N-substituted phenylalkylamines and their use as therapeutic agents

Abstract

The present invention provides N-substituted phenylalkylamines, methods of making the same, and methods of using such compounds, e.g., as receptor probes, as neurotransmission modulators, and as therapeutic agents, e.g., as central nervous system drugs. Also provided are pharmaceutical compositions and methods for their use in the treatment of certain diseases, such as serotonin neurotransmitter diseases, mental health disorders, and ion channel mediated diseases, such as seizure disorders.

Description

[0001] Nicholas Cozzi, Paul F. Daley

[0002] Cross-references

[0003] Priority is claimed under PCT Section 8(1) and Rule 4.10 to U.S. Application No. 63 / 355,632, filed on June 26, 2022. This patent is incorporated herein by reference as if fully set forth. Field of the Invention

[0004] The present disclosure relates in some aspects to N-substituted phenylalkylamine compounds. In some aspects, it also relates to methods of synthesizing these compounds, compositions containing these compounds, and methods of using these compounds, including administering them to a subject. In some aspects, the useful characteristics of the compounds include neuromodulatory activity. Background of the Invention

[0006] Tryptamine psychedelic compounds, such as psilocybin and DMT, have reemerged as promising therapeutic candidates for the treatment of a variety of psychiatric disorders, including depression, substance use disorders, and anxiety-related disorders (Vollenweider and Preller, Nat Rev Neurosci, 2020; 21(11): 611-624; D'Souza et al., Neuropsychopharmacol., 2022; 47(10): 1854-1862). In addition to their significant subjective effects on consciousness, there is growing interest in their physiological effects and their potential use in the treatment of physical and neurological disorders. Furthermore, while much progress has been made in recent years in understanding the structure-activity relationships underlying the effects of classic psychedelics, there remain many unanswered questions about the efficacy and potential risks of these compounds in the treatment of complex disorders that may lack effective treatments, such as mood disorders (e.g., depression, bipolar disorder) and psychoses (e.g., schizophrenia). As a result, there is an unmet need for novel alternative therapies, particularly those that can minimize side effects, increase accessibility, optimize efficacy, or even improve upon existing classical psychedelics by invoking new therapeutic mechanisms.

[0007] Provided herein are compounds, compositions, methods, uses and pharmaceutical kits that meet these needs and other needs, and have advantages and improvements that will become apparent from the disclosure below.

[0008] Incorporated by Reference

[0009] Each patent, publication and non-patent document cited in this application is hereby incorporated by reference in its entirety, as if each patent, publication and non-patent document were individually incorporated herein and as if each patent, publication and non-patent document were fully set forth herein. However, if such a reference is made, it is generally for the purpose of providing a context for discussing the features disclosed and, unless otherwise stated, it should not be construed as an admission that the document or underlying information is prior art or part of the common general knowledge in the art in any jurisdiction. Summary of the invention

[0010] Some embodiments of the present invention are briefly summarized below to provide a basic understanding of the present invention. This summary is not a broad overview of the present invention. Its purpose is not to identify the key or important elements of the present invention, or to define the scope of the present invention. Its sole purpose is to introduce some embodiments of the present invention in a simplified form as a preface to a more detailed description later.

[0011] In a first aspect, a compound represented by formula (II) or a pharmaceutically acceptable salt thereof is provided:

[0012]

[0013] wherein: m and n are each independently an integer from 1 to 13, provided that the sum of m+n is from 6 to 14;

[0014] X is O, S or NH;

[0015] R and R2 are each independently C1-C8 alkoxy, wherein each C1-C8 alkoxy is optionally substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, mercapto, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate;

[0016] R1 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, each of which is optionally substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate;

[0017] R3 is hydrogen or C1-C8 alkyl; and

[0018] Ph is phenyl which is optionally substituted with halogen, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0019] In some embodiments, R and R2 are both -OCH3.

[0020] In some embodiments, R3 is hydrogen, -CH3, or -CH2CH3. In some embodiments, R3 is hydrogen or -CH3. In some embodiments, R3 is -CH3 or -CH2CH3. In some embodiments, R3 is hydrogen. In some embodiments, R3 is -CH3. In some embodiments, R3 is -CH2CH3.

[0021] In some embodiments, R1 is F, Cl, Br or I. In some embodiments, R1 is Br. In some embodiments, R1 is C1-C8 alkyl. In some embodiments, R1 is —CH3 or —CH2CH3. In some embodiments, R1 is C1-C8 thioalkyl. In some embodiments, R1 is —SCH3. In some embodiments, R1 is unsubstituted phenyl. In some embodiments, R1 is phenyl substituted by azido or C1-C8 alkoxy.

[0022] In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NH.

[0023] In some embodiments, the sum of m+n is 8 to 12. In some embodiments, the sum of m+n is 9 to 11. In some embodiments, the sum of m+n is 10. In some embodiments, m is 6 and n is 4.

[0024] In another aspect, a compound selected from Table 4 or a pharmaceutically acceptable salt thereof is provided.

[0025] In some embodiments, the compound is

[0026]

[0027] or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0029] The present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of the compound described in the aforementioned embodiment or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0030] In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, or transdermal administration.

[0031] In some embodiments, the composition is in unit dosage form. In some embodiments, the unit dosage form includes a total amount of about 1 to about 500 mg, about 2.5 to about 250 mg, or about 5 to about 125 mg of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

[0032] In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of an additional active compound or a pharmaceutically acceptable salt thereof. In some embodiments, the additional active compound is selected from amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathy and anti-nociceptive agents, anti-migraine agents, antianxiety agents, antidepressants, antipsychotics, anti-post-traumatic stress disorder agents, dissociative agents, cannabinoids, immunostimulants, anticancer agents, antiemetics, anorectics, antiulcer agents, antihistamines, antihypertensive agents, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, hallucinogens, psychedelics, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants and vitamins; or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the additional active compound or a pharmaceutically acceptable salt thereof acts to increase the therapeutic effect, provide an additional therapeutic effect, reduce adverse effects, increase stability or shelf life, improve bioavailability, induce synergy, or alter pharmacokinetics or pharmacodynamics. In some embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, anti-neuropathy, anti-nociception, anti-migraine, anxiolytic, anti-depressant, anti-psychotic, anti-post-traumatic stress disorder, dissociative, immunostimulatory, anti-cancer, antiemetic, anorectic, anti-ulcer, antihistamine, antihypertensive, anticonvulsant, anti-epileptic, bronchodilator, neuroprotective, nootropic, hallucinogenic, psychedelic, sedative, or stimulant effect.

[0034] In another aspect, there is provided a compound as described in the above embodiments or a pharmaceutically acceptable salt thereof for use in treating a medical condition.

[0035] In another aspect, there is provided use of a compound as described in the above embodiments or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a medical condition.

[0036] In another aspect, a method for regulating a neurotransmitter in a mammal is provided, comprising administering to the mammal a therapeutically effective amount of a compound described in the above embodiments or a pharmaceutically acceptable salt thereof.

[0037] In another aspect, there is provided a method of treating a medical condition in a mammal in need of such treatment, the method comprising administering a compound as described in the above embodiments or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the medical condition is a disease associated with a neurotransmitter imbalance or insufficiency. In some embodiments, the disease associated with a neurotransmitter imbalance or insufficiency is a monoamine neurotransmitter disease. In some embodiments, the disease associated with a neurotransmitter imbalance or insufficiency is a serotonin neurotransmitter disease.

[0039] In some embodiments, the medical condition is a mental health disorder. In some embodiments, the mental health disorder is selected from schizophrenia, schizoaffective disorder, schizotypal disorder, acute transient psychotic disorder, delusional disorder, substance-induced psychotic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymic disorder, anxiety, phobia, bulimia, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance use disorder, substance-induced mood disorder, mood disorder associated with another health condition, disruptive behavior disorder, eating disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, and dissociative disorder.

[0040] In some embodiments, the medical condition is a seizure disorder. In some embodiments, the seizure disorder is epilepsy.

[0041] In some embodiments, the medical condition is a disease associated with a dysregulation or inadequate function of a voltage-gated ion channel. In some embodiments, the voltage-gated ion channel is a voltage-gated sodium channel. In some embodiments, the compound inhibits the activity of the voltage-gated sodium channel.

[0042] In some embodiments, the mammal has genetic variations associated with drug metabolism, including genetic variations associated with CYP2D6 or CYP3 A4 enzymes; or genetic variations associated with mental health disorders, trauma or stress-related disorders, depression or anxiety, including genetic variations in mGluR5 or FKBP5; or genetic variations associated with membrane transporters, such as SERT, DAT, NET or VMAT.

[0043] In some embodiments, the 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 the SIGMAR1 gene for the non-opioid sigma-1 receptor.

[0044] In some embodiments, the mammal is a human.

[0045] The present invention also provides a method for alleviating symptoms of a human mental health disorder, the method comprising identifying a human in need of such alleviating symptoms, and administering to the human a compound or a pharmaceutically acceptable salt thereof according to the above embodiment, or a pharmaceutical composition according to the above embodiment.

[0046] The present invention also provides a method for improving human mental health or function, the method comprising identifying a human in need of the improvement, and administering the compound or pharmaceutically acceptable salt thereof described in the above embodiment, or the pharmaceutical composition described in the above embodiment to the human.

[0047] The above content has been broadly and generally summarized certain relevant features of the present disclosure, so that the subsequent detailed description of the present invention can be better understood, and the contribution of the present invention to the art can be more fully appreciated. Therefore, this overview should be regarded as a brief summary of some of the purposes and embodiments disclosed herein, which is provided only for the benefit and convenience of the reader, and is not intended to limit the scope or equivalent scope legally enjoyed by the claims in any way. Additional features of the present invention will be described below. It should be understood by those skilled in the art that all disclosed specific compositions and methods are exemplary only and can be easily used as the basis for modifying or designing other compositions and methods for achieving the same purpose. It should be understood that such equivalent compositions and methods also belong to the scope and spirit of the present invention described in the claims.

[0048] The headings in this document are intended only to expedite the reader's review. They should not be construed as limiting the present invention in any way.

[0049] BRIEF DESCRIPTION OF THE DRAWINGS

[0050] In order to further illustrate various aspects of the present invention, it will be described in more detail with reference to certain exemplary embodiments shown in the accompanying drawings. It should be understood and appreciated that the accompanying drawings only illustrate embodiments of the present invention and should not be considered to limit its scope. They are provided merely as exemplary illustrations of some embodiments of the present invention. They are simply provided as exemplary illustrations of some embodiments of the present invention. Therefore, the present invention will be further described and explained with reference to the following drawings with additional particularity and details, but still only as examples.

[0051] Figure 1 A visual representation of the receptor affinity and functional activity of 2C-B and N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB).

[0052] Figure 2 It shows that XOB in CDCl3 1 H NMR spectra. Chemical shifts were referenced to the TMS peak at 0 ppm. Two-dimensional COSY was performed to unambiguously assign resonances. 1 The H integrals were normalized to the triplet resonance at 2.64 ppm, which has an assigned value of 2.00 protons (for the two benzylic protons).

[0053] Figure 3A shows the total ion chromatogram, Figure 3B The electron impact mass spectrum of XOB is shown. XOB elutes in the GC as a single peak at 11.068 minutes.

[0054] Figure 4A shows the absorbance chromatogram of XOB, Figure 4B The corresponding data are shown in tabular form. Liquid chromatography was performed using a Waters Acquity I-Class UPLC system equipped with a Waters HSS T3 column. The absorbance was monitored at a wavelength of 269 nm using a photodiode array detector. XOB(8) eluted as a single peak with a retention time of 1.53 minutes and accounted for 96.76% of the total peak area.

[0055] Figure 5A and Figure 5B A high resolution mass spectrum of XOB is shown. The mass spectra were acquired using a Waters Xevo G2-XS quadrupole time-of-flight (QTof) mass spectrometer operating in ESI positive mode.

[0056] Figure 6 TMD4 of human β2-adrenaline receptor and human 5-HT 2A Sequence alignment between TMD4 of receptors.

[0057] Figure 7TMD6 of human β2-adrenaline receptor and human 5-HT 2A Sequence alignment between TMD6 of receptors.

[0058] Figure 8 TMD7 of human β2-adrenaline receptor and human 5-HT 2A Sequence alignment between TMD7 of receptors.

[0059] Fig. 9 Human β2-adrenaline receptor ECL2 and human 5-HT 2A Sequence alignment between the ECL2 receptors.

[0060] Fig.10 Human β2-adrenaline receptor ECL3 and human 5-HT 2A Sequence alignment between the ECL3 receptors.

[0061] Fig.11A The chemical structure of the clozapine tracer is shown. Fig. 11B The chemical structure of the NAN-190 tracer is shown. Fig. 11C and Fig.11D Display of clozapine tracer with transiently expressed HiBiT-5-HT 2A saturated combination. Fig.11E and Fig.11F Display of clozapine tracer with transiently expressed HiBiT-5-HT 2c saturated combination. Fig.11G and Fig.11H Showing NAN-190 tracer with transiently expressed HiBiT-5-HT 1A saturated combination. Fig.11I The equilibrium dissociation constants (K D ).

[0062] Figures 12A-12D The binding properties of XOB and serotonin to the 5-HT receptor are shown. Increasing concentrations of unmodified XOB and serotonin competitively displace transiently expressed HiBiT-5-HT 2A ( Fig. 12A )、HiBiT-5-HT 2c ( Fig. 12B ) and HiBiT-5-HT 1A ( Fig. 12C ) fluorescent tracer. Fig.12D The equilibrium binding constant (K i ).

[0063] Fig.13 Clozapine tracer and HiBiT-5-HT 2ABinding properties in equilibrium and real time. (Top) Kinetic binding analysis; (Bottom) Binding properties in equilibrium and kinetic modes.

[0064] Fig.14 HiBiT-5-HT 2A Binding properties of serotonin to XOB in equilibrium and real time. Kinetic binding analysis of (top) serotonin and (bottom) XOB. The table shows the binding properties in equilibrium and kinetic modes.

[0065] Figures 15A-15C It shows that XOB is involved in 5-HT 2A , 5-HT 2B and 5-HT 2C Gq-mediated calcium flux agonist and antagonist activity on the receptor. 5-HT stably expressed in the Flp-In 293T-Rex-inducible cell line 2A ( Fig.15A ), 5-HT 2B ( Fig. 15B ) and 5-HT 2C ( Fig. 15C ) receptors in agonist mode (top) and antagonist mode (bottom), comparing XOB to positive controls (5-HT in agonist mode and clozapine in antagonist mode). 5-HT (3.2 nM) concentration was used in antagonist mode. All data represent the mean and SEM of three independent experiments (repeated measurements).

[0066] Figures 16A-16D Manual patch clamp analysis revealed that XOB is sensitive to hNa v 1.1 Acute effects. Fig.16A Representative I images of the same HEK cell at baseline (top), 4 min after perfusion with 10 μM XOB (middle), and 10 min after washout (bottom) are shown. Na Current trace. Fig. 16B Combined current-voltage (IV) relationships for baseline, 10 μM XOB, and post-washout cells are shown. Fig. 16C Representative peak I is shown Na The traces show the baseline initial scan (black) and 1, 5, and 10 μM XOB (grey) at 3.9 min after perfusion. The HEK cells used in AB stably express human Na v 1.1, while the HEK cells used in CD also express Na v 1.1 and Na v β1 subunit. Fig.16D Peak I is shown Na Evoked diary plots were performed using voltage steps from -120 mV to 0 mV every 5.21 s for 250 ms.

[0067] Figures 17A-17D Display, using automated patch clamp (SyncroPatch), XOB peak I Na It showed concentration-dependent inhibition. Fig.17A XOB peak I is shown Na The concentration response curve (IC 50 : 4.29 μM, 95% CI: 3.24 μM to 5.55 μM; slope: 1.45, 95% CI: 0.99 to 2.19). Fig. 17B SyncroPatch 384-well array showing Peak I of XOB perfusion Na Inhibition heatmap. The leftmost and rightmost columns show vehicle and 1 μM TTX conditions, respectively. Fig. 17C Representative single well peaks from SyncroPatch under vehicle (grey), 10 μM XOB (black), and 1 μM TTX (black) conditions are shown. Na track. Fig.17D Shows the normalized peak I Na Time course of inhibition showing the mean peak I of cells in each concentration group across all scans under baseline (<120 sec) or drug conditions (>120 sec). Na The dashed line indicates the start of drug infusion. v 1.1 and Na v β1 HEK cells.

[0068] Figures 18A-18C The XOB vs. IV relationship and hNa measured using automated patch clamp (SyncroPatch) are shown. v 1.1+Concentration response of the voltage dependence characteristics of h1. Fig.18A The effect of increasing XOB concentration on the IV curve is shown. Fig.18B Shows the use of Fig.18A The peak I caused by the voltage step from -120mV to -20mV in the IV data is Na density. Fig.18C The conductivity (G / G) between the support (open dots) and 3 μM XOB (solid dots) conditions is shown. Max ) voltage dependence and availability (I / I Max ) were compared with the voltage dependence of the 24-well plate. v 1.1 and Na v β1 HEK cells.

[0069] Figures 19A-19JShown are the effects of 10 μM XOB on membrane properties and action potential firing of layer V pyramidal neurons in the prefrontal cortex of wild-type mice. Fig.19A Displays the input resistance, Fig.19B Displays the resting membrane potential, Fig.19C Display 1 st AP threshold, Fig.19D Display capacitance, Fig.19E Displays the peak half-width, Fig.19F Display 1 st AP peak amplitude, Figure 19G Displays the maximum dV / dt, Fig.19H Displays minimum dV / dt, Fig.19I Displays the AP firing frequency when 400pA current is injected; Fig.19J Shown are the frequency-current relationships of PFC layer V pyramidal neurons at baseline (solid dots) and after perfusion of 10 μM XOB (open dots).

[0070] Fig. 20 Shown are representative action potential traces of layer V pyramidal neurons in the prefrontal cortex of wild-type mice at baseline (left column) and 10 μM XOB conditions (right column) at 0, 100, 200, 300, and 400 pA current injection. DETAILED DESCRIPTION

[0071] Although the various aspects and features of certain embodiments are summarized above, the following detailed description further illustrates several exemplary embodiments in detail to enable those skilled in the art to practice these embodiments and make and use the full scope of the invention as claimed. The examples are for illustrative purposes only and are not intended to limit the scope of the invention or its application, which includes all embodiments and formulations thereof, not just those explicitly described. It should be understood that those skilled in the art may make many modifications, substitutions, changes and variations to the embodiments, embodiments, applications and details of the invention described herein without departing from the spirit of the invention or the scope of the invention as claimed.

[0072] A. General Definitions and Terminology

[0073] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes reference to a combination of two or more active agents, and reference to "an excipient" includes a combination of two or more excipients. Although the term "one or more" may be used, its absence (or replacement with the singular) does not imply singular-only, but rather simply emphasizes the possibility of multiple agents or ingredients being present in a particular embodiment.

[0074] The terms "including," "comprising," "such as," and "having" are intended to be inclusive rather than exclusive (i.e., there may be additional elements in addition to the listed elements). Thus, the term "including," as used herein, is meant to be used interchangeably with the phrase "including but not limited to." The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless the context clearly dictates otherwise.

[0075] Unless otherwise stated, all numbers representing the quantity of ingredients, properties (such as concentrations, reaction conditions, etc.) used to describe and claim certain embodiments of the present invention should be understood as being modified by the term "about" in some cases. Therefore, in the embodiments, the numerical parameters listed in the written description and the appended claims are approximate values, which can vary according to the desired characteristics desired to be obtained in a particular embodiment. In the embodiments, "about" refers to plus or minus five percent (± 5%) of the unit of measurement. In the embodiments, the term "from" when used in the context of a numerical range includes the two boundary numbers within the range. For example, the phrase "from 1 to 10" includes the numbers 1 and 10. When the term "substantially" is used to modify the features or limitations herein, it should be understood in the context of the present invention and according to the knowledge in the art to provide appropriate certainty, for example, by measuring the meaning of "substantially" as a term of degree using standards recognized in the art, or by the range that can be determined by those skilled in the art.

[0076] In some embodiments (equivalently and abbreviated as "in embodiments"), numerical parameters should be interpreted in light of the number of reported significant digits and by applying ordinary rounding techniques. Although the numerical ranges and parameters setting forth the broad scope of some embodiments of the present invention are approximate, the numerical values ​​listed in the specific embodiments are reported as precisely as possible. The numerical values ​​presented in some embodiments may contain certain errors that are necessarily due to the standard deviation in their respective testing measurements.

[0077] A complete list of abbreviations used by organic chemists of ordinary skill in the art is given in the first issue of each volume of the Journal of Organic Chemistry; this list is usually presented in a table entitled "List of Standard Abbreviations"; the most recent list as of the date of this application is incorporated herein by reference as if fully set forth herein.

[0078] Unless otherwise defined, all technical and scientific terms herein have the meanings commonly understood by one of ordinary skill in the art to which the invention belongs, which may be referred to simply as "one skilled in the art". Further definitions that may help the reader understand the disclosed embodiments are as follows; however, it should be understood that these definitions are not intended to limit the scope of the invention, which should be properly interpreted and understood by reference to the entire specification (and any plain meanings known to one skilled in the relevant art) and in conjunction with the language used in the appended claims. The terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0079] In general, the nomenclature used herein and the procedures performed are those known in the art related to one or more aspects of the invention, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry and / or medicinal chemistry, and are well known and commonly used in these fields. Standard techniques and procedures will be those commonly performed according to conventional methods in the art.

[0080] "Alkyl" is understood to include straight or branched chain groups with any degree or degree of saturation, i.e., groups having only single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having a mixture of single bonds, double bonds, and triple carbon-carbon bonds. When a specific degree of saturation is desired, the expressions "alkanyl," "alkenyl," and "alkynyl" may also be used. Preferably, the alkyl group contains 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 group, the alkyl group may be optionally substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, cycloalkyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, and -SONH2.

[0081] "Alkyl" refers to a saturated branched, straight chain or cyclic alkyl radical derived from a single carbon atom of a parent alkane by removing a hydrogen atom. Typical alkyl groups include methyl; ethyl; propanyl such as prop-1-yl, prop-2-yl (isopropyl) and cycloprop-1-yl; butanyl such as but-1-yl, but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl) and cyclobut-1-yl; and the like.

[0082] "Alkenyl" refers to an unsaturated branched, straight chain or cyclic alkyl radical having at least one carbon-carbon double bond derived from a parent olefin by removing a hydrogen atom from a carbon atom. The radical may be in a cis or trans configuration about the double bond. Typical alkenyl groups include ethenyl; propenyl groups 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 groups 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-2-yl, but-1,3-dien-1-yl, but-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, and cyclobut-1,3-dien-1-yl; and the like.

[0083] "Alkynyl" refers to an unsaturated branched, straight chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived from a single carbon atom of a parent alkyne by removing a hydrogen atom. 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; and the like.

[0084] "Aryl" refers to a monovalent aromatic hydrocarbon radical derived from a single carbon atom of a parent aromatic ring system by removing a hydrogen atom. Typical aryl groups include radicals derived from acetylanthracene, acenaphthene, acetyphenanthrene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexaphene, hexene, hexene, trans-indolacene, homo-indolacene, indene, naphthalene, octaphene, octaphene, octoene, oleene, pentadiene, pentacene, pentene, pentylene, perylene, nonylene, phenanthrene, pinene, heptaene, pyrene, pyranol, rubrocene, triphenylene, trinaphthalene, etc. Preferably, the aryl group contains 6 to 20 or more preferably 6 to 12 carbon atoms.

[0085] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic combination containing 3 to 12 ring atoms or the number of atoms indicated. Cycloalkyl can include any number of carbons, for example, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms and 11 to 12 carbon atoms. Monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decalin and adamantane. When cycloalkyl is a monocyclic C 3-8 When the cycloalkyl group is a monocyclic C 3-6 In the case of cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may be substituted or unsubstituted.

[0086] "Cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing the following groups: at least one ring has one or more double bonds. However, if there are multiple double bonds, the double bonds cannot form a completely delocalized π electron system on all rings (otherwise the group will be an "aryl" as defined herein). When composed of two or more rings, these rings can be connected together in a fused manner. Cycloalkenyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms and 11 to 12 carbon atoms. Representative cycloalkenyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene and norbornadiene. The cycloalkenyl group can be unsubstituted or substituted.

[0087] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0088] "Heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group 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, bridged bicyclic compounds. The heteroatoms can also be oxidized, such as but not limited to -S(O)- and -S(O)2-. Heterocycloalkyl may include any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 or 3 to 12 ring members. Any suitable number of heteroatoms may be included in the heterocycloalkyl group, such as 1, 2, 3 or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl can include the following groups: aziridine, azetidine, pyrrolidine, piperidine, azepan, azooctane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxetane (tetrahydropyran), oxepane, thipropane, thibutane, thiolane (tetrahydrothiophene), thiolane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane or dithiane. Heterocycloalkyl can also be fused with aromatic or non-aromatic ring systems to form members including but not limited to indoline. Heterocycloalkyl can be unsubstituted or substituted. For example, heterocycloalkyl can be substituted by C1-6 alkyl or oxo (=O) and the like.

[0089] "Alkyl-heterocycloalkyl" refers to a group having an alkyl portion and a heterocycloalkyl portion, wherein the alkyl portion connects the heterocycloalkyl portion to the point of attachment. The alkyl portion is as defined above, except that the alkyl portion is at least divalent, i.e., alkylene, to connect to the heterocycloalkyl portion and the point of attachment. The alkyl portion may include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6, and C5-6. In some cases, the alkyl portion may not be present. The heterocycloalkyl portion is as defined above. Alkylheterocycloalkyl may be substituted or unsubstituted.

[0090] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, of which 1 to 5 ring atoms are heteroatoms, such as N, O or S. Heteroaryl can include any number of ring atoms, such as 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 or 3 to 12 ring members. Heteroaryl can include any suitable number of heteroatoms, 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 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 can include 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 can also be fused with an aromatic ring system (e.g., a benzene ring) to form members including but not limited to benzopyrrole (e.g., indole and isoindole), benzopyridine (e.g., quinoline and isoquinoline), benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine (e.g., phthalazine and cinnoline), benzothiophene and benzofuran. Other heteroaryl groups include heteroaromatic rings connected by bonds, such as bipyridine. Heteroaryl can be substituted or unsubstituted.

[0091] "Alkylheteroaryl" refers to a group having an alkyl portion and a heteroaryl portion, wherein the alkyl portion connects the heteroaryl portion to the point of attachment. The alkyl portion is as defined above, except that the alkyl portion is at least divalent, i.e., alkylene, to connect to the heteroaryl portion and the point of attachment. The alkyl portion may include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6, and C5-6. In some cases, the alkyl portion may not be present. The heteroaryl portion is as defined therein. Alkylheteroaryl may be substituted or unsubstituted.

[0092] "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 groups is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenoxy and benzyloxy. Alkoxy groups may be substituted or unsubstituted.

[0093] "Acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl attached through a carbonyl group as a substituent. Examples include formyl, acetyl, propionyl, benzoyl, and acryloyl. Acyl groups can be substituted or unsubstituted.

[0094] As defined herein, "aryloxy" refers to an aryl moiety connected to an oxygen atom, wherein the oxygen atom serves as a point of attachment to the rest of the molecule. Aryloxy may be substituted or unsubstituted. Exemplary aryloxy groups include phenoxy, tolyloxy (including p-tolyloxy, m-tolyloxy and o-tolyloxy), ethylphenoxy (including p-ethylphenoxy, m-ethylphenoxy and o-ethylphenoxy), naphthoxy, etc.

[0095] "Alkylamino" refers to groups such as N-alkylamino (i.e., R-NHR') and N,N-dialkylamino (i.e., R-NR'R"), wherein the amino group is independently substituted with one alkyl group (i.e., R') or two alkyl groups (i.e., R' and R"), respectively; wherein R represents an alkyl group as defined herein. Non-limiting examples of alkylamino include monoalkylamino or dialkylamino, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like. Alkylamino can be unsubstituted or substituted.

