Non-hallucinogenic 5-HT2a agonists and neurite growth compounds

Abstract

The present disclosure provides a method of treating a mental health and / or central nervous system disorder, or a stress-related disease, which may include administering to a pharmaceutical composition including a therapeutically effective amount of a non-hallucinogenic 5-HT2A receptor agonist or an effective amount of a compound that does not have an agonist activity on 5-HT2A serotonin receptor to a subject in need thereof.

Description

NON-HALLUCINOGENIC 5-HT2A AGONISTS AND NEURITE GROWTH COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No. 63 / 606,983, filed December 6, 2023, and from U.S. Provisional Application No. 63 / 606,714, filed December 6, 2023, both of which are hereby incorporated by reference in their entirety.FIELD

[0002] This disclosure relates generally to methods of treatment for various disorders using non-hallucinogenic 5-HT2A agonist compounds, and compounds for treating stress related disorders.BACKGROUND

[0003] The treatment of disorders such as major depressive disorder (MDD), treatmentresistant depression (TRD), substance use disorder (SUD), compulsive disorders, anxiety disorders, stress disorders, rumination and eating disorders, and the like using psychedelics has received recent attention. Known psychedelics consist of three main molecular classes. The first class are indoleamines, including N,N-dimethyltryptamine (DMT), 5-methoxy-DMT (5- MeO-DMT), psilocybin and 4-hydroxy-DMT. The second class are phenylalkylamines, which include mescaline, as well as synthetic mescaline analogs including 2,5-dimethoxy-4- iodoamphetamine (DOI) and 2, 5 -dimethoxy -4-bromoamphetamine (DOB). The third class of are ergolines, such as LSD. The phenylalkylamines are selective agonists of 5- HT2 receptors, including 5-HT2A, 5-HT2B and 5-HT2C receptors. The indoleamines and ergolines act as partial agonists of 5-HTi, 5-HT2, 5-HTe and 5-HT? receptors. LSD and other ergolines also act upon DI and D2 dopamine receptors and adrenergic receptors. Activation of 5-HT2A receptors located in cortical and subcortical structures of the brain are thought to mediate the subjective, behavioral and psychological effects of psychedelics in both animals and humans. In rodents, psychedelics have shown to elicit a ‘head twitch response’ which has been demonstrated to be a direct consequence of 5-HT2A activation. Similar observations have been made in humans where the administration of ketanserin, a 5-HT2A receptor antagonist, blocked most subjective effects induced by DMT, psilocin and LSD. In addition, psychedelic effects elicited by psilocybin have correlated with 5-HT2A receptor occupancy as measured by positron emission tomography in the prefrontal cortex (PFC) and other cortical regions in humans.

[0004] Despite the promising results identified in using such compounds in treatment, patients with comorbidities that may be considered risks for hallucinogenic 5-HT2A receptor agonist therapy (e.g., psychosis, bipolar disorder, etc.) may experience therapeutic utility / benefit taking a non-hallucinogenic 5-HT2A receptor agonist compound. In addition, non-hallucinogenic agents may have the potential to be safely dosed a) at home without medical supervision and / or b) at repeated intervals (e.g., daily or intermittently, such as weekly, monthly, bimonthly, etc.) as needed for optimal maintenance of therapeutic benefit. There remains a need to identify 5-HT2A receptor agonists which are non-hallucinogenic.

[0005] Rapid and effective treatments for stress-related disorders, such as depression, anxiety and post-traumatic stress disorder, remain a significant unmet medical need. Studies in humans and animals have shown that depression and stress exposure induce structural and functional changes in the brain. Signs of neuronal atrophy have been found in brain regions involved in stress-related behaviors, including prefrontal cortex and hippocampus. In animals, these structural changes have been shown to include loss of neurites, dendritic spines and synaptic contacts, as well as reduced hippocampal neurogenesis. Studies in humans and animals also have shown that depression and stress exposure decrease cerebral cortex and hippocampal levels of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival and synaptic plasticity. Together, these findings are consistent with the hypothesis that reduced BDNF may play a role in stress-related neuronal structural changes. In support of this hypothesis, chronic but not acute administration of typical antidepressant drugs, such as selective serotonin (5-HT) reuptake inhibitors (SSRIs), attenuate the effects of stress on neurogenesis, neuronal structure and BDNF levels in animals and demonstrate antidepressant and anxiolytic effects in humans. In addition, single administration of ketamine attenuates these effects of stress in animals and demonstrates rapid-acting antidepressant effects in humans. Thus, compounds that promote the generation and / or maintenance of neurites, spines, synapses and / or neurons upon single administration may have rapid therapeutic benefit in the treatment of stress-related disorders.

[0006] Tryptamines are a structural class of compounds containing an indolealkylamine backbone with reported psychedelic and non-psychedelic effects. Psychedelic tryptamines include compounds such as psilocybin, its active metabolite psilocin, and N,N- dimethyltryptamine (DMT). Psilocybin and psilocin are found in hundreds of species of hallucinogenic mushrooms and were used in Aztec rituals. DMT is present in ayahuasca, a hallucinogenic brew traditionally used in ceremonial settings in South America. Psilocybin andayahuasca have been reported to induce rapid and lasting clinical antidepressant efficacy following single administration. Data in rodents and nonhuman primates also suggest the potential for antidepressant-like effects of psilocybin, DMT or ayahuasca. These compounds exert functional activity at a variety of central nervous system receptors, including serotonin receptors, of which partial agonism at 5-HT2A receptors is believed to mediate the psychedelic effects. Psychedelic tryptamines have been reported to exhibit neuronal plasticity-promoting effects, including neuritogenesis, spinogenesis, synaptogenesis, hippocampal cell proliferation and / or hippocampal neurogenesis, which may underlie their therapeutic benefit in the treatment of stress-related disorders, such as depression. Specifically, psilocin and DMT were reported to significantly increase measures of neurite outgrowth in primary embryonic rat cortical neurons. There is published data on the effects of the reference 5-HT2A agonist, DOI, and antagonist, M100907, in NGF-induced neurite outgrowth in rat adrenal medulla pheochromocytoma-derived PC 12 cells.

