., surfactants, carriers, antioxidants, etc.) in an amount of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 8 The composition may be present in a concentration of 4%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, or about 80%.

[0181] E. Drug Combinations It should be readily understood that the disclosed compositions are not limited to a single compound combination, or (when formulated as a pharmaceutical composition) limited to only a single carrier, diluent and / or excipient, but may also include a combination of multiple compounds (including additional active compounds) and / or multiple carriers, diluents and excipients.Thus, the pharmaceutical compositions of the present disclosure may include a compound of formula (I) in combination with one or more other active agents (or derivatives and analogs thereof), together with one or more pharmaceutically acceptable carriers, diluents and / or excipients, and further together with one or more other active compounds.

[0182] In some embodiments, the formulations of the present disclosure are prepared to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf life, decrease an undesirable effect or property, alter a property in a desired manner (e.g., pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., neurotransmitter system), or provide a synergistic effect.

[0183] "Therapeutic effects" that may be increased or added with embodiments of the present disclosure include, but are not limited to, antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, pro-dissociative, immunostimulatory, anti-cancer, antiemetic, appetite stimulant, antiulcer, antihistamine, antihypertensive, anticonvulsant, anti-epileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, and stimulant effects.

[0184] "Synergy" should be understood to include an increase in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect that is greater than the additive contribution of the components acting alone. There are many methods known to those skilled in the art for determining whether there is synergy with respect to a particular effect, i.e., whether the effect of two or more components mixed together is greater than the sum of the effects of the individual components applied alone, thereby resulting in "1 + 1 > 2." Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol., 2019; 10: 1222) or the Loewe additivity 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 above-mentioned equations are the concentration-effect curve and the combination index curve, respectively. Each of the above-mentioned equations can be applied to experimental data to generate corresponding graphs, which can help evaluate the effect of drug combinations.

[0185] In some embodiments, the disclosed pharmaceutical compositions comprise an additional active compound, which in some embodiments is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathic and anti-nociceptive agents, anti-migraine drugs, anti-anxiety drugs, antidepressants, antipsychotic drugs, anti-PTSD drugs, dissociative drugs, cannabinoids, immunostimulants, anti-cancer drugs, antiemetics, appetite stimulants, anti-ulcer drugs, antihistamines, antihypertensive drugs, anticonvulsants, anti-epileptic drugs, bronchodilators, neuroprotective agents, nootropics, empathogens, psychedelics, plasticity promoters (e.g., psychoplastogens), monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins. In some embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, 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, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, pro-dissociative, immunostimulatory, anti-cancer, antiemetic, appetite-stimulating, antiulcer, antihistamine, antihypertensive, anticonvulsant, anti-epileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

[0186] In some embodiments, the additional active compound is tryptamine. As will be appreciated by those skilled in the art, tryptamine is a compound having the following general structure: N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 is as defined herein and as commonly understood in the art: [ka]

[0187] In some embodiments, R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, deuterium, halogen (F, Cl, Br, or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 and the intervening atom can be taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, or an optionally substituted heterocyclyl. N1 and R N2 The nitrogen to which R is attached N3 is a quaternary salt connected with R N3 is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0188] In some embodiments, the additional active compound is O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 6-allyl-N,N-diethyl-norlysergamide (AL-LAD), N,N-dibutyltryptamine (DBT), N,N-diethyltryptamine (DET), N,N-diisopropyl-tryptamine (DiPT), 5-methoxy-α-methyltryptamine (α,O-DMS), N,N-dimethyl-tryptamine (DMT), 2,α-dimethyltryptamine (2,α-DMT), α,N-dimethyltryptamine (α ,N-DMT), N,N-dipropyltryptamine (DPT), N-ethyl-N-isopropyltryptamine (EiPT), α-ethyltryptamine (AET), 6,N,N-triethylnorlysergamide (ETH-LAD), 3,4-dihydro-7-methoxy-1-methylcarboline (harmaline), 7-methoxy-1-methylcarboline (harmine), N,N-dibutyl-4-hydroxytryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl-4-hydroxytryptamine N,N-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, bufotenin), N,N-dipropyl-4-hydroxytryptamine (4-HO-DPT), N-ethyl-4-hydroxy-N-methyltryptamine (4-HO-MET), 4-hydroxy-N-isopropyl-N-methyltryptamine (4-HO-MiPT), 4-hydroxy-N-methyl- N-propyl-tryptamine (4-HO-MPT), 4-hydroxy-N,N-tetramethylenetryptamine (4-HO-pyr-T), 12-methoxyibogamine (ibogaine), N-butyl-N-methyltryptamine (MBT), N,N-diisopropyl-4,5-methylenedioxytryptamine (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylenedioxytryptamine (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxy-tryptamine (4,5-MDO-DMT), N,N-dimethyl-5,6-Methylenedioxytryptamine (5,6-MDO-DMT), N-isopropyl-N-methyl-5,6-methylenedioxytryptamine (5,6-MDO-MiPT), N,N-diethyl-2-methyltryptamine (2-Me-DET), 2,N,N-trimethyl-tryptamine (2-Me-DMT), N-acetyl-5-methoxytryptamine (melatonin), N,N-diethyl-5-methoxy-tryptamine (5-MeO-DET), N,N-diisopropyl-5-methoxytryptamine (5-Me O-DiPT), N,N,diallyl-5-methoxy-tryptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-isopropyl-4-methoxy-N-methyltryptamine (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyltryptamine (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyltryptamine (5,6-MeO-MiPT), 5-methoxy-N-methyl-tryptamine (5-MeO-N MT), 5-methoxy-N,N-tetramethylenetryptamine (5-MeO-pyr-T), 6-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl-tryptamine (5-MeO-TMT), N,N-dimethyl-5-methylthiotryptamine (5-MeS-DMT), N-isopropyl-N-methyltryptamine (MiPT), α-methyltryptamine (α-MT), N-ethyltryptamine (NET), N-methyltryptamine The tryptamine is selected from the group consisting of tryptamine (NMT), 6-propylnorlysergamide (PRO-LAD), N,N-tetra-methylenetryptamine (pyr-T), tryptamine (T), 7-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (tetrahydroharmine), or α,N-dimethyl-5-methoxytryptamine (α,N,O-TMS), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, or a combination thereof.

[0189] In some embodiments, the additional tryptamine is a "complex tryptamine" or other indoleamine, examples of which include iboga alkaloids, such as ibogaine, and their analogs, metabolites and derivatives, and β-carbolines.

[0190] In some embodiments, the additional active compound is a phenethylamine. As will be appreciated by those skilled in the art, a phenethylamine is a compound having the following general structure, where R N1 , R N2 , R α , R β , and R 2 ~R 6 each as taught herein and as commonly understood in the art: [ka]

[0191] In some embodiments, R N1 , R N2 , R α , R β , and R 2~6 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. 3 and R 4 taken together form an optionally substituted heterocyclyl, such as dioxole (as in 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 4taken together form an optionally substituted aryl, such as phenyl. In some embodiments, the phenethylamine is R N1 , R N2 , and further R N3 wherein each of R is independently an alkyl group or an aryl group, and all other substituents are as described above. In some embodiments, the phenethylamine comprises a quaternary ammonium cation wherein R N1 and R N2 The nitrogen to which R is attached N3 is a quaternary salt connected with R N3 is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0192] In some embodiments, the additional active compound is alpha-ethyl-3,4,5-trimethoxy-phenethylamine (AEM), 4-allyloxy-3,5-dimethoxyphenethylamine (AL), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH), 2,5-dimethoxy-4-ethylthioamphetamine (ALEPH-2), 2,5-dimethoxy-4-isopropylthioamphetamine (ALEPH-4), 2,5-dimethoxy-4-phenylthio-amphetamine (ALEPH-6), 2,5-dimethoxy-4-propylthio-amphetamine (ALEPH-7), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-8), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-9), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-10), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-11), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-12), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-13), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-14), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-15), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-16), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-17), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-18), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH-19 ... Amphetamine (ALEPH-7), 2,5-dimethoxy-α-ethyl-4-methylphenethylamine (ARIADNE), 3,4-diethoxy-5-methoxy-phenethylamine (ASB), 4-butoxy-3,5-dimethoxyphenethylamine (B), 2,5-dimethoxy-4,N-dimethylamphetamine (BEATRICE), 2,5-bismethylthio-4-methyl-amphetamine (BIS-TOM), 4-bromo-2,5,β-trimethoxyphenethylamine (BOB), 2,5,β-trimethoxy-4-methylphenethylamine (BOD), β-methyl 3,4-methylenedioxyphenethylamine (BOH), 2,5-dimethoxy-β-hydroxy-4-methylphenethylamine (BOHD), 3,4,5,β-tetramethoxy-phenethylamine (BOM), 4-bromo-3,5-dimethoxyamphetamine (4-Br-3,5-DMA), 2-bromo-4,5-methylenedioxyamphetamine (2-Br-4,5-MDA), 3,4-methylenedioxy-N-ethyl-amphetamine (MDEA), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-benzyloxy-3 ,5-Dimethoxyamphetamine (3C-BZ), 4-chloro-2,5-dimethoxyphenethylamine (2C-C), 2,5-dimethoxy-4-methyl-phenethylamine (2C-D), 2,5-dimethoxy-4-ethyl-phenethylamine (2C-E), 3,5-dimethoxy-4-ethoxyamphetamine (3C-E), 2,5-dimethoxy-4-fluorophenethylamine (2C-F), 2,5-dimethoxy-3,4-dimethylphenethylamine (2C-G), 2,5-dimethoxy-3,4-trimethylene-phenethylamine (2C-G-3), 2,5-Dimethoxy-3,4-tetramethylenephenethylamine (2C-G-4), 3,4-norbornyl-2,5-dimethoxyphenethylamine (2C-G-5), 1,4-dimethoxynaphthyl-2-ethylamine (2C-GN), 2,5-dimethoxy-phenethylamine (2C-H), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), 2,5-dimethoxy-4-nitro-phenethylamine (2C-N), 2,5-dimethoxy-4-isopropoxyphenethylamine (2C-O-4), 2,5-dimethoxy-4-propylphenethylamine 2,5-Dimethoxy-4-methyl-selenophenethylamine (2C-SE), 2,5-Dimethoxy-4-methylthiophenethylamine (2C-T), 2,5-Dimethoxy-4-ethyl-thiophenethylamine (2C-T-2), 2,5-Dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,6-Dimethoxy-4-isopropylthiophenethylamine (psi-2C-T-4), 2,5-Dimethoxy-4-propylthiophenethylamine (psi-2C-T-4), Phenethylamine (2C-T-7), 4-cyclopropylmethylthio-2,5-dimethoxyphenethylamine (2C-T-8), 4-(t)-butylthio-2,5-dimethoxy-phenethylamine (2C-T-9), 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine (2C-T-13), 4-cyclopropylthio-2,5-dimethoxyphenethylamine (2C-T-15), 4-(s)-butylthio-2,5-dimethoxy-phenethylamine (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine Netethylamine (2C-T-21), 3,5-dimethoxy-4-trideuteromethyl-phenethylamine (4-D), β,β-dideutero-3,4,5-trimethoxy-phenethylamine (β-D), 3,5-dimethoxy-4-methyl-phenethylamine (DESOXY), 2,4-dimethoxy-amphetamine (2,4-DMA), 2,5-dimethoxyamphetamine (2,5-DMA), 3,4-dimethoxyamphetamine (3,4-DMA), 2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine (DMCPA), 3,4-Dimethoxy-β-hydroxyphenethylamine (DME), 2,5-dimethoxy-3,4-methylenedioxy-amphetamine (DMMDA), 2,3-dimethoxy-4,5-methylenedioxyamphetamine (DMMDA-2), 3,4-dimethoxy-phenethylamine (DMPEA), 4-amyl-2,5-dimethoxyamphetamine (DOAM), 4-bromo-2,5-dimethoxy-amphetamine (DOB), 4-butyl-2,5-dimethoxyamphetamine (DOBU), 4-chloro-2,5-dimethoxyamphetamine (DO C), 2,5-dimethoxy-4-(2-fluoroethyl)amphetamine (DOEF), 2,5-dimethoxy-4-ethyl-amphetamine (DOET), 4-iodo-2,5-dimethoxyamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM(STP)), 2,6-dimethoxy-4-methylamphetamine (psi-DOM), 2,5-dimethoxy-4-nitroamphetamine (DON), 2,5-dimethoxy-4-propylamphetamine (DOPR), 3,5-dimethoxy-4-ethoxyphenethylamine (E), 2,4,5-triethoxyamphetamine (EEE), 2,4-diethoxy-5-methoxyamphetamine (EEM), 2,5-diethoxy-4-methoxyamphetamine (EME), 4,5-dimethoxy-2-ethoxyamphetamine (EMM), 2-ethylamino-1-(3,4-methylenedioxyphenyl)butane (ETHYL-J), 2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane (ETHYL-K), 6-(2-amino-propyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran ( F-2), 6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran (F-22), N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine (FLEA), 2,5-dimethoxy-3,4-(trimethylene)amphetamine (G-3), 2,5-dimethoxy-3,4-(tetra-methylene)amphetamine (G-4), 3,6-dimethoxy-4-(2-amino-propyl)benzonorbornane (G-5), 2,5-dimethoxy-3,4-dimethyl-amphetamine (GANESHA), 1,4-Dimethoxynaphthyl-2-isopropyl-amine (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-hydroxy-phenethylamine (HOT-17), 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA), 2,3,4-trimethoxy-phenethylamine (IM), 3,5-dimethoxy-4-isopropoxy Phenethylamine (IP), 5-ethoxy-2-methoxy-4-methylamphetamine (IRIS), 2-amino-1-(3,4-methylenedioxyphenyl)butane (J, BDB), 3-methoxy-4,5-methylenedioxyphenethylamine (LOPHOPHINE), 3,4,5-trimethoxy-phenethylamine (M), 4-methoxy-amphetamine (4-MA, PMA), 2,N-dimethyl-4,5-methylenedioxyamphetamine (MADAM-6), 3,5-dimethoxy-4-methallyloxyphenethylamine (MAL), 3,4- Methylenedioxyamphetamine (MDA), N-allyl-3,4-methylenedioxyamphetamine (MDAL), N-butyl-3,4-methylenedioxyamphetamine (MDBU), N-benzyl-3,4-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-methylenedioxyamphetamine N-isopropyl-3,4-methylenedioxyamphetamine (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-trimethyl-phenethylamine (MDMP), N-hydroxy-3,4-Methylenedioxyamphetamine (MDOH), 3,4-methylenedioxyphenethylamine (MDPEA), α,α-dimethyl-3,4-methylenedioxyphenethylamine (MDPH), 3,4-methylenedioxy-N-propargyl-amphetamine (MDPL), 3,4-methylenedioxy-N-propyl-amphetamine (MDPR), 3,4-dimethoxy-5-ethoxyphenethylamine (ME), 4,5-ethylenedioxy-3-methoxyamphetamine (MEDA), 4,5-diethoxy-2-methoxyamphetamine (M EE), 2,5-dimethoxy-4-ethoxyamphetamine (MEM), 4-ethoxy-3-methoxyphenethylamine (MEPEA), 5-bromo-2,4-dimethoxyamphetamine (META-DOB), 2,4-dimethoxy-5-methylthioamphetamine (META-DOT), 2,5-dimethoxy-N-methylamphetamine (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methylamphetamine (METHYL-DOB), 2-methylamino-1-(3,4-methylenedioxyphenyl)butane (METHYL-DMA) -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-tetra-methoxyamphetamine (TA), 4-ethoxy-3-ethylthio-5-methoxyphenethylamine (3-TASB), 3-ethoxy-4-ethylthio-5-methoxyphenethylamine (4-TASB), 3,4-diethoxy-5-methylthio, 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 Amphithiamin (3-TM), 3,5-dimethoxy-4-methylthiophenethylamine (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-methylthio-phenethylamine (4-TME), 3-ethoxy-4-methoxy-5-methylthiophenethylamine (5-TME), 3,4-methylenedioxy-2-methylthioamphetamine (2T-MMDA-3a), 2-methoxy-4,5-methylene-thiooxyamphetamine (4T-MMDA-2), 2,4,5-trimethoxyphenethylamine (TMPEA), 4-ethyl-5-methoxy-2-methylthioamphetamine (2-TOET), 4-ethyl-2-methoxy-5-methylthioamphetamine (5-TOET) ET), 5-methoxy-4-methyl-2-methylthioamphetamine (2-TOM), 2-methoxy-4-methyl-5-methylthio-amphetamine (5-TOM), 2-methoxy-4-methyl-5-methyl-sulfinylamphetamine (TOMSO), 3,5-dimethoxy-4-propylthiophenethylamine (TP), 3,4,5-triethoxyphenethylamine (TRIS), 3-ethoxy-5-ethylthio-4-methoxy-phenethylamine (3-TSB), 3,5-diethoxy-4-methylthiophenethylamine (4-TSB), 3,A phenethylamine selected from the group consisting of 4-diethoxy-5-ethylthio-phenethylamine (3-T-triS), 3,5-diethoxy-4-ethylthiophenethylamine (4-T-triS), (R)-2,5-dimethoxy-4-iodoamphetamine (R-DOI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.