[0096] "Alkylthio" or "thioalkyl" refers to the formula -SR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. In some embodiments, where R is aryl, the -SR moiety is referred to as "thioaryl". A non-limiting list of alkylthio or thioalkyl includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, phenylthio, and benzylthio. Alkylthio or thioalkyl can be substituted or unsubstituted.

[0097] As defined herein, "aryl amido" refers to an aryl moiety attached to an amide moiety, wherein the amide moiety serves as the point of attachment to the rest of the molecule. In some embodiments, the aryl amido has the formula Ar—C(=O)NH—* or Ar—NH—C(=O)—*, wherein Ar is an aryl group as defined herein, and * represents the point of attachment to the rest of the molecule. The aryl amido may be substituted or unsubstituted.

[0098] As defined herein, "alkylamido" refers to an alkyl moiety attached to an amide moiety, wherein the amide moiety serves as the point of attachment to the rest of the molecule. In some embodiments, the alkylamido has the formula Ak—C(=O)NH—* or Ak—NH—C(=O)—*, wherein Ak is an alkyl group as defined herein, and * represents the point of attachment to the rest of the molecule. The alkylamido may be substituted or unsubstituted.

[0099] "Haloalkyl" is understood to include any alkyl as defined above, wherein one or more hydrogen atoms are replaced by halogen (e.g., fluorine, chlorine, bromine or iodine). When the alkyl is replaced by more than one halogen, the prefix corresponding to the halogen substitution number can be used to refer to. For example, dihaloalkyl refers to an alkyl substituted by two halogen groups, which can be identical halogens, but are not necessarily identical halogens. The example of haloalkyl includes difluoromethyl (-CHF2), bromofluoromethyl (-CHBrF), trifluoromethyl (-CF3) and 2-fluoroethyl (-CH2CH2F). Other examples of haloalkyl include-CHF2,-CH2F,-CH2CF3,-CH2CHF2,-CH2CH2F,-CH(CH3)(CF3),-CH(CH3)(CHF2) and-CH(CH3)(CH2F).

[0100] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl groups may be substituted or unsubstituted.

[0101] "Haloalkoxy" refers to one or more hydrogen atoms in the -O-alkyl group replaced by halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). The halogens may be the same or different in each case. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoro-methoxy, and 2-fluoroisobutoxy. The haloalkoxy group may be substituted or unsubstituted.

[0102] "Sulfenyl" refers to a -SR group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, as defined herein. The sulfenyl group can be substituted or unsubstituted.

[0103] "Sulfinyl" refers to a -S(=O)-R group, wherein R may be the same as defined for mercapto. The sulfinyl group may be substituted or unsubstituted.

[0104] "Sulfonyl" refers to a -SO2R group, where R can be the same as defined for mercapto. "Alkylsulfonyl" specifically refers to a -SO2R group, where R is alkyl, as defined herein. Sulfonyl (or alkylsulfonyl) can be substituted or unsubstituted.

[0105] "Carboxyl" refers to a -RC(=O)O- group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, as defined herein. Carboxyl can be substituted or unsubstituted.

[0106] "Ester" and "C-carboxy" refer to a -C(=O)OR group, where R may be the same as defined for O-carboxy. "Alkyl ester" refers to a -C(=O)OR group, where R is alkyl, as defined herein. Esters and C-carboxy may be substituted or unsubstituted.

[0107] "Thiocarbonyl" refers to a -C(=S)R group, wherein R may be the same as defined for O-carboxy. The thiocarbonyl group may be substituted or unsubstituted.

[0108] "Trihalomethanesulfonyl" refers to a X3CSO2- radical where each X is a halogen.

[0109] "Trihalomethanesulfonylamino" refers to X3CS(O)2N(R A )-group, wherein each X is halogen, and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, as defined herein.

[0110] "S-sulfonylamino" refers to -SO2N(R A R B ) group, wherein R A and R B S-sulfonylamino may be substituted or unsubstituted.

[0111] "N-sulfonylamino" refers to RSO2N (R A )—group, where R and R A and N-sulfonylamino groups may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, as defined herein. N-sulfonylamino groups may be substituted or unsubstituted.

[0112] "Carbamoyl" includes O-carbamoyl and N-carbamoyl. "O-carbamoyl" refers to -OC(=O)N(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. O-carbamoyl may be substituted or unsubstituted. "N-carbamoyl" refers to ROC(=O)N(R A )—group, where R and R A and N-carbamoyl and N-carbamoyl may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, as defined herein.

[0113] "O-thiocarbamoyl" refers to -OC(=S)-N(RA R B ) group, wherein R A and R B O-thiocarbamoyl may be substituted or unsubstituted.

[0114] "N-thiocarbamoyl" refers to ROC(=S)N(R A )—group, where R and R A and N-thiocarbamoyl and N-thiocarbamoyl may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, as defined herein.

[0115] "C-amido" refers to -C(=O)N(R A R B ) group, wherein R A and R B C-amido may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, as defined herein.

[0116] "N-amido" refers to RC(=O)N(R A )—group, where R and R A and N-amido. The N-amido group may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, as defined herein. The N-amido group may be substituted or unsubstituted.

[0117] Unless otherwise specified, "optionally substituted" means that the group may not be substituted or may be substituted by one or more substituents listed for the group. Similarly, when a group is described as "unsubstituted or substituted", if substituted, the substituent may be selected from one or more indicated substituents. When multiple substituents are present, each substituent may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. If the "optionally substituted" or "substituted" group does not indicate a substituent, it means that the indicated "optionally substituted" or "substituted" group can be one or more independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), (heterocyclyl) alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thio The invention also includes but is not limited to: a monosubstituted amino group, a disubstituted amino group, a trisubstituted amino group, a trisubstituted amino group, a trisubstituted amino group, a trisubstituted amino group, a monosubstituted amino group, a disubstituted amino group, and a trisubstituted amino group.

[0118] Additional definitions and abbreviations are provided elsewhere in this document.

[0119] B. Compounds

[0120] Psychedelics are a unique class of psychoactive drugs defined by their ability to alter thoughts, feelings, and perceptions (Masters and Houston, The Varieties of Psychedelic Experience., Dell Publishing Co., Inc., 1966; Nichols, Pharmacol Rev., 2016; 68(2): 264-355). The main chemical classes of psychedelic drugs include phenylalkylamines, tryptamines, and lysergic acid amides (Nichols, Pharmacol Rev., 2016; 68(2): 264-355). The typical psychoactive effects of psychedelic phenylalkylamines such as 2-(4-bromo-2,5-dimethoxyphenyl)ethylamine (2C-B) (Shulgin and Carter, Psychopharmacol Commun 1., 1975; 93-98) on consciousness are mainly through the activation of 5-HT 2AIt is believed that 5-HT is mediated by the serotonin (5-HT) receptor subtype (Glennon et al., Life Sci., 1984; 35(25): 2505-2511; Titeler et al., Psychopharmacology (Berl), 1988; 94(2): 213-216; Vollenweider et al., Neuroreport, 1998; 9(17): 3897-3902). 2A Activation of the receptor is also important for the psychoactive properties of lysergic acid amides such as lysergic acid diethylamide (LSD) and tryptamines such as N,N-dimethyltryptamine (DMT) and psilocybin.

[0121] 5-HT 2A The receptor, like the β2 adrenergic receptor, belongs to the G protein-coupled receptor superfamily containing seven transmembrane domains (TMDs). The addition of a phenethoxyhexyl side chain to the β2 agonist salbutamol yields salmeterol, a β2 agonist with higher efficacy and longer duration of action in the treatment of bronchoconstriction associated with asthma and chronic obstructive pulmonary disease (COPD) (Johnson, Med Res Rev., 1995; 15(3): 225-257). Compared to the salbutamol molecule (11A), the extended linear size of the salmeterol molecule (25A) allows the side chain of salmeterol to bind to an accessory binding region within the β2 receptor that is distinct from the agonist binding domain and is referred to as the exosite (Johnson, Med Res Rev., 1995; 15(3): 225-257; Masureel et al., Nat Chem Biol., 2018; 14(11): 1059-1066).

[0122] Evidence from site-directed mutagenesis, chimeric β1 / β2 receptors, photoaffinity labeling, X-ray diffraction crystallography, and computer modeling of the β2 receptor indicates that the exosite is localized within TMDs 4, 6, and 7 and extracellular loops (ECLs) 2 and 3 of the β2 receptor (Green et al., J Biol Chem., 1996; 271(39):24029-24035; Isogaya et al., Mol Pharmacol., 1998; 54(4):616-622; Johnson, Med Res Rev., 1995; 15(3):225-257; Masureel et al., Nat Chem Biol., 2018; 14(11):1059-1066; Rong 1999). The X-ray crystal structure of salmeterol bound to the β2 receptor showed that the aryloxyalkyl tail occupies the cleft formed by the extracellular loops ECL2 and ECL3 and the extracellular terminal residues of TMD6 and TMD7 (Masureel et al., Nat Chem Biol., 2018; 14(11): 1059-1066).

[0123] The human β2 receptor and human 5-HT were aligned using the UniProt Align program (https: / / www.uniprot.org / ). 2A After comparing the amino acid sequences of 5-HT receptors, it was found that 2A The amino acid sequences in the three TMDs of the receptor have high sequence homology (70-94%) with the three TMDs that make up the β2 receptor exosite, while ECL2 and 3 show lower homology (conservation <50%). Based on these sequence homologies, it is hypothesized that 5-HT 2A The receptor, like the β2 receptor, contains an exosite that may bind to the modified 5-HT 2A The extended N-linked side chain of the agonist binds.

[0124] In the first aspect, the present invention provides substituted phenylalkylamine compounds with N-linked side chains. Phenylalkylamines are stimulants, stimulants / hallucinogens and / or psychedelic / psychedelic substances, and their chemical structures are similar to amphetamines, catecholamines, synthetic cathinones and other substances (Nelson et al., Emerg Med Clin North Am., 2014; 32(1): 1-28). Phenylalkylamines include natural and synthetic substances, including classic phenylethylamines, such as MDMA, MDEA and MBDB, and psychoactive phenylethylamines including mescaline-derived compounds, such as TMA, DOM, DOET, DOI and DOC. Recently described phenylalkylamines include bromobenzofurans, benzofurans, N-benzyl substituted phenylalkylamine species and the "2C series", such as 2C-I, 2C-E, 2C-B and other "2C-X" compounds (Schifano et al., World Psychiatry, 2015; 14(1): 15-26; Shulgin & Shulgin, PIHKAL: A Chemical Love Story, Transform Press, Berkeley, CA, 1991).

[0125] In some embodiments, the term "phenylalkylamine" refers to a phenylalkylamine having the structure of formula (A), wherein R N1 , R N2 , R α , R β and R 2 -R 6 Each of which is as defined herein and as understood in the art:

[0126]

[0127] In some embodiments of Formula (A), R N1 , R N2 , R α , R β and R 2 -R 6Each of which is independently hydrogen, halogen, C1-C5 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl (when RN, independently or with nitrogen closed ring), C3-C8 cycloalkenyl (when RN, independently or with nitrogen closed ring), aryl or heterocyclic group; including wherein R3 and R4 can be linked together to form dioxole (same as MDMA), furan, tetrahydrofuran, thiophene, pyrrole, pyridine, pyrrolidine, ethylene oxide, ethyleneimine, trimethylene oxide, pyran, piperidine, imidazole, thiazole, dioxane, morpholine, pyrimidine or other compounds, thereby producing a benzene heterocycle; and any of which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, thiol, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2 and -SONH.

[0128] In some embodiments of Formula (A), R N1 , R N2 , R α , R β and R 2 -R 6 Each of R is independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In some embodiments, R 3 and R 4 are linked together to form an optionally substituted heterocyclic group, such as dioxole (as with 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 4 are linked together to form an optionally substituted aryl group, such as a phenyl group. In some embodiments, the phenethylamine comprises a quaternary ammonium cation, wherein R N1 , R N2 and additional R N3 Each of R is independently alkyl or aryl, and all other substituents are as described above. In an embodiment, phenethylamine is a quaternary salt, wherein the additional R N3 With R N1 and R N2 The nitrogen bonded to it is connected; wherein R N3is 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.

[0129] In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include phenylalkylamines of formula (A) with an N-linked side chain. In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include phenylalkylamines of formula (A), wherein R N1 and R N2 One of is a side chain as described in the embodiments herein, and R N1 and R N2 The other one is as defined above.

[0130] In some embodiments, the term "phenylalkylamine" refers to 2C phenylethylamine. The 2C series phenylethylamines, referred to herein as "2C" or "2C-X" compounds, are ring-substituted phenylethylamines containing methoxy groups at positions 2 and 5 of the phenyl ring and typically a lipophilic substituent at position 4. In some embodiments, the 2C phenylethylamine is a phenylalkylamine having the structure of formula (B),

[0131]

[0132] In some embodiments of formula (B), R' and R" are independently selected from hydrogen, N, NO2, Cl, Br, F, I, CH3, CH3O-, CH3CH2O-, CH3CH2CH2O-, CF3O-, CF3CH2O-, CF3CH2CH2O-, CH3CH2-, CH3CH2CH2-, CH3S-, CH3CH2S-, (CH3)2CHS-, CH3CH2CH2S-, CH3CH2CH2CH2S-, (CH3)3CS-, CF3CH2-, CF3CH2CH2-, CF3S-, CF3CH2S-, CF3CH2CH2S-, FCH2CH2S-, or (CH2) 1-6 —, (CH2) 0-5 —, wherein (CH) is any fused (when CH2=0) or unfused 3, 4, 5 or 6 membered ring system, which may include a bridged ring system or an aromatic ring system. In some embodiments, R′ is hydrogen and R″ is as defined above. In some embodiments, R′ and R″ are both hydrogen.

[0133] In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include phenylalkylamines of formula (B) with N-linked side chains. In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include phenylalkylamines of formula (B) wherein the primary amine is substituted with a side chain as described in the embodiments herein.

[0134] Modification of the 2C aromatic ring at different positions produces different compounds with altered neurochemical effects. Many 2C compounds have effects on different subtypes of serotonin, 5-HT 2AThe 2C-B-type phenylalkylamine compounds of the present invention exhibit affinity for α1-adrenaline receptors, and some compounds interfere with the reuptake of dopamine, serotonin and norepinephrine, while 2C-B acts as an α1-adrenaline receptor agonist (Nichols, Pharmacology & Therapeutics. 2004; 101(2): 131–181; Villalobo et al., British Journal of Pharmacology. 2004; 141(7): 1167–1174). In some embodiments, the substituted phenylalkylamine compounds of the present invention comprise 2C-X with an N-linked side chain, wherein 2C-X is 2C-B, 2C-B-AN, 2C-B-Butterfly, 2C-B-Fly-NBOMe, 2C-B-Fly-NB2EtO5Cl, 2C-Bn, 2C-Bu, 2C-B-5-Hemifly, 2C-C, 2C-C-3, 2C-CN, 2C-CP, 2C- C-D, 2C-E, 2C-EF, 2C-F, 2C-G, 2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, 2C-GN, 2C-H, 2C -I, 2CB-Ind, 2C-iP, 2C-N, 2C-NH2, 2C-PYR, 2C-PIP, 2C-O, 2C-O-4, 2C-M0M, 2C-P, 2C-Ph, 2C-Se, 2C -T, 2C-T-2, 2C-T-3, 2C-T-4, 2C-T-5, 2C-T-6, 2C-T-7, 2C-T-8, 2C-T-9, 2C-T-10, 2C-T-11, 2C-T- 12. 2C-T-13, 2C-T-14, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-18, 2C-T-19, 2C-T-21, 2C-T-21.5, 2C-T Any of 2C-T-2, 2C-T-22, 2C-T-23, 2C-T-24, 2C-T-25, 2C-T-27, 2C-T-28, 2C-T-30, 2C-T-31, 2C-T-32, 2C-T-33, 2C-DFM, 2C-TFM, 2C-TFE, 2C-YN, 2C-V and 2C-AL, as such compounds are understood in the art and such compounds are amine substituted with side chains as defined herein.

[0135] As used herein, in the disclosure in the context of substituted phenylalkylamine compounds, the term "side chain" refers to an optionally substituted alkyl chain (e.g., an optionally substituted n-decyl). In some embodiments, one or more methylene units of the alkyl chain may be substituted with a heteroatom (e.g., oxygen; thereby introducing an ether bond into the side chain). In some embodiments, the alkyl chain is substituted. For example, in some embodiments, the side chain is aryl substituted (e.g., substituted with an optionally substituted benzene ring).

[0136] In some embodiments, the side chain has -(CH2) m X(CH2) n The structure of Ph, wherein X is a methylene group (CH2) or a heteroatom linker (e.g., O, S, NH, etc.). Ph is an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; m and n are each independently an integer from 1 to 20. In some embodiments, X is CH2. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NH. In some embodiments, the side chain is an aralkyloxyalkyl group (e.g., having the formula -(CH2) m O(CH2) n Ph side chain), and the disclosed compounds are N-aralkyloxyalkyl substituted phenylalkylamines.

[0137] In some embodiments, Ph is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In an embodiment, Ph is an optionally substituted 3, 4, 5, 6, 7, 8, 9 or 10 yuan aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In an embodiment, Ph is an optionally substituted aryl. In an embodiment, Ph is an optionally substituted phenyl. In an embodiment, Ph is an unsubstituted phenyl. In an embodiment, Ph is a phenyl substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic radical, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0138] In some embodiments, m is an integer from 1 to 20. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, m is 14. In embodiments, m is 15. In embodiments, m is 16. In embodiments, m is 17. In embodiments, m is 18. In embodiments, m is 19. In embodiments, m is 20. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, n is 14. In embodiments, n is 15. In embodiments, n is 16. In embodiments, n is 17. In embodiments, n is 18. In embodiments, n is 19. In embodiments, n is 20. In embodiments, the sum of m+n is from 4 to 16. In embodiments, the sum of m+n is from 6 to 14. In embodiments, the sum of m+n is from 7 to 13. In embodiments, the sum of m+n is from 8 to 12. In embodiments, the sum of m+n is from 9 to 11. In embodiments, the sum of m+n is 6. In embodiments, the sum of m+n is 7. In embodiments, the sum of m+n is 8. In embodiments, the sum of m+n is 9. In embodiments, the sum of m+n is 10. In embodiments, the sum of m+n is 11. In embodiments, the sum of m+n is 12. In embodiments, the sum of m+n is 13. In embodiments, the sum of m+n is 14. In an embodiment, m and n are selected from the following pair series: 1 and 9, 2 and 8, 3 and 7, 4 and 6, 5 and 5, 6 and 4, 7 and 3, 8 and 2, 9 and 1.

[0139] In some embodiments, the compound has the structure of formula (I)

[0140]

[0141] wherein: m and n are selected from the following pairs: 1 and 9, 2 and 8, 3 and 7, 4 and 6, 5 and 5, 6 and 4, 7 and 3, 8 and 2, 9 and 1; R and R2 are independently hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclic, any of which may be replaced at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl R1 represents 1-3 substituents independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclic group, wherein R1 can be replaced by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic group, amino, alkylamino, arylamido, alkylamido, mercapto, thioalkyl, thioaryl, alkylsulfonyl, alkylaminomethoxy ... R3 is hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, mercapto, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from halogen, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; and Ph is optionally substituted at one or more positions with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0142] In embodiments, m and n are selected from the following series of pairs: 1 and 9, 2 and 8, 3 and 7, 4 and 6, 5 and 5, 6 and 4, 7 and 3, 8 and 2, 9 and 1. In embodiments, m is 1 and n is 9. In embodiments, m is 2 and n is 8. In embodiments, m is 3 and n is 7. In embodiments, m is 4 and n is 6. In embodiments, m is 5 and n is 5. In embodiments, m is 6 and n is 4. In embodiments, m is 7 and n is 3. In embodiments, m is 8 and n is 2. In embodiments, m is 9 and n is 1.

[0143] In some embodiments, R and R2 are independently hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, any of which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, R is hydrogen. In an embodiment, R is C1-C8 alkyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is unsubstituted C1-C8 alkyl. In an embodiment, R is substituted C1-C8 alkyl. In an embodiment, R is C1-C8 alkoxy, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, R is unsubstituted C1-C8 alkoxy. In embodiments, R is substituted C1-C8 alkoxy. In embodiments, R is C1-C8 alkenyl, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic radical, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions. In embodiments, R is unsubstituted C1-C8 alkenyl. In embodiments, R is substituted C1-C8 alkenyl. In an embodiment, R is C1-C8 alkynyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is unsubstituted C1-C8 alkynyl. In an embodiment, R is substituted C1-C8 alkynyl.In an embodiment, R is a C3-C8 cycloalkyl group, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted C3-C8 cycloalkyl group. In an embodiment, R is a substituted C3-C8 cycloalkyl group. In an embodiment, R is a C3-C8 cycloalkenyl group, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted C3-C8 cycloalkenyl. In an embodiment, R is a substituted C3-C8 cycloalkenyl. In an embodiment, R is an aryl, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions. In an embodiment, R is an unsubstituted aryl. In an embodiment, R is a substituted aryl. In an embodiment, R is a heterocyclic radical, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic radical, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted heterocyclic radical. In an embodiment, R is a substituted heterocyclic radical.

[0144] In some embodiments, R2 is hydrogen.In embodiments, R2 is C1-C8 alkyl, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions.In embodiments, R2 is unsubstituted C1-C8 alkyl.In embodiments, R2 is substituted C1-C8 alkyl. In an embodiment, R is a C1-C8 alkoxy group, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted C1-C8 alkoxy group. In an embodiment, R is a substituted C1-C8 alkoxy group. In an embodiment, R is C1-C8 alkenyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is unsubstituted C1-C8 alkenyl. In an embodiment, R is substituted C1-C8 alkenyl. In an embodiment, R is C1-C8 alkynyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is unsubstituted C1-C8 alkynyl. In an embodiment, R is substituted C1-C8 alkynyl. In an embodiment, R is a C3-C8 cycloalkyl group, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted C3-C8 cycloalkyl group. In an embodiment, R is a substituted C3-C8 cycloalkyl group.In an embodiment, R2 is a C3-C8 cycloalkenyl group, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions. In an embodiment, R2 is an unsubstituted C3-C8 cycloalkenyl group. In an embodiment, R2 is a substituted C3-C8 cycloalkenyl group. In an embodiment, R2 is an aryl group, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions. In an embodiment, R2 is an unsubstituted aryl. In an embodiment, R2 is a substituted aryl. In an embodiment, R2 is a heterocyclic radical, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic radical, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is an unsubstituted heterocyclic radical. In an embodiment, R2 is a substituted heterocyclic radical.

[0145] In some embodiments, R1 represents 1-3 substituents, which are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, wherein one or more positions are optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 represents 1 substituent, which is selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, and the substituent is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 represents 2 substituents, which are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, wherein one or more positions are optionally substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 represents 3 substituents, which are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, wherein one or more positions are optionally substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0146] In some embodiments, R1 is hydrogen. In embodiments, R1 is halogen. In embodiments, R1 is F, Cl, Br or I. In embodiments, R1 is C1-C8 alkyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, R1 is unsubstituted C1-C8 alkyl. In embodiments, R1 is substituted C1-C8 alkyl. In an embodiment, R1 is C1-C8 alkoxy, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is unsubstituted C1-C8 alkoxy. In an embodiment, R1 is substituted C1-C8 alkoxy. In an embodiment, R1 is C1-C8 alkenyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is unsubstituted C1-C8 alkenyl. In an embodiment, R1 is substituted C1-C8 alkenyl. In an embodiment, R1 is C1-C8 alkynyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is unsubstituted C1-C8 alkynyl. In an embodiment, R1 is substituted C1-C8 alkynyl. In an embodiment, R1 is a C3-C8 cycloalkyl group, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is an unsubstituted C3-C8 cycloalkyl group. In an embodiment, R1 is a substituted C3-C8 cycloalkyl group.In an embodiment, R1 is a C3-C8 cycloalkenyl group, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is an unsubstituted C3-C8 cycloalkenyl group. In an embodiment, R1 is a substituted C3-C8 cycloalkenyl group. In an embodiment, R1 is an aryl group, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is an unsubstituted aryl. In an embodiment, R1 is a substituted aryl. In an embodiment, R1 is a heterocyclic radical, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic radical, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is an unsubstituted heterocyclic radical. In an embodiment, R1 is a substituted heterocyclic radical.

[0147] In some embodiments, R3 is hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from halogen, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0148] In some embodiments, R3 is hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate.

[0149] In embodiments, R3 is hydrogen. In embodiments, R3 is C1-C8 alkyl, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions. In embodiments, R3 is unsubstituted C1-C8 alkyl. In embodiments, R3 is substituted C1-C8 alkyl. In an embodiment, R3 is C1-C8 alkoxy, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions. In an embodiment, R3 is unsubstituted C1-C8 alkoxy. In an embodiment, R3 is substituted C1-C8 alkoxy. In an embodiment, R3 is C1-C8 alkenyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is unsubstituted C1-C8 alkenyl. In an embodiment, R3 is substituted C1-C8 alkenyl. In an embodiment, R3 is C1-C8 alkynyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is unsubstituted C1-C8 alkynyl. In an embodiment, R3 is substituted C1-C8 alkynyl. In an embodiment, R3 is C3-C8 cycloalkyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is unsubstituted C3-C8 cycloalkyl. In an embodiment, R3 is substituted C3-C8 cycloalkyl.In an embodiment, R3 is a C3-C8 cycloalkenyl group, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions. In an embodiment, R3 is an unsubstituted C3-C8 cycloalkenyl group. In an embodiment, R3 is a substituted C3-C8 cycloalkenyl group. In an embodiment, R3 is an aryl group, which is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate at one or more positions. In an embodiment, R3 is an unsubstituted aryl. In an embodiment, R3 is a substituted aryl. In an embodiment, R3 is a heterocyclic radical, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic radical, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is an unsubstituted heterocyclic radical. In an embodiment, R3 is a substituted heterocyclic radical.

[0150] In some embodiments, R3 is selected from halogen, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, R3 is halogen. In embodiments, R3 is alkyl. In embodiments, R3 is alkyl ester. In embodiments, R3 is hydroxyl. In embodiments, R3 is alkoxy. In embodiments, R3 is carboxyl. In embodiments, R3 is formyl. In embodiments, R3 is aryloxy. In embodiments, R3 is amino. In embodiments, R3 is alkylamino. In embodiments, R3 is arylamido. In embodiments, R3 is alkylamido. In embodiments, R3 is sulfhydryl. In embodiments, R3 is alkylthio. In embodiments, R3 is arylthio. In embodiments, R3 is alkylsulfonyl. In embodiments, R3 is alkylcarbamoyl. In an embodiment, R3 is arylcarbamoyl. In an embodiment, R3 is nitrate. In an embodiment, R3 is cyano. In an embodiment, R3 is nitrate.

[0151] In some embodiments, Ph is phenyl, which is optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, Ph is unsubstituted phenyl. In embodiments, Ph is substituted phenyl.

[0152] Table 1 shows exemplary side chain variants of Formula (I), which, according to the embodiments herein, can be claimed, for example, as individual compounds, as part of a composition comprising individual compounds, as part of a composition comprising a mixture, combinations of two (or more) compounds, and such compounds and / or compositions for use in the preparation of therapeutic agents, or (such compounds and / or compositions) for use in methods of modulating neurotransmission, methods of treating medical conditions or ameliorating symptoms thereof, and / or methods of improving mental health or function.