[0007] There is a need for novel compositions for the treatment of stress related disorders. Given the reported 5-HT2A receptor agonist activity and ability to promote neurite outgrowth associated with classical psychedelic compounds novel compounds may provide an improved therapeutic index for treating stress related disorders with reduced side effect profiles.SUMMARY

[0008] In aspects, the present disclosure provides methods of treating a mental health disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition wherein the composition comprises a therapeutically effective amount of a non- hallucinogenic 5-HT2A receptor agonist or a pharmaceutically acceptable salt thereof.

[0009] In aspects, the non-hallucinogenic 5-HT2A receptor agonist is selected from:7V-(3-chloro-5-methylbenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan- -amine;(4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5- dimethoxyphenyl)(imino)(methyl)-X^-sulfanone;(4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-X^- sulfanone;(2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)phenyl)(imino)(methyl)-X^‘ sulfanone;(R)- 1 -(2,5-dimethoxyphenyl)-2-((3-fluoro-5-methylbenzyl)amino)ethan- 1 -ol; andA-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxypyridin-4-yl)ethan-l -amine; or a pharmaceutically acceptable salt thereof (and combinations of the compounds).

[0010] In aspects, the pharmaceutical compositions are administered intracutaneously, subcutaneously, intravenously, intraarterially, intradermally, transdermally, orally, sublingually buccally, or intranasally.

[0011] In aspects, the mental health disorder is selected from mood disorders, addictive disorder, eating disorders, obsessive-compulsive disorders, sleep disorders, autism spectrum disorder, chronic pain conditions, and combinations thereof.

[0012] In aspects, the mental health disorder is selected from depression, anxiety, substance use disorder, Opioid use disorder, Alcohol use disorder, gambling, anorexia nervosa, bulimia, obsessive compulsive disorder, body dysmorphic disorder, narcolepsy, headaches, and combinations thereof.

[0013] In aspects, treating the mental health disorder includes reducing a symptom of the mental health disorder, preventing a symptom of the mental health disorder, or a combination thereof.

[0014] In aspects, the non-hallucinogenic 5-HT2A receptor agonist has antidepressant and anxiolytic effects.

[0015] In aspects, the pharmaceutical composition is administered as a single dose.

[0016] In aspects, the pharmaceutical composition is administered in repeat doses.

[0017] In aspects, the present disclosure exploits the different pharmacological and toxicological profiles, and thus the different functional characteristics possessed by novel compounds that do not have an agonist activity on the 5-HT2A serotonin receptor. Specifically, in embodiments, disclosed compounds induce neurite growth increasing neural plasticity and has many of the functional properties desirable for treating stress-related diseases or disorders such as PTSD and mood / depressive disorder.

[0018] In embodiments, the present disclosure provides methods of treating a stress-related disease or disorder, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a combination thereof, to a subject in need thereof.

[0019] In embodiments, the present disclosure provides methods of inducing neurite outgrowth, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a combination thereof, to a subject in need thereof.

[0020] In embodiments, the present disclosure provides methods of treating neuronal atrophy, comprising administering a therapeutically effective amount of a compound of Formula I, or a combination thereof, to a subject in need thereof.

[0021] In embodiments, the present disclosure provides methods of inducing structural neuroplasticity, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, to a subject in need thereof.

[0022] In embodiments, the stress-related disease or disorder is mood / depressive disorder, bipolar disorder, anxiety disorder, psychotic or delirium disorder, schizophrenia, schizoaffective disorder, personality disorder, abuse or neglect disorder, tic disorder, neurocognitive disorder, neurodevelopmental disorder, learning disorder, disruptive mood regulation disorder, intermittent explosive disorder, antisocial personality disorder, conduct disorder, behavioral and psychological symptoms of dementia, depression, anxiety, post- traumatic stress disorder (PTSD), or any combination thereof. In embodiments, the stress- related disease or disorder is depression, anxiety or post-traumatic stress disorder.

[0023] In embodiments, the compound has antidepressant and anxiolytic effects.

[0024] In embodiments, the administering includes intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual, buccal, or nasal route of administration. In embodiments, the methods include administering the compound as a single dose. In embodiments, the methods include administering the compound in repeated doses.

[0025] In embodiments, administration of the compound induces neurite outgrowth. In embodiments neurite outgrowth includes neurite number, neurite total length, number of neurite branch points per neuron or any combination thereof. In embodiments, the neurite outgrowth includes neurite outgrowth on prefrontal cortex neurons and / or hippocampal neurons.

[0026] Some embodiments are directed to the administration of the compound of Formula I and a therapeutic agent for the treatment of a stress related disorder, treating neural atrophy, inducing neural plasticity and / or inducing neurite growth. In embodiments, the therapeutic agent is administered simultaneously with, prior to or following administration of the compound of Formula I.

[0027] In embodiments, the present disclosure provides pharmaceutical composition comprising the compound of Formula I and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutically acceptable carrier is saline or purified water.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 shows the novel compound effects on average number of neurites, neurite length and number of branches per neuron, presented as percent of vehicle control response (horizontal dashed line at 100% reflects the vehicle response).