[0193] In some embodiments, the additional active compound is an ergoline. In some embodiments, the additional active compound is an ergot alkaloid. In some embodiments, the additional active compound is a lysergamide. As will be appreciated by those skilled in the art, a lysergamide 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 is as defined herein and as commonly understood in the art: [ka]

[0194] 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 14and are each independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 and the intervening atoms can combine to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, or an optionally substituted heterocyclyl. In some embodiments, the lysergic acid amide can include an additional R 6A But R 6 is a quaternary salt attached to the nitrogen to which R is attached; 6A is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0195] In some embodiments, the additional active compound is 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-(cyclopropyl-methanoyl)-lysergic acid diethylamide (1cP-LSD), 1-(1,2-dimethylcyclobutane-1-carbonyl)-lysergic acid diethylamide (1D-LSD), 1-propionyl-6-allyl-6-nor-lysergic acid diethylamide (1P-AL-LAD) , 1-(cyclopropylmethanoyl)-6-allyl-6-nor-lysergic acid diethylamide (1cP-AL-LAD), 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), lysergic acid 2,4-dimethylazetidide (i.e., LA-SS-Az, LSZ), lysergic acid piperidide (LSD-Pip), and lysergic acid methylisopropylamide (MIPLA).

[0196] Other tryptamines, phenethylamines, and lysergic acid amides that are useful as additional active compounds for purposes of the present invention, and are therefore contemplated for inclusion therein, are generally known in the art (see, e.g., Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997); Grob & Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi & Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacological Reviews, 2016; 68(2), 264-355; Glennon, Pharmacology Biochemistry and Behavior, 1999; 64, 251-256; each of which is incorporated by reference as if fully set forth herein).

[0197] F. Dosage and Administration In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount or an effective amount of the disclosed compound, such as for administration to a subject. Administering a "therapeutically effective amount" or "effective amount" of a pharmaceutical composition to a subject means administering an amount of the composition sufficient to achieve a desired effect. Where "effective amount" refers to an amount effective to treat a described disorder or condition in a subject, "therapeutic effect" is understood to mean one or more responses in a mammal following treatment that are deemed desirable and beneficial. Thus, depending on the mental health disorder being treated or the improvement in mental health or functioning sought, and on the one or more specific components in the disclosed composition under consideration, the responses will vary, but will be readily understood by those skilled in the art through an understanding of the disclosures herein and general knowledge in the art (e.g., by referring to the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for the described disorder).

[0198] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it can be administered in a single dose (in milligrams calculated based on the patient's body weight in kilograms), for example, at a dose of 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, at least 1.0 mg / kg, It may be present in an amount such as 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.

[0199] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it may be present in an amount such that a single dose (in milligrams, calculated based on the patient's weight in kilograms) is about 0.001 mg / kg to 0.1 mg / kg, e.g., about 0.001 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, and about 0.1 mg / kg, and ranges between these values. In some embodiments, the single dose is about 0.1 mg / kg to 1.0 mg / kg, e.g., about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, and about 1.0 mg / kg, and ranges between these values.

[0200] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it may be present in an amount such that a single dose (in milligrams calculated based on the patient's kilogram weight) is about 20 pg / kg body weight or less (e.g., less than 20 pg / kg, less than 15 pg / kg, less than 10 pg / kg, or less than 5 pg / kg body weight, e.g., 1-20 pg / kg body weight, e.g., 1-5 pg / kg, 5-10 pg / kg, 10-15 pg / kg, or 15-20 pg / kg, e.g., about 5 pg / kg, about 10 pg / kg, about 15 pg / kg, or about 20 pg / kg).

[0201] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it has a single dose (in milligrams calculated based on the patient's weight in kilograms) of less than about 20 ng / mL (e.g., 0.05-20 ng / mL, e.g., 0.1-15 ng / mL, 0.5-10 ng / mL, or 1-5 ng / mL, e.g., 0.05-0.1 ng / mL, 0.1-0.2 ng / mL, 0.2-0.3 ng / mL, 0.3-0.4 ng / mL, 0.4-0.5 ng / mL, 0.6-0.7 ng / mL, 0.8-0.9 ng / mL, 0.9-10 ng / mL, 10-12 ng / mL, 11-14 ng / mL, 12-16 ng / mL, 13-17 ng / mL, 14-15 ng / mL, 15-16 ng / mL, 16-17 ng / mL, 17-18 ng / mL, 18-19 ng / mL, 19-20 ng / mL, 20-21 ng / mL, 22-23 ng / mL, 23-24 ng / mL, 24-25 ng / mL, 25-26 ng / mL, 26-27 ng / mL, 27-28 ng / mL, 28-29 ng / mL, 29-30 ng / mL, 30-31 ng / mL, 31-32 ng / mL, 32-33 ng / mL, 33-34 ng / mL, 34-35 ng / mL, 35-36 ng / mL, 36-37 ng / mL, 37-38 ng / mL, The compound may be present in an amount such that the circulating drug plasma level is below the limit of detection (e.g., below 0.1 ng / mL).

[0202] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it may be administered in a single dose (whether or not such dose is present in a unit dosage form), e.g., 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, at least 95 mg, at least 10 ... 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.

[0203] In some embodiments, when a pharmaceutical composition contains a disclosed compound, it may be present in an amount such that a single dose (whether or not such a dose is present in a unit dosage form) is about 0.1 mg to 1.0 mg, e.g., 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 ranges therebetween. In some embodiments, a single dose is about 1 mg to 10 mg, e.g., 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 ranges therebetween. In some embodiments, a single dose is about 10 mg to 100 mg.

[0204] In some embodiments, when the pharmaceutical composition includes an additional active compound, for example, when the additional active compound is a phenethylamine or another tryptamine, it may be administered in a single dose (in milligrams calculated based on the patient's kilogram 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, at least 0.95 mg / kg, at least 0.95 mg / kg, at least 0.10 ... 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.

[0205] In some embodiments, when the pharmaceutical composition comprises an additional active compound, for example, when the additional active compound is a phenethylamine or tryptamine, it may be administered in a single dose (whether or not such dose is present in a unit dosage form), 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 an amount such as 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.

[0206] It will be understood that dosage may vary depending on whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability or susceptibility of the symptoms the treatment is targeting, the desired clinical endpoint, previous, concurrent, or subsequent treatments, the general health, age, sex, and race of the subject, bioavailability, the possibility of systemic, local, or local adverse side effects, the presence of other disorders or diseases in the subject, and other factors understood by those of skill in the art (e.g., medical history or family history).

[0207] The dosage, frequency, or duration may be increased or decreased as indicated by the desired clinical result, the state of the disease state or symptom, any adverse side effects of the treatment or therapy, or concomitant medications. One of ordinary skill in the art, together with the teachings of this disclosure, will understand the factors that can affect the dosage, frequency, and timing necessary to provide an amount sufficient or effective to provide a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0208] In some embodiments, the actual dose administered will be determined by a physician in light of relevant circumstances, including the disorder being treated, the selected route of administration, the actual composition or formulation being administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms; therefore, it will be understood that any dosage ranges disclosed herein are not intended to limit the scope of the present disclosure. In some cases, a dosage below the lower limit of the disclosed range may be sufficient, while a dosage above the range may be used without causing adverse side effects. For example, such a high dose may be divided into multiple lower doses for administration, which may be administered together or separately.

[0209] In some embodiments, the recommended dosage can be known by reference to the format of the formulation itself, particularly when the formulation is prepared in a single unit dosage form such as a capsule, tablet, or lozenge. In embodiments in which the formulation is prepared in multiple dosage forms, such as a liquid suspension and a topical formulation, the recommended dosage can be known by reference to the administration means, or by reference to the packaging and labeling, package insert, marketing materials, training materials, or other information and knowledge available to those skilled in the art or the public.

[0210] Therefore, another aspect of the present disclosure provides a pharmaceutical kit comprising the pharmaceutical composition or formulation of the present disclosure, the recommended administration guideline or prescription information therefor, and a suitable container.Individual unit dosage forms can be included in a multi-dose kit or container.The pharmaceutical preparation can also be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0211] G.Kit Another aspect of the present disclosure provides a pharmaceutical kit comprising the pharmaceutical composition or formulation of the present disclosure, its recommended administration guidelines or prescription information, and a suitable container.Individual unit dosage forms can be included in a multi-dose kit or container.The pharmaceutical preparation can also be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0212] The kit generally includes suitable packaging. The 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, if cross-reactivity and shelf life permit, several components may be combined in a single container. The kit may be in unit dosage form, bulk package (e.g., multi-dose package), or sub-unit dose. For example, a kit may be provided that includes a sufficient dosage of the compounds disclosed herein and / or additional pharmaceutically active compounds useful for the diseases detailed herein to provide effective treatment of an individual for an extended period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kit may also include multiple unit doses of the compound and instructions for use, and may be packaged in an amount sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0213] Preferably, information regarding dosing and proper administration (if necessary) is printed directly on the multi-dose kit (e.g., on the blister pack or other inner packaging holding the disclosed compositions or formulations); however, the disclosed kits may further include package inserts and other printed instructions (e.g., on the outer packaging) for administering the disclosed compositions and for their proper therapeutic use.

[0214] H.How to use In some aspects, methods of 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 a condition, such as a disease or disorder. In some embodiments, the disclosed compounds are used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a condition, such as a disease or disorder. In some embodiments, the disclosed compounds are administered as part of a therapy. 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 a therapeutically effective amount to a subject having a condition, such as a disease or disorder. In some embodiments, the condition is a mental health disorder. In some embodiments, the condition is a neurodegenerative disorder. In some embodiments, the condition is a pain disorder. In some embodiments, the disclosed compounds are administered to a healthy subject.

[0215] As used herein, the terms "subject," "user," "patient," and "individual" are used interchangeably and refer to any mammal, including mice, monkeys, livestock mammals, sport animals, and pet mammals such as dogs and cats, but preferably humans. Such terms are understood to include anyone with an indication for which the compounds, compositions, or methods described herein may be effective or who could otherwise benefit from the invention. In general, it will be understood that all of the compounds, compositions, and disclosed methods will be effective for all individuals, although individual differences are expected. The disclosed treatment methods can also be modified to treat multiple patients at once, including couples or families. Thus, these terms are also understood to refer to two or more individuals.

[0216] 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 comprising them are useful in methods of treating patients in need of such treatment.

[0217] a. Regulation of neurotransmission In some embodiments, the disclosed compounds modulate neurotransmission in a subject, such as after administration of a therapeutically effective amount to the subject. In embodiments, modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject. In embodiments, modulating neurotransmission includes, for example, modulating monoamine levels in the CNS and peripheral tissues. In embodiments, modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0218] In some embodiments, the disclosed compounds activate serotonin receptors. In some embodiments, the disclosed compounds agonize and / or antagonize serotonin receptors (5-HT receptors, e.g., 5-HT2 receptors). The 5-HT2 receptor family includes 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 Psilocytosis and other related psychoactive tryptamines are primarily expressed in the brain via 5-HT 2A However, many of these tryptamines (including psilocin) also bind to 5-HT receptors due to the high sequence homology between the three 5-HT2 receptor subtypes. 2B and 5-HT 2C It is also an agonist of the 5-HT2 receptor (Nichols, Pharmacol. Rev. 2016, 68, 264-355). Activation of all 5-HT2 receptor subtypes can result in reduced 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 5-HT receptor activation (ibid.), but 2B Activation of the 5-HT receptor has been linked to heart valve disease (Hutcheson et al., Pharmacol. Ther. 2011, 132(2):146-157). In embodiments, compounds, particularly compounds that may be used regularly or over relatively long periods of time, may be used to inhibit 5-HT receptor activity. 2B In some embodiments, the disclosed compounds have reduced activity (e.g., agonism) of 5-HT receptors, e.g., 5-HT 1A and 5-HT 1B 5-HT1 receptors, 5-HT 2A , 5-HT 2B and 5-HT 2CThe 5-HT2 receptor, such as 5-HT1, 5-HT2 receptor, and 5-HT6 receptors are stimulated or partially stimulated.

[0219] In some embodiments, the disclosed compounds are 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2C In vitro EC against any one or more of 5-HT6 50 (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 embodiments, the disclosed compounds are 5-HT 2A In vitro ECs against 50 (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 some embodiments, the disclosed compounds are 5-HT 2C In vitro ECs against 50 (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.

[0220] In some embodiments, the disclosed compounds inhibit 5-HT 2 receptors relative to other 5-HT 2 receptors. 2A In some embodiments, the disclosed compounds exhibit greater potency at the 5-HT1 receptor, another 5-HT2 receptor, e.g., 5-HT 2B and 5-HT 2C e.g., 5-HT compared with one or more of the 5-HT5, 5-HT6, and 5-HT7 receptors 2A It shows greater efficacy.

[0221] Determining agonism and antagonism, EC 50 and IC 50 Measurement of Gq-mediated calcium flux, respectively, can be determined according to methods available to those skilled in the art. In one example, measurement of Gq-mediated calcium flux can be used to measure 5-HT, a widely recognized target of psychedelic compounds.2A This is a known method for assessing modulation, e.g., activation, of a protein. 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 not as effective as full agonists (E MAX = 100%), the reduced maximum effect (E MAX ) and for example, in the case of the 5-HT receptor, serotonin corresponds to this.

[0222] The particular effects of the disclosed compounds may be due, at least in part, to their ability to activate serotonin receptors (e.g., 5-HT 2A , 5-HT 2C ), one potential approach for next-generation compounds with improved therapeutic efficacy, improved safety profiles, and reduced side effects may be to optimize selective serotonin receptor activation. Thus, in some embodiments, the disclosed compounds may bind to other serotonin receptors (e.g., 5-HT 2B receptor, or 5-HT 2C receptors) rather than 5-HT 2A In some embodiments, the disclosed compounds have high selectivity for the 5-HT receptor. 2B 5-HT receptors 2A In some embodiments, the disclosed compounds have high selectivity for the 5-HT receptor. 2C 5-HT receptors 2A In some embodiments, selectivity is enhanced over another receptor (e.g., 5-HT 2B receptors or 5-HT 2C receptors, such as serotonin receptors) compared to one receptor (e.g., 5-HT 2AThe half-maximal effective concentration (EC) of the disclosed compounds for the 50 ) is defined as the functional activity selectivity calculated by the ratio of 5-HT 2A EC 50 is 0.2 μM, and 5-HT 2B EC 50 is 1.0 μM, the compound 2B 5-HT receptors 2A It can be said to have a 5-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 the 5-HT receptor 2C receptor) (e.g., K i For example, the affinity selectivity of a hypothetical compound can be defined as the ratio of 5-HT 2A K i is 0.1 μM, and 5-HT 2B EC 50 is 1.0 μM, the compound 2B 5-HT receptors 2A It can be said to have a 10-fold affinity selectivity for the receptor.

[0223] In some embodiments, the disclosed compounds are 5-HT 2B 5-HT receptors 2A In embodiments, the disclosed compounds have affinity selectivity for the 5-HT receptor of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold relative to the comparator. 2B 5-HT receptors 2A The affinity selectivity for the receptor is improved.

[0224] In embodiments, the disclosed compounds are 5-HT 2B 5-HT receptors 2AIn embodiments, the disclosed compounds have a functional activity selectivity of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold for the 5-HT receptor compared to a comparator. 2B 5-HT receptors 2A The affinity selectivity for the receptor is improved.

[0225] In some embodiments, the disclosed compounds are 5-HT 2B 5-HT receptors 2C In embodiments, the disclosed compounds have affinity selectivity for the 5-HT receptor of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold relative to the comparator. 2B 5-HT receptors 2C The affinity selectivity for the receptor is improved.

[0226] In embodiments, the disclosed compounds are 5-HT 2B 5-HT receptors 2C In embodiments, the disclosed compounds have a functional activity selectivity of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold for the 5-HT receptor compared to a comparator. 2B 5-HT receptors 2C The affinity selectivity for the receptor is improved.

[0227] b. Regulation of neuroplasticity In some embodiments, the disclosed compounds modulate neurotransmission in a subject, such as after administration of a therapeutically effective amount to the subject. In some embodiments, modulation of neurotransmission contributes to the therapeutic effect of the disclosed compounds in a subject. In some embodiments, modulation of neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.

[0228] Neurotransmission refers to the transmission of information between neurons. When an action potential is generated, information is released by a neuron, resulting in the release of neurotransmitters into the synapse. Thus, neurotransmission can be quantified by measuring 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 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 synchrony of the activity of neuronal populations. Synchrony is measured as the coefficient of variation of spike rate, burst rate, and / or burst duration across neuronal populations. Synchrony is also measured as synchrony sharing, synchrony distance, and / or spike simplex.