[0153] Table 1. Exemplary side chain variants of Formula (I)

[0154]

[0155]

[0156] In some embodiments, the compound has the structure of Formula (II),

[0157]

[0158] or a pharmaceutically acceptable salt thereof, wherein m and n are each independently an integer from 1 to 13, provided that the sum of m+n is 6 to 14; X is O, S or NH; R and R2 are each independently C1-C8 alkoxy, wherein each C1-C8 alkoxy is optionally substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; R1 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 -C8 cycloalkenyl, aryl or heterocyclyl, each of which is optionally substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; R3 is hydrogen or C1-C8 alkyl; Ph is phenyl, optionally substituted by halogen, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0159] In some embodiments, m and n are each independently an integer from 1 to 13, provided that the sum of m+n is from 6 to 14. In embodiments m is 1. In embodiments m is 2. In embodiments m is 3. In embodiments m is 4. In embodiments m is 5. In embodiments m is 6. In embodiments m is 7. In embodiments m is 8. In embodiments m is 9. In embodiments m is 10. In embodiments m is 11. In embodiments m is 12. In embodiments m is 13. In embodiments n is 1. In embodiments n is 2. In embodiments n is 3. In embodiments n is 4. In embodiments n is 5. In embodiments n is 6. In embodiments n is 7. In embodiments n is 8. In embodiments n is 9. In embodiments n is 10. In embodiments n is 11. In embodiments n is 12. In embodiments n is 13. In embodiments, the sum of m+n is from 6 to 14. In embodiments, the sum of m+n is from 7 to 13. In embodiments, the sum of m+n is from 8 to 12. In embodiments, the sum of m+n is 9 to 11. In embodiments, the sum of m+n is 6. In embodiments, the sum of m+n is 7. In embodiments, the sum of m+n is 8. In embodiments, the sum of m+n is 9. In embodiments, the sum of m+n is 10. In embodiments, the sum of m+n is 11. In embodiments, the sum of m+n is 12. In embodiments, the sum of m+n is 13. In embodiments, the sum of m+n is 14.

[0160] In some embodiments, X is O, S, or NH. In embodiments, X is O. In embodiments, X is S. In embodiments, X is NH.

[0161] In some embodiments, R and R2 are each independently C1-C8 alkoxy, wherein each C1-C8 alkoxy is optionally substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, R is C1-C8 alkoxy. In embodiments, R is methoxy (-OCH3). In embodiments, R is unsubstituted C1-C8 alkoxy. In an embodiment, R is C1-C8 alkoxy, wherein C1-C8 alkoxy is substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is C1-C8 alkoxy. In an embodiment, R2 is methoxy (-OCH3). In an embodiment, R2 is unsubstituted C1-C8 alkoxy. In an embodiment, R2 is C1-C8 alkoxy, wherein the C1-C8 alkoxy is substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0162] In some embodiments, R1 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, each of which is optionally substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, R1 is hydrogen. In embodiments, R1 is halogen. In embodiments, R1 is F, Cl, Br or I. In embodiments, R1 is F. In embodiments, R1 is Cl. In embodiments, R1 is Br. In embodiments, R1 is I. In embodiments, R1 is C1-C8 alkyl. In an embodiment, R1 is methyl (-CH3) or ethyl (-CH2CH3). In an embodiment, R1 is methyl. In an embodiment, R1 is ethyl. In an embodiment, R1 is unsubstituted C1-C8 alkyl. In an embodiment, R1 is a C1-C8 alkyl substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is a C1-C8 alkoxy. In an embodiment, R1 is a methoxy (-OCH3). In an embodiment, R1 is an ethoxy (-OCH2CH3). In an embodiment, R1 is an unsubstituted C1-C8 alkoxy. In an embodiment, R1 is a C1-C8 alkoxy group substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is a C1-C8 thioalkyl. In an embodiment, R1 is a methylthio (-SCH3). In an embodiment, R1 is an ethylthio (-SCH2CH3). In an embodiment, R1 is an unsubstituted C1-C8 thioalkyl. In an embodiment, R1 is a C1-C8 thioalkyl substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is a C2-C8 alkenyl. In an embodiment, R1 is an unsubstituted C1-C8 alkenyl.In an embodiment, R1 is a C1-C8 alkenyl substituted with halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is a C2-C8 alkynyl. In an embodiment, R1 is an unsubstituted C1-C8 alkynyl. In an embodiment, R1 is a C1-C8 alkynyl substituted with halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is a C3-C8 cycloalkyl. In an embodiment, R1 is an unsubstituted C3-C8 cycloalkyl. In an embodiment, R1 is a C3-C8 cycloalkyl substituted by halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is a C3-C8 cycloalkenyl. In an embodiment, R1 is an aryl. In an embodiment, R1 is an unsubstituted aryl. In an embodiment, R1 is an aryl substituted with halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is a heterocyclic radical. In an embodiment, R1 is an unsubstituted heterocyclic radical. In an embodiment, R1 is a heterocyclic radical substituted with halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0163] In some embodiments, R3 is hydrogen or C1-C8 alkyl. In embodiments, R3 is hydrogen. In embodiments, R3 is C1-C8 alkyl. In embodiments, R3 is methyl (-CH3) or ethyl (-CH2CH3). In embodiments, R3 is methyl. In embodiments, R3 is ethyl.

[0164] In some embodiments, Ph is phenyl, which is optionally substituted by halogen, azido, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl. In embodiments, Ph is phenyl substituted by halogen, azido, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamido, alkylamido, sulfhydryl, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In embodiments, Ph is phenyl substituted by halogen. In an embodiment, Ph is phenyl substituted with F, Cl, Br or I. In an embodiment, Ph is phenyl substituted with azido. In an embodiment, Ph is phenyl substituted with alkyl. In an embodiment, Ph is phenyl substituted with alkyl ester. In an embodiment, Ph is phenyl substituted with hydroxy. In an embodiment, Ph is phenyl substituted with alkoxy. In an embodiment, Ph is phenyl substituted with methoxy. In an embodiment, Ph is phenyl substituted with carboxyl. In an embodiment, Ph is phenyl substituted with formyl. In an embodiment, Ph is phenyl substituted with aryl. In an embodiment, Ph is phenyl substituted with heterocyclyl. In an embodiment, Ph is phenyl substituted with amino. In an embodiment, Ph is phenyl substituted with alkylamino. In an embodiment, Ph is phenyl substituted with arylamido. In an embodiment, Ph is phenyl substituted with alkylamide. In an embodiment, Ph is phenyl substituted with thiol. In an embodiment, Ph is phenyl substituted with thioalkyl. In an embodiment, Ph is phenyl substituted with thioaryl. In an embodiment, Ph is phenyl substituted with alkylsulfonyl. In an embodiment, Ph is phenyl substituted with alkylcarbamoyl. In an embodiment, Ph is phenyl substituted with arylcarbamoyl. In an embodiment, Ph is phenyl substituted with nitro. In an embodiment, Ph is phenyl substituted with cyano. In an embodiment, Ph is phenyl substituted with nitrate.

[0165] In some embodiments, the compound has a structure of Formula (IIA), (IIB) or (IIC), as shown in Table 2 below, wherein m, n, X and Ph are as defined above for Formula (II).

[0166] Table 2 Formula (IIA), (IIB) and (IIC)

[0167]

[0168] In some embodiments, the compound has a structure of any one of Formulas (III)-(XXVI), as shown in Table 3 below.

[0169] Table 3. Formula (III)-(XXVI)

[0170]

[0171]

[0172] In some embodiments, the compound is selected from Table 4, wherein the compound has the following structure, wherein R, R1, R2, R3, m, X, n and Ph are as defined in the table:

[0173]

[0174] Table 4. Exemplary N-substituted phenylalkylamines

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207] In some embodiments, the compound is selected from:

[0208]

[0209]

[0210] or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0212] The individual compounds of the disclosed compositions should be understood to also include pharmaceutically acceptable salts of these compounds. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, which can be synthesized by conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of these drugs with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or in a mixture of the two; typically, non-aqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol or acetonitrile) are preferred. For therapeutic use, the salt of a compound is one in which the counterion is a pharmaceutically acceptable salt. A person of ordinary skill in the art can select a pharmaceutically acceptable counterion from a variety of available counterions. In specific applications,The selection of a particular anion or cation to prepare a salt may result in an increase or decrease in the solubility of the salt. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acetylphylline, acetate, acetylureaterate, adipate, alginate, aminosalicylate, ammonium, ammonia, ascorbate, aspartate, benzenesulfonate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edet ... edetate), calcium salt, camphor carbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulanate, cyclopentanepropionate, cyclopentylpropionate, d-aspartic acid, d-camphorsulfonate, d-lactate, decanoate, dichloroacetate, digluconate, dodecyl sulfate, edentate, edetate, edisylate, esylate, ethanesulfonate, ethylsulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronic acid salt, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, enanthate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hyaluronate, hyaluronamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothiosulfonate, 1-aspartate, 1-camphorsulfonate, 1-lactate, lactate, lactobionate, laurate, dodecylsulfonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, methanesulfonate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, myristate, N-methylglucamine ammonium salt, naphthalene disulfonate, naphthalenesulfonate, naphthalenesulfonate, nicotinate,Nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphate diphosphate, picrate, pivalate, polygalacturonate, potassium salt, propionate, pyrophosphate, sucrose, salicylate, salicyl sulfate, sodium salt, stearate, subacetate, succinate, sulfate, sulfosalicylate, sulfosalicylate, sullanate, tartrate, theochlorate, terephthalate, thiocyanate, thiosalicylate, methanesulfonate, tribromophenate, triethyl iodide, undecanoate, undecenoate, valerate, valproate, xinafoate, zinc salt, etc. (see Berge, et al., J. Pharm. Sci. 1997, 66, 1-19).

[0213] Certain compounds disclosed herein contain one or more ionizable groups (groups from which a proton can be removed (e.g., -COOH) or added (e.g., amine) or can be quaternized (e.g., amine). The present disclosure includes all possible ionic forms of such molecules and their salts.

[0214] The compounds described herein can exist in solid or liquid form. In the solid state, the compound can exist in crystalline or amorphous form, or in the form of a mixture thereof. It will be appreciated by those skilled in the art that crystalline or amorphous compounds can form pharmaceutically acceptable solvates. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during the crystallization process. Solvates may involve non-aqueous solvents, such as but not limited to ethanol, isopropanol, DMSO, acetic acid, ethanolamine or ethyl acetate, or may involve water as a solvent incorporated into the crystal lattice. Solvates in which water is added to the crystal lattice as a solvent are generally referred to as "hydrates". Hydrates include stoichiometric hydrates and mixtures containing different amounts of water. The subject matter described herein includes such solvates.

[0215] It will be further understood by those skilled in the art that certain compounds described herein in crystalline form (including various solvates thereof) may exhibit polymorphism (i.e., the ability to appear in different crystal structures). These different crystalline forms are generally referred to as "polymorphs". The subject matter disclosed herein includes such polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition in a compound. Polymorphs have the same chemical composition, but differ in packing, geometric arrangement, and other descriptive properties of the crystal solid state. Therefore, polymorphs may have different physical properties, such as shape, density, hardness, deformability, stability, and solubility characteristics. Polymorphs typically exhibit different melting points, infrared spectra, and X-ray powder diffraction patterns, which can be used for identification. It will be understood by those skilled in the art that different polymorphs can be produced, for example, by changing or adjusting the reaction conditions or reagents used to make the compound. For example, changes in temperature, pressure, or solvent may result in the production of polymorphs. Various factors such as recrystallization solvents, crystallization rates, and storage temperatures may result in a single crystalline form dominating. In addition, one crystalline form may spontaneously transform into another crystalline form under certain conditions.

[0216] The compounds described herein may contain one or more asymmetric centers and produce enantiomers, diastereomers and other stereoisomeric forms. In terms of absolute stereochemistry, each chiral center can be defined as (R)- or (S)-. The present invention includes all such possible isomers and mixtures thereof, including racemic forms and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques. A variety of methods for preparing optically active forms and determining activity are known in the art. Such methods include standard tests described herein and other similar tests well known in the art. Examples of methods that can be used to obtain optical isomers of compounds of the present invention include selective crystallization, enzymatic resolution, asymmetric synthesis (including asymmetric chemical synthesis and asymmetric enzyme synthesis), kinetic resolution and chiral chromatography (including chiral liquid chromatography, gas chromatography and high performance liquid chromatography). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, tautomeric forms are also included.

[0217] Also provided are compounds having at least one desired isotopic atom substituted in an amount above the natural abundance of the isotope, i.e., isotopically enriched analogs of the disclosed compounds. Isotopes are atoms having the same atomic number but different mass numbers, i.e., having the same number of protons but different numbers of neutrons. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, such as, respectively 2H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O and 36 In one non-limiting example, isotope-labeled compounds can be used in metabolic studies (using 14 C) Reaction kinetics studies (e.g. using 2 H or 3 H), 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 use in patients undergoing radiotherapy. In particular, NER273_F labeled compounds may be particularly suitable for PET or SPECT studies. In addition, compounds labeled with heavier isotopes (e.g., deuterium, i.e. 2 H) may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain circumstances. Isotopically labeled compounds of the invention can generally be prepared by carrying out the steps disclosed in the following schemes or examples and preparations, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0218] Prodrugs of the disclosed compounds are also provided. "Prodrugs" are precursors of biologically active drugs that can be chemically or metabolically converted to biologically active agents. Prodrugs can be converted to biologically active agents in vitro by chemical conversion processes. In vivo, prodrugs are converted to biologically active agents by metabolic processes, enzymatic processes, or degradation processes, and the prodrug portion is removed to form the biologically active agent. Typical examples of prodrugs include compounds with biologically unstable or cleavable (protective) groups on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce active compounds. Commonly used functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides. These functional groups can be attached to drug molecules by designing linkers that are cleaved under specific physiological conditions (e.g., enzymatic hydrolysis or pH-dependent cleavage). The choice of functional group depends on factors such as stability, ease of synthesis, enzyme activity, and the desired prodrug conversion rate.

[0219] Typically, the disclosed compounds are administered as part of a pharmaceutical composition or formulation 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 of 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 having a chromatographic purity 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% (of the desired compound), as determined by area normalization of the HPLC curve or other similar detection methods.

[0220] Preferably, the substantially pure compounds of the present disclosure are substantially free of any other active compounds that are not intended to be administered to a subject. In this context, "substantially free" is understood to mean that, in addition to the active compound intended to be administered to a subject, no other active compound can be detected by HPLC or other similar detection methods, or is below the required detection threshold as described above.

[0221] C. Pharmaceutical Compositions

[0222] In some aspects, provided herein are compositions, such as pharmaceutical compositions, comprising a disclosed compound, such as a compound of any disclosed formula or subformula thereof. A "pharmaceutical composition" is a composition comprising an amount (e.g., a unit dosage form) of a disclosed compound and a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments will not have a single separate carrier, diluent, or excipient, but will include a plurality of carriers, diluents, and / or excipients. The compositions can be prepared by standard pharmaceutical formulation techniques as described, for example, in Remington: The Science & Practice of Pharmacy (2020) 23th ed., Academic Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, NJ; Pharm. Principles of Solid Dosage Forms (1993), Technomic Pub. Co., Inc., Lancaster, Pa.; and Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; & Poznansky et al. Drug Delivery Systems (1980), RL Juliano, ed., Oxford, NY, pp. 253-315).

[0223] “Pharmaceutically acceptable” for use with an excipient, carrier, diluent, or other ingredient means that the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with human and animal cells without excessive toxicity, irritation, allergic response, or complications, and commensurate with a reasonable risk / benefit ratio.

[0224] In some embodiments, pharmaceutical compositions comprising the disclosed compounds can be administered by a variety of routes, including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal administration. In some embodiments, the compounds used in the methods of the present invention are effective as oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal compositions. Such compositions are prepared in a manner well known in the pharmaceutical field and include at least one active compound. (See, e.g., Remington, 2020).

[0225] The disclosed compositions are preferably formulated in unit dosage form, each dosage containing a therapeutically effective amount of active ingredient, such as the dosage disclosed below. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for subjects to be treated, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, and a suitable pharmaceutical carrier, diluent or excipient. Unit dosage forms are generally used for convenient administration and uniformity of dosage. A unit dosage form may contain a single or separate dose or unit, subdose, or an appropriate portion thereof (e.g., half a "full" dose of a "boost" dose as described below) of the administered pharmaceutical composition.

[0226] Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampoules and vials, which may include compositions in a freeze-dried or lyophilized state; for example, a sterile liquid carrier may be added prior to in vivo administration or delivery. Unit dosage forms also include ampoules and vials containing liquid compositions. Unit dosage forms also include compounds for transdermal administration, such as "patches" that are in contact with the epidermis (including mucous membranes) of a subject for a long or short period of time.

[0227] In some 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, solutions, etc.) and oral solid dosage forms. The disclosed pharmaceutical compositions can also be prepared as preparations suitable for intramuscular, subcutaneous, intraperitoneal or intravenous injection, including physiologically acceptable sterile aqueous or non-aqueous solutions, dispersants, suspensions or emulsions, liposomes and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0228] 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, lozenges, tablets, capsules, caplets, powders, pills, multi-particles, microbeads, 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. Therefore, in some embodiments, the disclosed oral solid dosage forms may be tablets (including suspension tablets, fast dissolving tablets, bite-disintegrating tablets, rapidly disintegrating tablets, effervescent tablets or caplets), pills, powders (including sterile packaged powders, dispensable powders or effervescent powders), capsules (including soft capsules or hard capsules, such as capsules made of animal-derived gelatin or plant-derived HPMC or "sprinkle capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulse release dosage forms, multi-particle dosage forms, pills, granules or aerosols. In other embodiments, the pharmaceutical preparation is in powder form. In other embodiments, the pharmaceutical preparation is in the form of tablets, including quick-dissolving tablets. In addition, the pharmaceutical preparation can be administered in a single capsule or multiple capsule dosage forms. In some embodiments, the pharmaceutical preparation is administered in the form of two, three, four or more capsules or tablets.

[0229] Oral solid dosage forms may contain pharmaceutically acceptable excipients, such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersants, suspending agents, disintegrants, viscosity-increasing agents, 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, ion dispersion regulators, disintegrants, surfactants, lubricants, colorants, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers (alone or in combination), and supplementary active compounds.

[0230] Supplementary active compounds include preservatives, antioxidants, antimicrobials (including biocides and biostats, such as antimicrobials, antivirals and antifungals). Preservatives can be used to inhibit microbial growth or increase the stability of active ingredients, thereby extending the shelf life of the preparation. 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, tocopherols, other vitamins or provitamins, and lipoic acid.

[0231] In some embodiments, the disclosed compositions are formulated as oral liquid dosage forms. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, solutions, etc. These oral liquid dosage forms can be formulated with any pharmaceutically acceptable excipients known to those skilled in the art for preparing liquid dosage forms, as well as solvents, diluents, carriers, excipients, etc. appropriately selected according to the solubility and other properties of the active agent and other ingredients. The solvent can be, for example, water, glycerol, syrup, alcohol, medium chain triglycerides (MCT) and combinations thereof.

[0232] Liquid dosage forms for oral administration can be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions, which may contain inactive diluents, such as water. Pharmaceutical preparations can be prepared into liquid suspensions or solutions, using sterile liquids, such as but not limited to oils, water, alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, emulsifiers, which can be added for oral or parenteral administration. Liquid formulations can also be prepared into single-dose or multi-dose beverages. Suspensions may contain oil. These oils include peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suitable oils also include carrier oils, such as MCT and long-chain triglyceride (LCT) oils. Suspension preparations may also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols (e.g., ethanol, isopropanol, hexadecanol), 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, the suspension may include an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion or an oil-in-water emulsion.

[0233] In some embodiments, a formulation comprising the disclosed composition and at least one dispersant or suspending agent is provided for oral administration to a subject. The formulation can be a powder and / or granules for suspension, and after mixing with water, a substantially uniform suspension can be obtained. The aqueous dispersion can include amorphous and non-amorphous particles composed of a variety of effective particle sizes, so that the drug is absorbed in a controlled manner over time.

[0234] The dosage form for oral administration can be an aqueous suspension selected from pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions and syrups. For example, see Singh et al. Encyclopedia of Pharm. Tech., 2nd Ed., 754-757 (2002). In addition to the disclosed compounds, the liquid dosage form can also contain additives, such as one or more (a) disintegrants, (b) dispersants, (c) wetting agents, (d) preservatives, (e) viscosity enhancers, (f) sweeteners or (g) flavoring agents.

[0235] The disclosed compositions may 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.

[0236] In other embodiments, the disclosed pharmaceutical compositions can be formulated into topical dosage forms. Topical dosage forms include transmucosal and transdermal preparations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. For such preparations, penetrants and carriers may be included in the pharmaceutical composition. Penetrants are known in the art and include detergents, bile salts, and fusidic acid derivatives for transmucosal administration. For transdermal administration, carriers that may be used include Lanolin, polyethylene glycol, alcohol, dermal penetration enhancers and combinations thereof.

[0237] D. Drug Combinations

[0238] It should be readily understood that the disclosed compositions are not limited to combinations of single compounds, or (when formulated as pharmaceutical compositions) are limited to a single single carrier, diluent and / or excipient alone, but may also include combinations of multiple compounds (including additional active compounds), and / or multiple carriers, diluents and excipients. Thus, the pharmaceutical compositions of the present invention may include a combination of a compound of formula (I) with one or more other active agents (or their derivatives and analogs), and one or more pharmaceutically acceptable carriers, diluents and / or excipients, and one or more other active compounds.

[0239] In some embodiments, the formulations of the invention will be prepared to enhance an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property (e.g., stability or shelf life), reduce an undesired effect or property, alter a property in a desired manner (e.g., pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide a synergistic effect.

[0240] "Therapeutic effects" that may be increased or added in embodiments of the present invention include, but are not limited to, antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, antianxiety, anti-depression, anti-psychotic, anti-PTSD, dissociative, immunostimulatory, anti-cancer, anti-emetic, anorectic, anti-ulcer, antihistamine, antihypertensive, anticonvulsant, anti-epileptic, bronchodilator, neuroprotective, hallucinogenic, psychedelic, sedative and stimulant effects.

[0241] "Synergy" is understood to include an increase in potency, biological activity, bioaccessibility, bioavailability or therapeutic effect that is greater than the additive contribution of the individual components acting alone. A variety of methods are known to those skilled in the art to determine whether synergy exists for a particular effect, that is, whether the effect of two or more components when mixed together is greater than the sum of the effects of each component when used alone, 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). 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) can also be used. The graphs corresponding to the above equations are the concentration-effect curve and the combination index curve, respectively. Each of the above equations can be applied to experimental data to generate corresponding graphs, which are helpful in evaluating the effects of drug combinations.

[0242] In some embodiments, the disclosed pharmaceutical composition comprises additional active compounds. In some embodiments, the additional active compounds are selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathy and anti-nociceptive agents, anti-migraine agents, antianxiety agents, antidepressants, antipsychotics, anti-post-traumatic stress disorder agents, dissociative agents, cannabinoids, immunostimulants, anticancer agents, antiemetics, appetite promoters, anti-ulcer agents, antihistamines, antihypertensive agents, anticonvulsants, antiepileptics, bronchodilators, neuroprotective agents, nootropics, hallucinogens, hallucinogens, plasticity inducing agents (e.g., psychoplasticizers), monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonin agents and vitamins. In some embodiments, the additional active compounds play a role in increasing the therapeutic effect, providing additional therapeutic effects, reducing adverse effects, increasing stability or shelf life, improving bioavailability, inducing synergy, increasing plasticity (e.g., neuroplasticity) or changing pharmacokinetics or pharmacodynamics.

[0243] In some embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anti-cancer, antiemetic, anorectic, anti-ulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, hallucinogenic, psychedelic, sedative, or stimulant effect.

[0244] In an embodiment, the additional active compound is a tryptamine. Those skilled in the art will appreciate that a tryptamine is a compound having the following general structure, wherein R N1 , R N2 , R ɑ , R β , R 2 , R 4 , R 5 , R 6 and R 7 As defined herein and as generally understood in the art:

[0245]

[0246] In some embodiments, R N1 , R N2 , R ɑ , R β , R 2 , R 4 , R 5 , R 6 and R 7 Each is independently hydrogen, deuterium, halogen (F, Cl, Br or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl. In addition, R N1 , R N2 , R ɑ , R β , R 2 , R 4 , R 5 , R 6 and R 7 Any two of the atoms and the intermediate atoms may be taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocyclyl. In an embodiment, the tryptamine is a quaternary ammonium salt, wherein the additional R N3 With R N1 and R N2 The nitrogen bonded to it is connected; wherein 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.

[0247] In some embodiments, the additional active compound is a tryptamine selected from the group consisting of: O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 6-allyl-N,N-diethyl-n-lysergic acid amide (AL-LAD), N,N-dibutyltryptamine (DBT), N,N-diethyltryptamine (DET), N,N-diisopropyltryptamine (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-triethyl-n-lysergic acid amide (ETH-LAD), 3,4-dihydro-7-methoxy-1-methylcarboline (Harmaline), 7-methoxy-1-methylcarboline (Harmine), N,N-dibutyl-4-hydroxytryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl-4-hydroxytryptamine (4-HO-DiPT), 4-hydroxy-N,N,N-trimethyltryptamine (4-HO-TMT), N,N-dimethyl-4-hydroxytryptamine (4-HO-DMT), N,N-dimethyl-5-hydroxytryptamine (5-HO-DMT, toad venom tryptamine), 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-propyltryptamine (4-HO-MPT), 4-hydroxy-N,N-tetramethylene-tryptamine (4-HO-pyr-T), 12-methoxyibogaine (Ibogaine), N-butyl-N-methyltryptamine (MBT), N,N-diisopropyl-4,5-methylenedioxytryptamine (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylenedioxytryptamine (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxytryptamine (4,5-MDO-DiPT), Methyldioxytryptamine (4,5-MDO-DMT), N,N-dimethyl-5,6-methylenedioxytryptamine (5,6-MDO-DMT), N-isopropyl-N-methyl-5,6-methylenedioxytryptamine (5,6-MDO-MiPT), N,N-diethyl-2-methyltryptamine (2-Me-DET), 2,N,N-trimethyltryptamine (2-Me-DMT), N-acetyl-5-methoxytryptamine (melatonin), N,N-diethyl-5-methoxytryptamine (5-MeO-DET), N,N-diisopropyl-5-methoxytryptamine (5-MeO-DiPT), N,N,diallyl-5-methoxytryptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-isopropyl-4-methoxy-N-methyltryptamine (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyltryptamine (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyltryptamine (5,6-MeO-MiPT), 5-methoxy-N-methyltryptamine (5-MeO-NMT), 5-methoxy-N,N-tetramethylenetryptamine (5-MeO-pyr-T), 6-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl-tryptamine (5-MeO -TMT), N,N-dimethyl-5-methylthiotryptamine (5-MeS-DMT), N-isopropyl-N-methyltryptamine (MiPT), α-methyltryptamine (α-MT), N-ethyltryptamine (NET), N-methyltryptamine (NMT), 6-propyl-n-lysergic acid amide (PRO-LAD), N,N-tetramethylenetryptamine (pyr-T), tryptamine (T), 7-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (THH) 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. ,

[0248] In some embodiments, the additional tryptamine will be a "complex tryptamine" or other indoleamine, including, for example, iboga alkaloids (eg, ibogaine) and their analogs, metabolites, and derivatives, as well as beta-carbolines.

[0249] In some embodiments, the additional active compound is phenethylamine. In some embodiments, and as will be appreciated by those skilled in the art, the phenethylamine may be a phenylalkylamine having the structure of formula (A), wherein R N1 , R N2 , R α , R β , and R 2 -R 6 Each of which is as defined herein and as commonly understood in the art.