[0029] Figure 2 shows the results from an experiment evaluating the effects of 8 concentrations of the reference 5-HT2A receptor agonist, DOI, on neurite outgrowth measures in rat embryonic cortical neuron cultures.

[0030] Figure 3 shows the effects of M100907 and NE-100 on average number of neurites, neurite length and number of branches per neuron, presented as percent of vehicle control response (horizontal dashed line at 100% reflects the vehicle response).

[0031] Figure 4 shows the results of mouse head twitch response for compounds 1-1, 1-2, 1-5 and 1-6.

[0032] Figure 5 shows the results of a rat forced swim test for compound 1-2.

[0033] Figure 6 shows the results of a rat forced swim test for compound 1-6.DETAILED DESCRIPTION

[0034] In embodiments, the present disclosure exploits the different pharmacological and toxicological profiles, and thus the different functional characteristics possessed by novel compounds. For example, in embodiments, the compounds do not have an agonist activity on the 5-HT2A serotonin receptor. Specifically, those novel compounds induce neurite growth increasing neural plasticity and have many of the functional properties desirable for treating stress-related diseases or disorders such as PTSD and mood / depressive disorder.

[0035] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0036] It is to be understood that this disclosure is not limited to the particular processes, compositions, or methodologies described, as these may vary. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the disclosure, the preferred methods, devices, and materials are now described.

[0037] It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.Definitions

[0038] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0039] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0040] In this specification, unless stated otherwise, the term “pharmaceutically acceptable” is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceuticallyacceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0041] The term “pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0042] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.

[0043] An “effective amount” means the amount compound or pharmaceutical formulation, that when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment.

[0044] The term “therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof. A “therapeutically effective amount”, in some embodiments, is a dose or amount of a compound or pharmaceutical formulation that is sufficient to result in prophylaxis after administration to a patient in need thereof.

[0045] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, such as a mammal. The mammal may be, for example, a mouse, a rat, a rabbit, a cat, a dog, a pig, a sheep, a horse, a non-human primate (e.g., cynomolgus monkey, chimpanzee), or a human.

[0046] The terms “administer,” “administering” or “administration” as used herein refer to administering a compound or pharmaceutically acceptable salt of the compound or a composition or formulation comprising the compound or pharmaceutically acceptable salt of the compound to a patient.

[0047] The compositions may be administered by any route, taking into consideration the specific condition for which it has been selected. The compositions may be delivered orally, by injection, inhalation (including orally, intranasally and intratracheally), ocularly, transdermally (via simple passive diffusion formulations or via facilitated delivery using, for example, iontophoresis, microporation with microneedles, radio-frequency ablation or the like), intravascularly, cutaneously, subcutaneously, intramuscularly, sublingually, intracranially, epidurally, rectally, intravesically, and vaginally, among others.

[0048] As used herein “neuroplasticity” refers to any neuronal plasticity, which can include for example neurite outgrowth. Neurite outgrowth can broadly refer to various parameters than can be measured on neurites, including but not limited to neurite number, neurite total length, number of neurite branch point per neuron or any combination thereof. Neuronal plasticity in general and neurite outgrowth in particular can occur in any neurons and neurites in the brain, including but not limited to prefrontal cortex neurons and / or hippocampal neurons. As used herein, a “disease or disorder that can benefit from neuroplasticity” may include any disease or disorder that can be treated by, or than can see one or more of its symptoms alleviate by a change in neuroplasticity in the patient’s brain, for example by neurite outgrowth, such as neurite outgrowth in prefrontal cortex neurons and / or hippocampal neurons.

[0049] The term “alkyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 8 carbon atoms. Alkyl groups may be optionally substituted as defined herein.

[0050] Examples of alkyl radicals include methyl, ethyl, w-propyl, isopropyl, / / -butyl, isobutyl, ec-butyl, / e / 7-butyl, pentyl, zso-amyl, hexyl, octyl, noyl and the like. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.

[0051] The term “halogen” refers to -F, -Cl, -Br, or -I atoms.

[0052] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.

[0053] As used herein, unless specifically indicated, the term “active ingredient” refers to a compound of any of the formulae as described herein.

[0054] The pharmaceutically acceptable excipients and adjuvants may be added to the compounds for a variety of purposes. In embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable carrier. In embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and / or diluent. In embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0055] In embodiments, the present disclosure provides compounds which act as agonists of a serotonin receptor. In embodiments, the present disclosure provides compounds which act as agonists of the 5-HT2A receptor. In one aspect, the compounds may be full agonists of the 5-HT2A receptor. In embodiments, the compounds are partial agonists of the 5-HT2A receptor. In embodiments, the compounds display selectivity for 5-HT2A receptor. In embodiments, the compounds are not 5-HT2A receptor agonists.