[0229] In some embodiments, the disclosed compounds modulate spike rate. The spike rate is the number of action potentials per second. In some embodiments, the disclosed compounds modulate burst rate. Neurons may fire a series of action potentials known as bursts in rapid succession. The burst rate is the number of bursts per second. In some embodiments, the disclosed compounds modulate spike contrast. Spike contrast is a measure of the variability of neuronal activity and is measured as the difference in the number of spikes occurring in the first and second halves of the recording period (i.e., 700 milliseconds). In some embodiments, the disclosed compounds modulate burst spike count. The burst spike count is the number of spikes per burst. In some embodiments, the disclosed compounds modulate burst duration. The burst duration is the average duration of the detected bursts. In some embodiments, neurotransmission is measured as burst amplitude. To obtain burst amplitude, an integral function with decay is calculated over the timestamps of the bursts. The burst amplitude is the peak value of the integral, which increases with the occurrence of frequent and numerous spikes.

[0230] In some embodiments, the disclosed compounds modulate oscillatory behavior. Oscillatory behavior is a measure of the variability of a parameter, measured as the standard deviation of the parameter over time within an experimental episode. In some embodiments, the disclosed compounds modulate the synchrony of activity in a neuronal population. Synchrony is a measure of the relative variability of activity across a neuronal population. In some embodiments, the disclosed compounds modulate shared synchrony. Shared synchrony is the average number of units involved in a population burst, with higher values ​​reflecting greater synchronization of bursts occurring across neuronal populations. In some embodiments, the disclosed compounds modulate synchronization distance. Synchrony distance is defined as the average distance from the center of a population burst to the onset of a burst within the population burst, with lower values ​​reflecting greater network synchrony. In some embodiments, the disclosed compounds modulate spike simplex. Spike simplex is a measure of the connectivity and complexity of a neuronal network, with higher values ​​reflecting greater synchronization between neurons.

[0231] In some embodiments, the disclosed compounds are used to enhance neuroplasticity. Neuroplasticity, also known as neuroplasticity or 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 the strengthening or weakening of connections (synapses) between neurons. Synaptic plasticity is often associated with learning and memory processes. Another form of plasticity is called structural plasticity, which involves changes in the physical structure of neurons, such as the growth of new dendritic branches or the formation of new synapses. In some embodiments, increased neuroplasticity contributes to the therapeutic effects of the disclosed compounds in a subject. In some embodiments, a disease or disorder in a subject is treated by administering the disclosed compounds to a subject to enhance neuroplasticity.

[0232] Neuroplasticity can be defined in terms of neuritogenesis, spine formation, and synaptogenesis in neurons. Neuritogenesis refers to the process by which neurons generate and extend their neurites (i.e., form axons and dendrites). Neuritogenesis is a critical 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 an important role in synaptic transmission and plasticity. Synaptogenesis refers to the formation of synapses, which are essential for the establishment and refinement of neural circuits, and is a fundamental process underlying learning, memory, and information processing in the brain.

[0233] In some embodiments, the disclosed compounds increase neuritogenesis. Neuritogenesis can be measured in terms of total neurite length, maximum neurite length, number of neurite nodes, and / or number of neurite terminals. In some embodiments, the disclosed compounds increase total neurite length. In some embodiments, the disclosed compounds increase maximum neurite length. In some embodiments, the disclosed compounds increase the number of neurite nodes. In some embodiments, the disclosed compounds increase the number of neurite terminals.

[0234] In some embodiments, administration of the disclosed compounds to a subject increases the number of dendritic branches, the number of dendritic intersections, the density of dendritic spines, the density of synapses (i.e., the number of synapses per neuron), or the total length of dendrites. These factors can be measured using Sholl analysis and other techniques known to those skilled in the art (Ly et al., ACS Pharmacol Transl Sci. 2020;4(2):452-460).

[0235] c.Treatment In some embodiments, the disclosed compounds are used to treat a medical condition, such as a disease or disorder. In embodiments, the disclosed compounds are used in the manufacture of a medicament for treating a condition, such as a disease or disorder. Methods are also provided for administering the disclosed compounds to a subject having a condition, such as a disease or disorder, thereby treating the condition.

[0236] In some embodiments, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds are administered to a subject 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 of such routes, one or more of the disclosed compounds and the disclosed compositions and formulations comprising them are useful in methods of treating patients in need of such treatment.

[0237] In some embodiments, a method for treating and / or preventing a condition in a mammal is provided, comprising administering a therapeutically effective amount of a disclosed compound or pharmaceutical composition to a mammal. In some embodiments, "treating" or "treatment" refers to treating a disease or disorder in a mammal, preferably a human, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with the disorder; (b) inhibiting the disorder, i.e., halting its development; (c) alleviating the disorder, i.e., causing its regression; (d) protecting against or alleviating symptoms or conditions caused by or associated with the disorder; (e) reducing, lowering, inhibiting, ameliorating, 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 worsening or progression of symptoms or conditions associated with or coexisting with the disorder. In some embodiments, treatment does not include prevention. In other embodiments, treatment does not include prevention. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be apparent to those of skill in the art in view of the teachings herein and the knowledge of those skilled in the art.

[0238] 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., movement 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.

[0239] i. Mental, behavioral or neurodevelopmental disorder In some embodiments, the disclosed compounds are used to treat psychiatric, behavioral, or neurodevelopmental disorders. In some embodiments, the disclosed compounds are administered, e.g., in a therapeutically effective amount, to a subject with a psychiatric, behavioral, or neurodevelopmental disorder, thereby treating the psychiatric, behavioral, or neurodevelopmental disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide a beneficial therapeutic effect in the treatment of psychiatric, behavioral, or neurodevelopmental disorders.

[0240] The ICD-11, incorporated herein by reference in its entirety, defines a "mental, behavioral, or neurodevelopmental disorder" as a syndrome characterized by clinically significant impairments in an individual's cognition, emotional regulation, or behavior that reflect dysfunction in the psychological, biological, or developmental processes underlying mental and behavioral functioning. Such disorders include, but are not limited to, neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety- or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically related to stress, dissociative disorders, eating (or appetite) disorders, elimination disorders, disorders of physical pain or physical experiences, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or antisocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorder, neurocognitive disorders, mental or behavioral disorders related to pregnancy, childbirth, or the postpartum period, sleep-wake disorders, sexual dysfunction, and gender dysphoria.

[0241] Mental, behavioral, or neurodevelopmental disorders not otherwise defined are understood to refer to disorders as defined by ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or "mental health disorder") generally refers to a disease state involving negative changes in emotions, moods, thoughts, and / or behaviors. Generally, mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotions, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of morbidity. The terms "mental disorder" and "mental health disorder," as well as terms defining specific diseases and disorders, generally refer to patients with ICD-11 criteria, or a diagnosis based thereon, but it will be understood that the disclosed methods are equally applicable to patients with comparable underlying disorders, regardless of whether the disorder is diagnosed based on the criteria of ICD-11, ICD-10, DSM-5, or DSM-IV (each of which is incorporated herein by reference in its entirety), whether the diagnosis is based on other clinically accepted criteria, or whether the patient has not yet received a formal clinical diagnosis.

[0242] In some embodiments, the disclosed compounds are used to treat mental health disorders. In some embodiments, the disclosed compounds are administered, for example, in a therapeutically effective amount, to a subject with a mental health disorder, thereby treating the mental health disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects in the treatment of mental health disorders. In some embodiments, the disclosed compounds and compositions are used to alleviate symptoms of mental health disorders. The symptoms of a mental health disorder to be treated can be determined by those skilled in the art by referring to the general understanding in the art of the disorder.

[0243] In some embodiments, measures of treatment effectiveness include subject or observer reports. In some embodiments, measures of treatment effectiveness include responses to questionnaires. Non-limiting representative examples of applicable measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), the Montgomery-Asberg Depression Rating Scale (MADRS), the Global Assessment of Functioning (GAF) scale, the Clinical Global Impression (CGI), the Substance Abuse Questionnaire (SAQ), the Mini-International Neuropsychiatric Interview 5 (MINI 5), the Columbia-Suicide Severity Rating Scale (C-SSRS), the Patient Health Questionnaire (PHQ-9), the Pittsburgh Sleep Quality Index (PSQI), the Interpersonal Reactivity Index (IRI), the Short Form (36) Health Survey (SF-36), the Self-Compassion Scale (SCS), the Trauma History Questionnaire (THQ), the Beck Depression Index (BDI), and related subject or observer-reported measures.

[0244] In some embodiments, the disclosed compounds are used to treat neurodevelopmental disorders. In some embodiments, a "neurodevelopmental disorder" is a neurological and / or cognitive disorder that occurs during development and involves significant difficulties in the acquisition and performance of a particular neurological function (e.g., intellectual, motor, language, or social function). In some embodiments, the neurodevelopmental disorder is intellectual developmental disorder, developmental speech or language disorder, autism spectrum disorder, developmental learning disorder, developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.

[0245] In some embodiments, the disclosed compounds are used to treat schizophrenia or another primary psychotic disorder. Generally, these disorders are characterized by a significant disturbance in reality and altered behavior, manifested as the experience of positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking and speech, and markedly disorganized behavior, as well as negative symptoms such as blunted or flattened affect, decreased motivation, and psychomotor impairment. In some embodiments, the disclosed compounds are used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or substance-induced psychotic disorder.

[0246] In some embodiments, the disclosed compounds are used to treat catatonia. In some embodiments, "catatonia" refers to a category of syndromes characterized by the simultaneous occurrence of several symptoms of reduced, increased, or abnormal psychomotor activity. In some embodiments, catatonia is associated with another psychiatric disorder. In some embodiments, catatonia is substance- or drug-induced.

[0247] In some embodiments, the disclosed compounds are used to treat mood disorders. As defined by ICD-11, mood disorders are classified according to the specific type of mood episode and its pattern over time. The main types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. In some embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar 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 embodiments, the depressive disorder is a single-episode depressive disorder, a major depressive episode disorder, a persistent depressive disorder (formerly known as dysthymia), a disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, a substance / drug-induced depressive disorder, a depressive disorder due to another medical condition, seasonal affective disorder, a mixed depressive anxiety disorder, or an unspecified depressive disorder. In embodiments, depression is assessed by 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 (BDI-II), the Zung Self-Rating Depression Scale (SDS), the Major Depression Inventory (MDI), the Center for Epidemiological Studies Depression Rating Scale (CED-D), the Rome Depression Rating Scale (RDI), the Hamilton Depression Rating Scale (HRSD), and the Carroll Depression Rating Scale (CRS).

[0248] In some embodiments, the disclosed compounds are used to treat anxiety or fear-related disorders. "Anxiety disorders" refers to a class of mental disorders that induce excessive or abnormal fear, anxiety, or worry. In some embodiments, the anxiety disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or substance-induced anxiety disorder.

[0249] In some embodiments, the disclosed compounds are used to treat obsessive-compulsive disorder or related disorders. Generally, these disorders are characterized by repetitive thoughts and behaviors, such as cognitive phenomena (obsessions, intrusive thoughts, and preoccupations). In some embodiments, the disorder is characterized by a compulsive need to accumulate possessions and distress related to discarding those possessions (i.e., hoarding disorder). In some embodiments, the disorder can be body-focused and characterized by repetitive and addictive behaviors (hair pulling, skin picking). In some embodiments, the disorder is obsessive-compulsive disorder, body dysmorphic disorder, olfactory reference disorder, hypochondriasis, hoarding disorder, body-focused repetitive behavior disorder, or substance-induced obsessive-compulsive disorder.

[0250] In some embodiments, the disclosed compounds are used to treat stress-related disorders. In some embodiments, stress-related disorders have an identifiable causative stressor, such as exposure to a stressful or traumatic event or series of such events or adverse experiences. The stressor may be within the realm of normal life experiences (e.g., divorce, socioeconomic problems) or may result from a threatening or traumatic experience. Generally, the nature and duration of symptoms occurring in response to the stressor distinguish the disorder from everyday stress. In embodiments, the disclosed compounds are used to treat post-traumatic stress disorder, complex post-traumatic stress disorder, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited interpersonal interaction disorder.

[0251] In some embodiments, the disclosed compounds are used to treat dissociative disorders. Dissociative disorders can be characterized by the involuntary interruption or cessation of one or more of the normal integration of identity, sensation, perception, emotion, thought, memory, motor control, or behavior. In some subjects, the symptoms of dissociative disorders can be severe, causing impairment in personal, social, educational, occupational, or other areas of functioning. In some embodiments, the disclosed compounds are used to treat dissociative neurological symptoms disorder, dissociative amnesia (including amnesia with dissociative fugue and amnesia without dissociative fugue), trance disorder, possession trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization-derealization disorder.

[0252] In some embodiments, the disclosed compounds are used to treat eating behavior disorders or eating disorders. Eating behavior disorders or eating disorders generally involve abnormal eating or eating behaviors that are not explained by another health condition, developmentally inappropriate, or culturally unacceptable. These disorders may involve a preoccupation with food and concerns about weight and body shape. In embodiments, the disclosed compounds are used to treat anorexia nervosa (including severely underweight anorexia, dangerously underweight anorexia, or normal-weight recovering anorexia), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination reflux disorder.

[0253] In some embodiments, the disclosed compounds are used to treat elimination disorders, including, for example, repeated urination into clothing or bed and repeated elimination of feces in inappropriate locations in individuals who have reached the developmental age at which bladder and bowel control is normally expected. In embodiments, the disclosed compounds are used to treat enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or fecal incontinence (including both fecal incontinence with and without constipation or overflow fecal incontinence).

[0254] In some embodiments, the disclosed compounds are used to treat bodily pain or bodily experience disorders. Bodily pain disorders typically involve bodily symptoms that cause the subject distress and to which the subject pays excessive attention. Bodily integrity discomfort generally involves a disturbance in an individual's bodily experience, manifested by persistent discomfort or strong feelings about the shape of the body. In some embodiments, the disclosed compounds are used to treat bodily pain disorders (including mild, moderate, and severe bodily pain disorders) or bodily integrity discomfort.

[0255] In some embodiments, the disclosed compounds are used to treat substance use or addictive behavior disorders. Substance use or addictive behavior disorders are mental and / or behavioral disorders that primarily result from the use of psychoactive substances (including pharmaceuticals and illegal or illicit substances) or as a result of specific repetitive rewarding and reinforcing behaviors. 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 cathinones, caffeine), hallucinogens, nicotine, volatile inhalants, dissociative drugs such as MDMA or MDA, ketamine, and phencyclidine, or another substance (including drugs and non-psychoactive substances). In some embodiments, the substance use disorder is selected from 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 an alcohol use disorder, and said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism.In some embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorder, gaming disorder). In some embodiments, substance use disorders can be screened using the Brief Screening for Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and Other Drugs (BSTAD), Tobacco, Alcohol, Prescription Drug, and Other Substance Use (TAPS), Opioid Risk Tool-OUD (ORT-OUD) chart, Drug Abuse Screening Test (DAST-10), and Tobacco, Alcohol, Prescription Drug, and Other Substance Use (TAPS).

[0256] In some embodiments, the disclosed compounds are used to treat impulse control disorders. Generally, impulse control disorders are characterized by a recurrent inability to resist urges, desires, or cravings to perform rewarding behaviors, despite long-term adverse consequences, such as harm to the subject or significant impairment in important areas of the subject's function. In some embodiments, impulse control behaviors include firefighting, theft, inappropriate sexual behavior, and violent emotional outbursts. In some embodiments, the disclosed compounds are used to treat pyromania, kleptomania, obsessive-compulsive behavior disorder, or intermittent explosive disorder.

[0257] In some embodiments, the disclosed compounds are used to treat disruptive behavior disorders or antisocial disorders. Such disorders can be broadly characterized by persistent behavioral problems, ranging from persistently defiant, disobedient, defiant, or malicious behavior to behaviors that violate the rights of others or norms, rules, or laws. In some embodiments, the disclosed compounds are used to treat 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 behavior disorder (including childhood-onset conduct and antisocial behavior disorder and adolescent-onset conduct and antisocial behavior disorder).

[0258] In some embodiments, the disclosed compounds are used to treat personality disorders.Personality disorders can generally be characterized by problems with perceiving one's own identity, self-worth, self-perception accuracy, and self-discipline, which manifest in patterns of cognition, emotional experience, emotional expression, and maladaptive behavior.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, controlling, borderline patterns). In some embodiments, the personality disorder is antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, masochistic or sadistic behavior, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, psychopathy, sociopathy, schizoid personality disorder, or schizotypal personality disorder.

[0259] In some embodiments, the disclosed compounds are used to treat paraphilia disorders. Paraphilia disorders can be characterized by persistent and intense patterns of atypical sexual arousal, the focus of which involves others who are unwilling or unable to consent due to their age or status. In some embodiments, the disclosed compounds are used to treat exhibitionism disorder, voyeurism disorder, pedophilic disorder, compulsive sexual sadism disorder, voyeurism disorder, other paraphilia disorders involving non-consenting individuals, or paraphilia disorders involving solitary or consenting individuals.

[0260] In some embodiments, the disclosed compounds are used to treat factitious disorder. Generally, factitious disorder can be characterized by intentionally misrepresenting, misrepresenting, inducing, or exacerbating medical, psychological, or behavioral signs and symptoms, or harm to oneself or others. Subjects with factitious disorder may seek treatment or otherwise present themselves or others as having an illness, injury, or disorder. In embodiments, the disclosed compounds are used to treat self-imposed factitious disorder or other-imposed factitious disorder.