[0250] In some embodiments, the additional active compound is a phenethylamine selected from the group consisting of α-ethyl-3,4,5-trimethoxyphenethylamine (AEM), 4-allyloxy-3,5-dimethoxyphenethylamine (AL), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH), 2,5-dimethoxy-4-ethylthioamphetamine (ALEPH-2), 2,5-dimethoxy-4-isopropylthioamphetamine (ALEPH-4), 2,5-dimethoxy-4-phenylthioamphetamine (ALEPH-6), 2,5-dimethoxy-4-propylthioamphetamine (ALEPH-7), 2,5-dimethoxy-α-ethyl-4-methylphenethylamine (ARIADNE), 3,4-dieth ... 4-Butyl-5-methoxyphenethylamine (ASB), 4-butoxy-3,5-dimethoxyphenethylamine (B), 2,5-dimethoxy-4,N-dimethylamphetamine (BEATRICE), 2,5-bis(methylthio)-4-methylamphetamine (BIS-TOM), 4-bromo-2,5,B-trimethoxyphenethylamine (BOB), 2,5,B-trimethoxy-4-methylphenethylamine (BOD), B-methoxy-3,4-methylenedioxyphenethylamine (BOH), 2,5-dimethoxy-B-hydroxy-4-methylphenethylamine (BOHD), 3,4,5,B-tetramethoxyphenethylamine (BOM), 4-bromo-3,5-dimethoxyphenethylamine (4-Br-3,5-DMA), 2- Bromo-4,5-methylenedioxyamphetamine (2-Br-4,5-MDA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-benzyloxy-3,5-dimethoxyphenethylamine (3C-BZ), 4-chloro-2,5-dimethoxyphenethylamine (2C-C), 2,5-dimethoxy-4-methylphenethylamine (2C-D), 2,5-dimethoxy-4-ethylphenethylamine (2C-E), 3.5-dimethoxy-4-ethoxyphenethylamine (3C-E), 2,5-dimethoxy-4-fluorophenethylamine (2C-F), 2.5-dimethoxy-3,4-dimethylphenethylamine (2C-G), 2,5-dimethoxy- Methoxy-3,4-trimethylenephenethylamine (2C-G-3), 2,5-dimethoxy-3,4-tetramethylenephenethylamine (2C-G-4), 3.4-norbornyl-2,5-dimethoxyphenethylamine (2C-G-5), 1,4-dimethoxynaphthyl-2-ethylamine (2C-GN), 2,5-dimethoxyphenethylamine (2C-H), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), 2.5-dimethoxy-4-nitratephenethylamine (2C-N), 2,5-dimethoxy-4-isopropoxyphenethylamine (2C-O-4), 2,5-dimethoxy-4-propylphenethylamine (2C-P), 4-cyclopropylmethoxy-3,5-dimethoxyphenethylamine (CPM), 2,5-dimethoxy-4-methylselenophenethylamine (2C-SE), 2,5-dimethoxy-4-methylthiophenethylamine (2C-T), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,6-dimethoxy-4-isopropylthiophenethylamine (psi-2C-T-4), 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), 4-cyclopropylmethylthio-2,5-dimethoxyphenethylamine (2C-T-8), 4-(t)-butylthio-2,5-dimethoxyphenethylamine (2C-T-9), 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine (2C-T-13 )、4-cyclopropylthio-2,5-dimethoxyphenethylamine (2C-T-15), 4-(s)-butylthio-2,5-dimethoxyphenethylamine (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine (2C-T-21), 3,5-dimethoxy-4-trideuteriomethylphenethylamine (4-D), B,B-dideuterio-3,4,5-trimethoxyphenethylamine (BD), 3,5-dimethoxy-4-methylphenethylamine (DESOXY), 2.4-dimethoxyamphetamine (2,4-DMA), 2,5-dimethoxyamphetamine (2,5-DMA), 3.4-dimethoxyamphetamine (3,4-DMA), 2-(2,5-dimethoxy-4-methylphenethylamine 2,5-dimethoxy-3,4-methylenedioxyamphetamine (DMMDA), 2,3-dimethoxy-4,5-methylenedioxyamphetamine (DMMDA-2), 3,4-dimethoxyphenethylamine (DMPEA), 4-pentyl-2,5-dimethoxyamphetamine (DOAM), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-butyl-2,5-dimethoxyamphetamine (DOBU), 4-chloro-2,5-dimethoxyamphetamine (DOC), 2,5-dimethoxy-4-(2-fluoroethyl)amphetamine (DOEF), 2,5-dimethoxy-4-ethylamphetamine (DOEF), amine (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-nitrate amphetamine (DON), 2,5-dimethoxy-4-propyl amphetamine (DOPR), 3,5-dimethoxy-4-ethoxyphenethylamine (E), 2,4,5-triethoxyamphetamine (EEE), 2,4-diethoxy-5-methoxyamphetamine (EEM), 2.5-diethoxy-4-methoxyamphetamine (EME), 4,5-dimethoxy-2-ethoxyamphetamine (EMM), 2-ethylamino-1-(3,4-methylenedioxyphenyl)butane (ETHYL-J), 2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane (ETHYL-K), 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran (F-2), 6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran (F-22), N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine (FLEA), 2,5-dimethoxy-3,4-(trimethylene)amphetamine (G-3), 2,5-dimethoxy-3,4-(tetramethylene)amphetamine (G-4), 3,6-dimethoxy-4-(2-aminopropyl)benzofuran Bornane (G-5), 2,5-dimethoxy-3,4-dimethylamphetamine (GANESHA), 1,4-dimethoxynaphthyl-2-isopropylamine (GN), 2,5-dimethoxy-4-ethylthio-N-hydroxyphenethylamine (HOT-2), 2,5-dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine (HOT-7), 4-(s)-butylthio-2,5-dimethoxy-N-hydroxyphenethylamine (HOT-17), 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA), 2,3,4-trimethoxyphenethylamine (IM), 3,5-dimethoxy-4-isopropoxyphenethylamine (IP), 5-ethoxy-2-methoxy-4-methyl Amphetamine (IRIS), 2-amino-1-(3,4-ethylenedioxyphenyl)butane (J, BDB), 3-methoxy-4,5-methylenedioxyphenethylamine (LOPHOPHINE), 3,4,5-trimethoxyphenethylamine (M), 4-methoxyamphetamine (4-MA, PMA), 2,N-dimethyl-4,5-methylenedioxyamphetamine (MADAM-6), 3,5-dimethoxy-4-methylallyloxyphenethylamine (MAL), 3,4-methylenedioxyamphetamine (MDA), N-allyl-3,4-methylenedioxyamphetamine (MDAL), N-butyl-3,4-methylenedioxyamphetamine (MDBU), N-benzyl-3,4-methylenedioxy Methyldioxyamphetamine (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 (MDHOET), N-isopropyl-3,4-methylenedioxyamphetamine (MDIP), N-methyl-3,4-methylenedioxyamphetamine (MDMA), 3,4-methylenedioxy-N-methylamphetamine (MDMC), N-methoxy-3,4-methylenedioxyamphetamine (MDMEO), N-(2-methoxyethyl)-3,4-methylenedioxyamphetamine (MDMEOET), 3,4-methylenedioxy-a,a,N-trimethylphenethylamine (MDMP), N-hydroxy-3,4-methylenedioxyamphetamine (MDOH), 3,4-methylenedioxyphenethylamine (MDPEA), α,α-dimethyl-3,4-methylenedioxyphenethylamine (MDPH), 3,4-methylenedioxy-N-propargylamphetamine (MDPL), 3,4-methylenedioxy-N-propylamphetamine (MDPR), 3,4-dimethoxy-5-ethoxyphenethylamine (ME), 4,5-ethylenedioxy-3-methoxyamphetamine (MED A), 4,5-diethoxy-2-methoxyamphetamine (MEE), 2,5-dimethoxy-4-ethoxyamphetamine (MEM), 4-ethoxy-3-methoxyphenethylamine (MEPEA), 5-bromo-2,4-dimethoxyamphetamine (META-DOB), 2,4-dimethoxy-5-methylthioamphetamine (META-DOT), 2,5-dimethoxy-N-methylamphetamine (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methylamphetamine (METHYL-DOB), 2-methylamino- 1-(3,4-methylenedioxyphenyl)butane (METHYL-J, MBDB), 2-methylamino-1-(3,4-ethylenedioxyphenyl)pentane (METHYL-K), 4-methoxy-N-methylamphetamine (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-N-methyl-4,5-methylenedioxyamphetamine (MMDA-2), 3,4-dimethoxy-2,3-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)-propoxyphenethylamine (MPM), 4,5-dimethoxy-2-methylthioamphetamine (ORTHO-DOT), 3,5-dimethoxy-4-propoxyphenethylamine (P), 3,5-dimethoxy-4- Phenylethoxyphenethylamine (PE), phenethylamine (PEA), 3,5-dimethoxy-4-(2-propynyloxy)phenethylamine (PROPYNYL), 3,5-diethoxy-4-methoxyphenethylamine (SB), 2,3,4,5-tetramethoxyamphetamine (TA), 4-ethoxy-3-ethylthio-5-methoxyphenethylamine (3-TASB), 3-ethoxy-4-ethylthio-5-methoxyphenethylamine (4-TASB), 3,4-diethoxy-5-methylthiophenethylamine (5-TASB), 4-(n)-butylthio-3,5-dimethoxyphenethylamine (TB), 4-ethoxy-5-methoxy-3-methylthiophenethylamine (3-TE), 3,5-dimethoxy-4-ethylthiophenethylamine (TE, 4-TE), 3,4-dimethoxy-2-methylthiophenethylamine (2-TIM), 2,4-dimethoxy-3-methylthiophenethylamine (3-TIM), 2,3-dimethoxy-4-methylthiophenethylamine (4-TIM), 3,4-dimethoxy-5-methylthiophenethylamine (3-TM), 3,5-dimethoxy-4-methylthiophenethylamine (4-TM), 3,4-trimethoxyphenethylamine (TMA), 3,5-dimethoxy-4-methylthiophenethylamine (4-TM), 3,4-dimethoxyphenethylamine (3-TIM), 2,3-dimethoxy-4-methylthiophenethylamine (4-TIM), 3,4-dimethoxyphenethylamine (3-TM), 3,5-dimethoxyphenethylamine (4-TM), 3,4-dimethoxyphenethylamine (3-TM), 3,5-dimethoxyphenethylamine (3 ... ), 2,4,5-trimethoxyamphetamine (TMA-2), 2,3,4-trimethoxyamphetamine (TMA-3), 2,3,5-trimethoxyamphetamine (TMA-4), 2.3.6-trimethoxyamphetamine (TMA-5), 2,4,6-trimethoxyamphetamine (TMA-6), 4,5-dimethoxy-3-ethylthiophenethylamine (3-TME), 3-ethoxy-5-methoxy-4-methylthiophenethylamine (4-TME), 3-ethoxy-4-methoxy-5-methylthiophenethylamine (5-TME), 3,4-methylenedioxy-2-methylthioamphetamine (2T- MMDA-3a), 2-methoxy-4,5-methylenethioxyamphetamine (4T-MMDA-2), 2,4,5-trimethoxyphenethylamine (TMPEA), 4-ethyl-5-methoxy-2-methylthioamphetamine (2-TOET), 4-ethyl-2-methoxy-5-methylthioamphetamine (5-TOET), 5-methoxy-4-methyl-2-methylthioamphetamine (2-TOM), 2-methoxy-4-methyl-5-methylthioamphetamine (5-TOM), 2-methoxy-4-methyl-5-methylsulfinylamphetamine (TOMSO), 3,5-dimethoxy-4-propylthio , 3,4,5-triethoxyphenethylamine (TRIS), 3-ethoxy-5-ethylthio-4-methoxyphenethylamine (3-TSB), 3,5-diethoxy-4-methylthiophenethylamine (4-TSB), 3,4-diethoxy-5-ethylthiophenethylamine (3-T-TRIS), 3,5-diethoxy-4-ethylthiophenethylamine (4-T-TRIS), (R)-2,5-dimethoxy-4-iodophenethylamine (R-DOI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or combinations thereof.

[0251] In some embodiments, the additional active compound is ergoline. In embodiments, the additional active compound is an ergot alkaloid. In embodiments, the additional active compound is lysergic acid amide. Those skilled in the art will appreciate that lysergic acid amide is a compound having the following general structure, wherein 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 As defined herein and as commonly understood in the art:

[0252]

[0253] 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 14 Each 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. N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 and R 14 Any two of and the intervening atoms in may be taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, or an optionally substituted heterocyclyl. In an embodiment, lysergic acid amide is a quaternary salt, wherein the additional R 6A With R 6 The nitrogen bonded to it is connected; wherein R 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.

[0254] In some embodiments, the additional active compound is a lysergic acid diethylamide selected from the group consisting of lysergic acid diethylamide (i.e., LSD, LSD-25, LAD, Delysid), 6-ethyl-6-demethyllysergic acid diethylamide (ETH-LAD), 6-propargyl-6-demethyllysergic acid diethylamide (PARGY-LAD), 6-allyl-6-demethyllysergic acid diethylamide (AL-LAD), 6-propyl-6-demethyllysergic acid diethylamide (PRO-LAD), 6-isopropyl-6-demethyllysergic acid diethylamide (IP-LAD), 6-cyclopropyl-6-demethyllysergic acid diethylamide (CIP-LAD), 6-butyl-6-demethyllysergic acid diethylamide (BU-LAD), 6-(2-fluoroethyl)-6-demethyllysergic acid diethylamide (FLUOROETH-LAD), 1-acetyl-lysergic acid diethylamide (i.e., ALD, ALD-52, N-acetyl 1-(cyclopropyl-formyl)-lysergic acid diethylamide (1cP-LSD), 1-(1,2-dimethylcyclobutane-1-carbonyl)-lysergic acid diethylamide (1D-LSD), 1-propionyl-6-allyl-6-demethyllysergic acid diethylamide (1P-LSD), 1-butyryl-lysergic acid diethylamide (1B-LSD), 1-pentanoyl-lysergic acid diethylamide (1V-LSD), 1-(cyclopropyl-formyl)-lysergic acid diethylamide (1cP-LSD), 1-(1,2-dimethylcyclobutane-1-carbonyl)-lysergic acid diethylamide (1D-LSD), 1-propionyl-6-allyl-6-demethyl ...(cyclopropyl-formyl)-lysergic acid diethylamide (1D-LSD), 1-(cyclopropyl-formyl)-lysergic acid diethylamide (1D-L Lysergic acid 2,4-dimethylazetidine (ie, LA-SS-Az, LSZ), lysergic acid piperidine (LSD-Pip), and lysergic acid methyl isopropylamide (MIPLA).

[0255] For the purposes of the present invention, other tryptamines, phenethylamines and lysergic acid amides that may be used as additional active compounds and are therefore contemplated for inclusion therein will be generally known in the art (see, for example, Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997); Grob & Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi & Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacological Reviews, 2016; 68(2), 264-355; Glennon, Pharmacology Biochemistry and Behavior, 1999; 64, 251-256; each of which is incorporated herein by reference as if fully set forth herein).

[0256] E. Dosage and dosage

[0257] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount or an effective amount of the disclosed compound, for example, for administration to a subject. Administering a pharmaceutical composition to a subject in a "therapeutically effective amount" or "effective amount" refers to administering a composition in an amount sufficient to achieve the desired effect. When an "effective amount" represents an amount that can effectively treat the disease or symptom of a subject, a "therapeutic effect" is understood to be a reaction in a mammal that is judged to be ideal and beneficial after treatment. Therefore, these reactions will vary depending on the mental health disorder to be treated or the improvement in mental health or function sought, as well as on the specific ingredients in the disclosed composition under consideration, but can be easily understood by a person of ordinary skill by understanding the disclosure herein and the general knowledge in the art (e.g., by reference to the symptoms of the disorder listed in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)).

[0258] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it is present in an amount such that a single dose (in milligrams per kilogram of patient body weight) is, 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 In some embodiments, the present invention relates to an amount of at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, and amounts within these ranges.

[0259] In some embodiments, when a pharmaceutical composition comprises a disclosed compound, it is present in an amount such that a single dose (in milligram doses calculated based on kilograms of body weight of the patient) is between about 0.01 mg / kg and 0.1 mg / kg, for example, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, and about 0.1 mg / kg, and ranges between these values. In some embodiments, a single dose is between about 0.1 mg / kg and 1.0 mg / kg, for example, 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.

[0260] In some embodiments, when a pharmaceutical composition includes a disclosed compound, it can be present in an amount such that a single dose (whether or not the dose is in a unit dosage form) is, for example, 25 mg or less (including doses of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, g, 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, and amounts within these ranges.

[0261] In some embodiments, when the pharmaceutical composition includes the disclosed compound, the amount present can be such that a single dose (whether or not the dose is present in a unit dosage form) is between about 0.1 mg and 1.0 mg, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, and about 1.0 mg, and the range between these values. In embodiments, a single dose is between about 1 mg and 10 mg, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg, and the range between these values. In some embodiments, a single dose is between about 10 mg and 100 mg.

[0262] In some embodiments, when the pharmaceutical composition includes an additional active compound, for example, when the additional active compound is phenethylamine or another tryptamine, it may be present in an amount such that a single dose (in milligrams per kilogram of patient weight) is, 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 In some embodiments, the present invention relates to an amount of at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, and amounts within these ranges.

[0263] In some embodiments, when the pharmaceutical composition includes an additional active compound, for example, when the additional active compound is phenethylamine or tryptamine, it can be present in an amount such that a single dose (whether or not such dose is present in a unit dosage form) is, for example, 25 mg or less (including doses of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 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, and amounts within these ranges.

[0264] It will be readily appreciated that dosages may vary depending on whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability or susceptibility of the symptoms being treated, the desired clinical endpoint, prior, concurrent or subsequent treatment, the general health, age, sex and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence or absence of other conditions or diseases in the subject, and other factors that will be appreciated by those skilled in the art (e.g., medical or family history).

[0265] Depending on the desired clinical outcome, the state of the pathology or symptoms, any adverse side effects of the treatment or therapy, or concurrently taken medications, the dosage, frequency, or duration may be increased or decreased. Those skilled in the art will understand the factors that may affect the required dosage, frequency, and duration based on the teachings of the present disclosure to provide a sufficient or effective amount to provide a therapeutic effect or benefit, and to do so based on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0266] It should be understood that in some embodiments, the actual dosage administered will be determined by the physician according to relevant circumstances, including the disease to be treated, the selected route of administration, the actual composition or preparation administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms, and therefore any dosage range disclosed herein is not intended to limit the scope of the present invention. In some cases, a dosage level below the lower limit of the disclosed range may be sufficient, while in other cases, a dosage above a certain range may be used without causing any harmful side effects, for example, such a larger dose may be divided into several smaller doses to be taken together or taken alone.

[0267] In some embodiments, especially when the formulation is prepared in a single unit dosage form (e.g., capsule, tablet or lozenge), the recommended dose should be known by reference to the form of the formulation itself. In other embodiments, when the formulation is prepared in multiple dosage forms, such as liquid suspensions and topical preparations, the recommended dose can be understood by reference to the mode of administration or by reference to the packaging and label, package inserts, marketing materials, training materials, or other information and knowledge available to those skilled in the art or the public.

[0268] Therefore, another aspect of the present disclosure provides a pharmaceutical kit containing a pharmaceutical composition or formulation of the present invention, a suggested administration guide or prescription information, and a suitable container. A single unit dosage form can be included in a multi-dose kit or container, and the pharmaceutical formulation can also be packaged into a single or multiple unit dosage form to ensure uniform dosage and ease of administration.

[0269] F. Kit

[0270] Another aspect of the present disclosure provides a pharmaceutical kit containing a pharmaceutical composition or formulation of the present invention, a suggested administration guide or prescription information, and a suitable container. A single unit dosage form can be included in a multi-dose kit or container, and the pharmaceutical preparation can also be packaged into a single or multiple unit dosage form to ensure uniform dosage and ease of administration.

[0271] The kit generally includes suitable packaging. The kit may include one or more containers containing any compound described herein. Each component (if there are multiple components) can be packaged in a separate container, or some components can be combined in one container where cross-reactivity and shelf life allow. The kit can be in unit dose form, large package (e.g., multi-dose package) or subunit dose form. For example, a kit containing a sufficient dose of a compound disclosed herein and / or another pharmaceutically active compound for a disease described in detail herein can be provided, thereby providing effective treatment for an individual over an extended period of time (e.g., one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months or longer). The kit can also include multiple unit doses of compounds and instructions for use, and the number of packages is sufficient for storage and use by pharmacies (e.g., hospital pharmacies and dispensing pharmacies).

[0272] Preferably, information regarding dosage and proper administration (if necessary) will be printed directly on the multiple-dose kit (e.g., on a blister pack or other inner package containing a composition or formulation of the invention); however, the kits of the invention may also include package inserts and other printed instructions (e.g., on the outer package) for administering the disclosed compositions and their appropriate therapeutic uses.

[0273] G. How to use

[0274] In some aspects, provided herein are methods of using the disclosed compounds. In some embodiments, the disclosed compounds are used to modulate neurotransmission. In embodiments, the disclosed compounds are used to treat conditions, such as diseases or disorders. In embodiments, the disclosed compounds are used to manufacture drugs for treating and / or preventing conditions (such as diseases or disorders). In embodiments, the disclosed compounds are administered as part of treatment. In embodiments, the disclosed compounds are administered together with psychotherapy, psychological support or patient monitoring. In embodiments, the disclosed compounds are administered to subjects suffering from conditions (such as diseases or disorders) in a therapeutically effective amount. In embodiments, the condition is a mental health disorder. In embodiments, the condition is a neurodegenerative disease. In embodiments, the condition is an inflammatory disease. In embodiments, the condition is pain and / or inflammation. In embodiments, the disclosed compounds are administered to healthy subjects.

[0275] As used herein, the terms "subject," "user," "patient," and "individual" are used interchangeably to refer to any mammal, including rodents, apes, mammalian farm animals, mammalian sports animals, and mammalian pets, such as canines and felines, but preferably humans. Such terms should be understood to include people who have an indication that the compounds, compositions, or methods described herein may be effective, or people who may benefit from the present invention. In general, all compounds, compositions, and disclosed methods are applicable to all individuals, although individual differences are to be expected and should be understood. The disclosed treatment methods can also be modified to treat multiple patients, including couples or families, at the same time. Therefore, these terms will also be understood to refer to two or more individuals.

[0276] 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 embodiments, when administered by one or more such routes, the disclosed compounds and disclosed compositions and formulations comprising them can be used in methods of treating patients in need of such treatment.

[0277] a. Research Tools

[0278] In some embodiments, the disclosed compounds are used as research tools, e.g., to participate in in vitro, in vivo, or computer simulations to determine the structure and function of receptors. In embodiments, the disclosed compounds can be used for receptor, ion channel, enzyme, and transporter binding studies. In embodiments, the disclosed compounds can be used for mapping and functional studies.

[0279] In embodiments, radiolabeled disclosed compounds can be used to identify binding sites. In embodiments, radiolabeled disclosed compounds can be used for tissue imaging.

[0280] In some embodiments, the disclosed compounds can be used as research tools for 5-HT2 receptors. In some embodiments, the disclosed compounds can be used as research tools for 5-HT2 receptors. 2A In one embodiment, the disclosed compounds can be used as 5-HT receptor research tools. 2B In one embodiment, the disclosed compounds can be used as 5-HT receptor research tools. 2C Research tools for receptors. In embodiments, the research tools are receptor probes that can be used to determine downstream events of receptor-ligand interactions, such as calcium regulation, kinase, phosphatase and phospholipase activation, and lipid trafficking. In embodiments, the receptor is a recombinant receptor. In embodiments, the receptor is a wild-type receptor.

[0281] In some embodiments, the disclosed compounds can be used as research tools, such as receptor probes, for 5-HT2 receptors of mammalian origin. In embodiments, the disclosed compounds can be used as research tools, such as receptor probes for 5-HT2 receptors of human (Homo sapiens) origin. In embodiments, the disclosed compounds can be used as research tools, such as receptor probes, for 5-HT2 receptors of non-human primate origin. Non-limiting examples of non-human primate 5-HT2 receptors include chimpanzee (Pan troglodytes) and rhesus monkey (Macaca mulatta) 5-HT2 receptors.

[0282] In some embodiments, the disclosed compounds can be used as research tools, such as receptor probes, for 5-HT2 receptors of rodent origin. Non-limiting examples of rodent 5-HT2 receptors include receptors from mice (Mus musculus) and rats (Rattus norvegicus). Common laboratory mouse strains include C57BL / 6 and BALB / c, and common laboratory rat strains include Sprague-Dawley and Wistar. The disclosed compounds in the embodiments can be used as research tools, such as receptor probes, for 5-HT2 receptors from zebrafish. Non-limiting examples of zebrafish 5-HT2 receptors include receptors from Daniospp., such as receptors from Danio rerio. In the embodiments, the disclosed compounds can be used as research tools, such as receptor probes for 5-HT2 receptors from nematodes. In a non-limiting example, the disclosed compounds can be used to detect the 5-HT2 receptors of Caenorhabditis elegans. In the embodiments, the disclosed compounds can be used as research tools, such as receptor probes for 5-HT2 receptors of dogs, chickens, frogs or cattle.

[0283] Sequences can be retrieved by consulting a nucleotide database (e.g., Genbank) or an amino acid database (e.g., UniProtKB), as known to those skilled in the art. As examples, sequences 1-45 in Table 5 are available at UniProtKB (www.uniprot.org) by reference to the following accession numbers; they are also disclosed in the priority document of this article and are incorporated herein as if fully set forth herein.

[0284] Table 5. Exemplary receptor sequences

[0285]

[0286]

[0287]

[0288] b. Serotonin receptor ligands

[0289] The 5-HT receptor system contains 14 different receptors, which are divided into 7 receptor families (5-HT1 to 5-HT7). Except for the 5-HT3 ligand-gated ion channel, all 5-HTR families are G protein-coupled receptors (GPCRs) (Gothert, Pharmacol Rep., 2013; 65(4):771-86). In a representative example, 5-HT 2A The receptor has seven transmembrane helices and an intracellular amphipathic helix H8, similar to other GPCRs. The receptor contains a ligand binding site, called the orthosteric site, and an accessory site, a laterally extending cavity that connects the orthosteric site to the plasma membrane. Herein, the laterally extending cavity may be referred to as the "extended binding site" or "external binding site."

[0290] In some embodiments, the disclosed compounds bind to a serotonin (5-HT) receptor. In embodiments, the 5-HT receptor is a subfamily 1 (5-HT1) receptor. In embodiments, the 5-HT receptor is a subfamily 2 (5-HT2) receptor. In embodiments, the 5-HT2 receptor is a subtype 2A, 2B, or 2C (5-HT 2A , 5-HT 2B 5-HT 2C ) receptor. In embodiments, the 5-HT receptor is a subfamily 4 (5-HT4) receptor. In embodiments, the receptor is a 5-HT receptor of subfamily 5 (5-HT4) receptor. In embodiments, the receptor is a 5-HT receptor of subfamily 6 (5-HT6) receptor. In embodiments, the 5-HT receptor is a subfamily 7 (5-HT7) receptor. In embodiments, the receptor is from a mammal. In embodiments, the receptor is from a human. In embodiments, the receptor is recombinant.

[0291] In some embodiments, the disclosed compounds bind to the serotonin (5-HT) receptor at multiple sites, such as the orthosteric site and the extended binding site. In embodiments, the disclosed compounds bind to the 5-HT receptor at one or more sites, such as the orthosteric site and the extended binding site. In embodiments, the disclosed compounds bind to the 5-HT2 receptor at one or more sites, such as the orthosteric site and the extended binding site. In embodiments, the disclosed compounds bind to one or more 5-HT2 receptor subtypes (e.g., 5-HT2 receptors) at one or more sites (e.g., the orthosteric site and the extended binding site). 2A , 5-HT 2B and 5-HT 2C) binding. In embodiments, the disclosed compounds bind to the 5-HT4 receptor at one or more sites, such as the orthosteric site and the extended binding site. In embodiments, the disclosed compounds bind to the 5-HT5 receptor at one or more sites, such as the orthosteric site and the extended binding site.

[0292] In embodiments, the disclosed compounds bind to the 5-HT6 receptor at one or more sites, such as the orthosteric site and the extended binding site. In embodiments, the disclosed compounds bind to the 5-HT7 receptor at one or more sites, such as the orthosteric site and the extended binding site. In embodiments, the receptor is from a mammal. In embodiments, the receptor is from a human. In embodiments, the receptor is recombinant.

[0293] After complexing with the antagonist zotepine, it was found that the extended binding site spanned transmembrane domains (TMD) 4 and 5 and was surrounded by hydrophobic residues on TMD3, TMD4, TMD5 and extracellular loop (ECL) 2. The glycine residue at the 5.42x43 position at the entrance of the lateral extension cavity is essential for the formation of the external site. This glycine positioning is only conserved in the 5-HT2 receptor family (Kimura et al., Nat Struct Mol Biol., 2019; 26(2): 121-128). 5-HT 1B and 5-HT 2B An extended binding site for the receptor has also been described (McCorvy & Roth, Pharmacology & Therapeutics, 2015; 150: 129-142).