[0056] Activation of 5- HT2A receptors located in cortical and subcortical structures of the brain are thought to mediate the subjective, behavioral, and psychological effects of psychedelics in both animals and humans. In rodents, psychedelics have shown to elicit a ‘head twitch response’ which has been demonstrated to be a direct consequence of 5-HT2A activation. Similar observations have been made in humans where the administration of ketanserin, a 5-HT2A receptor antagonist, blocked the majority of subjective effects induced by dimethyltryptamine (DMT), psilocybin and lysergic acid diethylamide (LSD). In addition, psychedelic effects elicited by psilocybin have correlated with 5-HT2A receptor occupancy as measured by positron emission tomography in the prefrontal cortex (PFC) and other cortical regions in humans. While 5-HT2A is the predominant driver of psychedelic effects in humans, other serotonin receptors, like 5-HT2C and 5-HT1A, are likely contributing to the overall psychedelic experience including both visual and attention-altering effects in humans.Compounds

[0057] In embodiments, the present disclosure provides for a compound of Formula I:wherein:R1is benzyl wherein the benzyl is optionally substituted with one or more of D, halogen, or Ci-Ce alkyl;R2is H or Ci-Ce alkyl;R3and R4are independently H, D, or Ci-Ce alkyl;R3and R4are independently H, D, or halogen; n is 0 or 1;A is CR7, C(R7R8)C(R9) or C(R7R8)C(R9R10)C(Rn); or when B is absent is CR7R8, C(R7R8)C(R9R10), or C(R7R8)C(R9R10)C(RnR12);B is CR7R8, C(R7R8)C(R9R10), or is absent; andR7, R8, R9, R10, R11, and R12are independently H, D, Ci-Ce alkyl, or halogen.

[0058] In embodiments, the compound of Formula I is selected from Table 1 :Table 1

[0059] or a pharmaceutically acceptable sa t thereof.

[0060] In embodiments, the present disclosure provides for the following compounds:Table 2

[0062] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is a compound selected from:7 zyl)-2-(l / 7-indol-3-yl)ethan-l -amine;7V-(3-chloro-5-methylbenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan-l -amine;7V-(3-chloro-5-methylbenzyl)-3-(2,5-dimethoxyphenyl)propan-l -amine;(4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5- dimethoxyphenyl)(imino)(methyl)-X^-sulfanone;(4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-X^- sulfanone;(2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)phenyl)(imino)(methyl)-X^‘ sulfanone;(R)- 1 -(2,5-dimethoxyphenyl)-2-((3-fluoro-5-methylbenzyl)amino)ethan- 1 -ol;A-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxypyridin-4-yl)ethan-l -amine; or a pharmaceutically acceptable salt thereof and combinations thereof.

[0063] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is A-(3-chloro- 5-methylbenzyl)-2-(l / 7-indol-3-yl)ethan-l -amine :or a pharmaceutically acceptable salt thereof.

[0064] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is A-(3-chloro- 5-methylbenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan-l -amine:or a pharmaceutically acceptable salt thereof.

[0065] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is A-(3-chloro- 5-methylbenzyl)-3-(2,5-dimethoxyphenyl)propan-l -amine:or a pharmaceutically acceptable salt thereof.

[0066] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is (4-(2-((3- chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-X^-sulfanone:or a pharmaceutically acceptable salt thereof.

[0067] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is (4-(2-((2- hydroxybenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-X^-sulfanone:or a pharmaceutically acceptable salt thereof.

[0068] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is (2,5- dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)phenyl)(imino)(methyl)-X^-sulfanone:or a pharmaceutically acceptable salt thereof.

[0069] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is A-(3-chloro- 5-methylbenzyl)-2-(2,4,5-trimethoxyphenyl)ethan-l -amine:or a pharmaceutically acceptable salt thereof.

[0070] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is (A)-l-(2,5- dimethoxyphenyl)-2-((3 -fluoro-5-methylbenzyl)amino)ethan- 1 -ol :or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist is 7V-(3-chloro- 5-methylbenzyl)-2-(2,5-dimethoxypyridin-4-yl)ethan-l -amine:or a pharmaceutically acceptable salt thereof.

[0072] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist may include Compound 2-1 (A-(3-chloro-5-methylbenzyl)-2-(l / 7-indol-3-yl)ethan-l-amine), Compound 2- 2 (A-(3-chloro-5-methylbenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan-l-amine), Compound 2-3 (A-(3-chloro-5-methylbenzyl)-3-(2,5-dimethoxyphenyl)propan-l-amine), Compound 2-4 ((4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-X6- sulfanone), Compound 2-5 ((4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5- dimethoxyphenyl)(imino)(methyl)-X6-sulfanone), Compound 2-6 ((2, 5 -dimethoxy -4-(2-((2- methoxybenzyl)amino)ethyl)phenyl)(imino)(methyl)-X6-sulfanone), Compound 2-7 (N-(3- chloro-5-methylbenzyl)-2-(2,4,5-trimethoxyphenyl)ethan-l-amine), Compound 2-8 ((A)-l- (2,5-dimethoxyphenyl)-2-((3-fluoro-5-methylbenzyl)amino)ethan-l-ol), Compound 2-9 (N- (3-chloro-5-methylbenzyl)-2-(2,5-dimethoxypyridin-4-yl)ethan-l -amine), or pharmaceutically acceptable salts thereof, or combinations thereof.

[0073] In embodiments, the compounds of the present disclosure are in the form of a pharmaceutically acceptable salt. In embodiments, the compounds of the present disclosure are in the form of a free base.

[0074] In embodiments, there is provided a method of treating a mental health disorder in a subject in need thereof, including: administering to the subject a pharmaceutical composition including a therapeutically effective amount of a non-hallucinogenic 5-HT2A receptor agonist, thereby treating the mental health disorder in the subject.Compositions

[0075] Embodiments herein are directed to a composition comprising a compound of Formula I, or a combination thereof and a pharmaceutically acceptable excipient.

[0076] While it may be possible for the compounds described herein to be administered as the raw chemical, it is also possible to present them as a composition. Accordingly, provided herein are compositions which comprise one or more of certain compounds disclosed herein,together with one or more pharmaceutically acceptable excipients thereof and optionally one or more other therapeutic ingredients. The excipient(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation of the composition is dependent upon the route of administration chosen. Any of the well-known techniques and excipients may be used as suitable and as understood in the art. The compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0077] In embodiments, the compositions for use in accordance with embodiments herein can be formulated in conventional manner using one or more physiologically acceptable excipients.