[0261] In some embodiments, the disclosed compounds are used to treat neurocognitive disorders. Neurocognitive disorders may be characterized by a primary clinical deficit in acquired (as opposed to developmental) cognitive function, such that the subject experiences a decline from a previously achieved level of functioning. In some embodiments, the disclosed compounds are used to treat delirium. In some embodiments, the delirium is associated with another disease or disorder. In some embodiments, the delirium is associated with psychoactive substances (including drugs and illicit or illegal substances). In some embodiments, the disclosed compounds are used to treat mild neurocognitive disorders. In some embodiments, the disclosed compounds are used to treat amnesic disorders. In some embodiments, the amnesic disorder is associated with another disease or disorder. In some embodiments, the delirium is associated with psychoactive substances (including drugs and illicit or illegal substances). In some embodiments, the disclosed compounds are used to treat dementia. In some embodiments, the dementia is associated with Alzheimer's disease, Parkinson's disease, cerebrovascular disease, Lewy body disease, or psychoactive substances (including drugs and illicit or illegal 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 Activities Questionnaire (FAQ), Dementia Assessment 8 (AD8), Mini-Cog, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).

[0262] 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 pregnancy or postpartum period associated syndrome is accompanied by significant mental and behavioral features, including depression. 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 that are 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 that are not accompanied by psychotic symptoms.

[0263] In some embodiments, the disclosed compounds are used to treat sleep-wake disorders. Sleep-wake disorders generally involve difficulty initiating or maintaining sleep (e.g., insomnia), excessive sleepiness (e.g., hypersomnia), breathing disorders during sleep (e.g., obstructive sleep apnea (OSA), central sleep apnea (CSA), sleep-related hypoventilation disorder, sleep-related hypoxemia disorder, snoring, catatonia, Cheyne-Stokes respiration, and sleep-disordered breathing (SRBD)), disturbances in sleep-wake schedules (e.g., circadian rhythm sleep-wake disorders), abnormal movements during sleep, or behavioral or psychological events occurring during sleep onset, during sleep, or awakening from sleep (e.g., parasomnia). In some embodiments, the disclosed compounds are used to treat insomnia disorder, hypersomnia disorder, sleep-related breathing disorder, circadian rhythm sleep-wake disorder, or parasomnia.

[0264] In some embodiments, the disclosed compounds are used to treat sexual dysfunction. Sexual dysfunction can be defined as a syndrome in which a subject may have difficulty experiencing personally satisfying non-coercive sexual activity. In some embodiments, the disclosed compounds are used to treat sexual dysfunction associated with hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, ejaculation disorder, or pelvic organ prolapse.

[0265] In some embodiments, the disclosed compounds or compositions thereof are used in cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry 1999;56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009;23(1):168-174), contingency management-based therapy (e.g., as described in Psychol Addict Behav 2009;23(1):168-174, J Consul Clin Psychol 2005;73(2):354-59; or In Case Reports in Psychiatry, Vol. 2012, Article ID 731638), motivational interviewing-based therapy (e.g., as described in J Consul Clin Psychol 2001;69(5):858-62), meditation-based therapy, such as transcendental meditation-based therapy (e.g., as described in J Consul Clin Psychol 2000;68(3):515-52), or the treatment approaches used by MAPS to treat patients with PTSD (such as those described in Mithoefer, M(2017).Manual for MDMA-Assisted Psychotherapy in the Treatment of Post-Traumatic Stress Disorder), and are administered in conjunction with psychotherapy, such as psychosocial or behavioral therapy, including (or adapted from) any of these.

[0266] In some embodiments, the disclosed compounds and compositions can be administered in combination with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is not necessary or desirable, or no particular type of psychotherapy is necessary or desirable, but any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in a particular therapy and to choose between any such therapies (or decide to discontinue any particular therapy) while still receiving clinically significant therapeutic benefits is one advantage of the present invention. Furthermore, patients can participate in a number of other therapeutically beneficial activities. Such participation can occur after or in conjunction with administration of the composition, including breathing exercises, meditation and concentration exercises, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or interacting with pets or animals. It should be understood that such participation can occur with or without the participation or guidance of a therapist.

[0267] In some embodiments, the "psychotherapy" specifically refers to "psychedelic-assisted psychotherapy." Psychedelic-assisted psychotherapy broadly includes a variety of related approaches involving at least one session in which a patient takes a psychedelic drug and, while under the influence of the drug, is monitored, supported, or otherwise involved by one or more trained mental health professionals (see, e.g., Schenberg 2018). Protocols have been developed to standardize procedures that emphasize a high 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).

[0268] In some embodiments, psychotherapy using the disclosed compounds is conducted in widely spaced sessions. These sessions can occur as frequently as weekly, but are often conducted approximately once a month or less frequently. In most cases, a small number of sessions, approximately one to three, are required for a patient to experience significant clinical progress, as indicated, for example, by a reduction in symptoms of the mental health disorder being treated. In some embodiments, psychotherapy involves multiple sessions, some of which involve the administration of the disclosed compounds ("medication-assisted psychotherapy"); in other embodiments, patients participate in psychosocial or behavioral therapy without the co-administration of medications or without the administration of the disclosed compounds.

[0269] In some embodiments, the disclosed compounds or compositions are administered in conjunction with standardized psychological treatment or support, which refers to any accepted modality of standard psychotherapy or counseling sessions, either in person or virtually (e.g., via telemedicine or using a web program or mobile application), once a week, twice a week, or as needed, by a human therapist or a virtual or AI "therapist." As used herein, "therapist" refers to a person who treats a patient using the disclosed compositions and methods, regardless of whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, although it will be understood that certain requirements apply to certain aspects of medication-assisted therapy (e.g., prescribing, dispensing, or administering medications, providing psychotherapeutic support). In some embodiments, "person" can also include AI.

[0270] In some embodiments, if a 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 a claimed embodiment of the present disclosure, the patient will participate in a treatment protocol or disclosed method or be administered a composition of the present invention as part of such a method.

[0271] Preferably, when the disclosed pharmaceutical compositions are administered, such administration occurs without or with reduced risk of side effects requiring medical supervision, thus allowing treatment at home or otherwise outside of a clinic without the need for such supervision and / or without the need for additional adjunctive psychological therapy (although this may also be provided in certain embodiments herein).

[0272] In some embodiments, the disclosed compositions can be administered in combination with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is not necessary or desirable, or no particular type of psychotherapy is necessary or desirable, but any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in a particular therapy, as well as the flexibility to choose between any such therapies (or decide to discontinue any particular therapy) while still receiving clinically significant therapeutic benefits, is one advantage of the present invention. Furthermore, patients can participate in numerous other therapeutically beneficial activities. Such participation can occur after or in conjunction with administration of the composition, including breathing exercises, meditation and concentration exercises, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or interacting with pets or animals. It should be understood that such participation can occur with or without the participation or guidance of a therapist.

[0273] In some cases, specific individualized approaches (i.e., "personalized" or "precision" medicine) may be utilized based on individual characteristics, including drug metabolism (e.g., CYP2D6, or CYP3A4) or individual genetic variations. The term "genetic variation" refers to a change in a gene sequence compared to a reference sequence (e.g., a commonly occurring sequence and / or a wild-type sequence). Genetic variations can be mutations, such as recombination events or substitution / deletion / insertion events, e.g., point mutations and splice site mutations.

[0274] In some embodiments, the genetic variation affects drug metabolism, including metabolism of the disclosed compositions, and is a genetic variation 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, CYP4F9, CYP4F10, CYP4F11, CYP4F12, CYP4F13, CYP4F14, CYP4F15, CYP4F16, CYP4F17, CYP4F18, CYP4F19 ... P4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0275] In some embodiments, the disclosed compositions are taken with compounds that are metabolized by the same one or more CYP enzymes as the disclosed compositions to allow for lower dosage intake, increase the effective bioavailability of one or both, or affect drug metabolism or pharmacokinetics. In some embodiments, the dose of the disclosed compositions is adjusted, such as decreased when administered to subjects known to be poor metabolizers of the active compounds in the composition (e.g., with genetic variations in CYP2D6 and / or CYP3A4) or increased when administered to subjects known to be extensive metabolizers. In some embodiments, patients are tested using routine means known to those skilled in the art to determine whether they are extensive or extensive metabolizers of one or more such CYP enzymes.

[0276] In some embodiments, the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which is involved in mood and anxiety symptoms in humans. In another embodiment, the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene, which 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 compounds. In some embodiments, the genetic variation is an exclusion criterion for administration of the disclosed compounds.

[0277] In some embodiments, the treated mammal has altered epigenetic regulation of a gene whose expression is associated with a mental health condition or susceptibility to a mental health treatment, such as, for example, the SIGMAR1 gene for the non-opioid sigma-1 receptor.

[0278] ii. Neurodegenerative disorders In some embodiments, the disclosed compounds are used to treat neurodegenerative disorders. In some embodiments, the disclosed compounds are administered to a subject with a neurodegenerative disorder, for example, in a therapeutically effective amount. In some methods described herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects in the treatment of neurodegenerative disorders.

[0279] The term "neurodegenerative disorder" refers to a class of progressive, chronic, and debilitating conditions characterized by the gradual loss of structure and function of neurons within the central nervous system (CNS) or peripheral nervous system (PNS). These disorders involve the degeneration, impairment, or death of nerve cells, resulting in a decline in cognitive, motor, and / or sensory abilities.

[0280] Neurodegenerative disorders can be classified according to primary 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 the primary molecular abnormality (Dugger B, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology. 2017:9(7);a028035). These disorders may be associated with 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).

[0281] In some embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis or Charcot's disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia including vascular dementia, Huntington's disease, Ritiko-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.

[0282] iii. Pain disorders In some embodiments, the disclosed compounds are used to treat pain disorders. In some embodiments, the disclosed compounds are administered to a subject with a pain disorder, e.g., in a therapeutically effective amount. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide a beneficial therapeutic effect in treating pain disorders.

[0283] "Pain disorder" refers 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 be of various etiologies, including, but not limited to, nociceptive, neuropathic, psychogenic, idiopathic, or radicular origin. In embodiments, the compounds are used to treat neuropathic pain. In embodiments, the compounds are used to treat psychogenic pain. In embodiments, the compounds are used to treat idiopathic pain. In embodiments, the compounds are used to treat radicular pain.

[0284] Pain disorders can manifest as acute or chronic pain and can affect various parts of the body, such as the musculoskeletal, nervous, gastrointestinal, or visceral systems. Pain can manifest as, but is not limited to, postherpetic pain, trigeminal neuralgia, posterior headache, or pubic pain. In embodiments, the disclosed compounds are used to treat pain associated with chemotherapy (e.g., chemotherapy-associated 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.

[0285] In some embodiments, pain is assessed using the Pain, Enjoyment, and General Activity Scale (PEG), Numerical Rating Scale (NRS), Visual Analog Scale (VAS), Behavioral Pain Scale (BPS), and Facial Pain Scale-Revised (FPS-R).

[0286] iv. Inflammatory diseases Inflammation is a key immune response to tissue injury, such as microbial infection, acute injury, chemical irritant, or other dysregulation of normal tissue function. The inflammatory process is a hallmark of the innate immune system, whereby molecular patterns of tissue damage are recognized and responded to by various inflammatory substances, such as cytokines and chemokines. These inflammatory substances act directly to remove harmful stimuli and initiate various signaling responses to restore damaged tissue to a homeostatic state. While this response is often self-terminating, resolution of inflammation can fail for multiple reasons, prolonging the inflammatory response to a chronic stage (Ahmed AU. Front Biol. 2011:6(4):274-281). Chronic inflammation is often associated with or underlies a variety of pathological conditions, including major cardiovascular and neuropsychiatric disorders (Nichols CD. Cardiovasc Psychiatry Neurol 2009:475-108).

[0287] Recent evidence supports the role of 5-HT in mediating the termination of the inflammatory response. 2A This suggests a significant role for serotonin receptor subtypes. 2A Receptors are found throughout the body, including 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 hallucinogen compounds, and has been implicated in the mechanisms underlying neuropsychiatric disorders such as schizophrenia (Nichols CD. Cardiovasc Psychiatry Neurol. 2009;475108). 2AReceptors are found in multiple immune-related tissues, such as the spleen, thymus, and circulating lymphocytes, as well as 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 in these tissues 2A Research on receptors has shed light on their role in regulating immune responses (Flanagan TW, Nichols CD. Int Rev Psychiatry. 2018 Aug;30(4):363-375).

[0288] 5-HT in the brain 2A Due to its significant action on the psychedelic compound 5-HT 2A Several studies have been conducted to evaluate the effects of receptors on inflammation regulation. One such study found that (R)-2,4-dimethoxy-4-iodoamphetamine ((R)-DOI) could potently suppress TNF-α-induced inflammation. This study also found that the psychedelic compounds 2C-BCB, LA-SS-Az, and LSD induced the same effect, albeit with slightly less potency (Yu et al., J Pharmacol Exp Ther. 2008;327:316-323). Notably, the potency required to achieve the anti-inflammatory effects of some psychedelic compounds is in the low picomolar range, which is approximately 500 times more potent than conventional corticosteroids at their target. Anti-inflammatory doses of psychedelics may also be below the threshold for producing subjective or behavioral effects, meaning they may exhibit anti-inflammatory effects without causing a psychedelic "trip."

[0289] This study, as well as subsequent in vitro and in vivo studies, demonstrated that (R)-DOI inhibited TNF-α-induced expression of genes encoding intercellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), the proinflammatory cytokines IL-6 and IL-1β, and the chemokine monocyte chemoattractant protein-1 (MCP1). (R)-DOI also blocked NF-κB activation and nuclear translocation, nitric oxide synthase activity, and downregulated the 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 psychedelic compounds potently suppress selected important pro-inflammatory biomarkers while leaving others unaffected. For biomarkers where suppression is evident, the suppression is so potent that even relatively high drug doses do not suppress below baseline levels, returning levels to baseline (Nichols CD. Neuropharmacol. 2022;219:109232). Thus, some psychedelics can reduce the expression of certain important inflammatory components without significantly impairing the immune response. This mechanism of action is unique among known anti-inflammatory and immunomodulatory agents and may be advantageous because it predicts fewer side effects, such as opportunistic infections, associated with broad-spectrum immunosuppressants such as corticosteroids (ibid.).

[0290] Psychedelics have therapeutic potential as anti-inflammatory drugs, but there is considerable variability in the efficacy of different psychedelics. Due to the diversity of chemical structures among psychedelics, 5-HT 2AIt has been hypothesized that functional selectivity at receptors may occur, whereby specific ligands engage specific subsets of amino acid residues within the receptor's binding pocket, inducing stable conformational states that bind to different anti-inflammatory signaling effectors. This hypothesis is supported by the distinct peripheral effects of (R)-DOI and (R)-DOTFM, the former inducing anti-inflammatory effects in a mouse asthma model, whereas the latter does not (Flanagan et al., ACS Pharmacol Transl Sci. 2024). This finding is consistent with the findings of the anti-inflammatory phenethylamine 5-HT 2A This confirms previous studies 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 relationships of anti-inflammatory agents with receptor agonist properties remain unclear.

[0291] In some embodiments, the disclosed compounds are potent anti-inflammatory agents that act on specific inflammatory mediators, thereby restoring chronically inflamed tissues to a healthy state. In some embodiments, the anti-inflammatory effects are exerted without broadly suppressing the immune system, which may be beneficial for treating inflammatory diseases where steroids are contraindicated or the condition is steroid-resistant.

[0292] In some embodiments, the disclosed compounds reduce an 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 an 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, where the increase indicates increased expression of the inflammatory response gene encoding the biomarker. In some embodiments, increased expression of an inflammatory response gene can be associated with chronic inflammation. In some embodiments, decreased expression of an inflammatory response gene can be associated with chronic inflammation.

[0293] 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. Without being bound by theory, the disclosed compounds may inhibit 5-HT 2A Compounds may exert their anti-inflammatory effects due to functional selectivity at the receptor, whereby they engage specific amino acid residues within the receptor and stabilize it in a conformation that triggers anti-inflammatory signaling pathway effectors.

[0294] In some embodiments, the biomarker of inflammatory response gene expression is mRNA. In some embodiments, the biomarker of 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. An inflammatory substance is a protein that activates an inflammatory response. Inflammatory substances include, for example, 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. Anti-inflammatory agents include, for example, 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 pro-inflammatory or anti-inflammatory. For example, leukemia inhibitory factor, interferon-α, IL-6, and transforming growth factor (TGF-β) can act as either a pro-inflammatory cytokine or an anti-inflammatory cytokine under various circumstances (Zhang JM, An J. Int Anesthesiol Clin. 2007 Spring;45(2):27-37).

[0295] In some embodiments, the inflammatory response gene is ICAM1. In some embodiments, the biomarker for an inflammatory response is an 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 an inflammatory response is a 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 an inflammatory response is an 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 an inflammatory response is an 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 an inflammatory response is an IL-6 gene product. In some embodiments, the biomarker is IL-6 mRNA. In embodiments, the biomarker is IL-6 protein.