[0294] Methods for determining binding to 5-HT receptors are available to those skilled in the art, including, for example, in vitro and computer-generated methods. For example, Kimura et al. describe constructing a 5-HT receptor. 2A R, crystallized the receptor with inverse agonists and antagonists, and determined binding using microcrystallometry and the molecular docking software Glide (Schrodinger) (Kimura et al., Nature Structural & Molecular Biology, 2019; 26: 121-128). Wacker et al. described how to use X-ray crystallography to resolve and engineer 5-HT 2B The structure of LSD bound to the receptor. 2A and 5-HT 2B Homology between receptors, 5-HT 2B Receptors used as 5-HT 2A X-ray crystallography has also been used to determine the expression of 5-HT receptors.2A The structures of 5-HT R in complex with LSD and the inverse agonist methiothepine, while cryo-electron microscopy of the prototypical hallucinogen 25CN-NBOH in complex with an engineered Gαq heterotrimer has been used to determine 2A The active state of 5-HT R (Kim et al., Cell. 2020 Sep 17; 182(6): 1574-1588.e19). Homology modeling based on the crystal structure of β(2)-adrenergic receptor and G protein-bound opsin has also been used to simulate 5-HT 2A R (Isberg et al., J Chem Inf Model., 2011; 51(2):315-25).

[0295] In addition, similar strategies used to elucidate the ADRB2 exosite can be applied to the 5-HT receptor, such as docking and mutagenesis studies. For example, site-directed mutagenesis and evaluation of salmeterol-promoted cAMP accumulation led to the identification of amino acids in TMD4 (residues 149-174) that contribute to the β2 receptor exosite (Green et al., J Biol Chem., 1996; 271(39): 24029-35). Using [ 125 Direct photoaffinity labeling of the salmeterol binding site in the human β2 receptor with iodine-salmeterol azide and X-ray diffraction analysis of salmeterol bound to ADRB2 showed that TMD6 and TMD7 also contribute to the exosite (Masureel et al., Nat. Chem. Biol. 2018; 14(11): 1059-1066; Rong et al., Biochemistry, 1999; 38(35): 11278-11286). 125 I] In the iodine azide salmeterol photolabeling study, the radioiodinated phenyl azide portion of the photoaffinity probe (corresponding to the terminal phenyl ring in salmeterol) was specifically attached to tryptophan 313 in TMD7 (Rong et al., Biochemistry, 1999; 38(35): 11278-11286). A third study used chimeric β1 / β2 receptors and alanine-substituted β2 receptor mutants, and TMD7 was also identified as part of the external site. The study identified tyrosine 308 and tyrosine 316 in TMD7 as sites for interaction with the methylene and side chain ether oxygen near the protonated amine of salmeterol, respectively (Isogaya et al., Mol. Pharmacol. 1998; 54: 616-622).

[0296] 5-HT 2ABoth the R and ADRB2 receptors adopt different conformations in response to different ligands. This movement and the resulting remodeling of the surrounding membrane affect the pharmacological activity of known ligands, such as full, partial, or inverse activators of the receptor. For example, Shan et al. showed different 5-HT in response to the partial agonist LSD and the inverse agonist ketanserin. 2A R conformation (Shan et al., PLoS Comput Biol. 2012; 8(4): el002473). Regarding ADRB2 ligand studies, most receptor residues exhibit different response patterns, even between functionally similar ligands, and few receptor residues have response patterns consistent with classical agonism (Kahsai et al., Nat Chem Biol. 2011; 7(10): 692-700). Different conformational states of the 5-HT receptor may lead to different pharmacological outcomes, including those associated with hallucinations. See, e.g., Weinsten, AAPS J 7: E871-884. Therefore, in one aspect, the provided 5-HT receptor ligands can be used to elucidate the structural basis and mechanism of different 5-HT receptor activation states, such as 5-HT 2A R, 5-HT 2B R and 5-HT 2C R.

[0297] In some embodiments, the disclosed compounds have increased binding affinity for the 5-HT receptor compared to a comparator. In embodiments, the disclosed compounds have decreased binding affinity for the 5-HT receptor compared to a comparator. In embodiments, the disclosed compounds have increased binding affinity for a 5-HT receptor subtype and decreased binding affinity for another serotonin receptor subtype. In embodiments, the receptor is 5-HT 2A In one embodiment, the receptor is 5-HT 2B In one embodiment, the receptor is 5-HT 2C Receptor. In one embodiment, the disclosed compounds, such as N-substituted 2C-B (e.g., XOB; see Examples 1 and 2), have increased affinity for the 5-HT2 receptor compared to a comparator. In embodiments, the comparator is a corresponding unsubstituted phenylalkylamine. For example, in embodiments, the comparator of XOB is 2C-B. In other embodiments, the comparator is serotonin.

[0298] In some embodiments, the disclosed compounds have increased selectivity or specificity for 5-HT receptors relative to comparators. In embodiments, the disclosed compounds have increased selectivity or specificity for 5-HT2 receptors, such as 5-HT 2A , 5-HT 2B and 5-HT2C The receptor has relatively high selectivity. In embodiments, the comparator is an unsubstituted phenylalkylamine, including, for example, a compound having the same phenylalkylamine head group but lacking a side chain. In embodiments, the disclosed compounds have fewer off-target effects, including, for example, adverse reactions.

[0299] There are a variety of strategies that can be used to determine binding affinity and specificity. Of note, the results of a binding assay describe the strength of the interaction between the ligand and the target, not whether the ligand functions as an agonist or antagonist. Radioligand binding experiments represent a sensitive and quantitative technique for determining the binding affinity between a compound and a receptor. The general framework of a radioligand binding assay involves preparing tissue bearing the target receptor and incubating it with a radiolabeled ligand until equilibrium is reached. The equilibrium is then disrupted, the radiolabeled ligand binds to the receptor, the free radioligand is isolated, the radioactivity (e.g., radioactivity bound to the tissue) is quantified, and the results are analyzed, e.g., using specialized computer software. Nonspecific binding is measured under the same conditions by incubating the tissue in the presence of unlabeled ligand at a concentration that saturates the target receptor. Specific binding is calculated by subtracting nonspecific binding from total binding.

[0300] The use of radioligands can facilitate the determination of binding affinity in a number of different experimental settings, including kinetic experiments, in which the time course of ligand binding and dissociation is determined, competition binding assays, dissociation binding assays, saturation binding assays, and quantitative autoradiography and image analysis (Maguire et al., Methods Mol Biol. 2012;897:31-77).

[0301] In some embodiments, affinity can be assessed by determining the inhibition constant between an N-aralkyloxyalkyl substituted phenylalkylamine and a receptor (e.g., a 5-HT2 receptor). i ) can be described as the concentration at which 50% of the radiolabeled ligand (e.g., agonist) is displaced by the test ligand. Therefore, as shown in the Cheng-Prusoff equation, the observed K i Can be used to determine K i , where K i =IC 50 / (l+[R] / K d ), where IC 50 is the concentration of competitive inhibitor that produces 50% inhibition, R is the concentration of radioligand used in the competition binding assay, and K d is the equilibrium dissociation constant of the radioligand in the assay.

[0302] Competition binding assays (also called radioligand displacement assays) can be used to determine K iGenerally, the effect of the test ligand on the interaction between the radiolabeled ligand and the receptor preparation is assessed, for example, the extent of displacement of the radiolabeled ligand is assessed.

[0303] In some cases, the displaced radioligand may be an antagonist, e.g., [ 3 H] Ketanserin to 5-HT 2A and[ 3 H]Mesulergine to 5-HT 2C In some cases, the displaced radioligand may be an agonist, e.g. 3 H]LSD for 5-HT 2B However, for comparison purposes, it is best to keep the assay conditions consistent, as displacement by antagonists may reflect binding to active and inactive receptor conformations, whereas displacement by agonists may reflect binding to the active conformation (Toro-Sazo et al., PLoS One, 2019; 14(l): e0209804). Binding assays are further described in Roth's National Institutes of Mental Health Psychoactive Drug Screening Program, Assay Protocol Book, Version III, 2018.

[0304] In some embodiments, the disclosed compounds have an effect on 5-HT 2A , 5-HT 2B and 5-HT 2A Any one or more of has a binding affinity of 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 have a binding affinity for 5-HT 2A , 5-HT 2B and 5-HT 2A Any one or more of has a binding affinity of about 10 μM, 5 μM, 1 μM, 0.5 μM or 0.1 μM. In an embodiment, the disclosed compounds have a binding affinity for 5-HT 2A , 5-HT 2B and 5-HT 2A Any one or more of has increased binding affinity. 2A , 5-HT 2B and 5-HT 2A In the embodiment, compared with the comparator, the disclosed compound has a higher content of 5-HT 2A , 5-HT 2B and 5-HT 2AIn one embodiment, the comparator is serotonin. In one embodiment, the comparator is a corresponding unsubstituted phenylalkylamine. In one embodiment, the comparator of XOB is 2C-B. For example, XOB has a reduced binding affinity for 5-HT. 2A The binding affinity of 5-HT is 2.6 μM (see Example 2). 1A In contrast, in cells expressing human or rat 5-HT 2A Receptor heterologous cells used [ 125 In vitro competitive binding studies of 2C-B showed high affinity for 2C-B, K I 0.88 nM and 0.66 nM respectively (McLean et al., J Med Chem., 2006; 49(19): 5794-5803). In addition, serotonin 1A , 5-HT 2A and 5-HT 2C The receptor exhibits a moderate K I The values ​​were 330 nM, 470 nM and 120 nM, respectively. In the embodiment, the disclosed compounds have an inhibitory effect on 5-HT 2A , 5-HT 2B and 5-HT 2A The binding affinity of any one or more of is increased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 500-fold, 1000-fold, or at least 1000-fold.

[0305] In embodiments, the disclosed compounds have an effect on 5-HT relative to the comparator. 2A , 5-HT 2B and 5-HT 2A In some embodiments, the disclosed compounds have a binding affinity for 5-HT compared to a comparator. 2A receptors over another serotonin receptor (e.g., 5-HT 2B Receptors and / or 5-HT 2C In embodiments, the disclosed compounds have increased selectivity for 5-HT receptors compared to comparators. 2A Receptor selectivity for 5-HT 2B In one embodiment, the disclosed compounds have increased selectivity for 5-HT receptors compared to the comparator. 2A Receptor selectivity for 5-HT 2CIn embodiments, the disclosed compounds have increased selectivity for 5-HT receptors compared to comparators. 2A Receptor selectivity for 5-HT 2B Receptors and 5-HT 2C The receptors are more selective.

[0306] In some embodiments, the disclosed compounds selectively inhibit 5-HT 2A EC50, the half maximal effective concentration of the receptor 50 binds to another receptor (e.g., a serotonin receptor such as 5-HT 2B 5-HT receptor 2C receptors), for example, if the compound's 5-HT 2A EC 50 0.2μM, 5-HT 2A EC 50 1.0 μM, then it can be said that the compound has an effect on 5-HT 2A The receptor is selective for 5-HT 2B In one embodiment, the disclosed compounds have a 5-HT 2A Receptor selectivity for 5-HT 2B The selectivity of the disclosed compounds for 5-HT receptor is about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold higher. 2A Receptor selectivity for 5-HT 2C The receptor selectivity is about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold greater.

[0307] In some embodiments, the disclosed compounds have a serotonin receptor, such as the 5-HT2 receptor (e.g., 5-HT 2A , 5-HT 2B and 5-HT 2A ) has an increased binding rate at serotonin receptors (e.g., 5-HT2 receptors (e.g., 5-HT 2A , 5-HT 2B and 5-HT 2A ) has a reduced binding rate at 5-HT. In embodiments, the comparator is serotonin. In embodiments, the comparator is a corresponding unsubstituted phenylalkylamine. In embodiments, the comparator of XOB is 2C-B. In embodiments, the disclosed compounds have a reduced binding rate at 5-HT 2A , 5-HT 2B and 5-HT 2AThe binding rate of any one or more of the 5-HT is increased by about 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 200 times, or at least 200 times. In embodiments, the disclosed compounds are 2A , 5-HT 2B and 5-HT 2A The binding rate of any one or more of the XOB is reduced by about 2 times, 5 times, 10 times, 20 times, 30 times, 50 times, 70 times, 80 times, 90 times, 100 times, 200 times, or at least 200 times. For example, in embodiments, XOB is in 5-HT 2A The binding rate at 50° is approximately 24 times slower than that of serotonin (see Example 2).

[0308] c. Regulate neurotransmission

[0309] In some embodiments, the disclosed compounds modulate neurotransmission in a subject, for example, after administering a therapeutically effective amount to the subject. In embodiments, a disease or disorder in a subject may be treated by administering a disclosed compound to a subject to modulate neurotransmission.

[0310] In some embodiments, regulating neurotransmission includes regulating serotonin neurotransmission. In some embodiments, the disclosed compounds can regulate the activity of 5-HT receptors (5-HTR). 5-HTR is a G protein-coupled receptor (GPCR) that acts through Gai, Gαq / 11 or Gas pathways and affects various signaling mechanisms throughout the body. Regulating such receptors can produce unique and overlapping pharmacological effects (Zieba et al., Int J Mol Sci., 2022; 23(1): 10).

[0311] The three 5-HT2 receptor subtypes are all G-protein-linked single protein molecules of similar size and homology, containing 458-471 amino acids. 2A , 5-HT 2B and 5-HT 2C The pharmacology of serotonin has been characterized, and functional activities such as agonism and antagonism can be determined based on certain events in the resulting signal transduction cascade. See, for example, Pithadia & Jain, J Clin Med Res. 2009; 1(2): 72-80 and Raote et al., Serotonin Receptors in Neurobiology, Chapter 6, Boca Raton (FL): CRC Press / Taylor & Francis; 2007.

[0312] 5-HT 2AActivation leads to activation of the GPCR subunit Gαq / 11 and the effector enzyme phospholipase C (PLC), thereby promoting the release and accumulation of inositol triphosphate (IP3), diacylglycerol (DAG) and PKC (Singh et al., Int'l J Neuropsychopharmacol, 2009; 12(5): 651-665). In one embodiment, the released inositol phosphate (IP) can be used as an indicator of 5-HT2 receptor signaling activity. For example, see 5-HT 2A , 5-HT 2B and 5-HT 2C The formation of the receptor: inositol monophosphate (IP-1) is described in Eshleman et al., Biochem Pharmacol, 2018; 158: 27-34. In addition, the accumulation of IP3 leads to the release of calcium, which can be activated by Ca 2+ Load cells with sensitive fluorescent dyes, apply test ligands, and measure the dye versus released Ca 2+ The resulting spectral shift is monitored. Methods for analyzing 5-HT2 receptor function are described, for example, in Klein et al. ACS Pharmacol Transl Sci 2021; 4(2):533-542.

[0313] IP3 accumulation itself, such as the accumulation of total radiolabeled IP (such as inositol monophosphate, inositol bisphosphate and inositol triphosphate), can also be used to measure receptor activation and desensitization, including time. In one example, a decrease in basal levels of IP3 provides a measure of antagonism (Raote et al., Serotonin Receptors in Neurobiology, Chapter 6, Boca Raton (FL): CRC Press / Taylor & Francis; 2007).

[0314] In some embodiments, the disclosed compounds can modulate the activity of 5-HT receptors, including any of activation, inhibition, partial activation, and partial inhibition of receptor activity. In embodiments, the disclosed compounds are 5-HT receptor ligands that bind to, activate, block, inhibit, or otherwise affect (e.g., by allosteric modulation) the activity of 5-HT receptors. In embodiments, the disclosed compounds are 5-HT2 receptor ligands, such as 5-HT 2A Receptors, 5-HT 2B Receptors and 5-HT 2C One or more ligands for a receptor.

[0315] In some embodiments, the disclosed compounds agonize the 5-HT2 receptor. In embodiments, the disclosed compounds antagonize the 5-HT2 receptor. In embodiments, the disclosed compounds partially agonize the 5-HT2 receptor. In embodiments, the disclosed compounds partially antagonize the 5-HT2 receptor. (See, e.g., Example 2; Figure 1 ) In one embodiment, the 5-HT2 receptor is 5-HT 2A In one embodiment, the 5-HT2 receptor is a 5-HT 2B In one embodiment, the 5-HT2 receptor is a 5-HT 2C Receptor.

[0316] In some embodiments, the disclosed compounds have an effect on 5-HT 2A , 5-HT 2B and 5-HT 2A Any one or more of the EC 50 (agonist mode), which 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 have an effect on 5-HT 2A , 5-HT 2B and 5-HT 2A Any one or more of the EC 50 (agonist mode), which is about 10 μM, 5 μM, 1 μM, 0.5 μM or 0.1 μM. In embodiments, the disclosed compounds have an effect on 5-HT 2A , 5-HT 2B and 5-HT 2A Any one or more of the EC 50 (antagonist mode), which 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 have an effect on 5-HT 2A , 5-HT 2B and 5-HT 2A Any one or more of the EC 50 (antagonist mode), which is about 10 μM, 5 μM, 1 μM, 0.5 μM or 0.1 μM. For example, XOB antagonizes 5-HT 2A , its EC 50 is 1.3μM.

[0317] In some embodiments, modulating neurotransmission comprises modulating voltage-gated ion channel activity. In some embodiments, the disclosed compounds modulate voltage-gated calcium ions (Ca 2+ ) channels, voltage-gated chloride (Cl - ) channels, voltage-gated potassium ions (K + ) channels and voltage-gated sodium ions (Na+ ) channel (VGSC).

[0318] In some embodiments, the disclosed compounds have a binding affinity for VGSC of 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 have a binding affinity for VGSC of about 10 μM, 5 μM, 1 μM, 0.5 μM, or 0.1 μM. In embodiments, the disclosed compounds have an increased binding affinity for VGSC relative to the comparator. In embodiments, the comparator is serotonin. In embodiments, the comparator is the corresponding unsubstituted phenylalkylamine. In embodiments, the comparator of XOB is 2C-B. For example, XOB has an affinity for 5-HT. 2A The binding affinity of 2C-B was 2.6 μM (see Example 2). In contrast, 2C-B did not bind to VGSC. In embodiments, the disclosed compounds have a binding affinity for VGSC that is increased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 500-fold, 1000-fold, or at least 1000-fold compared to the comparator.

[0319] In some embodiments, the disclosed compounds are VGSC inhibitors. In some embodiments, the disclosed compounds have an in vitro IC 50 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 in vitro IC of the disclosed compounds on VGSCs 50 About 10μM, 5μM, 1μM, 0.5μM or 0.1μM. For example, XOB is a VGSC inhibitor with an IC 50 is 4.29 μM (see Example 2).

[0320] b. Treatment

[0321] In some embodiments, the disclosed compounds are used to treat medical conditions, such as diseases or disorders. In embodiments, the disclosed compounds are used to manufacture drugs for treating conditions (such as diseases or disorders). Also provided are methods of administering the disclosed compounds to a subject suffering from a condition (such as a disease or disorder), thereby treating the condition.

[0322] In some embodiments, the disclosed compounds and pharmaceutical compositions thereof are used to treat serotonin-mediated diseases. In embodiments, when the disclosed compounds are administered to a subject in a pharmacologically effective amount, they provide a beneficial therapeutic effect on the treatment of serotonin-mediated diseases. Serotonin-mediated diseases include mental health disorders, neurodegenerative diseases, pain syndromes, headaches (such as migraines), and inflammation, among others.

[0323] 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 by one or more such routes, the disclosed compounds and disclosed compositions and formulations comprising the same can be used in methods of treating patients in need of such treatment.

[0324] In an embodiment, the present invention provides a method for treating and / or preventing a disorder in a mammal, the method comprising administering a therapeutically effective amount of a disclosed compound or pharmaceutical composition to a mammal. In some embodiments, "treatment" or "therapy" refers to treating a disease or disorder in a mammal (preferably a human being), and includes causing a desired biological or pharmacological effect, such as: (a) preventing the disorder from occurring in a subject who may be susceptible to the disorder but has not yet been diagnosed with the disorder; (b) inhibiting the disorder, i.e., preventing its development; (c) alleviating the disorder, i.e., causing it to subside; (d) protecting or alleviating symptoms or pathologies caused by or associated with the disorder; (e) reducing, lowering, inhibiting, improving or preventing the onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with the disorder; and (f) preventing or inhibiting the deterioration or progression of symptoms or pathologies associated with the disorder or comorbid with the disorder. Based on the teachings herein and the knowledge in the art, a person of ordinary skill in the art will understand other such measurements, benefits and alternative or clinical endpoints, whether alone or in combination.

[0325] As used herein, "effective amount", "pharmacologically effective amount" or "therapeutically effective amount" refers to an amount of an active agent that is non-toxic and sufficient to provide the desired therapeutic effect and has a reasonable benefit / risk ratio in any medical treatment. The effective amount will vary depending on the subject and the disease condition being treated or the health benefit being sought, the subject's weight and age, the severity of the disease condition or the degree of health benefit being sought, the mode of administration, etc., all of which can be readily determined by those skilled in the art.

[0326] As used herein, "therapeutic effect" or "therapeutic efficacy" refers to responses in mammals (preferably humans) that are judged to be desirable and beneficial following treatment. Thus, those responses will vary, but will be readily appreciated by those skilled in the art, depending on the disease being treated or the improvement in mental health or function being sought, as well as on the particular ingredients of the formulations of the invention being considered.

[0327] Treatment effectiveness measures include any outcome measure, endpoint, effect measure, or effectiveness measure in clinical or medical practice or research that is used to assess the positive and negative effects of an intervention or treatment, whether patient-reported (e.g., questionnaires), based on other patient data (e.g., patient monitoring), collected through laboratory tests, such as blood tests, urine samples, etc., through medical examination by a physician or other medical professional, or through digital tools or means, such as electronic tools, such as online tools, smartphones, wireless devices, biosensors, or health apps.

[0328] In some embodiments, measurement of treatment effectiveness will include assessment. "Assessment" refers to any means or method used on a patient, whether before, during, after, or in time independent of a particular treatment regimen, to measure, estimate, or evaluate the patient's properties, abilities, symptoms, disorders, or other characteristics, whether qualitatively or quantitatively, and whether performed by a therapist or other clinician (e.g., an interview), the patient themselves (e.g., a self-report questionnaire), a third party, or a computer, including a medical device (e.g., a device defined by the FDA or other regulatory agency) or other devices (e.g., a medical sensor or biosensor, a watch or fitness tracker or "wearable device"), and whether scored by a human decision maker or artificial intelligence, machine learning, or a computer algorithm. Assessments can be computer-assisted, and other computer-assisted assessments can be performed in addition to the above assessments. The term "computer-assisted" in "computer-assisted assessment" refers to assessments performed using electronic tools (e.g., online tools, smartphones, wireless devices, or health applications) (also referred to as "digital phenotyping" in some such examples). Computer-assisted assessment will include the use of electronic psychiatric note taking systems in which the therapist will record relevant clinical information during treatment through face-to-face interaction with the patient, and will also include the use of computer systems in which the therapist and patient interact virtually (synchronously or asynchronously), as well as in which the patient interacts only with a computer ("computer" is used broadly to refer to any electronic tool suitable for such purposes, including desktops, laptops, and notebook computers; tablets, smartphones and other mobile devices; watches, fitness trackers, and personal electronic devices; etc.). One or more other aspects of psychosocial therapy, behavioral therapy, or medication-assisted treatment may also be "computer-assisted" in that one or more steps of such treatment involve the use of a computer to supplement or replace some of the work that would otherwise be performed by the therapist.

[0329] i. Mental, behavioral or neurodevelopmental disorders

[0330] In some embodiments, the disclosed compounds are used to treat mental, behavioral or neurodevelopmental disorders. In some embodiments, the disclosed compounds are administered, for example, in a therapeutically effective amount to a subject suffering from a mental, behavioral or neurodevelopmental disorder, thereby treating the mental, behavioral or neurodevelopmental disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide a beneficial therapeutic effect for treating a mental, behavioral or neurodevelopmental disorder.

[0331] ICD-11, which is incorporated herein by reference in its entirety, defines "mental, behavioral, or neurodevelopmental disorder" as a syndrome characterized by clinically significant disturbances in an individual's cognition, emotional regulation, or behavior that reflect dysfunction in psychological, biological, or developmental processes that underlie mental and behavioral functioning. These 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, feeding (or eating) disorders, elimination disorders, disorders of physical pain or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or antisocial disorders, personality disorders (and related features), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders related to pregnancy, childbirth, or the puerperium, sleep-wake disorders, sexual dysfunction, and gender incongruence.

[0332] If a mental, behavioral, or neurodevelopmental disorder is not defined, it should be understood to refer to the disorders defined in ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or "mental health disorder") generally refers to a disease condition involving negative changes in emotions, moods, thinking, and / or behavior. In general, a mental health disorder is characterized by clinically significant disturbances in an individual's cognition, emotions, behavior, or a combination thereof, resulting in impaired function, distress, or increased risk of distress. Although the terms "mental disorder" and "mental health disorder" and terms defining specific diseases and disorders should generally refer to the criteria in ICD-11 or patients diagnosed based on such criteria, it should be understood that the disclosed methods are equally applicable to patients with the same underlying disorder, whether the disorder is diagnosed based on the criteria in 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.

[0333] In some embodiments, the disclosed compounds are used to treat mental health disorders. In some embodiments, the disclosed compounds (e.g., in a therapeutically effective amount) are administered to a subject suffering from a mental health disorder to treat the mental health disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide a beneficial therapeutic effect for treating a mental health disorder. In some embodiments, the compounds and compositions of the present invention are used to alleviate the symptoms of a mental health disorder. The symptoms of the mental health disorder to be treated should be able to be determined by those skilled in the art by reference to the general understanding of the disorder in the art.

[0334] In some embodiments, the measure of therapeutic effect includes a report of the subject or observer. In some embodiments, the measurement of therapeutic effect includes answers to a questionnaire. Non-limiting representative examples of applicable measurements of symptom improvement include Generalized Anxiety Disorder Rating Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini-International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Responsiveness Index (IRI), Brief (36) Health Questionnaire (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject or observer reported measurements.

[0335] In some embodiments, the disclosed compounds are used to treat schizophrenia (or another primary psychotic disorder, as defined in DSM-IV, DSM-5, ICD-10, or ICD-11). Such disorders may be characterized by severe impairment of reality and behavioral changes, manifested by positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking and speech, and severe disorganized behavior, as well as the emergence of negative symptoms such as blunted or apathetic affect, lack of arousal, and psychomotor impairment. For decades, serotonin receptors, especially 5-HT 2A Receptors have long been a target for antipsychotic therapy (Schmidt et al., Life Sci. 1995; 56(25): 2209-2222), and recent studies support the use of 5-HT 2AAntagonists treat negative symptoms in patients with schizophrenia (Romeo et al., Psychiatry Res. 2023; 321: 115104). In some embodiments, the disclosed compounds are used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychosis, delusional disorder or substance-induced psychosis. In some embodiments, the measurement of the therapeutic effect of treating schizophrenia or related psychosis includes the Clinical Global Impression Scale (CGI), the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Symptom Scale (PANSS), the Negative Symptom Assessment Scale (SANS), the Positive Symptom Assessment Scale (SAPS), the 16-item Negative Symptom Assessment (NSA-16), the Deficit Syndrome Schedule (SDS), the Negative Symptom Clinical Assessment Interview (CAINS) and the Brief Negative Symptom Scale (BNSS).

[0336] In some embodiments, the disclosed compounds are used to treat mood disorders. According to the definition of ICD-11, mood disorders are classified according to the specific types of mood episodes and their changing patterns over time. The main types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. 5-HT 2A Receptor antagonism is a common mechanism of many antipsychotic drugs approved by the FDA for the treatment of mood disorders (Casey et al., Biochem.Pharmacol.2022; 200: 115028). In some embodiments, mood disorders are bipolar disorders or related disorders (e.g., bipolar I disorder, bipolar II disorder, cyclothymic disorder), depression (e.g., mono-depression, recurrent depression, dysthymia, mixed depression anxiety) or substance-induced mood disorders. In some embodiments, the measurement of the therapeutic effect of treating mood disorders (e.g., bipolar disorder) includes general behavior inventory (GBI), mood disorder questionnaire (MDQ), Young mania rating scale, Bech-Rafaelsen mania rating scale, Altman mania self-rating scale and self-report mania inventory.