[0078] In embodiments, the composition is a formulation comprising an active ingredient, and optionally a pharmaceutically acceptable carrier, diluent or excipient. The term “active ingredient” can interchangeably refer to an “effective ingredient” and is meant to refer to any agent that is capable of inducing a sought-after effect upon administration. Examples of active ingredient include, but are not limited to, chemical compound, drug, therapeutic agent, small molecule, etc. In embodiments, the active ingredient is a compound of Formula I or a combination thereof.

[0079] When employed as pharmaceuticals, the compounds can be administered in the form of compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

[0080] Administration of the disclosed compounds or compositions may be oral administration. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The compounds can be contained in such formulation’s compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The artisan can refer to various pharmacologic references for guidance. For example, Modern Pharmaceutics, 5th Edition, Banker & Rhodes, CRC Press (2009); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 13th Edition, McGraw Hill, New York (2018) can be consulted.

[0081] In embodiments, a method of treating a disease or disorder associated with sodium channel mediated activity comprises administering a compound or a composition of embodiments disclosed herein. In embodiments, the compound is in a therapeutically effective amount. In embodiments, the therapeutically effective amount is an amount disclosed herein.

[0082] Some embodiments disclosed herein also include compositions which contain, as the active ingredient, one or more of the compounds disclosed herein in combination with one or more pharmaceutically acceptable carriers (excipients).

[0083] In embodiments, a method of making a composition comprises mixing the active ingredient with an excipient, diluting the active ingredient using an excipient, or enclosing the active ingredient within a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, as well as soft and hard gelatin capsules.

[0084] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose, including eutectic solvents, eutectic-based ionic liquids, or ionic liquids. The compositions can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[0085] The compositions can be formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intradural, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, buccal, sublingual and intraocular), intravitreal, or intravaginal administration although the most suitable route may depend upon for example the conditionand disorder of the recipient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound disclosed herein ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired composition.

[0086] Compositions of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0087] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All compositions for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0088] For preparing solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally therapeutically effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.01 to about 1000 mg of the active ingredient.

[0089] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0090] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0091] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0092] In embodiments, the compositions administered to a patient can be in the form of compositions described above. In embodiments, these compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. In embodiments, the pH of the compound preparations is about 3 to about 11, about 5 to about 9, about 5.5 to about 6.5, or about 5.5 to about 7.5. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0093] Preferred unit dosage compositions are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0094] It should be understood that in addition to the ingredients particularly mentioned above, the compositions described above may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.

[0095] In embodiments, the therapeutically effective amount can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound in a composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, composition of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0096] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.

[0097] The active compound can be effective over a wide dosage range and can be generally administered in a therapeutically effective amount. It will be understood, however,that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0098] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0099] The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. In addition, the route of administration may vary depending on the condition and its severity.

[0100] In embodiments, the pharmaceutically acceptable carrier is saline or purified water.

[0101] The composition can be used in any of the methods disclosed herein.

[0102] The compositions described herein can be formulated, for example, by employing conventional vehicles or diluents, as well as additives of a type appropriate to the mode of desired administration (for example, excipients, preservatives, etc.) according to techniques known in the art of pharmaceutical formulation. The compositions described herein can also be formulated as is, without any carrier. The compositions can be formulated in a variety of unit dosage forms depending upon the method of administration. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, sprays, granules, etc.MethodsMethods of Treating Stress-Related Diseases and Disorders

[0103] In embodiments, the present disclosure provides methods of treating a stress-related disease or disorder, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, or a combination thereof, to a subject in need thereof.

[0104] The dosage of the composition to achieve a therapeutic effect will depend on factors such as the formulation, pharmacological potency of the composition, age, weight and sex ofthe patient, condition being treated, severity of the patient's symptoms, route of delivery, and response pattern of the patient. It is also contemplated that the treatment and dosage of the compositions may be administered in unit dosage form and that one skilled in the art would adjust the unit dosage form accordingly to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the competency and discretion of a skilled physician and may be varied by titration of the dosage to the particular circumstances to produce the therapeutic effect. Further, one of skill in the art would be able to calculate any changes in effective amounts of the compositions due to changes in the composition components or dilutions. In one aspect, the compositions may be diluted 2-fold. In another aspect, the compositions may be diluted 4-fold. In a further aspect, the compositions may be diluted 8-fold.

[0105] In embodiments, the methods include administering the compound as a single dose. In embodiments, the methods include administering the compound in repeated doses.

[0106] The effective amounts may be provided as a single dose or on regular schedule, i.e., on a daily, weekly, monthly, or yearly basis or on an irregular schedule with varying administration days, weeks, months, etc. To reduce the occurrence of possible side effect associated with the dose, an effective amount may be provided as a split dose, where the single dose is split into two doses, that are administered apart, usually over several hours. For example, a single dose may be split into two doses, administered 1 hour apart, 2 hours apart, 3 hours apart, 4 hours apart, 5 hours apart, 6 hours apart, 7 hours apart, 8 hours apart, or more. Alternatively, the therapeutically effective amount to be administered may vary. In one aspect, the therapeutically effective amount for the first dose is higher than the therapeutically effective amount for one or more of the subsequent doses. In another aspect, the therapeutically effective amount for the first dose is lower than the therapeutically effective amount for one or more of the subsequent doses. Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every 2 weeks, about every 3 weeks, about every month, about every 2 months, about every 3 months and about every 6 months. The number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner.