[0296] In some embodiments, the inflammatory response gene is IL-9. In some embodiments, the biomarker for an inflammatory response is an 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 an inflammatory response is an 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 an inflammatory response is an 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 an inflammatory response is an Arg-1 gene product. In some embodiments, the biomarker is Arg-1 mRNA. In some embodiments, the biomarker is Arg-1 protein.

[0297] In some embodiments, the inflammatory response gene is Gm-csf. In some embodiments, the biomarker for an inflammatory response is a 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 an inflammatory response is a 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 an inflammatory response is an 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 an inflammatory response is a TGF-β gene product. In some embodiments, the biomarker is TGF-β mRNA. In some embodiments, the biomarker is TGF-β protein.

[0298] In some embodiments, the inflammatory response biomarker is a cytokine. Cytokines are small signaling proteins that coordinate the interactions of various cell types involved in amplifying and regulating 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 to sites of tissue injury. In some embodiments, the chemokine biomarker is CCL-1 through CCL-28, CXCL-1 through 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 particular inflammatory diseases, comorbidities, or patient attributes will be known to those of skill in the art (see Sreedhar R, et al., General Mechanisms of Immunity and Inflammation. In: Watanabe K & Arumugam S. eds. Japanese Kampo medicines for the treatment of common diseases: Focus on inflammation. Academic Press; 2017: Chapter 3; Germolec DR et al., Markers of Inflammation. Methods Mol Biol. 2018; 1803:57-79; Calder PC et al., Br J Nutr. 2013 Jan; 109 Suppl 1:S1-34).

[0299] In some embodiments, the disclosed compounds bring the level of inflammatory response biomarkers in subjects closer to baseline levels. "Baseline levels" refer to the levels of biomarkers observed in healthy populations that do not experience inflammation. Baseline levels vary depending on the biomarker and are known to those skilled in the art or can be measured by standard techniques (Calder PC et al., Br J Nutr. 2013 Jan;109 Suppl 1:S1-34).

[0300] In some embodiments, the disclosed compounds reduce the level of an inflammatory biomarker. In some embodiments, the disclosed compounds do not reduce the level of an inflammatory biomarker below baseline. In some embodiments, the disclosed compounds reduce the level of an inflammatory biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, the disclosed compounds reduce the level of an inflammatory biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) to within about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of its baseline level. In some embodiments, 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, it is a plasma sample.

[0301] In some embodiments, the disclosed compounds increase the level of an anti-inflammatory biomarker. In some embodiments, the disclosed compounds do not elevate the level of a pro-inflammatory biomarker above baseline. In some embodiments, the disclosed compounds increase the level of a pro-inflammatory biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, 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.

[0302] In some embodiments, the dosage of the disclosed compounds used to elicit an anti-inflammatory effect is sub-behavioral. In some embodiments, the disclosed compounds are used at a dosage of about 0.001-0.01 mg / kg, about 0.01-0.05 mg / kg, about 0.05 mg / kg-0.1 mg / kg, about 0.1 mg / kg-0.2 mg / kg, about 0.4 mg / kg-0.3 mg / kg, about 0.3 mg / kg-0.4 mg / kg, or about 0.4 mg / kg-0.5 mg / kg to elicit an anti-inflammatory effect.

[0303] 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 in the manufacture of a medicament for treating inflammatory diseases or reducing inflammation.

[0304] 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.

[0305] In some embodiments, the disclosed compounds are useful for treating inflammatory conditions in patients with autoimmune disorders or other immune-compromised conditions. 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.

[0306] 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 disease or disorder is steroid-resistant nephrotic syndrome (SRNS), steroid-resistant inflammatory bowel syndrome (IBS), steroid-resistant asthma, steroid-resistant acute graft-versus-host disease, steroid-resistant ulcerative colitis, steroid-resistant Crohn's disease, steroid-resistant chronic obstructive pulmonary disease (COPD), steroid-resistant pulmonary fibrosis, steroid-resistant leukemia, steroid-resistant rheumatoid arthritis, or steroid-resistant idiopathic nephropathy.

[0307] 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 the corticosteroid formulation, coadministration of live or attenuated live vaccines (e.g., when immunosuppressive doses are used), systemic fungal infection, osteoporosis, uncontrolled hyperglycemia, adrenal suppression, Cushing's syndrome, diabetes, glaucoma, cataracts, joint infections, uncontrolled hypertension, herpes simplex keratitis, myopathy, certain mental disturbances and / or psychiatric disorders, and chickenpox infection. Further exemplary contraindications include peptic ulcer disease, congestive heart failure, and viral or bacterial infections uncontrolled by anti-infective or antibacterial agents.

[0308] In embodiments, the disclosed compounds are useful for treating skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, bladder inflammation, stomach inflammation, intestinal inflammation, nerve inflammation, eye inflammation, and brain inflammation.

[0309] In some embodiments, the inflammatory disease is any of acne vulgaris, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis including osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathies such as ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteroarthritis associated with inflammatory bowel disease, Whipple's disease and Behcet's disease, septic arthritis, gout (also known as gouty arthritis, crystalline synovitis, and 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).

[0310] In some embodiments, the inflammatory disease is any of long COVID syndrome, food allergy, post-Lyme disease 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 disease including hypertension, endocarditis, myocarditis, heart valve dysfunction, congestive heart failure, myocardial infarction, diabetic heart abnormalities, vascular inflammation (including arteritis, phlebitis, and vasculitis); arterial blockage including arteriosclerosis and stenosis. inflammatory cardiac hypertrophy, peripheral arterial disease, aneurysm, embolism, dissection, pseudoaneurysm, vascular malformation, 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.

[0311] In some embodiments, the inflammatory disease is a dermatitis disorder. Without being bound by theory, dermatitis refers to skin inflammation that can occur chronically due to skin barrier dysfunction, abnormal inflammatory response, and persistent itching (Nakahara T et al., J Dermatol. 2021; 48(2): 130-139; Beck LA et al., JID Innov. 2022; 2(5): 100131). Commonalities among dermatitis disorders include redness, persistent itching, and dry skin, but the clinical phenotypes of dermatitis disorders are highly heterogeneous, reflecting the diversity and complexity of the underlying mechanisms that lead to the disorder (Renert-Yuval Y et al., J Allergy Clin Immunol. 2021; 147(4): 1174-1190.e1). Many of the inflammatory substances involved in chronic inflammation are also involved in the inflammatory response to dermatitis disorders, including, but not limited to, CCL17, CCL18, CCL22, CCL27, IL-4, IL-13, IL-17A, IL-18, IL-19, IL-22, IL-26, IL-33, MMP12, and Th2 (Ahn K et al., Curr Opin Immunol. 2020;66:14-21; Renert-Yuval Y et al., J Allergy Clin Immunol. 2021;147(4):1174-1190.e1; Furue M et al., Iran J Immunol. 2019;16(2):97-107; Sroka-Tomaszewska J, Trzeciak M. Int J Mol Sci. 2021;22(8):4130; Fallon et al., Nat Genetics, 2009, 41:602-608). Effective treatments for dermatitis disorders often target inflammatory pathways, thereby modulating the inflammatory response and improving the symptoms of dermatitis disorders (Wollenberg A et al., Br J Dermatol. 2014;170 Suppl 1:7-11).

[0312] In some embodiments, the inflammatory disease is a dermatitis disorder including atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic eczema, discoid eczema, varicose eczema, herpetic dermatitis, neurodermatitis, autosensitization dermatitis, stasis dermatitis, suppurative dermatitis, dyshidrotic eczema, follicular eczema, spongiotic dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

[0313] In some embodiments, the dermatitis disorder is atopic dermatitis. In some embodiments, the dermatitis disorder is chronic photosensitive dermatitis. In some embodiments, the dermatitis disorder is eczema. In some embodiments, the dermatitis disorder is atopic eczema. In some embodiments, the dermatitis disorder is contact eczema. In some embodiments, the dermatitis disorder is dry eczema. In some embodiments, the dermatitis disorder is seborrheic eczema. In some embodiments, the dermatitis disorder is discoid eczema. In some embodiments, the dermatitis disorder is varicose eczema. In some embodiments, the dermatitis disorder is herpetic dermatitis. In some embodiments, the dermatitis disorder is neurodermatitis. In some embodiments, the dermatitis disorder is herpetic dermatitis. In some embodiments, the dermatitis disorder is autosensitized dermatitis. In some embodiments, the dermatitis disorder is stasis dermatitis. In some embodiments, the dermatitis disorder is suppurative dermatitis. In some embodiments, the dermatitis disorder is dyshidrotic eczema. In some embodiments, the dermatitis disorder is follicular eczema. In some embodiments, the dermatitis disorder is spongiotic dermatitis. In some embodiments, the dermatitis disorder is hand dermatitis. In some embodiments, the dermatitis disorder is diaper dermatitis. In some embodiments, the dermatitis disorder is occupational contact dermatitis. In some embodiments, the dermatitis disorder is lichen planus-like atopic dermatitis.

[0314] In some embodiments, the inflammatory disease is atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic eczema, dyshidrosis, discoid eczema, venous eczema, herpetic dermatitis, neurodermatitis, and autosensitized dermatitis, stasis dermatitis, miliaria suppurativa, lichen planus, dermatitis including psoriasis (including plaque psoriasis), nail psoriasis, pruritic psoriasis, scalp psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis; rosacea, scleroderma (including morphea); pharmacologically induced eczema, including those caused by legal or illegal drugs and chemicals. chronic neurogenic inflammation, including primary and 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, heart valve dysfunction, hepatitis, pyogenic spondylitis, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infections (lymphangitis, lymphadenitis, bacterial cystitis, bacterial encephalitis, pandemic influenza) encephalitis, viral encephalitis, viral hepatitis (including types A, B, and C); inflammatory bowel disease including Crohn's disease; inflammatory cardiac hypertrophy, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, ovarian inflammation, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, otitis, pancreatitis, parkinsonism, Son's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, interstitial pneumonia, polycystic nephritis, polymyositis, proctitis, prostatitis, psoriasis, meningitis, portal vein disease, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sepsis (including bacteremia and viremia); sinusitis, spastic colon, strictures, stomatitis, stroke, inflammation associated with surgical complications, synovitis, tendinitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection (including graft-versus-host disease (GVHD));Th1-mediated inflammatory diseases, bladder trigonitis, tuberculosis, tumors, urethritis, bursitis, uveitis, vaginitis, vasculitis (including Buerger's disease, cerebral vasculitis, Churg-Strauss arteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell arteritis, Golfer's vasculitis, Henoch-Schönlein purpura, hypersensitivity vasculitis, Kawasaki disease, microscopic polyarteritis / polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu's arteritis, Wegener's granulomatosis, systemic lupus erythematosus (SLE), relapsing polychondritis, and Behçet's disease); ulcerative colitis, including ulcerative proctitis, left-sided colitis, pancolitis, and fulminant colitis; and vulvitis.

[0315] 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 can be detected from biological specimens, such as a subject's blood, for example, plasma or serum, or saliva. In one example, inflammation can be detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell count from a blood test. CRP can also be detected in saliva samples. Salivary CRP is not synthesized locally in the oral cavity, and may reflect a more systemic level of inflammation compared to other inflammatory biomarkers such as cytokines (Szabo & Slavish, Psychoneuroendocrin. 202;124:105069). In addition, clinical pathology data, such as hematology data on red blood cell parameters, platelet count, total white blood cell count, and white blood cell differentiation and morphology, coagulation data on clotting time and fibrinogen, and clinical chemistry data on total protein, albumin and globulin, liver enzymes, kidney parameters, electrolytes, and bilirubin, can provide an early indication of the presence and potential location of inflammation in the absence of specific data on immune tissues. See, for example, Germolec et al., Methods Mol Biol. 2018;1803:57-79 and Luo et al., Clin Lab. 2019 1;65(3).

[0316] v. Ophthalmological 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 a leading cause 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, resulting in neovascularization and subsequent vision-threatening scarring of the cornea (Vaidyanathan U et al., Med Hypothesis Discov Innov Ophthalmol. 2019;8(3):163-176). Corticosteroids are often used to control ocular inflammatory responses, but this treatment is immunosuppressive and can lead to uncontrolled pathogen replication, loss of an intact corneal epithelial barrier, increased intraocular pressure, and ultimately vision loss (Fung AT et al., Clin Exp Ophthalmol. 2020;48(3):366-401). In contrast, modulation with 5-HT receptor agonists has been shown to have anti-inflammatory and anti-angiogenic properties, as well as the ability to reduce intraocular pressure (Foster T et al., Invest Ophthalmol Vis Sci. 2020;61(7):429).

[0317] In some embodiments, the disclosed compounds can be used to alleviate or ameliorate or prevent ophthalmic diseases or disorders, non-limiting examples of which are described herein.

[0318] In some embodiments, administration of the disclosed compounds reduces intraocular pressure in a subject. In some embodiments, the disclosed compounds are used to treat ocular hypertension. In some embodiments, the disclosed compounds are used to treat glaucoma. In some embodiments, the glaucoma is open-angle glaucoma, normal-tension glaucoma, angle-closure glaucoma, congenital glaucoma, neovascular glaucoma, pigmentary glaucoma, exfoliation glaucoma, uveitis glaucoma, or glaucoma caused by another factor (e.g., cataract, tumor, eye injury).

[0319] In some embodiments, the disclosed compounds are used to treat allergic conjunctivitis, including vernal conjunctivitis and atopic keratoconjunctivitis; dry eye syndrome and meibomian gland dysfunction; cataracts; keratoconus; bullous keratopathy and other keratopathy; Fuchs' endothelial corneal dystrophy; ocular cicatricial pemphigoid; conditions associated with photoreactive keratotomy (PRK) healing and other corneal healing; conditions associated with tear lipid breakdown 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; rosacea with or without meibomian gland dysfunction; post-cataract; persistent corneal erosions; and inflammation associated with corneal trauma, corneal transplants, and refractive surgery.

[0320] In some embodiments, the ophthalmological disease or disorder is an inflammatory disease. In some embodiments, the ophthalmological disease or disorder is macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis, conjunctivitis, keratitis, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber's disease, retinal detachment, retinal pigment epithelium detachment, rubeosis iridis, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinal choroidal neovascularization, or a combination thereof.

[0321] In some embodiments, the ophthalmic disease is macular degeneration. In some embodiments, the ophthalmic disease is keratoconjunctivitis. In some embodiments, the ophthalmic disease is conjunctivitis. In some embodiments, the ophthalmic disease is keratitis. In some embodiments, the ophthalmic disease is diabetic retinopathy. In some embodiments, the ophthalmic disease is retinopathy of prematurity. In some embodiments, the ophthalmic disease is polypoidal choroidal vasculopathy. In some embodiments, the ophthalmic disease is ischemic proliferative retinopathy. In some embodiments, the ophthalmic disease is retinitis pigmentosa. In some embodiments, the ophthalmic disease is cone dystrophy. In some embodiments, the ophthalmic disease is proliferative vitreoretinopathy. In some embodiments, the ophthalmic disease is retinal artery occlusion. In some embodiments, the ophthalmic disease is retinal vein occlusion. In some embodiments, the ophthalmic disease is Leber's disease. In some embodiments, the ophthalmic disease is retinal detachment. In some embodiments, the ophthalmic disease is retinal pigment epithelial detachment. In some embodiments, the ophthalmic disease is rubeosis iridis. In some embodiments, the ophthalmic disease is corneal neovascularization. In some embodiments, the ophthalmic disease is retinal neovascularization. In some embodiments, the ophthalmic disease is choroidal neovascularization. In some embodiments, the ophthalmic disease is retinal choroidal neovascularization.

[0322] I. Examples The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Example 1: Synthesis of 4-(2-hydroxyethyl)-7-methyl-N,N-diethyltryptamine (Compound 2) [ka]

[0323] To a stirred solution of 4-bromo-2-nitrotoluene (3.00 g, 13.9 mmol) in THF (116 mL) cooled to approximately −41 °C in an acetonitrile / dry ice bath, vinylmagnesium bromide (99.2 mL, 41.7 mmol, 0.45 M in THF) was added dropwise, and the reaction was stirred for 12 h and finally warmed to room temperature. Upon completion as determined by TLC, 100 mL of saturated aqueous NH4Cl was poured into the reaction and the layers were separated. The aqueous phase was extracted with ether (3 × 50 mL), and the combined organic layers were dried over sodium sulfate. The mixture was then concentrated under reduced pressure and purified using flash column chromatography (9:1 hexane:EtOAc eluent, silica) to afford 1.22 g (42%) of 4-bromo-7-methyl-1H-indole.

[0324] 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.28 - 7.26 (m, 1H), 7.21 (d, J= 7.6 Hz, 1H), 6.87 (dq, J = 7.6, 0.9 Hz, 1H), 6.62 (dd, J = 3.3, 2.2 Hz, 1H), 2.46 (d, J = 0.9 Hz, 3H). [ka]

[0325] To a stirred solution of 4-bromo-7-methyl-1H-indole (651 mg, 3.10 mmol) and Pd(PPh3)4 (107 mg, 0.093 mmol) in toluene (18.2 mL) was added tributyl(vinyl)tin (1.81 mL, 6.20 mmol) under an inert atmosphere. The mixture was then heated at 110 °C for 12 h. After completion as judged by TLC, the mixture was concentrated under reduced pressure and stirred with 8% w / v aqueous KF solution for 1 h. The mixture was then filtered through Celite, washed with DCM (3 × 75 mL), concentrated under reduced pressure, and purified by flash column chromatography (19:1 hexane:EtOAc to 9:1 hexane:EtOAc eluent, silica) to afford 443 mg (91%) of 4-vinyl-7-methyl-1H-indole.