[0337] ii. Neurodegenerative diseases

[0338] In some embodiments, the disclosed compounds and compositions thereof are used to treat neurodegenerative diseases. In embodiments, a therapeutically effective amount of a disclosed compound or a pharmaceutical composition thereof is administered to a subject in need to treat a neurodegenerative disease. In embodiments, administration of a therapeutically effective amount of a disclosed compound slows or prevents the progression of neurodegeneration. In embodiments, administration of a therapeutically effective amount of a disclosed compound can reduce the incidence or severity of at least one symptom of a neurodegenerative disease.

[0339] Neurodegeneration can be assessed by measuring markers of neuronal loss, such as cerebrospinal fluid markers, such as visinin-like protein 1 (VILIP-1), tau, and p-tau181 (Tarawneh et al., Neurol. 2015; 72(6): 656-665). Cognitive decline can also be used as a measure of neurodegenerative diseases. Methods for assessing cognitive decline, such as comprehensive neuropsychological tests, are known to those skilled in the art. Exemplary cognitive assessments include the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). For example, see Toh et al., Transl Neurodegener, 2014; 3: 15. Measurement methods for specific situations can also be used to assess cognitive decline and progression of disease states, such as the Unified Huntington's Disease Rating Scale (UHDRS).

[0340] Neurodegenerative diseases, e.g., diseases or disorders include, e.g., dementia, Alzheimer's disease, Huntington's disease, multiple sclerosis, and Parkinson's disease. A characteristic of neurodegenerative diseases is neuronal cell death, which is associated, among other things, with the promotion of inflammation. See, e.g., Chan et al., Annu Rev Immunol. 2015; 33: 79-106 and Chi et al., Int J Mol Sci. 2018; 19(10): 3082. Neurodegenerative diseases can be classified according to the main clinical features, e.g., dementia, Parkinson's disease, or motor neuron disease, the anatomical distribution of the neurodegenerative disease, e.g., frontotemporal lobar degeneration, extrapyramidal disease, or spinocerebellar degeneration, or the main molecular abnormality (Dugger & Dickson, Cold Spring Harb Perspect Biol. 2017; 9(7): a028035).

[0341] iii. Pain and inflammation

[0342] In some embodiments, the disclosed compounds and compositions thereof are used to treat pain disorders and / or inflammation. In embodiments, a therapeutically effective amount of a disclosed compound or a pharmaceutical composition thereof is administered to a subject in need thereof to treat pain disorders and / or inflammation. In embodiments, administration of a therapeutically effective amount of a disclosed compound may reduce the incidence or severity of at least one symptom of a pain disorder and / or an inflammatory disorder.

[0343] In some embodiments, the pain disorder treated by the disclosed compounds is a chronic pain disorder. Chronic pain disorders include, for example, central pain, complex regional pain syndrome, phantom pain such as phantom limb pain, neuropathic pain, fibromyalgia, arthritis, spinal stenosis, temporomandibular joint syndrome, intestinal diseases, surgery-related pain, and pain associated with a disease or disorder, such as pain associated with cancer.

[0344] In some embodiments, the disclosed compounds and compositions thereof are used to treat headaches. In an embodiment, a therapeutically effective amount of the disclosed compounds or compositions thereof is administered to a subject in need thereof to treat headaches. Headaches include tension headaches, migraines, and cluster headaches, among others.

[0345] In some embodiments, disclosed compounds and compositions thereof are used to reduce inflammation, such as systemic inflammation. In embodiments, disclosed compounds and compositions thereof are used to treat inflammatory diseases. In embodiments, a therapeutically effective amount of disclosed compounds or pharmaceutical compositions thereof are administered to a subject in need to treat inflammatory diseases. Inflammatory diseases include, for example, Alzheimer's disease, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease and ulcerative colitis.

[0346] The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with or described in terms of actual or potential tissue damage.” 2A Agonists and 5-HT 2A The mechanism by which serotonin modulators such as antagonists relieve pain remains unclear, but the synaptic plasticity associated with such compounds may alter the pathological changes in neural connections in chronic pain states, potentially leading to a reduction in pain intensity and duration (Castellanos et al., Reg Anesth Pain Med. 2020; 45(7): 486-494). 2A R activation has been shown to promote anti-inflammatory effects, such as reducing TNF-α-induced inflammation. For example, see Pelletier & Siegel, Mol Interv., 2009; 9(6): 299-301, Flanagan et al., Sci Rep. 2019; 9(l): 13444, Nichols et al., Clin Pharmacol Then 2017; 101(2): 209-219; Int Rev Psychiatry. 2018; 30(4): 363-375, Okamoto et al., Neuroscience. 2005; 130(2): 465-74.

[0347] Pain (e.g., chronic pain) and its improvement (e.g., reduction of symptoms) can be measured according to known methods, such as by subject report, pain diary, pain scale, applicable questionnaire (assessment of chronic pain and its impact on physical, emotional and social function), ecological momentary assessment and computerized versions thereof. For example, see Salaffi et al., Best Practice & Research Clinical Rheumatology, 2015; 29 (1): 164-186 and Hawker et al., Arthritis Care Res (Hoboken). 2011; 63 Suppl 11: S240-52. Exemplary questionnaires include visual analog scale for pain (VAS Pain), numerical rating scale for pain (NRS Pain), McGill Pain Questionnaire (MPQ), short McGill Pain Questionnaire (SF-MPQ), chronic pain rating scale (CPGS), short 36 body pain scale (SF-36BPS), intermittent and persistent osteoarthritis pain measurement (ICOAP), migraine diagnostic questionnaire, migraine screening questionnaire (MS-Q), fibromyalgia questionnaire (FSQ).

[0348] The reduction of inflammation (e.g., chronic systemic inflammation) can be measured according to various methods available to those skilled in the art. Inflammation biomarkers can be detected from biological samples (e.g., blood (e.g., plasma or serum) or saliva of subjects). In one example, inflammation can be detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell counts in blood tests. CRP can also be detected in saliva samples. Saliva CRP is not synthesized locally in the oral cavity, and compared with other inflammatory biomarkers (e.g., cytokines), it may reflect a more systemic level of inflammation (Szabo & Slavish, Psychoneuroendocrinology.202; 124: 105069). In addition, in the absence of specific data of immune tissue, clinical pathological data (e.g., hematological data of red blood cell parameters, platelet count, total white blood cell count, white blood cell differentiation and morphology, coagulation time and coagulation data of fibrinogen, and clinical chemistry data of total protein, albumin and globulin, liver enzymes, renal parameters, electrolytes and bilirubin) can provide preliminary signs of the presence and potential location of inflammation. For example, see Germolec et al., Methods Mol Biol. 2018; 1803:57-79 and Luo et al., Clin Lab. 2019 1; 65(3).

[0349] iv. Ion channel mediated diseases

[0350] In some embodiments, the disclosed compounds and compositions thereof are used to treat ion channel-mediated diseases. "Ion channel-mediated disorders" refer to diseases or disorders associated with ion channel (e.g., voltage-gated ion channels or ligand-gated ion channels) dysfunction. In embodiments, a therapeutically effective amount of a disclosed compound or pharmaceutical composition thereof is administered to a subject in need to treat an ion channel-mediated disorder. In embodiments, an ion channel-mediated disorder is a calcium ion (Ca 2+ ) channel, chloride ion (Cl - ) channels, potassium ions (K + ) channels and sodium ions (Na + )aisle.

[0351] In some embodiments, the disclosed compounds modulate calcium ions (Ca 2+ ) channel, chloride ion (Cl - ) channels, potassium ions (K + ) channels and sodium ions (Na + ) channels. In embodiments, the ion channel is voltage-gated. In embodiments, the ion channel is ligand-gated. In embodiments, the disclosed compounds modulate voltage-gated calcium ions (Ca 2+ ) channels, voltage-gated chloride (Cl - ) channels, voltage-gated potassium ions (K + ) channels and voltage-gated sodium ions (Na + ) channels. In embodiments, regulating the activity of an ion channel comprises blocking (e.g., inhibiting or reducing) the activity of the ion channel. In embodiments, regulating the activity of an ion channel comprises activating the ion channel.

[0352] In some embodiments, the disclosed compounds or compositions thereof are used to treat epileptic seizure disorders, such as epilepsy. In an embodiment, a therapeutically effective amount of a disclosed compound or a pharmaceutical composition thereof is administered to a subject in need to treat an epileptic seizure disorder. In an embodiment, administration of a therapeutically effective amount of a disclosed compound can reduce the incidence of epileptic seizures and / or the severity of an epileptic seizure disorder. In an embodiment, an epileptic seizure disorder is an epileptic seizure disorder. In an embodiment, an epileptic seizure is a focal epileptic seizure. In an embodiment, an epileptic seizure is a systemic epileptic seizure. In an embodiment, administration of a disclosed compound to a subject results in a reduction in the severity of epilepsy comorbidities (e.g., anxiety and depression), and / or an improvement in quality of life, for example, as assessed using the Epilepsy Quality of Life Questionnaire (QOLIE-31).

[0353] Epilepsy is a burst of uncontrolled electrical activity between neurons that results in temporary abnormalities in muscle tone or movement, behavior, sensation, or consciousness (Epilepsy Types, Johns Hopkins Medicine, accessed June 24, 2022). Ion channels are an essential component of neuronal function due to their role in maintaining cellular ionic and electrical homeostasis. Certain subunits are expressed only in the brain, and ion channel dysfunction may lead to epilepsy, which is characterized by recurrent seizures (Armijo et al., Curr Pharm Des. 2005; 11(15): 1975-2003; Graves, QJM: An Int'l J Med., 2006; 99(4): 201–217). Various anti-epileptic treatments reduce membrane excitability by interacting with neurotransmitter receptors or ion channels, for example, phenytoin and carbamazepine inhibit sodium channel activation, thereby reducing the high-frequency repetitive firing of associated action potentials (Macdonald & Kelly, Epilepsia. 1995; 36 Suppl 2: S2-12). Non-limiting examples of epilepsy comorbidities that may benefit from the disclosed compounds include depression, anxiety, and migraine (Keezer et al., Lancet Neurol. 2016; 15(1): 106-15).

[0354] Determining whether the disclosed compound regulates the activity of ion channels can be achieved by monitoring the electrophysiological activity of cells. For example, the patch clamp technique can measure the current through the cell membrane ion channel. See, for example, Lenkey et al., PLoS One.2010; 5 (12): el5568, Liu et al., Assay Drug Dev Technol.201; 9 (6): 628-34 and Dolzer, Methods Mol Biol.2021; 2188: 21-49. Patch clamp experiments can be performed on cultured cells, acutely isolated cells or acute vibrating slices. In addition, the fluorescence resonance energy transfer (FRET) technique using membrane potential sensitive dyes can measure the voltage-gated sodium channel activity in stably transfected cell lines (Felix et al., Assay Drug Dev Technol.2004 June; 2 (3): 260-8).

[0355] v.Psychological function

[0356] In some embodiments, the present invention provides methods for improving mental health and / or function (e.g., cognitive function). Improvements in mental health and function may include one or more of the following: reduction in neuroticism or psychological defenses, enhancement of creativity or openness to experience, improvement in decision-making ability, enhancement of well-being or satisfaction, and improvement in the ability to fall asleep or stay asleep. In addition, improvements in mental health and function may include improvements or return to baseline in processing speed, learning and memory, autobiographical memory, transformation, and IQ. These measurements are easy to understand and comprehend based on common techniques. For example, see the cognitive function aspects reviewed by Ahern and Semskova in Neuropsychology. 2017; 31(l): 52-72. Exemplary measures of improved mental health and / or function include the Global Assessment of Functioning (GAF) scale, the Sleep Quality Scale (SQS), and other sleep quality measures (see, e.g., Fabbri et al., Int J Environ Res Public Health. 2021; 18(3): 1082, and the Social Functioning Scale (SFS) (see, e.g., Chan et al., Psychiatry Res. 2019; 276: 45-55). In some embodiments, the present invention provides methods for improving the mental health and / or function (e.g., cognitive function) of healthy people (e.g., "healthy normal people"), and thus the present invention will include "improving health" in some embodiments.

[0357] Vi. Combination of medication with psychotherapy

[0358] In some embodiments, a disclosed compound or composition thereof is administered with a psychotherapy, such as a psychosocial therapy or a behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapies (e.g., as described in Arch. Gen. Psychiatry, 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1):168-174), contingency management-based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1):168-174; in J. Consul. Clin. Psychol., 2005; 73(2):354-59; or in Case Reports in Psychiatry, Vol. 2012, Article ID 731638), motivational interviewing-based therapy (e.g., as described in J. Consul. Clin. Psychol., 2001; 69(5):858-62), or meditation-based therapy, such as transcendental meditation-based therapy (e.g., as described in J. Consul. Clin. Psychol. 2000; 68(3):515-52).

[0359] In some embodiments, the disclosed compounds or compositions thereof are administered in combination with psychotherapy. "Psychotherapy" may refer to "psychedelic-assisted psychotherapy." Broadly speaking, psychedelic-assisted psychotherapy encompasses a range of related approaches that include at least one session in which the patient takes a psychedelic and is monitored, supported, or otherwise involved by one or more trained mental health professionals while under the influence of the psychedelic (e.g., see Schenberg, Front. Pharmacology, 2018;9(733). Protocols have been developed for standardized procedures that emphasize a high level of care (e.g., see Johnson et al., J. Psychopharmacol., 2008;22, 603-620), such as the MAPS approach to using MDMA to treat patients with PTSD (e.g., see the Multidisciplinary Association for the Study of Psychedelics (MAPS) Manual of MDMA-Assisted Psychotherapy in the Treatment of Posttraumatic Stress Disorder (2015), available at: http: / / www.maps.org / research-archive / mdma / MDMA-Assisted-Psychotherapy-Treatment-Manual-Version7-19Augl5-FINAL.pdf).

[0360] In some embodiments, psychotherapy with a compound or composition of the invention is carried out in widely spaced sessions, typically with two administrations of the compound of the invention (a first dose and a "boost" dose, although in some embodiments only a single dose is administered) per session. The frequency of these sessions can be weekly, but more often monthly or less. In most cases, patients only need a small number of treatments (approximately one to three) to achieve significant clinical progress, such as a reduction in the symptoms of the mental health disorder being treated. In some embodiments, psychotherapy includes multiple sessions, some of which are administered with a compound of the invention ("psychedelic-assisted psychotherapy", as described above, and "drug-assisted psychotherapy"); in other embodiments, patients participate in psychosocial or behavioral therapy, but are not administered medications at the same time, or are not administered with a compound of the invention.

[0361] In some embodiments, the compounds or compositions of the present invention are administered together with standardized psychotherapy or support, which refers to any acceptable standard psychotherapy or counseling modality, whether once a week, twice a week, or as needed; whether in person or virtually (e.g., through telemedicine or through a web program or mobile application); and whether with a human therapist or a virtual or AI "therapist". "Therapist" as used herein refers to a person who treats a patient using the compositions and methods of the present invention, whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or instructor, although it is understood that certain requirements will apply to certain aspects of treatment. Medication-assisted therapy (e.g., prescribing, dispensing, or administering medications, providing psychotherapy support). In some embodiments, "people" may also include AI.

[0362] In some embodiments, a patient will participate in a treatment regimen or method of the invention, or be administered a composition of the invention as part of such a method, if the patient meets certain specific inclusion criteria, does not meet certain specific exclusion criteria, does not meet any specific withdrawal criteria during the course of treatment, and meets the requirements of the claimed embodiments of the invention.

[0363] Preferably, when the pharmaceutical compositions of the present invention are administered, such administration does not present side effects requiring physician supervision or reduces the risk of side effects, thereby allowing treatment to be performed at home or outside of a clinic without such supervision, and / or otherwise without the need for adjunctive psychotherapy (although this may also be provided in certain embodiments herein).

[0364] In some embodiments, the compounds and compositions of the present invention can be administered in conjunction with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is not required or desired, or a specific type of psychotherapy is not required or desired, but any disclosed method can be used in conjunction with one or more psychotherapy sessions. One of the advantages of the present invention is the flexibility to engage in specific therapies and to choose between any such therapies (or to decide to forgo any specific therapy) while still achieving a clinically significant therapeutic effect.

[0365] In some embodiments, the patient will engage in one or more therapeutically beneficial activities, wherein such engagement is subsequent to or in conjunction with administration of a provided compound or composition, including breathing exercises, meditation and concentration exercises, focusing on an object or mantra, listening to music, physical exercise, yoga, stretching or physical exercise, journaling, grounding techniques, positive self-talk, or interacting with a pet or animal, and it is understood that such engagement can occur with or without the involvement or guidance of a therapist.

[0366] H. Examples

[0367] The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0368] General methods and procedures

[0369] Drugs and reagents : All drug recording solutions used in electrophysiological experiments were prepared on the day of recording. XOB was dissolved in 100% ethanol (EtOH). Tetrodotoxin (TTX) citrate was from Alomone Labs. Reagents and solvents were from Sigma-Aldrich (St. Louis, MO) or other specified commercial sources.

[0370] Statistical analysis: All data analyses of recorded INa were performed using the software packages Clampfit v10.4 (Molecular Devices), Microsoft Excel, Graph Pad Prism v9.0 (San Diego, CA). Active and passive neuronal properties recorded from brain slices were analyzed using custom MATLAB (Math Works) software. Unless otherwise stated, results are presented as mean ± SE.

[0371] Example 1: Synthesis of XOB

[0372] Test compound N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) was synthesized according to Scheme 1.

[0373]

[0374] Scheme 1 Synthesis of N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutyloxy)hexane-1-amine (XOB). 2C-B was condensed with (4-((6-bromohexyl)oxy)butyl)benzene in acetonitrile to afford XOB in 50% yield. It was purified by silica gel column chromatography using a mobile phase of CH2Cl2:MeOH 95:5 containing 10 mM triethylamine.

[0375] 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) was synthesized according to the method of Shulgin and Carter (Shulgin and Shulgin 1975 #715). 2C-B free base (5.74 g, 22.07 mmol) was dissolved in 50 mL of acetonitrile with stirring to give a clear, colorless solution. Triethylamine (4.22 mL, 30.0 mmol) and sodium iodide (126 mg, 0.758 mmol) were added and the mixture became slightly milky. Stir for 10 minutes and then (4-((6-bromohexyl)oxy)butyl)benzene (5.21 mL, 18.04 mmol) was added with continued stirring. The turbid reaction mixture was slightly exothermic, rising from 18.7°C to 21.2°C in 90 minutes. The reaction was stirred at ambient temperature and progress was monitored by TLC (silica gel, MeOH:CH2Cl2 1:9). After 144 hours, the reaction turned orange and was considered complete. The reaction mixture was filtered and the volatiles were removed by rotary evaporation to give about 11.8 g of an orange waxy solid. The crude product was dissolved in 60 mL of mobile phase (CH2Cl2:MeOH; 95:5, containing 10 mM triethylamine) and chromatographed on a 4.8 cm x 30 cm silica gel (600 g, 200-400 mesh) column. 20 mL of positive fractions were collected and combined, and the volatiles were removed by rotary evaporation to give 4.43 g (50% yield from 2C-B) of N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) as a light brown waxy solid.

[0376] pass 1 H NMR ( Figure 2 ), GC / MS (Figure 3) and LC / MS / MS ( Figure 4A , 4B and 5) analyses confirmed the predicted structure.

[0377] NMR: Proton NMR spectra were acquired using a 500 MHz Bruker Avance NEO spectrometer equipped with an iProbe in CDC13 containing 0.1% tetramethylsilane (TMS). 2D COSY spectra were acquired for unambiguous assignment of resonances. 1H NMR (500MHZ, CDCl3) δ1.38 (4H, m, J = 6.5Hz), δ1.55 (2H, p, J = 7Hz), δ1.61 (2H, m, J = 2.5Hz ), δ1.68(2H,m,J=2.5Hz), δ1.93(2H,p,J=7Hz), δ2.64(2H,t,J=7Hz), δ2.97(2H,p,J=7H z), δ3.22 (4H, m, J = 5.5Hz), δ3.34 (2H, t, J = 6.5Hz), δ3.40 (2H, t, J = 6.5Hz), δ3.78 (3H, s ), δ3.85(3H,s), δ6.91(1H,s), δ7.04(1H,s), δ7.18(3H,d,J=7Hz), δ7.28(2H,t,J=7Hz)

[0378] GC-MS: The samples were dissolved in ethyl acetate and analyzed by GC-MS using an Agilent 6890 gas chromatograph equipped with a 7673 autosampler / injector and an Agilent 5973 mass selective detector (MSD) system. GC-MS parameters: the inlet was operated in splitless mode, the injector temperature was 250°C; the injection volume was 1 μL; the column was Agilent 19091A-105HPULTRA1, 50 m×0.20 mm×0.33 μm film thickness; the oven temperature was 50°C for 0.5 min, increased to 95°C (10°C / min), maintained for 2 min, increased to 260°C (20°C / min), maintained for 4.75 min; the carrier gas was hydrogen; the pressure was 10 psi; the flow rate was 29.6 mL / min; the MSD transfer line heater temperature was 280°C; the MS scan range was m / z 40-500; the total run time was 20 min.

[0379] LCMS-MS:Liquid chromatography high-resolution mass spectrometry (LC-HRMS) was performed using a WatersAcquity I-Class UPLC system equipped with a Waters HSS T3 column (2.5 μm particle size, size 2.1 mm × 30 mm). The system was operated in gradient mode with a mobile phase of 0.1% formic acid in water and 0.1% formic acid in acetonitrile at a flow rate of 0.6 mL / min. The analytical sample was diluted with a mixture of acetonitrile and water (1:1 v / v) to a final concentration of 1 mg / mL. 0.1 μL of this prepared solution was then injected for analysis. Chemical purity was assessed by integrating the chromatographic peak at a wavelength of 269 nm using a photodiode array (PDA) detector. High-resolution mass spectra were acquired online with a PDA detector using a Waters Xevo G2-XS quadrupole time-of-flight (QTof) mass spectrometer operating in ESI positive mode. For both low and high collision energy mass spectra, data were recorded using Waters MSe experiments and processed using Unifi software (version 1.8).

[0380] Example 2: Pharmacology of XOB

[0381] Purpose: Based on human β2 receptor and human 5-HT 2A Amino acid sequence alignments between receptors (see e.g. Figure 6-10 ), assuming that 5-HT 2A The receptor, like the β2 receptor, contains a 5-HT 2A To test this, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutyloxy)hexan-1-amine (XOB) was synthesized as a putative 5-HT 2A exosite probe. 1A , 5-HT 2A , 5-HT 2B and 5-HT 2C The binding and functional activity of XOB were tested at the 1:1 receptor. In addition, in earlier studies, it was observed incidentally that XOB produced a strong and long-lasting local anesthetic effect after contact with mucosa. Therefore, to test the hypothesis that XOB also affects electrical signal transduction, we evaluated its effects on the human voltage-gated sodium channel (VGSC) Na co-expressed in human embryonic kidney (HEK) cells. v 1.1a subunit and Na v The sodium current generated by the β1 subunit (I Na In addition, we tested the acute effects of XOB on neuronal excitability in mouse cortical brain slices using patch clamp electrophysiology.

[0382] Methods: Measuring target engagement in transiently expressed HiBiT-5-HT receptors:We sought to compare the binding properties of XOB and the endogenous ligand serotonin at several 5-HT receptors using the NanoBRET target engagement assay. This assay quantifies the dynamic interaction between a ligand and its cognate HiBiT-tagged GPCR on the surface of living cells by competitive binding to a fluorescent tracer (Boursier et al., J Biol Chem., 2020; 295(15):5124-5135). For this evaluation, we used a 5-HT 1A , 5-HT 2A 5-HT 2C DNA constructs of receptors that are genetically fused to an N-terminal HiBiT tag and produce bright light upon high-affinity complementation with LgBiT, an impermeable 18 kDa subunit derived from NanoLuc (Killoran et al., Molecules., 2021;26(10):2857).

[0383] First, for each receptor, we determined the binding constant for one of two fluorescent tracers, including the NanoBRET-590 fluorophore (Killoran et al., Molecules, 2021;26(10):2857) conjugated to either clozapine or NAN-190. To this end, HEK293 cells transiently expressing HiBiT-tagged receptors were treated with increasing concentrations of fluorescent tracer in the absence or presence of excess unmodified ligand ( Figures 11A-11I These saturation binding analyses yielded the binding constant (K D ) showed that clozapine tracer had an effect on 5-HT 2A and 5-HT 2C The affinities of the NAN-190 tracer for 5-HT 1A The receptor affinity is 28 nM.

[0384] With the binding constants of the fluorescent tracers in hand, we further assessed the binding affinities of unmodified XOB and serotonin at these receptors. HEK293 cells transiently expressing HiBiT-tagged receptors were tested by competitively displacing fixed ECs with increasing concentrations of unmodified XOB or serotonin (1 μM-30 μM). 80 The concentration of fluorescent tracer ( Figures 12A-12D The binding constant was calculated according to the Cheng-Prusoff equation (Cheng and Prusoff, Biochem Pharmacol., 1973; 22(23): 3099-3108).

[0385] We chose to further compare XOB and serotonin in 5-HT 2AThe binding kinetics of the receptors may be more relevant for predicting potency. First, we determined the kinetic constants of the clozapine tracer. To this end, cells transiently expressing HiBiT-5-HT were treated with varying concentrations of the clozapine tracer in the presence and absence of excess unmodified clozapine. 2A HEK293 cells with the receptor and monitoring binding over 30 min ( Fig.13 ). The binding affinity derived from this kinetic analysis matched that derived from the saturation binding experiments and showed moderate binding affinity and fast dissociation rate. We further investigated the binding affinity of 80 The expression of serotonin and XOB in the presence of clozapine tracer was monitored over 30 min with HiBiT-5-HT 2A The binding affinities obtained by kinetics are generally comparable to those obtained by equilibrium analysis, but also indicate that XOB has a strong affinity for 5-HT 2A The receptor's weak potency is probably emphasized by its slow on-rate, which is two orders of magnitude slower than that of serotonin.

[0386] Cell lines: Stable expression of human VGSC subunit Na v Human embryonic kidney (HEK) 293 cells 1.1 (GenBank accession number NP 008851.3) were a gift from Dr. Massimo Mantegazza. Human VGSCβ1 subunit (GenBank accession number NP001028.1) cDNA was transfected into this line to generate a second stable line. Cells were cultured in Dulbecco's modified Eagle's medium containing (4.5 g / L D-glucose, L-glutamine, 110 mg / L sodium pyruvate, 200 μg / mL G418, 100 U / mL penicillin / streptomycin). All cells were maintained in a 37°C incubator containing 5% CO2.

[0387] animal: Wild-type C57BL / 6J mice were obtained from Jackson Laboratory. Male and female pups aged 17–23 days postnatal were used for electrophysiological experiments. The animals were maintained at the University of Michigan Department of Laboratory Animal Medicine. All procedures were performed in accordance with the NIH and approved by the University of Michigan IACUC.