[0107] In embodiments, the administering includes intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual, buccal, or nasal route of administration.

[0108] Although the compositions may be administered alone, they may also be administered in the presence of one or more pharmaceutical carriers that are physiologically compatible. The carriers may be in dry or liquid form and must be pharmaceutically acceptable. Liquid compositions may be sterile solutions or suspensions. When liquid carriers are utilized, they may be sterile liquids. Liquid carriers may be utilized in preparing solutions, suspensions, emulsions, syrups and elixirs. In one aspect, the compositions may be dissolved a liquid carrier. In another aspect, the compositions may be suspended in a liquid carrier. One of skill in the art of formulations would be able to select a suitable liquid carrier, depending on the route of administration. The compositions may alternatively be formulated in a solid carrier. In one aspect, the composition may be compacted into a unit dose form, i.e., tablet or caplet. In another aspect, the composition may be added to unit dose form, i.e., a capsule. In a further aspect, the composition may be formulated for administration as a powder. The solid carrier may perform a variety of functions, i.e., may perform the functions of two or more of the excipients described below. For example, a solid carrier may also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, glidant, compression aid, binder, disintegrant, or encapsulating material. In one aspect, a solid carrier acts as a lubricant, solubilizer, suspending agent, binder, disintegrant, or encapsulating material. The composition may also be sub-divided to contain appropriate quantities of the compositions. For example, the unit dosage can be packaged compositions, e.g., packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids

[0109] Where the compositions include a pharmaceutical carrier(s), the amount of the pharmaceutical carrier(s) is determined by the solubility and chemical nature of the peptides, chosen route of administration and standard pharmacological practice. The pharmaceutical carrier(s) may be solid or liquid and may incorporate both solid and liquid carriers / matrices. A variety of suitable liquid carriers is known and may be readily selected by one of skill in the art. Such carriers may include, e.g., dimethylsulfoxide (DMSO), saline, buffered saline, purified water, cyclodextrin, hydroxypropyl-beta-cyclodextrin (HPpCD), n-dodecyl-P-D- maltoside (DDM) and mixtures thereof. Similarly, a variety of solid (rigid or flexible) carriers and excipients are known to those of skill in the art.

[0110] In embodiments, the stress-related disease or disorder is mood / depressive disorder, bipolar disorder, anxiety disorder, psychotic or delirium disorder, schizophrenia, schizoaffective disorder, personality disorder, abuse or neglect disorder, tic disorder, neurocognitive disorder, neurodevelopmental disorder, learning disorder, disruptive mood regulation disorder, intermittent explosive disorder, antisocial personality disorder, conduct disorder, behavioral and psychological symptoms of dementia, depression, anxiety, post- traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, stress disorders, rumination, eating disorders, or a combination thereof.[OHl] PTSD is a serious, chronic, life-threatening psychiatric disorder. Psychiatric symptoms of PTSD are debilitating and occur after experiencing a single traumatic event or repeated traumatic experiences, such as violence, accidents, sexual and / or childhood abuse, natural disasters, terrorism, and war. Symptoms include recurring and intrusive negative thoughts or recollections of the traumatic event, cognitive disruption, hyperarousal to event related cues, and avoidance behaviors that persist for longer periods than a month after experiencing a traumatic event. Overall reduction in the quality of life is common in individuals with PTSD leading to disability and can affect physical health with manifestation of other comorbidities such as cardiovascular disease, concomitant mental health conditions and suicidality.

[0112] Two serotonin reuptake inhibitors (SSRIs) are currently approved for the treatment of PTSD, sertraline (Zoloft®) and paroxetine (Paxil®), which, increase the level of serotonin in the synaptic cleft. Sertraline and paroxetine have demonstrated moderate efficacy in reducing PTSD symptoms, but rarely result in full disorder remission. These pharmacotherapies also have problematic side effects and generally require long-term and / or consistent use to maintain effectiveness, although long-term compliance is poor. Studies have demonstrated that administering stand-alone sertraline or paroxetine reported significantly decreased reduction in PTSD symptoms compared to currently available behavioral interventions.

[0113] Based on the low response rate to existing pharmacotherapy, the most recent clinical practice guidelines recommend psychotherapy as the first-line treatment for PTSD. Specifically, the American Psychological Association (APA) and US Departments of Defense and Departments of Veterans Affairs (DoD / VA) practice guidelines recommend Cognitive Processing Therapy (CPT), Cognitive Behavioral Therapy (CBT), Prolonged Exposure Therapy (PET), Brief Eclectic Psychotherapy (BEP), Narrative Exposure Therapy (NAT), andEye-Movement Desensitization and Reprocessing (EMDR), as first-line treatment for PTSD as these treatments have repeatedly demonstrated efficacy in reducing symptoms of PTSD in randomized clinical trials. However, it has been shown that CPT and PE therapy did not lead to remission or even clinically meaningful reductions in symptoms in the majority of patients with PTSD. This is consistent with several studies that estimate that between 40%-60% of patients receiving any treatment for PTSD do not respond adequately and / or continue to meet diagnostic criteria after receiving treatment.

[0114] One of the symptoms of PTSD is learned avoidance behavior. Avoidance is a safety-seeking or protective response in response to trauma. However, as this avoidance behavior becomes more extreme, a person's quality of life may lessen. One type of behavioral therapy for PTSD is Exposure Therapy which can reduce anxiety and ultimately eliminating avoidance behavior and improving the quality of life for a subject having PTSD.