[0326] 1 H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.30 - 7.24 (m, 1H), 7.19 (d, J= 7.4 Hz, 1H), 7.11 (dd, J = 17.7, 11.1 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.79 (dd, J = 3.3, 2.1 Hz, 1H), 5.87 (dd, J= 17.7, 1.4 Hz, 1H), 5.34 (dd, J = 11.1, 1.4 Hz, 1H), 2.51 (s, 3H). [ka]

[0327] To a solution of 4-vinyl-7-methyl-1H-indole (204 mg, 1.30 mmol) in THF (7.29 mL) was added borane-THF complex (1.30 mL, 1.30 mmol, 1 M in THF) at room temperature. After 1 h, the reaction was complete by TLC, after which hydrogen peroxide (0.477 mL, 7.79 mmol, 50%) and KOH (7.79 mL, 7.79 mmol, 1 M in HO) were added sequentially. After 2 h, the intermediate was consumed by TLC, and the reaction was quenched by the addition of water (10 mL) and saturated aqueous NH4Cl (10 mL). The reaction mixture was then extracted with ethyl acetate (3 × 20 mL) and washed with brine (50 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (4:1 hexane:EtOAc eluent, silica) to afford 147 mg (65%) of 4-(2-hydroxyethyl)-7-methyl-1H-indole.

[0328] 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.16 (t, J = 2.8 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.62 (dd, J = 3.2, 2.0 Hz, 1H), 3.98 (t, J = 6.7 Hz, 2H), 3.18 (t, J = 6.7 Hz, 2H), 2.48 (s, 3H). [ka]

[0329] To a stirred solution of 4-(2-hydroxyethyl)-7-methyl-1H-indole (204 mg, 1.16 mmol) and triethylamine (0.487 mL, 3.49 mmol) in DCM (7.28 mL) was added trimethylacetyl chloride (0.215 mL, 1.75 mmol) and DMAP (142 mg, 1.16 mmol) at room temperature. After 0.5 h, the reaction was determined to be complete by TLC, quenched by the addition of water (3 mL), and extracted with DCM (3 × 10 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (9:1 hexane:EtOAc eluent, silica) to afford 283 mg (94%) of 2-(7-methyl-1H-indol-4-yl)ethyl-2,2-dimethylpropanoate.

[0330] 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.23 (t, J = 2.4 Hz, 1H), 6.94 (dd, J = 7.3, 0.9 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.66 (dd, J = 3.3, 2.0 Hz, 1H), 4.37 (t, J = 7.3 Hz, 2H), 3.20 (t, J = 7.3 Hz, 2H), 2.48 (s, 3H), 1.18 (s, 9H). [ka]

[0331] To a stirred solution of 2-(7-methyl-1H-indol-4-yl)ethyl-2,2-dimethylpropanoate (203 mg, 0.783 mmol) in EtO (3.19 mL) was added a solution of oxalyl chloride (0.068 mL, 0.798 mmol) in EtO (1.00 mL) over 5 min at 0 °C. After 1 h, the reaction was complete by TLC, and diethylamine (0.083 mL, 0.798 mmol) in EtO (4.19 mL) was added dropwise at 0 °C. After stirring for 0.5 h, the reaction was quenched by the addition of CHCl (40 mL), and the organic phase was washed successively with 5% w / v aqueous NaHSO (20 mL), followed by saturated aqueous NaHCO (20 mL), and finally brine (20 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and the crude crystalline product was triturated with EtO to give 188 mg (62%) of 2-(7-methyl-3-[N,N-diethylglyoxylamido]-1H-indol-4-yl)ethyl-2,2-dimethylpropanoate.

[0332] 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 7.93 (d, J = 3.3 Hz, 1H), 7.06 (s, 2H), 4.33 (t, J = 6.4 Hz, 2H), 3.70 (t, J = 6.4 Hz, 2H), 3.55 (q, J = 7.1 Hz, 2H), 3.34 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.16 (s, 9H). [ka]

[0333] To a slurry of lithium aluminum hydride (105 mg, 2.77 mmol) in THF (2.10 mL) was slowly added a solution of 2-(7-methyl-3-[N,N-diethylglyoxylamido]-1H-indol-4-yl)ethyl-2,2-dimethylpropanoate (188 mg, 0.486 mmol) in THF (2.10 mL). The mixture was stirred at 70 °C for 16 h, after which the reaction was determined to be complete by NMR. The mixture was cooled to room temperature, and excess hydride was destroyed by careful addition of wet THF. The solid that formed was removed by filtration and washed with hot THF. The filtrate and washings were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude tryptamine residue was dissolved in EtOAc (0.5 mL), and MeOH (0.1 mL) was added. To this solution was added oxalic acid (43.8 mg, 0.486 mmol) in EtOAc (1.0 mL), and the mixture was cooled to −20° C. overnight. The mother liquor was then decanted, and the precipitate was triturated with EtOAc (5 × 3 mL) to give 150 mg (85%) of the oxalate salt of 4-(2-hydroxyethyl)-7-methyl-N,N-diethyltryptamine (compound 2).

[0334] 1 H NMR (600 MHz, D2O) δ 7.34 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 3.90 (t, J = 7.2 Hz, 2H), 3.52 - 3.47 (m, 2H), 3.38 - 3.30 (m, 6H), 3.23 (t, J = 7.2 Hz, 2H), 2.48 (s, 3H), 1.33 (t, J = 7.3 Hz, 6H).

[0335] HRMS (LC-MS) m / z: [M+H] + C 17 H 26 Calculated N2OH value 275.212338; measured value 275.2146. Example 2: Synthesis of 4-(2-hydroxyethyl)-7-methyl-N,N-dimethyltryptamine (Compound 1) [ka]

[0336] To a stirred solution of 2-(7-methyl-1H-indol-4-yl)ethyl-2,2-dimethylpropanoate (127 mg, 0.490 mmol) in EtO (1.62 mL) was added a solution of oxalyl chloride (0.042 mL, 0.499 mmol) in EtO (1.00 mL) over 5 min at 0 °C. After 1 h, the reaction was complete by TLC, and dimethylamine (0.25 mL, 0.499 mmol, 2 M in THF) was added dropwise at 0 °C. After stirring for 0.5 h, the reaction was quenched by the addition of CHCl (40 mL), and the organic phase was washed successively with 5% w / v aqueous NaHSO (20 mL), followed by saturated aqueous NaHCO (20 mL), and finally brine (20 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and the crude crystalline product was triturated with EtO to give 114 mg (65%) of 2-(7-methyl-3-[N,N-dimethylglyoxylamido]-1H-indol-4-yl)ethyl-2,2-dimethylpropanoate.

[0337] 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 7.89 (d, J = 3.4 Hz, 1H), 7.02 (s, 2H), 4.31 (t, J = 6.4 Hz, 2H), 3.66 (t, J = 6.4 Hz, 2H), 3.08 (s, 3H), 3.00 (s, 3H), 2.46 (s, 3H), 1.13 (s, 9H). [ka]

[0338] To a slurry of lithium aluminum hydride (68.8 mg, 1.81 mmol) in THF (1.44 mL) was slowly added a solution of 2-(7-methyl-3-[N,N-dimethylglyoxylamido]-1H-indol-4-yl)ethyl-2,2-dimethylpropanoate (114 mg, 0.318 mmol) in THF (1.44 mL). The mixture was stirred at 70 °C for 16 h, after which the reaction was determined to be complete by NMR. The mixture was cooled to room temperature, and excess hydride was destroyed by careful addition of wet THF. The solid that formed was removed by filtration and washed with hot THF. The filtrate and washings were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude tryptamine residue was dissolved in EtOAc (0.5 mL), and MeOH (0.1 mL) was added. To this solution was added oxalic acid (28.6 mg, 0.318 mmol) in EtOAc (1.0 mL), and the mixture was cooled to −20° C. overnight. The mother liquor was then decanted, and the precipitate was triturated with EtOAc (5 × 3 mL) to give 42 mg (39%) of the oxalate salt of 4-(2-hydroxyethyl)-7-methyl-N,N-dimethyltryptamine (Compound 1).

[0339] 1 H NMR (600 MHz, D2O) δ 7.28 (s, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 3.84 (t, J = 7.1 Hz, 2H), 3.50 - 3.42 (m, 2H), 3.34 - 3.28 (m, 2H), 3.22 - 3.13 (m, 2H), 2.93 (s, 6H), 2.43 (s, 3H).

[0340] HRMS (LC-MS) m / z: [M+H] + C 15 H 22 Calculated N2OH value 247.181038; measured value 247.1815. Example 3: Synthesis of 4-(2-methoxyethyl)-7-methyl-N,N-dimethyltryptamine (Compound 3) [ka]

[0341] To a stirred solution of 4-(2-hydroxyethyl)-7-methyl-1H-indole (461 mg, 2.63 mmol) in THF (17.5 mL) and triethylamine (1.10 mL, 7.89 mmol) was added dropwise under atmospheric pressure at 0 °C. After 0.5 h, the mixture was complete by TLC and concentrated under reduced pressure. The resulting crude residue was dissolved in DMF (8.75 mL) and added to a slurry of sodium methoxide (4.26 g, 78.9 mmol) in DMF (8.75 mL) at 0 °C. The resulting mixture was stirred for 12 h and was complete by TLC. The reaction was diluted with HO (50 mL), extracted with EtOAc (4 × 50 mL), and washed with brine (6 × 30 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (9:1 hexane:EtOAc eluent, silica) to afford 169 mg (34%) of 4-(2-methoxyethyl)-7-methyl-1H-indole.

[0342] 1 H NMR (600 MHz, CDCl3) δ 8.17 (s, 1H), 7.23 - 7.19 (m, 1H), 6.98 - 6.95 (m, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.63 (ddd, J= 3.0, 2.1, 0.8 Hz, 1H), 3.74 (t, J = 0.9 Hz, 2H), 3.41 (s, 3H), 3.20 (t, J= 7.5 Hz, 2H), 2.48 (s, 3H). [ka]

[0343] To a stirred solution of 4-(2-methoxyethyl)-7-methyl-1H-indole (169 mg, 0.893 mmol) in EtO (3.78 mL) was added a solution of oxalyl chloride (0.077 mL, 0.911 mmol) in EtO (1.00 mL) over 5 min at 0 °C. After 1 h, the reaction was complete by TLC, and dimethylamine (1.34 mL, 2.68 mmol, 2 M in THF) was added dropwise at 0 °C. After stirring for 0.5 h, the reaction was quenched by the addition of CHCl (40 mL), and the organic phase was washed successively with 5% w / v aqueous NaHSO (20 mL), followed by saturated aqueous NaHCO (20 mL), and finally brine (20 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and the crude crystalline product was triturated with Et2O to give 156 mg (61%) of 3-N,N-dimethylglyoxylamido-4-(2-methoxyethyl)-7-methyl-1H-indole.

[0344] 1 H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.90 - 7.82 (m, 1H), 7.09 - 6.99 (m, 2H), 3.68 - 3.58 (m, 4H), 3.34 (s, 3H), 3.08 (s, 3H), 3.01 (s, 3H), 2.44 (s, 3H). [ka]

[0345] To a slurry of lithium aluminum hydride (131 mg, 3.46 mmol) in THF (2.44 mL) was slowly added a solution of 3-N,N-dimethylglyoxylamido-4-(2-methoxyethyl)-7-methyl-1H-indole (156 mg, 0.541 mmol) in THF (2.44 mL). The mixture was stirred at 70 °C for 16 h, after which the reaction was confirmed to be complete by NMR. The mixture was cooled to room temperature, and excess hydride was destroyed by careful addition of wet THF. The solid that formed was removed by filtration and washed with hot THF. The filtrate and washings were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude tryptamine residue was dissolved in EtOAc (0.5 mL) and MeOH (0.1 mL) was added. To this solution was added oxalic acid (48.7 mg, 0.541 mmol) in EtOAc (1.0 mL), and the mixture was cooled to -20 °C overnight. The mother liquor was then decanted and the precipitate was triturated with EtOAc (5×3 mL) to give 135 mg (71%) of the oxalate salt of 4-(2-methoxyethyl)-7-methyl-N,N-dimethyltryptamine (compound 3).

[0346] 1 H NMR (600 MHz, D2O) δ 7.32 - 7.23 (m, 1H), 7.01 - 6.96 (m, 1H), 6.92 - 6.86 (m, 1H), 3.75 - 3.69 (m, 2H), 3.44 (d, J = 12.8 Hz, 2H), 3.32 (s, 3H), 3.31 - 3.25 (m, 2H), 3.23 - 3.16 (m, 2H), 2.92 (s, 6H), 2.42 (s, 3H).

[0347] HRMS (LC-MS) m / z: [M+H] + C 16 H 24 Calculated N2OH value 261.196688; measured value 261.1983. Example 4: Synthesis of 4-(2-methoxyethyl)-7-methyl-N,N-dimethyltryptamine (Compound 4) [ka]

[0348] To a stirred solution of 4-(2-methoxyethyl)-7-methyl-1H-indole (148 mg, 0.782 mmol) in EtO (3.18 mL) was added a solution of oxalyl chloride (0.073 mL, 0.860 mmol) in EtO (1.00 mL) over 5 min at 0 °C. After 1 h, the reaction was complete by TLC, and dimethylamine (0.194 mL, 1.88 mmol) in EtO (4.18 mL) was added dropwise at 0 °C. After stirring for 0.5 h, the reaction was quenched by the addition of CHCl (40 mL), and the organic phase was washed successively with 5% w / v aqueous NaHSO (20 mL), followed by saturated aqueous NaHCO (20 mL), and finally brine (20 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and the crude crystalline product was triturated with Et2O to give 107 mg (43%) of 3-N,N-diethylglyoxylamido-4-(2-methoxyethyl)-7-methyl-1H-indole.

[0349] 1 H NMR (600 MHz, CDCl3) δ 9.17 (s, 1H), 7.87 (s, 1H), 7.09 - 7.02 (m, 2H), 3.68 - 3.59 (m, 4H), 3.52 (q, J = 7.1 Hz, 2H), 3.37 - 3.30 (m, 5H), 2.46 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). [ka]

[0350] To a slurry of lithium aluminum hydride (82.1 mg, 2.16 mmol) in THF (1.53 mL) was slowly added a solution of 3-N,N-diethylglyoxylamido-4-(2-methoxyethyl)-7-methyl-1H-indole (107 mg, 0.338 mmol) in THF (1.53 mL). The mixture was stirred at 70 °C for 16 h, after which the reaction was determined to be complete by NMR. The mixture was cooled to room temperature, and excess hydride was destroyed by careful addition of wet THF. The solid that formed was removed by filtration and washed with hot THF. The filtrate and washings were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude tryptamine residue was dissolved in EtOAc (0.5 mL), and MeOH (0.1 mL) was added. To this solution was added oxalic acid (30.4 mg, 0.338 mmol) in EtOAc (1.0 mL), and the mixture was cooled to -20 °C overnight. The mother liquor was then decanted and the precipitate was triturated with EtOAc (5×3 mL) to give 61 mg (48%) of the oxalate salt of 4-(2-methoxyethyl)-7-methyl-N,N-diethyltryptamine (compound 4).

[0351] 1 H NMR (600 MHz, D2O) δ 7.28 (d, J = 8.2 Hz, 1H), 6.99 (t, J = 6.1 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 3.77 - 3.70 (m, 2H), 3.46 - 3.38 (m, 2H), 3.33 (s, 3H), 3.31 - 3.25 (m, 6H), 3.22 - 3.17 (m, 2H), 2.43 (s, 3H), 1.30 - 1.26 (m, 6H).

[0352] HRMS (LC-MS) m / z: [M+H] + C 18 H 28 Calculated N2OH value 289.227988; measured value 289.2299.

[0353] Example 5: In vitro receptor binding assay Method: Membranes were treated with 5-HT. 2A / HEK293 cells, 5-HT 2B / HEK293 cells and 5-HT 2C The reference and screening compounds were extracted from HEK293 cells. 8 four-fold serial dilutions of the reference and screening compounds were performed in 100% DMSO. 1 μL of the serially diluted reference and screening compounds was transferred to an assay plate. 100 μL / well of membrane and 100 μL / well of radioligand were then added. 3 H-LSD was added and incubated for 1 hour at room temperature. The reaction mixture was filtered through a GF / C plate using a PerkinElmer Filtermate Harvester, and the plate was washed. The filter plate was dried at 50°C for 1 hour. The bottom of the filter plate was sealed using PerkinElmer Unifilter-96 backing seal tape. 50 μL of PerkinElmer Microscint 20 cocktail was added to each well of the assay plate, and the antibody was captured on the filter plate using a PerkinElmer MicroBeta2 Reader. 3 H was counted.