[0388] Manual Sodium Current Recording: Sodium currents (I) were measured at room temperature using a manual whole-cell patch clamp technique and previously described electrophysiological methods (Chen et al., J Biol Chem., 2012; 287(46): 39061-39069). Na). Cells were seeded on 12 mm diameter clear glass poly-D-lysine coated coverslips (Neuvitro) and used for electrophysiological recordings within 48 h after seeding. Cells were identified using an AIR upright confocal microscope (Nikon). Micropipettes were obtained from 1.5 mm outer diameter capillary glass tubes (Harvard Apparatus) using a P-97 horizontal puller (SutterInstrument Co.). The micropipettes were then polished using an MF-830 microforge (Narishige) to obtain a resistance between 2.0 and 5.0 MΩ. The intracellular solution contained the following components (in mM): 1 NaCl, 125 N-methyl-D-glucamine, 2 MgCl2, 10 EGTA, 40 HEPES, 5 phosphocreatine-tris, 2 Mg-ATP, 0.2 Na2-GTP, 0.1 leupeptin, 270-275 mOsm, pH 7.2, with H2SO4. The extracellular solution contained the following components (in mM): 120 NaCl, 1 BaCl2, 2 MgCl2, 0.2 CdCl2, 1 CaCl2, 20 sucrose, 10 glucose, 10 HEPES, 10 tetraethylammonium chloride, 300-305 mOsm, pH 7.35 (with NaOH). Signals were amplified using a Multiclamp 700B amplifier (Molecular Devices). Data were acquired using a Digidata 1440A interface (Molecular Devices) and analyzed offline using pClamp10. Pipette and whole-cell capacitances were fully compensated, and series resistance was estimated and compensated for 50%. Signals were low-pass filtered at 10 kHz, and data were sampled at 20 kHz. Residual linear capacitance and leakage currents were eliminated using an online P / 4 subtraction. All manual patch clamp experiments were performed with gravity perfusion of the XOB at a flow rate of 2-3 mL / min. Unless otherwise stated, all manual whole-cell I»NER609 recordings under XOB conditions were performed after 3.9 min of perfusion.

[0389] Automated Sodium Current Recording (SyncroPatch):Automated whole-cell sodium current recordings were performed on a SyncroPatch 384 at the University of Michigan Chemical Genomics Center according to Nanion's standard procedures. Single-well medium resistance chips were used. Immediately before recording, HEK 293 cells were detached with TryplE, quantified with an automated cell counter (Nano EnTek), and then resuspended in extracellular solution at a concentration of 800,000 cells per ml. The extracellular solution contained the following components (in mM): 140 NaCl, 4 KCl, 2 CaCl2, 1 MgCl2, 5 glucose, 10 HEPES, 298 mOsm. pH 7.4, NaOH. The intracellular solution contained the following components (in mM): 110 KF, 10 NaCl, 10 KCl, 10 EGTA, 10 HEPES, 285 mOsm, pH 7.2, KOH. Currents were digitized at 20 kHz and low-pass filtered at 5 kHz. Series resistance was automatically compensated. Leakage current was subtracted using the leak correction method implemented in PatchControl384, where 1 or 2 square wave pulses were stepped from a holding potential of -80 mV to -60 mV for 10 ms. The combined IV protocol used to examine activation and inactivation was sampled at 10 kHz and low-pass filtered at 5 kHz. To determine I Na amplitude and voltage dependence of activation, I Na From a holding potential of -80 mV, a step to -120 mV was induced for 500 ms, followed by a pre-step to -10 mV for 50 ms. The membrane was hyperpolarized back to -120 mV for 500 ms before a 500 ms test pulse ranging from -120 mV to +30 mV in 5 mV increments was applied. Immediately following the test pulse, the voltage dependence of inactivation was determined by stepping down to -10 mV for 50 ms from the same voltage described for activation. Quality control criteria for the IV protocol of the SyncroPatch were set at capacitance <35 pF, peak I Na Greater than -200pA, series resistance between 1 and 35MΩ, seal resistance >200MΩ. Peak I Na was normalized to the cell capacitance to obtain the current density, which was used to plot the IV curve and calculate the conductivity using the following formula: g = I ÷ (VV rev ).

[0390] Where g is the conductance, I is the current, V is the test potential, V rev is the measured reversal potential. The peak current is normalized to the maximum peak I Na Amplitude. V 1 / 2 Activation indicates the appearance of half-peak I Na The normalized voltage dependence of the activation and inactivation curves was fitted with the following Boltzmann equation:

[0391] Where V 1 / 2 is the membrane potential at the midpoint of the curve, and k is the slope factor. Peak I Na The protocol was sampled at 20 kHz and low-pass filtered at 5 kHz. The holding potential of the membrane was raised from -80 mV to -120 mV for 500 ms and then dropped to -10 mV for 500 ms to elicit peak I Na , then returns to -80mV. Peak I Na The protocol repeated the scan at 0.1 Hz throughout the drug infusion to monitor the compound effect over 42 scans. Normalized peak I Na Inhibition was calculated using the following equation:

[0392] Peak I Na Density suppression = 1-(I drug ÷I Reference ).

[0393] Among them I Reference is the average peak I induced from the first 10 scans under perfusion of Nanion standard external (reference) solution Na density, and I Drug is the mean peak I evoked from the last scan after 3.5 min of vehicle, TTX, or XOB perfusion Na Density. Peak I Na The quality control settings of the protocol are the same as those of the IV protocol, except that the cell capacitance is less than 30 pF. Figure 2 XOB concentration response curve in A, normalized peak I using the four-parameter variable slope inhibitor-response equation in GraphPad Prism Na Density inhibition data were fitted with nonlinear regression. The data point for 1 pM XOB was set equal to the vehicle response, while the data point for 1 mM XOB was set equal to the response of 1 μM TTX.

[0394] Brain slice preparation:Acute brain slices were prepared as described previously (Hull et al., Ann Clin Transl Neur., 2020; 7(ll): 2137-2149). Briefly, mice were anesthetized with isoflurane and decapitated. The brain was carefully removed from the skull and placed in ice-cold carbogen-aerated slicing solution containing (in mM): 110 sucrose, 62.5 NaCl, 2.5 KCl, 6 MgCl2, 1.25 KH2PO4, 26 NaHCO3, 0.5 CaCl2, 20 D-glucose, pH 7.35-7.40. The brain was blocked and the prefrontal cortex was cut into 250 μm thick coronal slices using a vibrating slicer (Electron Microscopy Sciences). The slices were placed in an aerated holding chamber filled with slicing solution and incubated at room temperature for 30 minutes, then placed in 1:1 slices: artificial cerebrospinal fluid (ACSF) at 35°C for 30 minutes. ACSF contained mM (125 NaCl; 2.5 KCl; 1 MgCl2; 1.25 KH2PO4; 26 NaHCO3; 2 CaCl2; and 20 D-glucose (pH 7.35-7.40). The slices were then placed in a holding chamber containing 100% ACSF and aerated at room temperature for at least 30 minutes before recording.

[0395] Action potential recording and analysis:Individual brain slices were placed in an RC-26 recording chamber (Warner Instruments) and perfused with gassed ACSF at a flow rate of 2–3 mL / min, equipped with an inline heater (Warner Instruments) to maintain the recording temperature at 33–35 °C. Layer 5 pyramidal neurons were identified based on their large soma size, shape, and position using an AIR upright confocal microscope (Nikon) equipped with IR-DIC optics and a 40X water immersion objective. Only vertically oriented pyramidal cells were selected for recording. The resistance of the recording electrodes was 4–8 MΩ, and the solution contained (in mM): 140 K-gluconate, 4 NaCl, 0.5 CaCl2, 10 HEPES, 5 EGTA, 5 creatine phosphate, 2 Mg-ATP, and 0.4 GTP (pH 7.2–7.3 with KOH). The junction potential was calculated to be 14.3 mV using a P-clamp junction potential calculator, and all values ​​shown in the study are uncorrected. The resting membrane potential was defined as the membrane potential occurring in current clamp <10 s after the initial interruption of baseline or immediately after XOB perfusion in voltage clamp mode, after a break at -94.3 mV. Repetitive action potential discharges were evoked in whole-cell current clamp from a resting membrane potential of -20 pA to +400 pA with 1 s long current injections in steps of 10 pA. Each scan was separated by a 1 s long 0 pA current injection. Data were acquired at 20 kHz and filtered at 10 kHz. Cells with access resistance >20 MΩ or RMP depolarization greater than -64.3 mV measured in voltage clamp were not used. A bridge balance was used to compensate for access resistance and pipette capacitance. Whole-cell capacitance was measured in voltage clamp using P-clamp whole-cell capacitance compensation, starting from -94.3 mV with 10 mV depolarization steps. Automated action potential (AP) quantification and analysis were performed using custom MATLAB (Math Works) software. AP was defined as the voltage exceeding 0 mV after dV / dt>10 mV / ms, which was defined as the AP threshold. Input resistance was calculated using Ohm's law after 250 ms of injection of -10 pA current from the resting membrane potential.

[0396] 5-HT receptor binding assay:

[0397] NanoBRET-based ligand binding assay:HEK293 cells expressing HiBiT-labeled 5-HT receptors were treated with serial dilutions of fluorescent tracers in the presence or absence of 30 μM competing unmodified ligands. The culture plates were briefly mixed and incubated at room temperature for 90 minutes. To measure BRET, cells were treated with 2X detection solution containing 100-fold dilutions of LgBiT (Promega) and 50-fold dilutions of furanazine live cell substrate (Promega) in Opti-MEM. The plates were mixed for 10 minutes to allow HiBiT / LgBiT complementation. The filtered luminescence was then measured using a GloMax Discover microplate reader (Promega) equipped with a 450nm (8nm bandpass) filter (donor) and a 600nm longpass filter (acceptor). BRET was calculated by dividing the acceptor>600nm light output by the donor 450nm emission. The values ​​were background corrected by subtracting the BRET value from the sample treated with an excess of unmodified ligand.

[0398] For competitive displacement experiments, at fixed EC 80 The cells were treated with serial dilutions of the unmodified ligand in the presence of 100% concentration of fluorescent tracer. The plate was briefly mixed and incubated at room temperature for 90 min. The cells were then treated with 2X detection solution and BRET measurements were performed as described above. Affinity values ​​(K I ) is based on the observed IC 50 The values ​​were calculated using the Cheng-Prusoff equation (Cheng and Prusoff, Biochem Pharmacol., 1973; 22(23): 3099-3108).

[0399] Kinetic measurements of ligand binding to HiBiT-labeled 5-HT receptors: To determine the binding kinetics of the clozapine tracer, cells were treated with 2X detection solution, which contained a 100-fold dilution of LgBiT (Promega) and a 50-fold dilution of furazolidinone live cell substrate (Promega) in Opti-MEM without phenol red. To determine specific binding, control wells were also treated with clozapine at a final concentration of 30 μM. The plates were mixed for 15 minutes before the addition of serially diluted clozapine tracers. After brief mixing, kinetic readings were immediately collected on a GloMax Discover microplate reader (Promega).

[0400] For the binding kinetics of the unmodified ligand, cells were first treated with 2X detection solution as described above, and control wells were additionally treated with excess clozapine. After 15 minutes of incubation, cells were treated with serial dilutions of the unmodified ligand and a fixed EC80 concentration of clozapine tracer. After brief mixing, kinetic measurements were immediately collected on a GloMax Discover microplate reader (Promega).

[0401] Data Analysis: Saturation KD values ​​were derived from “single site binding” fits and competition IC values ​​were derived from “log(inhibitor) vs. response variable slope” fits using GraphPad Prism software. 50 Then according to the Cheng-Prusoff equation, IC 50 The binding affinity of the unmodified ligand (KI) was derived from the values ​​of , where [L] is the concentration of the fluorescent ligand in the assay and KD is its affinity in a saturation binding experiment:

[0402]

[0403] The kinetic analysis of the fluorescent tracer was plotted using the association kinetics-thermal fitting of two or more concentrations. The kinetic constant (k on and k off) and the binding constant (K D ) (Tummino et al., Biochemistry-US., 2008: 47(20): 5481-5492). The kinetic analysis of the unmodified compound was plotted using competitive binding kinetics fitting (Motulsky-Mahan model of competitive binding kinetics) (Motulsky and Mahan, Mol Pharmacol., 1984; 25(1): 1-9). The binding affinity and other kinetic constants were determined based on the resulting curves.

[0404] 5-HT receptor function assay:The stably expressed 5-HT2 receptor Flp-In 293T-Rex tetracycline inducible system (Invitrogen, mycoplasma-free) was used for calcium flux assays as previously described and used (Klein et al., ACS Pharmacol Transl Sci., 2021; 4(2): 533-542). The cell line was maintained in DMEM containing 10% FBS, 10 μg / mL blasticidin (Invivogen) and 100 μg / mL hygromycin B (GoldBio). The day before the assay, receptor expression was induced with tetracycline (2 μL / mL) and inoculated into DMEM containing 1% dialyzed FBS. On the day of the assay, cells were incubated with Fluo-4 direct dye (Invitrogen, 20 μl / well) at 37 ° C for 1 hour and then reconstituted in drug buffer (20 mM HEPES-buffered HBSS, pH 7.4) containing 2.5 mM probenecid. After dye loading, allow cells to balance to room temperature for 15 minutes, then put into FLIPRTETRA fluorescence imaging plate reader (Molecular Devices). In drug buffer (HBSS buffered with 20mM HEPES, pH 7.4), the drug is diluted to 5 times of final concentration, and supplemented with 0.3% BSA and 0.03% ascorbic acid without fatty acid. The drug dilution is dispensed into 384-well plastic plates and put into FLIPRTETRA for drug stimulation. Fluorescence readings are programmed to record 10 seconds of baseline fluorescence (1 reading / second), then 5 μl of drug is added to each well and read for a total of 2 minutes (1 reading / second). The fluorescence in each well is standardized to the mean value of the first 10 readings of baseline fluorescence, and then the maximum multiple peak value is calculated to increase. Peak value is plotted as a function of drug concentration, and data are standardized to 5-HT stimulation percentage. For antagonist mode, 3.2nM5-HT is used to stimulate the culture plate to measure calcium flux blocking reaction. Data were plotted and nonlinear regression was performed using “log(agonist) vs. response” in GraphPad Prism9 to derive Emax and EC 50 parameter estimate.

[0405] result: The binding affinities of HiBiT-tagged receptors transiently expressed in HEK293 cells for XOB and serotonin indicate that serotonin is involved in the regulation of 5-HT 1A , 5-HT 2A and 5-HT 2C K on receptor I The values ​​were 330nM, 470nM, and 120nM, respectively, which are consistent with the reported values. The binding affinity of XOB is significantly lower in 5-HT 1A Receptor K I =2.6μM, in 5-HT1A and 5-HT 2C Receptor K I >10μM( Figures 12A-12D ).

[0406] The binding affinity from the kinetic analysis matched that from the saturation binding experiments and showed a moderate association rate and a fast dissociation rate. We monitored the binding of the peptide at fixed EC for 30 min. 80 Concentrations of serotonin and XOB in the presence of clozapine tracer and HiBiT-5-HT 2A The combination of Fig.14 ). The binding affinities derived from kinetics are generally comparable to those derived from equilibrium analyses, but also indicate that XOB is 2A The weak potency of β-catenin may be explained by its slow on-rate, which is approximately 24 times slower than that of serotonin.

[0407] To measure the functional activity of 5-HT2 receptors, a functional assay was performed measuring the expression of human 5-HT2 stably expressed in the T-Rex tetracycline-inducible cell line. 2A , 5-HT 2B and 5-HT 2C Gq-mediated calcium flux activity of the receptor ( Figures 15A-15C ). XOB exhibited little or no measurable agonist activity at any 5-HT2 receptor at concentrations up to 10 μM. However, when XOB was tested for its competitiveness with 5-HT in the antagonist mode, XOB showed no measurable agonist activity at any 5-HT2 receptor. 2A (IC 50 =1.3 μM), which is consistent with the measured affinity (K I =2-3 μM) values. However, XOB was less potent in blocking 5-HT 2B and 5-HT 2C The 5-HT receptor mediated calcium flux response produced <50% inhibition at concentrations up to 10 μM, thus showing that 5-HT 2A Antagonists are selective for the closely related 5-HT2 receptor.

[0408] XOB inhibits Na by manual and automated patch clamp v 1.1 Sodium current generated: The investigation of XOB regulation of VGSC function began with manual whole-cell patch clamp studies of human Na+ stably expressed in HEK cells. v 1.1 Preliminary analysis of 10 μM XOB mediated by I_NER681 ( Fig.16A ). In three cells, acute perfusion of 10 μM XOB increased the mean Na at 0 mV. v 1.1 Peak I NaThe density decreased by 94.1±1.31% compared with the baseline. v The acute inhibition of 1.1 persisted, and after washing out XOB for 10 minutes, only the original baseline I at 0 mV was restored. Na The density of 10 μM XOB was 17.5 ± 3.64%. v 1.1 Inhibition of current-voltage (IV) relationship Fig. 16B We next examined human Na v Does co-expression of the β1 subunit, which is an integral part of the VGSC structure in native cells (O'Malley, Annu Rev Physiol., 2015;77:481-504), alter the acute inhibitory effect of XOB at 10 μM, 5 μM, and 1 μM concentrations? Fig. 16C ). After 3.9 minutes of perfusion, 10μM and 5μM XOB caused Na v 1.1 Peak I Na 1μM XOB reduced Na v 1.1 Peak I Na A decrease of 35.3% (Table 6). Fig.16D Shows expression of hNa v Acute I in l.l+hbl cells Na Dial plot of the perfusion time course of inhibition at concentrations of 10, 5, and 1 μM XOB.

[0409] Table 6. Peak I plotted every 5.21 seconds using a voltage step from -120mV to 0mV for 250ms Na Induced diary chart

[0410]

[0411] In order to effectively characterize XOB-mediated I Na To investigate the concentration-response relationship of inhibition, we used a high-throughput automated patch clamp technique (Nanion SyncroPatch 384) to record the expression of hNa v 1.1+hbl HEK cells. XOB in peak I Na IC of the generated concentration-response curve 50 The value is 4.29μM, and the slope is 1.45 ( Fig.17A ; Table 7). At 10 μM, XOB decreased the baseline peak value I Na The peak I Na The level of inhibition was similar to that of 1 μM TTX, which reduced the peak I NaThe heat map shows the effect of vehicle (0.1% EtOH), 1 μM TTX, or increasing concentrations of XOB on Na v 1.1 Peak I Na The relative level of inhibition ( Fig. 17B ). Representative peak I using a protocol from -120 mV to -10 mV in the presence of vehicle, 10 μM XOB, or 1 μM TTX. Na Tracer such as ( Fig. 17C ) as shown. Fig.17D Peak I for all recordings under baseline and drug conditions is shown Na The average peak I of cells in each concentration group was scanned. Na value.

[0412] Table 7. XOB concentration response curve parameters

[0413]

[0414]

[0415] Further exploration of XOB to reduce peak I Na To investigate the mechanism of action, we ran the protocol to elicit an IV relationship to test whether XOB regulates Na in a concentration-dependent manner. v 1.1+b1 I Na The IV curves in the presence of vehicle, 1 μM TTX or increasing concentrations of XOB are shown in Figure 2. Fig.18A and as shown in Table 8. The peak I corresponding to the -20mV step of the IV curve Na Density Fig.18B As expected from the manual patch clamp experiments, groups of cells perfused with 3, 5, or 10 μM XOB all showed a peak I at -20 mV compared to vehicle. Na The density of 1 μM TTX (-15.84 ± 2.16 pA / pF) and 10 μM XOB (-17.46 ± 3.1 pA / pF) was significantly inhibited by 1 μM TTX (-15.84 ± 2.16 pA / pF) and 10 μM XOB (-17.46 ± 3.1 pA / pF). Na When analyzing the voltage dependence of sodium conductance, no effects were observed. However, perfusion of 3 μM XOB did result in an increase in I Na The voltage dependence of availability was significantly shifted by -5.7 mV (P value: 0.023; unpaired t test, see Fig.18C and Table 9). This hyperpolarized shift in the voltage dependence of inactivation may be due to the XOB response to Na vThe inhibitory effect of a factor of 1.1.

[0416] Table 8. Concentration-dependent inhibition of XOB by spike protocol using automated patch clamp (SyncroPatch) in HEK cells stably co-expressing human Na v 1.1 and Na v β1I Na Peak value.

[0417]

[0418]

[0419] Table 9. Voltage dependence of conductance (G / G) under vehicle (black) and 3 μM XOB (orange) conditions Max ) and voltage dependence of availability

[0420] Vector (n=25) 3 μM XOB (n=22) Capacitance(pF) 11.06±0.9 11.17±1.0 <![CDATA[Activate V 1 / 2 (mV)]]> -39.97±2.1 -34.32±1.8 <![CDATA[Activation slope coefficient (mV -1 )]]> 6.16±0.9 6.18±1.1 <![CDATA[inactivated V 1 / 2 (mV)]]> -54.76±1.8 -60.46±1.5* <![CDATA[Inactivation slope coefficient (mV -1 )]]> -6.35±0.6 -6.41±0.7

[0421] *P value: 0.023; unpaired t test

[0422] Acute effects of 10 μM XOB on layer V pyramidal neurons in the mouse prefrontal cortex

[0423] In the present study, the effects of different concentrations of XOB on Na vAfter investigating the effects of 1.1+b1 function, we wondered whether this observed inhibition of sodium channels in principal neurons of heterologous systems translated to in vivo models. Therefore, we recorded passive and active properties of layer V pyramidal neurons in prefrontal cortex (PFC) slices from wild-type mice (Figure 19). Acute perfusion of 10 μM XOB resulted in a decrease in the maximum firing rate of PFC layer V pyramidal neurons by approximately 12 Hz when 400 pA current was injected (baseline = 24.88 ± 2.07 Hz; 10 μM XOB = 14 ± 1.82 Hz). 10μM XOB induced a depolarization of the resting membrane potential by ±8.45±1.15mV (baseline=-71.7±1.04mV vs.10μM XOB=-63.25±1.15mV), and significantly decreased the first AP peak amplitude (baseline=47.4±1.42mV vs.10μM XOB=41.21±2.92mV), maximum dV / dt (baseline=471.73±27.12mV / ms vs.10μM XOB=402.68±46.20mV / ms), minimum dV / dt (baseline=-103±6.28mV / ms vs.10μM XOB=-91.32±8.95mV / ms), and first AP threshold (baseline=-42.84±1.02mV vs.10μM XOB=41.21±2.92mV). After perfusion of 10 μM XOB, no significant changes in input resistance (baseline = 104.52 ± 21.84 MΩ vs. 10 μM XOB = 100.08 ± 30.18 MΩ) or spike width (baseline = 0.72 ± 0.02 ms vs. 10 μM XOB = 0.76 ± 0.06 ms) were observed. (See Figures 19A-19J and Table 11)

[0424] Table 10. Peak I obtained by IV curves induced by voltage steps from -120 mV to -20 mV using automated patch clamp (SyncroPatch) Na density

[0425]

[0426] Table 11. Effects of 10 μM XOB on membrane properties and action potential firing of layer V pyramidal neurons in the prefrontal cortex of wild-type mice

[0427]

[0428] discuss:Tryptamine psychedelic compounds, such as psilocybin and DMT, have reemerged as promising therapeutic candidates for the treatment of a variety of psychiatric disorders, including depression, substance abuse, and anxiety-related disorders (Vollenweider and Preller, Nat Rev Neurosci, 2020; 21(11): 611-624; D'Souza et al., Neuropsychopharmacol., 2022; 47(10): 1854-1862).

[0429] Phenylalkylamine psychedelics such as 2C-B also have clinically desirable properties, such as oral activity of 12-24 mg, low sympathomimetic effects, and a duration of action of 4-8 hours (Shulgin and Carter, Psychopharmacol Commun., 1975; 1(1):93-98; Papaseit et al., Front Pharmacol., 2018; 9:206), and preliminary evidence that they are effective in psychiatric disorders (Gonzalez et al., Biomed Res Int., 2015; 2015). 2A Receptor heterologous cells used [ 125 I]-2,5-dimethoxy-4-iodoamphetamine ([ 125 In vitro competitive binding studies using DOI) showed that it has a high affinity for 2C-B, K I 0.88 nM and 0.66 nM, respectively (McLean et al., J Med Chem., 2006; 49(19): 5794-5803). Functionally, through in vitro Ca 2+ Mobilization test measures the effect of 2C-B on 5-HT 2A (EC 50 =2.1 nM), 5-HT 2B (EC 50 =57 nM) and 5-HT 2C (EC 50 =43 nM) receptors showed high efficacy (Luethi et al., Neuropharmacol., 2018; 134: 141-148). 2A The receptor has high affinity and potency and has been shown to act as a partial agonist at PLC-, PLA2-, and G q -coupled Ca 2+mediated assays (McLean et al., J Med Chem., 2006; 49(19):5794-5803; Moya et al., J Pharmacol Exp then, 2007; 321(3):1054-1061; Rickli et al., Neuropharmacol., 2015; 99:546-553; Luethi et al., Neuropharmacol., 2018; 134:141-148). Interestingly, 2C-B has been reported to be able to transiently express 5-HT 2A 5-HT receptor in Xenopus oocytes 2A The responses produced in the oocyte model are likely to represent the inward currents induced by Ca. 2+ Transiently by activating transiently overexpressed 5-HT 2A The chloride current generated by receptor coupling to PLC has raised questions about its physiological relevance to the actions of 2C-B and related phenylalkylamines in mammalian neurons.

[0430] In this study, we sought to explore the chemical space of 2C-B binding to serotonin receptors by synthesizing extended side chain compounds XOB as probes of putative exosites, similar to the adrenergic β2 receptor exosite (McCorvy et al., Nat Struct Mol Biol., 2018; 25(9):787-796; Kim et al., Cell, 2020; 182(6):1574-1588). We hypothesized that the aralkyloxyalkyl side chain would enhance the affinity and slow down the binding of XOB to 5-HT compared to the parent 2C-B molecule. 2A Although XOB does show a slower on-rate than 2C-B, it is more sensitive to 5-HT receptor binding. 2A The affinity of the receptor is reduced and the 2B , 5-HT 2C and 5-HT 1A Functionally, XOB binds very poorly to 5-HT receptors. 2A The receptors show a certain degree of selective antagonism ( Figures 15A-15C ).

[0431] Rather than XOB and the hypothesized 5-HT 2ARather than enhancing interactions at the receptor exosite, the aralkyloxyalkyl side chain extension on XOB increases nonspecific interactions with the lipid bilayer or another membrane protein. The unexpected finding that XOB inhibits VGSC suggests that XOB may act off-target on another membrane protein. At low micromolar concentrations, XOB significantly reduced peak I Na density, and make I Na Voltage-dependent hyperpolarization of fast inactivation ( Figures 17A-17D ) Preliminary experiments using manual patch clamp showed that XOB inhibited the expression of h Na in HEK cells. v 1.1+I produced by hbl Na . After XOB elution I Na The lack of recovery is consistent with the slow binding rate observed in our analysis of 5-HT receptor binding kinetics and the lipophilicity of the molecule. Na To investigate the inhibitory range of the mitochondria, we used a high-throughput patch clamp technique.

[0432] We observed that XOB has a strong affinity for Na v 1.1+bl generated I Na The inhibition was concentration-dependent, IC 50 The value of XOB in 5-HT 2A The affinity of the receptor (K I =2.6 μM) and potency (IC 50 =1.3μM). In addition to blocking the peak I Na In addition, XOB also affects Na v Although XOB had no significant effect on the voltage dependence of activation, 3 μM XOB resulted in an increase in I Na The voltage dependence of rapid inactivation undergoes a dramatic hyperpolarizing shift. This shift in the voltage dependence of availability provides mechanistic insight into the inhibitory effects of Xob on VGSCs. In the presence of Xob, more VGSCs in the brain will be inactivated or unavailable at hyperpolarized membrane potentials. This shift is expected to reduce window currents and increase AP thresholds, ultimately reducing the intrinsic excitability of neurons in the presence of Xob.