[0115] Depressive disorders are characterized by low mood, feeling sad or hopeless, increased irritability, sleep disturbance, lowered energy and feeling tired, poor concentration, lowered self-esteem or feeling worthless, lack of interest or pleasure in things, slowed movement, thinking they would be better off dead and self-harm, and actively considering and attempting suicide, and include major depressive disorder, bipolar depression, treatment resistant depression, and dysthymic disorder.

[0116] In embodiments, the stress-related disease or disorder is depression, anxiety or post- traumatic stress disorder.

[0117] In embodiments, the compound has antidepressant and anxiolytic effects.

[0118] Serotonin receptors (i.e., 5-HT receptors), are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. The receptors mediate both excitatory and inhibitory neurotransmission. The 5-HT receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. The 5- HT receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. They are the target of a variety of pharmaceutical and recreational drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens. There are a variety of 5-HT receptors (e.g., 5-HTi, 5-HT2, 5-HTS, 5-HT4, 5-HTs, 5-HTe, 5-HT?) which have differing functions. There are also 5- HT receptor subtypes (e g., 5-HTIA, 5-HTIB, 5-HTID, 5-HTIE, 5-HTIF, 5-HT2A, 5-HT2B, 5- HT2C, 5-HTSA, 5-HTSB). For example, 5-HT2A is involved in addiction, anxiety, appetite, cognition, imagination, learning, memory, mood, perception, sexual behavior, sleep, thermoregulation and vasoconstriction. In another example, 5-HT2c is involved in addiction, anxiety, appetite, GI motility, heteroreceptor for norepinephrine and dopamine, locomotion, mood, sexual behavior, sleep, thermoregulation and vasoconstriction.

[0119] The compositions comprising a compound of compound of Formula I, or a combination thereof can be administered alone or in combination with one or more additional therapeutic agents. The phrases “combination therapy”, “combined with” and the like refer to the use of more than one medication or treatment simultaneously to increase the response. The composition of the present invention might for example be used in combination with other drugs or treatment in use to stress-related diseases or disorders. In embodiments, the therapeutic agent is administered simultaneously with, prior to or following administration of the compound of Formula I.

[0120] Therapeutic agents for combination treatments may include SSRIs (e.g., citalopram, fluoxetine, sertraline, etc.), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, etc.), N-methyl-D-aspartate (NMDA) receptor modulators (e.g., ketamine, D- cycloserine, memantine, etc.), histone deacetylase inhibitors (e.g., valproic acid, b- hydroxybutyrate, etc.), serotonin 2A receptor agonists (e.g., N,N-dimethyltryptamine, lysergic acid diethylamide, psilocybin, etc.), entactogens (e.g., 3,4-methylenedioxymethamphetamine, 3, 4-m ethylenedi oxyamphetamine, etc.), lithium chloride, neurotrophic factors (e.g., BDNF, insulin-like growth factor 1, nerve growth factor, glial-derived growth factor, etc.), acetylcholine receptor modulators (e.g., donepezil, scopolamine, etc.) and others.

[0121] Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption (reuptake) into the presynaptic cell. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having strong affinity for the serotonin transporter and only weak affinity for the norepinephrine and dopamine transporters. SSRIs include fluoxetine, paroxetine, sertraline, escital opram and citalopram.

[0122] In embodiments, administration of the compound induces neurite outgrowth. In embodiments neurite outgrowth includes neurite number, neurite total length, number of neurite branch points per neuron or any combination thereof. In embodiments, the neurite outgrowth includes neurite outgrowth on prefrontal cortex neurons and / or hippocampal neurons.

[0123] In embodiments, the method comprises administering a therapeutic agent.

[0124] In embodiments, the compound of Formula I, or a combination thereof, is administered prior to, simultaneously with or following administration of the therapeutic agent.Neurite Outgrowth

[0125] Signs of neuronal atrophy have been found in brain regions involved in stress- related behaviors, including prefrontal cortex and hippocampus. In animals, these structural changes have been shown to include loss of neurites, dendritic spines and synaptic contacts, as well as reduced hippocampal neurogenesis. It has been shown that chronic, but not acute, administration of typical antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), attenuate the effects of stress on neurogenesis and neuronal structure in animals and demonstrate antidepressant and anxiolytic effects in humans. Thus, compounds that promote the generation and maintenance of neurites, spines, synapses and / or neurons upon single administration may have rapid therapeutic benefit in the treatment of stress-related disorders. Neurite outgrowth is measured by increasing neurite number, neurite total length and total number of branch points.

[0126] Some embodiments are directed towards a method of inducing neurite outgrowth, comprising administering a therapeutically effective amount of a compound of Formula I, or a combination thereof, to a subject in need thereof.

[0127] In embodiments, neurite outgrowth includes neurite number, neurite total length, number of neurite branch points per neuron or any combination thereof. In embodiments, neurite outgrowth includes neurite outgrowth on prefrontal cortex neurons and / or hippocampal neurons.

[0128] In embodiments, the subject has a stress-related disease or disorder.

[0129] In embodiments the stress-related disease or disorder is mood / depressive disorder, bipolar disorder, anxiety disorder, psychotic or delirium disorder, schizophrenia, schizoaffective disorder, personality disorder, abuse or neglect disorder, tic disorder,neurocognitive disorder, neurodevelopmental disorder, learning disorder, disruptive mood regulation disorder, intermittent explosive disorder, antisocial personality disorder, conduct disorder, behavioral and psychological symptoms of dementia, depression, anxiety, post- traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, stress disorders, rumination, eating disorders, or a combination thereof.