[0354] Results: Table 2 summarizes the binding affinities measured for compounds 1-4. [Table 2-1] [Table 2-2]

[0355] The dose-response curves for compounds 1-4 are shown in Figures 1-4, respectively, and correspond to the tabulated data below. [Table E5C1] [Table E5C2] [Table E5C3] [Table E5C4]

[0356] The results show that compounds 1, 2, and 4 inhibit 5-HT 2A and 5-HT 2B than 5-HT 2C This indicates that the affinity selectivity for

[0357] Example 6: In vitro receptor binding assay Method (5-HT 2A and 5-HT 2C IP-One Functional Activity Assay): Intracellular accumulation of IP-1 was measured at WuXi AppTec Co., Ltd. (Hong Kong) Discovery Biology Unit using the IP-One HTRF Assay Kit (Cat. No. 62IPAPEJ, Cisbio) according to its standard protocol. Briefly, reference and screening compounds were diluted 3.16-fold in 100% DMSO in 10 steps using a Bravo. 70 nL of compound was added to the assay plate using an Echo555. 14 μL / 7500 cells / well of 5-HT was added. 2A Expression of HEK293 or 5-HT 2CExpressing HEK293 cells were added to the assay plate and incubated at 37°C for 60 minutes. 3 μL of IP-1 d2 reagent working solution and 3 μL of IP-1 Tb cryptate antibody working solution were added to all wells. Plates were incubated at room temperature for 1 hour, and fluorescence was read at 620 nm and 665 nm using an EnVision multimode plate reader (PerkinElmer). The ratio of acceptor to donor emission signals (665 / 620) was calculated for each individual well and inserted into the standard curve to obtain the logarithmic concentration of IP levels. After IP-1 was reciprocal transformed, the average background control signal was subtracted from each well, and values ​​were normalized to the maximum response value of 5-HT at 3 μM (100%). %MAX was calculated by taking the average normalized maximum response value for each compound at the highest concentration tested. Data were then analyzed using a four-parameter nonlinear regression curve fitting function in GraphPad Prism 5 (GraphPad Software, San Diego, CA) to determine potency (EC 50 ) values ​​were generated. The plot shown shows normalized IP-1 values ​​versus compound concentration. The corresponding numerical data are parameter estimates of the concentration-response curves using a four-parameter nonlinear regression curve fitting function in GraphPad Prism 10.

[0358] Method (5-HT 2B IP-One Functional Activity Assay: Intracellular accumulation of IP-1 was measured at WuXi AppTec Co. Ltd. (Hong Kong) Discovery Biology Unit using the IP-One HTRF Assay Kit (Cat. No. 62IPAPEJ, Cisbio) according to their standard protocol. Briefly, 5-HT 2BHEK293 cells were seeded into 384-well plates and incubated overnight at 37°C and 5% CO2. Reference and screening compounds were serially diluted 3.16-fold in 100% DMSO using a Bravo™. 70 nL of compound was added to the cell plate using an Echo555™. The plate was incubated for 60 minutes at 37°C. 3 μL of IP-1 d2 reagent working solution and 3 μL of IP-1 Tb cryptate antibody working solution were added to all wells. The plate was incubated for 1 hour at room temperature and then read for fluorescence at 620 nm and 665 nm using an EnVision multimode plate reader (PerkinElmer). The ratio of acceptor to donor emission signals (665 / 620) was calculated for each individual well and inserted into the standard curve to obtain the logarithmic concentration of IP levels. After conversion to log-base IP-1, the average background control signal was subtracted from each well, and values ​​were normalized to the maximum response value of 5-HT at 3 μM (100%). %MAX was calculated by taking the average normalized maximum response value at the highest concentration tested. Data were then analyzed using a four-parameter nonlinear regression curve fitting function in GraphPad Prism 5 (GraphPad Software, San Diego, CA) to determine potency (EC 50 ) values ​​were generated. The parameter constraint "Top=100" was set to 5-HT 2B The plot shown shows normalized IP-1 values ​​versus compound concentration. The corresponding numerical data are parameter estimates of the concentration-response curves using a four-parameter nonlinear regression curve fitting function in GraphPad Prism 10. The "Top=100" parameter constraint was not enabled in the plot analysis shown.

[0359] Method (5-HT 2A Calcium (Ca) flux functional activity assay): 5-HT 2A Gq-mediated calcium flux downstream of receptor activation was measured using human 5-HT 2AMeasurements were performed using HEK293 cells stably expressing the receptor (Braden et al., 2006). Cells were seeded (30,000 cells / well) in DMEM supplemented with 1% (v / v) dialyzed fetal bovine serum (Gibco, catalog no. A33820-01) onto black 96-well poly-D-lysine-coated plates with clear bottoms and maintained overnight at 37°C in a humidified atmosphere of 5% CO. The next day, the medium was aspirated and replaced with 100 μL HBSS supplemented with 30 mM HEPES (pH 7.4) and loaded with 5 μM Fluo-2 AM HA (ION Biosciences, San Marcos, TX) and 2.5 mM aqueous probenecid (Thermo Fisher Scientific, Waltham, MA). Plates were incubated at 37°C for 1 hour, washed once with 100 μL of HBSS-HEPES, and maintained in 100 μL of HBSS-HEPES supplemented with 2.5 mM aqueous probenecid. The plate of dye-loaded cells was placed in a FlexStation 3 microplate reader (Molecular Devices, Sunnyvale, CA) set at 37°C, and fluorescence was monitored (excitation 485 nm; emission 525 nm; cutoff 515 nm). The plate was read for 30 seconds (2-second intervals) to establish baseline fluorescence, after which 50 μL of test compound was administered and read for an additional 120 seconds. After acquiring calcium flux traces for each sample, the area under the curve (AUC) was calculated for the 150-second run time, and the baseline (unstimulated) was subtracted. Data were analyzed using a four-parameter nonlinear regression curve fitting function in GraphPad Prism 10.2.0 (GraphPad Software, San Diego, CA) to determine potency (EC 50 ) and maximum response (MAX) values ​​were generated. MAX values ​​were normalized to the maximum 5-HT response (100%) and minimum 5-HT response (0%) on the same plate. Each concentration point was tested in triplicate.

[0360] Results: Table 3 summarizes the functional activity data for compounds 1-4. [Table 3-1] [Table 3-2]

[0361] The dose-response curves for Compound 1 are shown in Figure 5 (IP-One) and Figure 6 (Ca flux). The dose-response curves for Compound 2 are shown in Figure 7 (IP-One) and Figure 8 (Ca flux). The dose-response curves for Compound 3 are shown in Figure 9 (IP-One) and Figure 10 (Ca flux). The dose-response curves for Compound 4 are shown in Figure 11 (IP-One) and Figure 12 (Ca flux). These data correspond to the tabulated data below. [Table E6C1] [Table E6C2] [Table E6C3] [Table E6C4]

[0362] The results showed that compounds 1–4 inhibited 5-HT in the IP-One assay. 2B Compound 1 did not activate the 5-HT receptor in the IP-One assay. 2B 5-HT receptors 2A It showed greater than five-fold selectivity for activating the receptor.

[0363] Example 7: Anti-inflammatory properties of compounds The anti-inflammatory properties of the disclosed compounds are evaluated in a mouse model of allergic asthma according to the method described in Flanagan et al., ACS Pharmacology & Translational Science 2020, 4(2), 488-502.

[0364] Procedure: Respiratory pathogen-free Brown Norway (RijHsd-BN) rats used in this example are housed singly in a pathogen-free animal facility with a 12-hour / 12-hour light / dark cycle and free access to food and water. The animal protocol follows the "Guide for the Care and Use of Laboratory Animals" (Committee on Updates to the Guide for the Care and Use of Laboratory Animals, National Academies Press, Washington, DC (2011)). Rats are allowed to acclimate for at least 1 week before initiating sensitization with chicken ovalbumin grade V (OVA).

[0365] For sensitization, Brown Norway rats (7-9 weeks old) were intraperitoneally injected with 2.0 mg of chicken OVA (500 μL) emulsified in 2.0 mL of Imject Alum [Al(OH)3 / Mg(OH)2] on days 0 and 7 as described by Elwood et al. J Allergy Clin Immunol. 1991, 88(6), 951-60. The OVA challenge 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).

[0366] Rats treated with OVA alone were exposed to 10 mg of OVA slowly dissolved in 10 mL of 0.9% sterile saline in a 15 L (38.00 × 19.05 × 19.7 cm) acrylic induction chamber three times a week. No more than six animals were exposed per challenge. OVA aerosol was generated at a 1.0% OVA concentration for a total of 30 minutes using an ultrasonic nebulizer combined with a Pari Proneb pump, as described in Palmans et al., Am J. Respir Crit Care Med. 2000, 161, 627-635.

[0367] For drug exposure, rats, in groups of 3-4 rats / group, are exposed to the appropriate concentration of drug dissolved in sterile saline in a total volume of 4.5 mL using the inExpose nasal-only inhalation system 30 min before each OVA challenge. Each 4.5 mL sample is aerosolized using a nebulizer in combination with a Pari Proneb pump. Exposure lasts for 15 min. All respiratory parameters are measured 48 h after the final OVA exposure.

[0368] To minimize the influence of circadian rhythm, all respiratory recordings were performed 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; Pazhouhan et al., PLoS One. 2017, 12(10), e0187249). To measure airway responsiveness to MeCh, a noninvasive biased-flow ventilated whole-body plethysmography system was used in spontaneously breathing, unrestrained rodents. The plethysmograph was ventilated at a continuous flow rate of 2.5 L / min. A differential pressure transducer was connected to the main chamber with one pole and to the reference chamber with the second pole. The transducer measured the pressure difference between the two chambers caused by the respiratory cycle (primarily inspiration and expiration). Computer software provides an analysis of the breath-by-breath pressure signal and computationally converts the pressure difference into a dimensionless, empirically established value, enhanced pause or PenH.

[0369] Numerous experiments (Nau et al., Am J Physiol. Lung Cellular Mol Physiol 2015, 308(2), L191-198; Flanagan et al., Life Sci. 2019, 236, 116790; Hamelmann et al., Am. J. Respir. Crit. Care Med. 1997, 156, 766-775; Djuric et al., Brain, Behav. Immun. 1998, 12(4), 272-84) have shown that PenH is a reliable and sensitive measure of bronchoconstriction and is a superior measure for assessing the degree of bronchoconstriction compared with other derived parameters such as box pressure or box flow (Djuric et al., Brain, Behav. Immun. 1998, 12(4), 272-84). PenH also faithfully reproduces the results of forced ventilation techniques such as the flexiVent (flexiVent, SCIREQ, Montreal, CA) (Nau et al., American Journal of Physiology. Lung Cellular and Molecular Physiology 2015, 308(2), L191-198).

[0370] In the assay, the chamber pressure signal is calibrated by dynamically injecting 5 mL of room air via a syringe. Then, rats are placed in the chamber, and the plethysmograph records baseline data for 5 minutes after a 10-minute acclimation period. After baseline PenH measurements, either aerosolized saline (0.9% NaCl solution) or increasing concentrations of MeCh in water (4, 8, 16, and 32 mg / mL) are nebulized through the inlet of the plethysmography chamber for 3 minutes, followed by 3-minute PenH measurements. A vibrating mesh nebulizer is used to generate the aerosol. After recording, a 7-minute washout period is performed during which rats are provided with fresh air to prevent MeCh gradients. Data are presented as the mean SEM of maximum PenH values ​​per group.

[0371] Results: The results may indicate that certain disclosed compounds have potent anti-inflammatory properties, more specifically, they may reduce PenH max and suppress pulmonary inflammation.

[0372] Example 8: Evaluation of ocular inflammation after compound application Objective: Ocular inflammation and uveitis encompass sight-threatening diseases 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), and neuropeptides, such as substance P (Bignami et al., Curr Drug Targets. 2016;17(11):1265-74), can contribute to ocular inflammation.

[0373] Methods: Ocular inflammation is assessed according to known methods with modifications. For example, ocular inflammation can be assessed in an induced model of uveitis (see, e.g., WO2015074137, which describes an endotoxin-induced model in Example 1 and an LPS-induced model in Example 2), a chemical cauterization model of corneal inflammation (see, e.g., WO2015074137, Example 4), or in a human subject at risk of experiencing or currently experiencing such inflammation.

[0374] Results and Significance: Application, e.g., topical application, of the disclosed compounds can prevent and / or reduce ocular inflammation. Reduced ocular inflammation can result in improvement in symptomatology associated with ocular inflammation, including, but not limited to, ocular redness, pain, and changes in vision (e.g., blurred vision).

[0375] Example 9: In vivo model for assessing atopic dermatitis after application of compounds Objective: Atopic dermatitis or eczema is characterized by chronic inflammation, which can lead to inflammatory symptoms such as skin irritation. In some embodiments, the disclosed compounds and compositions are useful for treating atopic dermatitis. The purpose 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 uses a flaky tail mouse strain that harbors a mutation in the gene encoding 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). Topical application of ovalbumin to challenge these mice results in symptoms resembling atopic dermatitis. Mice typically develop eczema and elevated levels of inflammatory skin biomarkers after ovalbumin application. Exemplary measures of efficacy include skin flakiness, cutaneous type 2 helper T cells (Th2) and cytokine (such as IL4, IL5 and IL10) levels.

[0376] Methods: The protocol for applying ovalbumin to the skin of flaked-tail mice has been described (ibid.). Briefly, the abdomens of 3- to 5-week-old mice were shaved 24 hours before the skin application of an ovalbumin suspension (50 μg in 50 μL PBS), which was then applied to the abdomen as previously described (ibid.).

[0377] There are two experimental groups: in group 1, mice are pretreated with the disclosed compounds before and during ovalbumin application to examine their effectiveness in preventing and inhibiting the development of atopic dermatitis. In group 2, mice are treated with the disclosed compounds 4-5 weeks after ovalbumin treatment (after atopic dermatitis symptoms appear) to examine the compound's effectiveness in treating symptoms. For each compound tested, the compound is administered at several doses (e.g., intravenously, intramuscularly, or by oral gavage) to examine dose-dependent effects. After each experiment, mice are euthanized, and skin punch biopsies are taken from each abdomen, snap-frozen in liquid nitrogen, and homogenized in HTAB buffer. Samples are centrifuged, and the supernatants are subjected to cytokine profiling by ELISA for levels of biomarkers (e.g., Th2, IL4, IL5, and IL10) using protein standards for quantification.

[0378] Results: The results are expected to show that administration of the disclosed compounds or compositions prevents, inhibits, and / or treats symptoms of atopic dermatitis.

[0379] Example 10: In vitro metabolic stability of compounds The purpose of this experiment is to evaluate the metabolic stability of the disclosed compounds in an in vitro assay. The liver is the main site of drug metabolism in the body, and liver microsomes, hepatocytes, and liver S9 fractions can be used to determine the in vitro intrinsic clearance of compounds. 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).

[0380] Methods: Liver microsome stability assays are performed according to available methods, for example, as described in U.S. Patent Application Publication No. 2008 / 0045588, with modifications. Briefly, the assay is performed with 1 mg / mL liver microsomal protein using an NADPH-generating 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). Test compounds are prepared as 20% aqueous acetonitrile 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 removed at 0, 15, 30, 45, and 60 minutes and diluted with ice-cold acetonitrile (200 μL) to terminate the reaction. Samples are centrifuged at 12,000 RPM for 10 minutes to precipitate the protein. The supernatant is transferred to a microfuge tube and saved for LC / MS / MS analysis of the degradation half-life of the test compound.

[0381] Results and Significance: The results show a measure of the in vitro intrinsic clearance of the disclosed compounds. Such data provides a prediction of the metabolic stability and clearance of the compounds.

[0382] Example 11: In vivo evaluation of the behavioral effects of compounds using HTR Head-twitch response (HTR) in mice is induced by 5-HT 2A HTR is a behavioral test that reflects receptor activation and can predict psychedelic effects in humans (Halberstadt et al., J Psychopharmacol. 2011;25(11):1548-1561). 2A Receptor agonists and non-psychedelic 5-HT 2A Due to its ability to reliably distinguish from receptor agonists, it has been widely used as a behavioral surrogate for psychedelic effects in humans (Halberstadt & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3).

[0383] Methods: The HTR assay was performed according to the method described in Klein et al., Neuropharmacol, 2018;142:231-239 to evaluate the effects of the disclosed compounds in mice. Male C57BL / 6J mice (6-8 weeks old) were obtained and housed in a vivarium that met all requirements for laboratory animal care and treatment. Mice were housed up to four per cage in a climate-controlled room with a reverse light cycle (lights on at 19:00, lights off at 07:00) and provided with free access to food and water except during behavioral testing. Testing was performed between 10:00 and 18:00. All animal experiments were conducted in accordance with applicable guidelines and approved by the appropriate animal care committee.

[0384] HTR is assessed using a head-mounted magnet and magnetometer detection coil, as previously described (Halberstadt & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3, Halberstadt & Geyer, Neuropharmacol, 2014;77:200-7; Nichols et al., ACS Chem Neurosci. 2015;6(7):1165-1175). Briefly, mice are anesthetized, and a small neodymium magnet is attached to the dorsal skull using dental cement. After a 2-week recovery period, HTR experiments are performed in a well-lit room, with at least 7 days between sessions to avoid carryover effects.