[0433] Indeed, acute perfusion of 10 μM XOB significantly reduced the maximal AP firing frequency, AP peak amplitude, AP depolarization and repolarization rates (dV / dt), and depolarized the resting membrane potential and AP threshold of layer V pyramidal neurons in mouse PFC in brain slices ( Figures 19A-19J , Fig. 20 ). 5-HT 2AA particularly predominant expression of the receptor is found in cortical layer V pyramidal neurons, where they are enriched in the apical dendritic compartment (Willins et al., Synapse, 1997; 27(1):79-82; Jakab and Goldman-Rakic, Proc Natl Acad Sci USA, 1998; 95(2):735-740; Weber and Andrade, Front Neurosci, 2010; 4:36). 5-HT on layer V pyramidal neurons 2A Receptor activation is generally thought to be excitatory (making the cell more likely to spike), presumably through Gα q coupling pathway, while 5-HT 1A The receptor is thought to activate G protein-coupled inwardly rectifier K + The GIRK channel inhibits pyramidal neurons (Araneda and Andrade, Neuroscience, 1991; 40(2): 399-412; Andrade, Ann NY Acad Sci., 1998; 861(1): 190-203; Andrade, Neuropharmacol., 2011: 61(3): 382-386). 2A Since XOB has dual antagonistic effects on 5-HT receptors and VGSCs, we hypothesized that XOB would have an inhibitory effect on the excitability of PFC layer V pyramidal neurons. We believe that XOB significantly reduced the AP discharge frequency, peak amplitude, and depolarization and repolarization rates of PFC layer V pyramidal neurons due to its inhibition of VGSCs. 2A The excitatory effect of the agonist is expected to be due to the 5-HT 2A Antagonism results in no change or hyperpolarization of the resting membrane potential. The significant depolarization of the resting membrane potential challenges this expectation as well as that of classical VGSC blockers, raising the possibility that XOB modulates other ionic conductances that contribute to the resting membrane potential. The lack of significant changes in input resistance raises the possibility that other ion channels may open in response to XOB, masking the expected changes in input resistance caused by VGSC inhibition. Although no significant changes in spike half-widths indicative of modulation of other voltage-dependent conductances were observed after XOB superfusion, VGSC inhibition by XOB has negligible effects on membrane potential and input resistance when measured in the resting state because most VGSCs in the neuron are nonconducting.

[0434] Future Analysis of XOB vs 5-HT 2A Acute effects of knockout mice on layer V pyramidal neurons will help isolate 5-HT 2Aand VGSC antagonism to the contribution of XOB excitatory inhibition. It is worth noting that the mice used in this study were young (approximately 3 weeks after birth), and neurodevelopmental factors should be considered when interpreting the effects of XOB on neuronal excitability, including the age-dependence of 5-HT receptor expression in the rodent cortex (Beique et al., J Neurosci., 2004; 24(20): 4807-4817). In addition, neurons recorded from the medial PFC were not further subdivided into the prelimbic cortex, infralimbic cortex, and anterior cingulate cortex. Therefore, this study may have obscured regional specific differences in the effects of XOB on mPFC neurons. Another limitation of these physiological data concerns the differences in 5-HT between humans and rodents. 2A Differences in the amino acid sequence of the receptor. Although highly conserved, the divergent regions between humans and rodents may affect the binding of ligands to 5-HT 2A Functional interactions of 5-HT receptor binding (Dougherty and Aloyo, Psychopharmacol (Berl), 2011; 215(3): 581-593). In future slice physiological studies, humanized 5-HT 2A Receptor transgenic rodent models may have greater physiological relevance.

[0435] Since XOB is effective for 5-HT 1A The receptor exhibits negligible binding affinity and is 2A Instead of 5-HT 2B and 5-HT 2C The receptor exhibits selectivity, and we attribute the serotonergic component of its effect on the intrinsic excitability of layer V pyramidal neurons to 5-HT 2A Antagonistic effect. In addition to intrinsic regulation, 5-HT 2A The receptors can also affect neuronal excitability through circuit-level synaptic effects that cannot be measured in our current clamp experiments using XOB. 2AAgonists increase the frequency of excitatory postsynaptic potentials and currents, especially asynchronous (non-electrically evoked) release in PFC layer V pyramidal neurons (Aghajanian and Marek, Neuropharmacol., 1997; 36(4-5):589-599; Aghajanian and Marek, Brain Res., 1999; 825(1-2):161-171; Marek and Aghajanian, Eur J Pharmacol., 1999; 367(2-3):197-206; Andrade, Ann NY Acad Sci., 1998; 861(1):190-203; Andrade, Neuropharmacol., 2011: 61(3):382-386). 2A In the absence of an agonist (such as DOI), we expect XOB to significantly reduce the amplitude and frequency of EPSCs in layer V pyramidal neurons. 2A Receptors are also expressed on cortical GABAergic interneurons (Willins et al., Synapse, 1997; 27(1):79-82; Jakab and Goldman-Rakic, Proc Natl Acad Sci USA, 1998; 95(2):735-740; Santana et al., Cereb Cortex., 2004; 14(10):1100-1109). v 1.1 is thought to be localized primarily in the axon initial segments of parvalbumin-positive (PV+) GABAergic fast-firing interneurons in the cortex, and we expect that XOB will reduce the excitability of cortical PV+ interneurons (Ogiwara et al., J Neurosci., 2007; 27(22): 5903-5914). Future evaluation of the effects of XOB on GABAergic interneurons and other isolated VGSC subtypes will be instructive.

[0436] Clinically effective drugs for the treatment of schizophrenia and bipolar disorder have different effects on 5-HT 2A Atypical antipsychotics exhibit significant antagonist (or inverse agonist) activity at D2 receptors (e.g., risperidone, clozapine) and VGSCs (e.g., carbamazepine, lamotrigine), targets that are considered important contributors to their therapeutic effects. Pharmacologically, atypical antipsychotics interact with D2 receptors and 5-HT 2A The dual antagonism of 5-HT receptors is related to the action of 5-HT receptors (Stahl, Antipsychotics and Mood Stabilizers: Stahl's Basic Psychopharmacology, Cambridge University Press, 2008). 2AAntagonism can improve negative symptoms and reduce adverse extrapyramidal symptoms often observed in antipsychotic treatment (Meltzer, Neuropsychopharmacol, 1999; 25(1): 1-9). Targeted sequencing of a large patient population has shown that VGSCs are involved in the pathophysiology of schizophrenia (Rees et al., Biol Psychiatry., 2019; 85(7): 554-562). In addition, lamotrigine adjunctive therapy has shown efficacy in the treatment of schizophrenia, possibly by regulating cortical excitability and glutamate transmission (Large et al., Psychopharmacol., 2005; 181: 415-436). Overall, these findings highlight the role of XOB as a 5-HT inhibitor. 2A The strong translational value of new classes of receptors and VGSCs that exhibit effects.

[0437] In conclusion, we report the discovery of a new structural class of substituted phenylalkylamines that antagonize 5-HT 2A The XOB is a promising tool for the treatment of psychiatric disorders, including 5-HT receptors and VGSCs, two key molecular targets for the treatment of psychiatric disorders. As a leader in the treatment field, XOB offers advances in the development of more targeted treatments for psychiatric disorders with fewer side effects. As a tool, XOB has the potential to advance our understanding of 5-HT 2A The understanding of the complex roles of receptors and VGSCs in many neuropsychiatric diseases is intriguing. Although further characterization and structural optimization may be beneficial, XOB represents a good starting point for further exploration in chemical neuroscience and biological psychiatry.

[0438] Example 4: Synthesis of Disclosed N-Substituted Phenylalkylamine Compounds

[0439] Additional N-substituted phenylalkylamines, such as compounds of formula (I) or (II), can be synthesized according to the general reaction sequence shown in Scheme 2.

[0440]

[0441] Scheme 2 General Synthesis of Compounds of Formula (I) and (II)

[0442] Briefly, a suitable phenylalkylamine precursor is reacted with a side chain precursor (e.g., Br(CH2) m X(CH2) n Ph (shown above) generates compounds of formula (I) or (II) by nucleophilic substitution of a leaving group (in this exemplary case, bromide) with a phenylalkylamine under condensation conditions.

[0443] In this embodiment, potassium iodide is used to accelerate the nucleophilic substitution reaction. It is a well-known technique to add inorganic iodide salts (e.g., potassium iodide, sodium iodide) to improve the efficiency of nucleophilic substitution reactions. However, potassium iodide is not essential for the reaction. Those skilled in the art can determine whether potassium iodide should be added and, if so, how much should be used.

[0444] In this embodiment, triethylamine is used as an exemplary base. However, those skilled in the art will recognize that other bases may also be used. For example diisopropylethylamine (DIPEA) and pyridine are common organic bases. Similarly, although acetonitrile is described as an exemplary solvent, according to the knowledge of those of ordinary skill in the art, acetonitrile may be replaced by another suitable solvent.

[0445] The synthesis of any other necessary starting materials or reagents will be apparent to those skilled in the art in view of this disclosure and general references known in the art. (See, for example, Green et al., "Protective Groups in Organic Chemistry," (Wiley, 2nd ed. 1991); Harrison et al., "Compendium of Synthetic Organic Methods," Vols. 1-8 (John Wiley and Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry," Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al. al, "Reagents for OrganicSynthesis," Volumes 1-17, Wiley Interscience; Trost et al., "ComprehensiveOrganic Synthesis," Pergamon Press, 1991; "Theilheimer'sSynthetic Methods ofOrganic Chemistry," Volumes 1-45, Karger, 1991; March, "Advanced OrganicChemistry," Wiley Interscience, 1991; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis," John Wiley & Sons, 1995; Glennon et al. 1986. J. Med. Chem., 29 (2), 194-199; Nichols et al. 1991. J. Med. Chem., 34 (1), 276-281; ​​Kedrowski et al., 2007. Organic Letters, 9 (17), 3205-3207; Heravi & Zadsirjan. 2016. Current Organic Synthesis, 13 (6), 780-833; Keri et al., 2017. European J. Med. Chem., 138, 1002-1033; Pérez-Silanes et al., 2001. J. Heterocyclic Chem, 38 (5), 1025-1030) and EP1937626 (US8648214), which describe the synthesis of salmeterol and its analogs, all of which can be combined with the contents disclosed herein to synthesize the compounds of the present invention. ).

[0446] Example 5: Synthesis of N-substituted phenylalkylamine analogs with different side chains

[0447] Objective: To synthesize and physically characterize novel N-substituted analogs of phenylalkylamines with isomeric side chains.

[0448] Methods: To further explore 5-HT 2A , 5-HT 2B and 5 2C To expand the binding site of the receptor, the position of the heteroatom "hinge" in the analog series was shifted along the methylene unit to create isomeric side chain variants.

[0449] For example, for a 10-carbon side chain, "1 and 9", "2 and 8", "3 and 7", "4 and 6", "5 and 5", "7 and 3", "8 and 2", or "9 and 1" variants, as well as "oxygen-free" compounds containing only methylene units will be synthesized and compared (see Table 1). Such compounds are synthesized according to Examples 1 and 4 and the above discussion, wherein the exemplary "6 and 4" side chains are replaced by "1 and 9", "2 and 8", "3 and 7", "4 and 6", "5 and 5", "7 and 3", "8 and 2", or "9 and 1" variants, as well as "oxygen-free" side chains containing only methylene units. A series of N-substituted phenylalkylamines conforming to formula (I) or (II) will also be synthesized. In other examples, the phenylalkylamine 5-HT can be modified according to the methods described. 2A Receptor ligands such as 2C-I, 2C-E, 2C-T, mescaline, and others known to those skilled in the art.

[0450] Results: Specific reaction conditions and isolation procedures will be determined empirically for each target compound. New compounds will be analyzed by thermal analysis, proton and carbon nuclear magnetic resonance spectroscopy ( 1 H NMR, 13 C NMR), GC-MS, LC-MS, X-ray diffraction and elemental analysis were used for physical characterization. The described synthesis is simple and utilizes chemical methods known to those skilled in the art, and is expected to produce new N-substituted phenethylamine compounds. These compounds may exhibit improved properties, such as enhanced binding affinity, specificity or duration of action.

[0451] Example 6: Evaluation of in vitro pharmacological activity of disclosed compounds

[0452] Purpose: Receptor screening will be performed to characterize the binding properties and functional activities of disclosed compounds at various receptors, channels, and transporters. Results will facilitate comparisons with unsubstituted phenylalkylamines and other psychedelic drugs. Additionally, the data will be used to support or modify the primary exosite hypothesis, while structure-activity analysis of the data will aid in the design of new compounds.

[0453] Methods: Published compounds were synthesized and submitted to the Psychoactive Drug Screening Program (PDSP) sponsored by the National Institute of Mental Health. The PDSP screen included the evaluation of 45 receptor and transporter binding sites. Most screens were performed using cloned human receptors, but there are some exceptions. For example, see the PDSP screen and results of DALT and its derivatives (Cozzi & Daley, Bioorganic & Medicinal Chemistry Letters, 2016; 26(3): 959-964; Klein et al., Neuropharmacology, 2018; 142: 231-239).

[0454] Briefly, test compounds were dissolved in DMSO and tested at 10 mM in a competition assay with a radioactive probe compound. A secondary assay was performed at the identified receptor or transporter using 12 concentrations of test compound tested in triplicate to test sites that exhibited >50% inhibition at 10 mM to generate a competition binding isotherm. K i The values ​​were obtained from the best-fit IC values ​​after nonlinear regression of these binding isotherms using the Cheng-Prusoff equation (Cheng & Prusoff, Biochem Pharmacol., 1973; 22(23): 3099-108). 50 For data analysis and comparison, K i The value is converted to pK i (-log K i )value.

[0455] Binding assays were performed using the following radioligands: 3 H]8-OH-DPAT(5-HT 1A ),[ 3 H]GR125743(5-HT 1B / 1D ),[ 3 H]5-HT(5-HT 1E ),[ 3 H]ketanserin (5-HT 2A ),[ 3H]LSD(5-HT 2A / 2B / 6 / 7 ),[ 3 H]Mesulerg (5-HT 2C ),[ 3 H]Citalopram (serotonin transporter), [ 3 H] prazosin (α1A / 1B / 1D), [ 3 H] Rauwolfia alkaloids (α2,5-HT 2A / 2B ),[ 125 I] Pindolol (b1), [ 3 H]CGP12177(b2,b3),[ 3 H] Nisoxetine (norepinephrine transporter), [ 3 H]SCH23390(D1,D5),[ 3 H]N-methylspiroperidone (D2 / 3 / 4), [ 3 H]WIN35428 (dopamine transporter), [ 3 H]DAMG0 (μ-opioid), [ 3 H]DADLE (6-opioid), [ 3 H]U69593 (κ-opioid), [ 3 H]muscimol(GABA A ),[ 3 H]funitrazam (central acting benzodiazepine), [ 3 H]PK11195 (peripheral benzodiazepine), [ 3 H]pyrilamine (Hl), [ 3 H]thiooctidine (H2), [ 3 H]α-methylhistamine (H3), [ 3 H] histamine (H4), [ 3 H]QNB(Mle5),[ 3 H] -Pentazocine (S1) and [ 3 H]DTG(s2).

[0456] The experimental protocol can be obtained from the NIMH PDSP website, such as "Assay Protocol Book, Version III, March 2018, Bryan L. Roth, MD, PhD". Briefly, both primary and secondary radioligand binding assays were performed in appropriate binding buffers. dTotal binding and nonspecific binding were determined in the absence and presence of 10 μM of appropriate reference compounds, respectively. The plates were incubated for 90 minutes at room temperature and in the dark. The samples were vacuum filtered onto a 96-well filter mat soaked in 0.3% polyethyleneimine (PEI) using a 96-well Filtermate collector and then washed three times with cold wash buffer to terminate the reaction. The scintillation mixture was then melted onto a microwave-dried filter on a hot plate and the radioactivity was counted using a Microbeta counter.

[0457] Results: Based on the head groups of the psychedelic lead compounds, the disclosed compounds are expected to have an effect on 5-HT 2A receptors show affinity. However, if the side chain is understood in accordance with the teachings herein, 2A If receptor exosite interactions occur in a manner similar to the binding of XOB, binding affinity and efficacy would be expected to be altered.

[0458] Example 7: Metabolic Stability

[0459] Purpose: Determine the metabolic stability of the disclosed compounds. Metabolic stability analysis measures the intrinsic clearance (CL) of the compounds. int ), providing information that can be used to calculate other key pharmacokinetic parameters such as bioavailability and half-life (t 1 / 2 ) data.

[0460] method: High throughput analysis was used to determine the metabolic stability of the disclosed compounds and their non-deuterated analogs in various matrices, including human liver microsomes, and LCMS analysis was used to quantify the percentage of compound remaining after incubation. Briefly, the disclosed compounds were mixed with liver microsomes and activated. After incubation, acetonitrile was added to terminate the reaction. The samples were then centrifuged and the supernatant dried. The residue was reconstituted and analyzed by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using a non-compartmental model. The half-life (t 1 / 2 ) was estimated from the slope of the initial linear range of the logarithmic plot of compound remaining (%) versus time, assuming first-order kinetics.

[0461] Results and significance: The clearance rate and half-life of the disclosed compounds may be altered compared to a comparator (e.g., a corresponding unsubstituted phenethylamine). These features provide advantages such as increased or decreased duration of action, thereby facilitating use in the therapeutic applications described herein.

[0462] Example 8: In vitro metabolic analysis

[0463] Purpose: Determine whether the disclosed compounds are metabolized and identify their metabolites.

[0464] method: In vitro studies were performed to evaluate the metabolism and metabolites of the disclosed compounds in human liver microsomes (e.g., S9 hepatocytes). Briefly, the disclosed compounds were incubated with human liver microsomes and / or various recombinant enzymes to determine metabolism and metabolite formation. After incubation, the supernatant was directly analyzed by ultra-performance liquid chromatography-mass spectrometry.

[0465] Phase I and / or Phase II metabolites are identified using mass spectrometry (MS). The remaining compound percentage and half-life of the disclosed compound (parent compound) are determined. MS data (e.g., extracted ion chromatograms) show the parent and major metabolites. The metabolic transformation of each observed metabolite is elucidated, and the mass, peak area, and retention time of the metabolite are determined. Metabolic analysis can also be performed according to the methods described in Muller & Rentsch, Anal Bioanal Chem, 2012; 402: 2141-2151 and Pedersen et al., Drug Metab Dispos, 2013; 41: 1247-1255.

[0466] Results and significance: Compounds that are metabolized in vivo may produce pharmacologically active or chemically reactive metabolites that may produce unexpected effects or potential toxicity. The FDA’s Guidance for Industry on Drug Metabolite Safety Testing emphasizes the importance of performing in vitro metabolite analysis early in drug development, as metabolites that are unique or disproportionate in humans may require additional toxicology studies.

[0467] Example 9: In vitro CYP enzyme inhibition

[0468] Purpose: Evaluate the interaction of disclosed compounds with cytochrome P450 (CYP450) enzymes. Such interactions will provide insight into metabolism-mediated drug-drug interactions, which occur when a compound affects the pharmacokinetics (e.g., absorption, distribution, metabolism, and excretion) of a concomitantly administered drug by altering the activity of drug-metabolizing enzymes and / or drug transporters.

[0469] method: In vitro studies were performed to evaluate the inhibitory effects of the disclosed compounds on recombinant human CYP450 isozymes. Recombinant human CYP450 isozymes were used to metabolize the fluorogenic probe substrate into fluorescent products. The inhibition of human P450 isoforms was measured by the decrease in fluorescence after treatment with different concentrations of the disclosed compounds.

[0470] In short, the disclosed compounds are incubated at different concentrations in a mixture containing a buffer, an enzyme, and a substrate. Then, the fluorescence is measured using a plate reader, and the percentage of inhibition can be inferred from the readings. Alternatively, the inhibitory effect of the disclosed compounds on CYP enzymes can be evaluated using high performance liquid chromatography. The inhibitory effect is evaluated using the Michaelis-Menten method. CYP enzyme inhibition can be performed according to the method described in Lin et al., J Pharm Sci. 2007 96(9):2485-95 and Wojcikowski et al., Pharmacol Rep. 2020Jun; 72(3):612-621.

[0471] Results and significance : Metabolic enzymes in the liver, such as CYP450 enzymes, are responsible for most of the drug metabolism that occurs in the body. Six CYP450 enzymes metabolize 90% of drugs, of which the two most important metabolizing enzymes are CYP3A4 and CYP2D6 (Lynch & Price, Am Fam Physician. 2007; 76(3): 391-6). Compounds can interact with these enzymes by inhibiting enzyme activity (CYP inhibition) or inducing gene expression (CYP induction).

[0472] Example 10: In vitro evaluation of MDCKII MDR1 cell membrane permeability and interaction with P-glycoprotein (P-gp)

[0473] Purpose: Evaluation of Permeability and Transport of Disclosed Compounds. Permeability was evaluated using MDCK (Madin-Darby Canine Kidney) cells, and the effect of P-glycoprotein (P-gp) was evaluated to determine drug transport.

[0474] method: Bidirectional permeability studies (apical to basolateral [AB] and basolateral to apical [BA]) were performed to assess the apparent permeability of the disclosed compounds. In addition, an assessment was performed to determine whether the disclosed compounds act as P-gp substrates in MDCKII-MDR1 and simulated MDCKII cell lines.

[0475] Briefly, the disclosed compounds and reference compounds were evaluated in the absence and presence of P-gp inhibitors from two directions. MDCKII and MDCKII-MDR1 cells were incubated in transport buffer at the apical [A] and basolateral [B]. The disclosed compounds were then added to each side of the cells and incubated. The transport rate of the disclosed compounds was determined in the absence or presence of P-gp inhibitors. After incubation, the disclosed compounds will permeate the cells from the AB and BA directions, and the permeability of the cells is measured using an LC MS / MS system. The efflux rate of the disclosed compound is calculated to determine whether it is a P-gp substrate.

[0476] Results and significance: This screen provides insight into the movement of the disclosed compounds in biological systems. The compounds are classified as follows (Cambridge MedChem Consulting, ADME, 2019):

[0477] Papp(nm / s) Classification >150 High permeability 50-150 Medium permeability <50 Low permeability

[0478] The mass balance is expressed as a percentage (%) and is calculated using the following formula:

[0479] Recovery % = 100x(CD(t)+CR(t)) / C0

[0480] where CD(t) is the concentration measured in the donor well at time t (expressed as an IS ratio), CR(t) is the concentration measured in the receiving well at time t (expressed as an IS ratio), and C0 is the initial concentration in the donor solution (expressed as an IS ratio).

[0481] The percentage of cell integrity was calculated using the following formula:

[0482] % integrity = 100x [1-RFU basolateral / RFU apical]

[0483] LY RFU values ​​were normalized by the background mean. If the efflux ratio in the absence of inhibitor was >2 and this ratio was significantly reduced in the presence of P-gp inhibitor, the test article was considered to be a P-gp substrate.

[0484] For the purpose of explanation, the foregoing description uses specific terms to provide a thorough understanding of the present invention. However, it is obvious to those skilled in the art that specific details are not required to practice the present invention. Therefore, the above description of specific embodiments of the present invention is for illustration and description purposes only. It is not intended to be exhaustive or to limit the present invention to the precise form disclosed; obviously, many modifications and changes can be made in view of the above teachings. These embodiments are selected and described in order to best explain the principles of the present invention and its practical application by illustrating specific examples, so that those skilled in the art can best utilize the present invention and various embodiments with various modifications suitable for the specific purposes envisioned, when these uses exceed the specific examples disclosed. Therefore, the scope of the present invention is defined only by the following claims and their equivalents.

Claims

1. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof: in: m and n are each independently an integer from 1 to 13, provided that the sum of m+n is from 6 to 14; X is O, S or NH; R and R2 are each independently C1-C8 alkoxy, wherein each C1-C8 alkoxy is optionally substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, mercapto, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; R1 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, each of which is optionally substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, alkylthio, arylthio, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; R3 is hydrogen or C1-C8 alkyl; and Ph is phenyl which is optionally substituted with halogen, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R and R2 are both -OCH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, -CH3 or -CH2CH3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is F, Cl, Br or I.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R1 is Br. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-C8 alkyl group.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R1 is -CH3 or -CH2CH3.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-C8 thioalkyl group.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is -SCH3.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted phenyl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is a phenyl group substituted by an azide group or a C1-C8 alkoxy group.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O. 13 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the sum of m+n is 8 to 12. 14 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the sum of m+n is 9 to 11. 15 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the sum of m+n is 10.

16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein m is 6 and n is 4.

17. A compound selected from Table 4 or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound is 19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein the compound is 20. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

21. The pharmaceutical composition of claim 20, wherein the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous or transdermal administration.

22. The pharmaceutical composition of claim 21, wherein the composition is in unit dosage form.

23. The pharmaceutical composition of claim 22, wherein the unit dosage form comprises a total amount of about 1 to about 500 mg, about 2.5 to about 250 mg, or about 5 to about 125 mg of the compound or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition of claim 23, wherein the composition is an immediate release, controlled release, sustained release, extended release or modified release formulation.

25. The pharmaceutical composition of claim 20, further comprising a therapeutically effective amount of an additional active compound or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 25, wherein the additional active compound is selected from amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathic and anti-nociceptive agents, anti-migraine agents, antianxiety agents, antidepressants, antipsychotics, anti-PTSD agents, dissociative agents, cannabinoids, immunostimulants, anticancer agents, antiemetics, anorectics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, hallucinogens, psychedelics, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants and vitamins; or pharmaceutically acceptable salts thereof.

27. The pharmaceutical composition of claim 25, wherein the additional active compound or a pharmaceutically acceptable salt thereof acts to increase therapeutic effect, provide additional therapeutic effect, reduce adverse effects, increase stability or shelf life, improve bioavailability, induce synergistic effects, or alter pharmacokinetics or pharmacodynamics.

28. The pharmaceutical composition of claim 27, wherein the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anticancer, antiemetic, anorectic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, nootropic, hallucinogenic, psychedelic, sedative or stimulant effect.

29. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in treating a medical condition.

30. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a medical condition.

31. A method for regulating a neurotransmitter in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

32. A method of treating a medical condition in a mammal in need of such treatment, the method comprising administering a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the medical condition is a disease associated with an imbalance or inadequate function of a neurotransmitter.

34. The method of claim 33, wherein the disease associated with neurotransmitter imbalance or insufficiency is a monoamine neurotransmitter disease.

35. The method of claim 34, wherein the disease associated with neurotransmitter imbalance or insufficiency is a serotonin neurotransmitter disease.

36. The method of claim 32, wherein the medical condition is a mental health disorder.

37. The method of claim 36, wherein the mental health disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, schizotypal disorder, acute transient psychotic disorder, delusional disorder, substance-induced psychotic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymic disorder, anxiety, phobia, bulimia, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance use disorder, substance-induced mood disorder, mood disorder related to another health condition, disruptive behavior disorder, eating disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, and dissociative disorder.

38. The method of claim 32, wherein the medical condition is a seizure disorder.

39. The method of claim 28, wherein the seizure disorder is epilepsy.

40. The method of claim 32, wherein the medical condition is a disease associated with dysregulation or inadequate function of voltage-gated ion channels.

41. The method of claim 40, wherein the voltage-gated ion channel is a voltage-gated sodium channel.

42. The method of claim 41, wherein the compound inhibits the activity of the voltage-gated sodium channel.

43. A method according to any one of claims 31-42, wherein the mammal has a genetic variation associated with drug metabolism, including a genetic variation associated with a CYP2D6 enzyme or a CYP3A4 enzyme; or a genetic variation associated with a mental health disorder, a trauma or stress-related disorder, depression or anxiety, including a genetic variation of mGluR5 or FKBP5; or a genetic variation associated with a membrane transporter, such as SERT, DAT, NET or VMAT.

44. The method of any one of claims 31-43, wherein the 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 the SIGMAR1 gene for the non-opioid sigma-1 receptor.

45. The method of any one of claims 31-44, wherein the mammal is a human.

46. ​​A method of alleviating a symptom of a mental health disorder in a human, the method comprising identifying a human in need of such alleviating and administering to the human a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof.

47. A method of alleviating symptoms of a mental health disorder in a human, the method comprising identifying a human in need of such alleviating symptoms and administering to said human the pharmaceutical composition of claim 20.

48. A method of alleviating symptoms of a mental health disorder in a human, the method comprising identifying a human in need of said alleviating, and administering to said human the pharmaceutical composition of any one of claims 21-28.

49. A method of improving human psychological health or function, the method comprising identifying a human in need of said improvement and administering to said human a compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof.

50. A method of improving psychological health or function in a human, the method comprising identifying a human in need of said improvement and administering to said human the pharmaceutical composition of claim 20.

51. A method of improving the psychological health or function of a human, the method comprising identifying a human in need of said improvement and administering to said human a pharmaceutical composition according to any one of claims 21-28.

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