[0385] Test compounds are dissolved in an appropriate solvent, such as water containing 5% Tween 80, and administered IP at 5 or 10 mL per kg of body weight immediately before testing. Different doses are tested to generate dose-response curves. Mice are injected with drug or vehicle, and HTR activity is recorded for 30 min within a glass cylinder surrounded by a magnetometer coil. The coil voltage is low-pass filtered (cutoff frequency 2 e 10 kHz), amplified, digitized (sampling rate 20 kHz), and then filtered offline (bandpass 40 e 200 Hz) using a Powerlab / 8SP (ADInstruments, Colorado Springs, CO, USA) with LabChart v 7.3.2.

[0386] Head twitches are manually identified based on the following criteria: 1) sinusoidal wavelets; 2) evidence of at least two consecutive head movements at a frequency of 40 Hz (usually shown as bipolar peaks); 3) amplitude above the level of background noise; 4) duration <0.15 seconds; and 5) stable coil voltage immediately before and after each response.

[0387] The number of head twitches is analyzed using one-way analysis of variance (ANOVA). Post-hoc pairwise comparisons between selected groups are performed using Tukey's Studentized Range method. The entire recording is examined for head twitches. Because efficacy calculations can be confounded by long periods of inactivity, in some cases shorter time blocks are analyzed to accommodate compounds with a short duration of action. ED 50 Values ​​and 95% confidence limits are cal...

Claims

1. Compound of formula (1): 【Chemistry 1】 or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, comprising the formula: R １ is -(CH ２ ) ２ OH, -(CH ２ ) ３ OH, -CH ２ OH, -(CH ２ ) ３ O-C １ ~C ６ Alkyl, -(CH ２ ) ２ O-C １ ~C ６ Alkyl, —CH ２ O-C １ ~C ６ Alkyl, -(CH ２ ) ３ OPO ３ H ２ , -(CH ２ ) ２ OPO ３ H ２ , or -CH ２ OPO ３ H ２ and R ２ is C １ ~C ６ is alkyl; and R' and R" are both C １ ~C ６ Is alkyl; or R' is H and R" is C １ ~C ６ Alkyl or -CH ２ -C ６ ~C １２ aryl, and ６ ~C １２ Aryl is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylmethyl, C ６ ~C １２ optionally substituted with aryl, F, Cl, Br, or I; or R′ and R″ together form a 4- to 6-membered heterocyclyl, said heterocyclyl being C １ ~C ６ optionally substituted with alkyl; The compound or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

2. R １ But -(CH ２ ) ２ OH, -(CH ２ ) ３ OH, or -CH ２ 10. The compound of claim 1, wherein R is OH, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

3. R １ But -(CH ２ ) ３ O-C １ ~C ６ Alkyl, -(CH ２ ) ２ O-C １ ~C ６ Alkyl, or -CH ２ O-C １ ~C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R is alkyl.

4. R １ But -(CH ２ ) ３ OCH ３ , -(CH ２ ) ２ OCH ３ , or -CH ２ OCH ３ 4. The compound of claim 3, wherein:

5. R １ But -(CH ２ ) ２ OCH ３ 5. The compound of claim 4, wherein:

6. R １ But -(CH ２ ) ３ OPO ３ H ２ , -(CH ２ ) ２ OPO ３ H ２ , or -CH ２ OPO ３ H ２ 2. The compound of claim 1, wherein:

7. R １ But -(CH ２ ) ２ OPO ３ H ２ 7. The compound of claim 6, wherein:

8. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein is methyl.

9. R' and R" are both C １ ~C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R is alkyl.

10. 10. The compound of claim 9, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both methyl.

11. 10. The compound of claim 9, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both ethyl.

12. 10. The compound of claim 9, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both isopropyl.

13. R' is H and R" is C １ ~C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R is alkyl.

14. 14. The compound of claim 13, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is methyl.

15. 14. The compound of claim 13, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is ethyl.

16. 14. The compound of claim 13, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is isopropyl.

17. R' is H and R" is -CH ２ -C ６ ~C １２ aryl, and ６ ~C １２ The aryl is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C ３ -C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylmethyl, C ６ ~C １２ 10. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with aryl, F, Cl, Br, or I.

18. R" is -CH ２ -phenyl, said phenyl being C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylmethyl, C ６ ~C １２ 18. The compound of claim 17, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with aryl, F, Cl, Br, or I.

19. 20. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein said phenyl is unsubstituted.

20. 20. The compound of claim 18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein said phenyl is methyl substituted.

21. R" is -CH ２ -(2-methylphenyl), -CH ２ -(3-methylphenyl), or -CH ２ -(4-methylphenyl), or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

22. R′ and R″ together form a 4- to 6-membered heterocyclyl, said heterocyclyl being C １ ~C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with alkyl.

23. R' and R" together form C １ ~C ６ 23. The compound of claim 22, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, which forms an azetidinyl optionally substituted with alkyl.

24. 24. The compound of claim 23, wherein said azetidinyl is unsubstituted.

25. The azetidinyl is C １ ~C ６ 24. The compound of claim 23, which is alkyl substituted.

26. R' and R" together 【Chemistry 2】 or 【Transformation 3】 26. The compound of claim 25, wherein

27. The compound has the formula (1A): 【Chemistry 4】 10. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

28. R' and R" are both C １ ~C ６ 28. The compound of claim 27, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein:

29. 29. The compound of claim 28, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both methyl.

30. 29. The compound of claim 28, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both ethyl.

31. 29. The compound of claim 28, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both isopropyl.

32. R' is H and R" is C １ ~C ６ 28. The compound of claim 27, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein:

33. 33. The compound of claim 32, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is methyl.

34. 33. The compound of claim 32, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is ethyl.

35. 33. The compound of claim 32, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is isopropyl.

36. R' is H and R" is -CH ２ -C ６ ~C １２ aryl, and ６ ~C １２ The aryl is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C ３ -C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylmethyl, C ６ ~C １２ 28. The compound of claim 27, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with aryl, F, Cl, Br, or I.

37. R" is -CH ２ -phenyl, said phenyl being C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylmethyl, C ６ ~C １２ 37. The compound of claim 36, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with aryl, F, Cl, Br, or I.

38. 38. The compound of claim 37, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein said phenyl is unsubstituted.

39. 38. The compound of claim 37, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein said phenyl is methyl substituted.

40. R" is -CH ２ -(2-methylphenyl), -CH ２ -(3-methylphenyl), or -CH ２ -(4-methylphenyl), or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

41. R′ and R″ together form a 4- to 6-membered heterocyclyl, said heterocyclyl being C １ ~C ６ 28. The compound of claim 27, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with alkyl.

42. R' and R" together form C １ ~C ６ 42. The compound of claim 41, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, which forms an azetidinyl optionally substituted with alkyl.

43. 43. The compound of claim 42, wherein said azetidinyl is unsubstituted.

44. The azetidinyl is C １ ~C ６ 43. The compound of claim 42, which is alkyl substituted.

45. R' and R" together 【Transformation 5】 or 【Transformation 6】 45. The compound of claim 44, wherein

46. The compound has the formula (1B): 【Transformation 7】 10. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

47. R' and R" are both C １ ~C ６ 47. The compound of claim 46, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein:

48. 48. The compound of claim 47, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both methyl.

49. 48. The compound of claim 47, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both ethyl.

50. 48. The compound of claim 47, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein R' and R" are both isopropyl.

51. R' is H and R" is C １ ~C ６ 47. The compound of claim 46, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein:

52. 52. The compound of claim 51, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is methyl.

53. 52. The compound of claim 51, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is ethyl.

54. 52. The compound of claim 51, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein R" is isopropyl.

55. R' is H and R" is -CH ２ -C ６ ~C １２ aryl, and ６ ~C １２ The aryl is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C ３ -C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylmethyl, C ６ ~C １２ 47. The compound of claim 46, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with aryl, F, Cl, Br, or I.

56. R" is -CH ２ -phenyl, said phenyl being C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylmethyl, C ６ ~C １２ 56. The compound of claim 55, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with aryl, F, Cl, Br, or I.

57. 57. The compound of claim 56, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein said phenyl is unsubstituted.

58. 57. The compound of claim 56, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, wherein said phenyl is methyl substituted.

59. R" is -CH ２ -(2-methylphenyl), -CH ２ -(3-methylphenyl), or -CH ２ -(4-methylphenyl), or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

60. R′ and R″ together form a 4- to 6-membered heterocyclyl, said heterocyclyl being C １ ~C ６ 47. The compound of claim 46, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, optionally substituted with alkyl.

61. R' and R" together form C １ ~C ６ 61. The compound of claim 60, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof, which forms an azetidinyl optionally substituted with alkyl.

62. 62. The compound of claim 61, wherein said azetidinyl is unsubstituted.

63. The azetidinyl is C １ ~C ６ 62. The compound of claim 61, which is alkyl substituted.

64. R' and R" together 【Transformation 8】 or 【Chemistry 9】 64. The compound of claim 63, wherein

65. A compound selected from Table 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate or solvate thereof.

66. The compound is 【Chemistry 10】 or 【Chemistry 11】 66. The compound of claim 65, wherein:

67. 67. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

68. 68. The pharmaceutical composition of claim 67, wherein the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

69. 68. The pharmaceutical composition of claim 67, wherein the composition is provided in a unit dosage form.

70. 70. The pharmaceutical composition of claim 69, comprising the compound in a total amount of about 0.01 to 100 mg.

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

72. 72. The pharmaceutical composition of claim 71, wherein the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory drugs, analgesics, anti-neuropathic and anti-nociceptive drugs, anti-migraine drugs, anti-anxiety drugs, antidepressants, antipsychotic drugs, anti-PTSD drugs, dissociative drugs, cannabinoids, immunostimulants, anti-cancer drugs, antiemetics, appetite stimulants, antiulcer drugs, antihistamines, antihypertensive drugs, anticonvulsants, anti-epileptic drugs, bronchodilators, neuroprotective agents, nootropics, empathogens, psychedelics, plasticity inducers, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic drugs, NMDA modulators, NMDA antagonists, and vitamins.

73. 67. A method of modulating neurotransmission in a subject, comprising administering to the subject a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

74. The regulation of neurotransmission is ２Ａ or 5-HT ２Ｃ 74. The method of claim 73, comprising stimulating a receptor.

75. 67. A method of increasing neuroplasticity in a subject, comprising administering to said subject a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

76. 67. A method of treating a medical condition in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

77. 77. The method of claim 76, wherein the medical condition is a disorder associated with dysregulation or insufficient function of serotonergic neurotransmission.

78. 77. The method of claim 76, wherein the medical condition is a psychiatric, behavioral, or neurodevelopmental disorder.

79. 78. The method of claim 77, 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, eating or purging disorder, somatic pain disorder or somatic experiencing disorder, substance use or addictive behavior disorder, impulse control disorder, disruptive or antisocial behavior disorder, personality disorder, paraphilia, factitious disorder, neurocognitive disorder, psychiatric or behavioral disorder related to pregnancy, childbirth or the postpartum period, sleep-wake disorder, or sexual dysfunction.

80. 78. The method of claim 77, wherein the compound is administered in conjunction with one or more psychotherapy sessions.

81. 77. The method of claim 76, wherein the medical condition is inflammation or an inflammatory disease.

82. 82. The method of claim 81, wherein the inflammation is skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, cystitis, stomach inflammation, intestinal inflammation, nerve inflammation, eye inflammation, or brain inflammation.

83. 82. The method of claim 81, wherein the inflammatory disease is an acute inflammatory disease.

84. 82. The method of claim 81, wherein the inflammatory disease is a chronic inflammatory disease.

85. 82. The method of claim 81, wherein the inflammatory disease is a steroid-resistant disease.

86. 82. The method of claim 81, wherein 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.

87. 82. The method of claim 81, wherein the inflammatory disease is dermatitis.

88. 88. The method of claim 87, wherein the dermatitis is atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic eczema, discoid eczema, varicose eczema, herpetic dermatitis, neurodermatitis, autosensitization dermatitis, stasis dermatitis, suppurative dermatitis, dyshidrotic eczema, follicular eczema, spongiotic dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

89. 82. The method of claim 81, wherein the subject has a compromised immune system.

90. 82. The method of claim 81, wherein the subject has an autoimmune disorder.

91. 82. The method of claim 81, wherein the subject has a contraindication to corticosteroids.

92. 82. The method of claim 81, wherein treating inflammation or an inflammatory disease comprises reducing the level of an inflammatory biomarker by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%.

93. 93. The method of claim 92, wherein the inflammatory biomarker is an inflammatory response gene product.

94. 94. The method of claim 93, wherein the inflammatory response gene product is mRNA.

95. 95. The method of claim 94, 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.

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

97. 97. The method of claim 96, 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.

98. 82. The method of claim 81, wherein the medical condition is an ophthalmic disease.

99. 99. The method of claim 98, wherein the ophthalmic disease is an inflammatory disease.

100. 82. The method of claim 81, wherein the medical condition is a neurodegenerative disorder.

101. 101. The method of claim 100, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis or Charcot's disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia including vascular dementia, Huntington's disease, Litiko-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.

102. 67. A compound according to any one of claims 1 to 66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment of a medical condition.

103. 67. Use of a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a medicament for treating a medical condition.

104. 68. A method of modulating neurotransmission in a subject, comprising administering to the subject the pharmaceutical composition of claim 67.

105. The regulation of neurotransmission is ２Ａ or 5-HT ２Ｃ 105. The method of claim 104, comprising stimulating a receptor.

106. 68. A method of increasing neuroplasticity in a subject, comprising administering to the subject the pharmaceutical composition of claim 67.

107. 68. A method of treating a medical condition in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 67.

108. 108. The method of claim 107, wherein the medical condition is a disorder associated with dysregulation or insufficient function of serotonergic neurotransmission.

109. 108. The method of claim 107, wherein the medical condition is a psychiatric disorder, a behavioral disorder, or a neurodevelopmental disorder.

110. 110. The method of claim 109, 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, eating or purging disorder, somatic pain disorder or somatic experiencing disorder, substance use or addictive behavior disorder, impulse control disorder, disruptive or antisocial behavior disorder, personality disorder, paraphilia, factitious disorder, neurocognitive disorder, psychiatric or behavioral disorder related to pregnancy, childbirth or the postpartum period, sleep-wake disorder, or sexual dysfunction.

111. 110. The method of claim 109, wherein the composition is administered in conjunction with one or more psychotherapy sessions.

112. 108. The method of claim 107, wherein the medical condition is inflammation or an inflammatory disease.

113. 113. The method of claim 112, wherein the inflammation is skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, cystitis, stomach inflammation, intestinal inflammation, nerve inflammation, eye inflammation, or brain inflammation.

114. 113. The method of claim 112, wherein the inflammatory disease is an acute inflammatory disease.

115. 113. The method of claim 112, wherein the inflammatory disease is a chronic inflammatory disease.

116. 113. The method of claim 112, wherein the inflammatory disease is a steroid-resistant disease.

117. 113. The method of claim 112, wherein 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.

118. 113. The method of claim 112, wherein the inflammatory disease is dermatitis.

119. The method of claim 118, wherein the dermatitis is atopic dermatitis, chronic photosensitive dermatitis, eczema, atopic eczema, contact eczema, dry eczema, seborrheic eczema, discoid eczema, varicose eczema, herpetic dermatitis, neurodermatitis, autosensitization dermatitis, stasis dermatitis, suppurative dermatitis, dyshidrotic eczema, follicular eczema, spongiotic dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.

120. 113. The method of claim 112, wherein the subject has a weakened immune system.

121. 113. The method of claim 112, wherein the subject has an autoimmune disorder.

122. 113. The method of claim 112, wherein the subject has a contraindication to corticosteroids.

123. 113. The method of claim 112, wherein treating inflammation or an inflammatory disease comprises reducing the level of an inflammatory biomarker by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%.

124. 124. The method of claim 123, wherein the inflammatory biomarker is an inflammatory response gene product.

125. 125. The method of claim 124, wherein the inflammatory response gene product is mRNA.

126. 126. The method of claim 125, 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.

127. 125. The method of claim 124, wherein the inflammatory response gene product is a protein.

128. 128. The method of claim 127, wherein the protein is ICAM1, VCAM1, MCP1, IL-6, IL-1β, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-β.

129. 113. The method of claim 112, wherein the medical condition is an ophthalmic disease.

130. 130. The method of claim 129, wherein the ophthalmic disease is an inflammatory disease.

131. 113. The method of claim 112, wherein the medical condition is a neurodegenerative disorder.

132. 132. The method of claim 131, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis or Charcot's disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia including vascular dementia, Huntington's disease, Lytcho-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.

133. A pharmaceutical composition according to any one of claims 67 to 72 for use in the treatment of a medical condition.

134. 73. Use of a pharmaceutical composition according to any one of claims 67 to 72 for the manufacture of a medicament for the treatment of a medical condition.

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