[0130] In embodiments, the method comprises administering a therapeutic agent.

[0131] In embodiments, the compound of Formula I, or a combination thereof, is administered prior to, simultaneously with or following administration of the therapeutic agent.Neural Atrophy

[0132] It has been shown that chronic stress from conditions such as PTSD can cause neural atrophy and decrease the number of synapses within cortical and limbic circuits, which are associated with the regulation of mood, cognition, and behavior. It has been shown that chronic, but not acute, administration of typical antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), attenuate the effects of stress on neurogenesis and neuronal structure in animals and demonstrate antidepressant and anxiolytic effects in humans. Neural plasticity, and therefore neural atrophy, can be improved by the induction of neurite growth. Therefore, compounds that promote neural plasticity and neurite growth may have therapeutic benefit in the treatment of stress-related disorders.

[0133] Some embodiments are directed towards a method of treating neuronal atrophy, comprising administering a therapeutically effective amount of a compound of Formula I, or a combination thereof, to a subject in need thereof.

[0134] In embodiments, administration of the compound induces neurite outgrowth. In embodiments neurite outgrowth includes neurite number, neurite total length, number of neurite branch points per neuron or any combination thereof. In embodiments, the neurite outgrowth includes neurite outgrowth on prefrontal cortex neurons and / or hippocampal neurons.

[0135] In embodiments, the subject has a stress-related disease or disorder.

[0136] In embodiments the stress-related disease or disorder is mood / depressive disorder, bipolar disorder, anxiety disorder, psychotic or delirium disorder, schizophrenia, schizoaffective disorder, personality disorder, abuse or neglect disorder, tic disorder,neurocognitive disorder, neurodevelopmental disorder, learning disorder, disruptive mood regulation disorder, intermittent explosive disorder, antisocial personality disorder, conduct disorder, behavioral and psychological symptoms of dementia, depression, anxiety, post- traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, stress disorders, rumination, eating disorders, or a combination thereof.

[0137] In embodiments, the method comprises administering a therapeutic agent.

[0138] In embodiments, the compound of Formula I, or a combination thereof, is administered prior to, simultaneously with or following administration of the therapeutic agent.Neural Plasticity

[0139] Neuroplasticity is the ability of the brain to form and reorganize synaptic connections, especially in response to learning or experience or following an injury. It has been shown that exposure to stress causes a consistent suppression of neural plasticity. Therefore, traumatic events, such as events causing PTSD, can alter the neural connections and neural plasticity of the brain. However, the neuroplasticity can be used to mitigate the effects of PTSD. It has been shown that chronic, but not acute, administration of typical antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), attenuate the effects of stress on neurogenesis and neuronal structure in animals and demonstrate antidepressant and anxiolytic effects in humans. Neural plasticity can be improved by the induction of neurite growth. As such, compounds that promote neural plasticity may have therapeutic benefit in the treatment of stress-related disorders.

[0140] Some embodiments are directed towards a method of inducing structural neuroplasticity, comprising administering a therapeutically effective amount of a compound of Formula I, or a combination thereof, to a subject in need thereof.

[0141] In embodiments, the compound has antidepressant and anxiolytic effects.

[0142] In embodiments, administration of the compound induces neurite outgrowth. In embodiments neurite outgrowth includes neurite number, neurite total length, number of neurite branch points per neuron or any combination thereof. In embodiments, the neurite outgrowth includes neurite outgrowth on prefrontal cortex neurons and / or hippocampal neurons.

[0143] In embodiments, the subject has a stress-related disease or disorder.

[0144] In embodiments the stress-related disease or disorder is mood / depressive disorder, bipolar disorder, anxiety disorder, psychotic or delirium disorder, schizophrenia, schizoaffective disorder, personality disorder, abuse or neglect disorder, tic disorder, neurocognitive disorder, neurodevelopmental disorder, learning disorder, disruptive mood regulation disorder, intermittent explosive disorder, antisocial personality disorder, conduct disorder, behavioral and psychological symptoms of dementia, depression, anxiety, post- traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, stress disorders, rumination, eating disorders, or a combination thereof.

[0145] In embodiments, the method comprises administering a therapeutic agent.

[0146] In embodiments, the compound of Formula lor a combination thereof, is administered prior to, simultaneously with or following administration of the therapeutic agent.Methods of administering non-hallucinogenic compounds

[0147] In embodiments, the compounds of the present disclosure are not hallucinogenic. The subject may, In embodiments, experience no hallucinogenic effects or reduced hallucinogenic effects after administration of the compounds of the present disclosure, relative to traditional 5-HT2A receptor agonist which are considered hallucinogenic.

[0148] In embodiments, the subject has a central nervous system or mental health disorder. In embodiments, the subject has a disorder selected from Neurodevelopmental Disorders, Intellectual Disabilities, Intellectual Disability (Intellectual Developmental Disorder), Global Developmental Delay, Unspecified Intellectual Disability (Intellectual Developmental Disorder), Communication Disorders, Language Disorder, Speech Sound Disorder (previously Phonological Disorder), Childhood-Onset Fluency Disorder (Stuttering), Social (Pragmatic) Communication Disorder, Unspecified Communication Disorder, Autism Spectrum Disorder, Autism Spectrum Disorder, Attention-Deficit / Hyperactivity Disorder, Attention- Deficit / Hyperactivity Disorder, Other Specified Attention-Deficit / Hyperactivity Disorder, Unspecified Attention-Deficit / Hyperactivity Disorder, Specific Learning Disorder, Specific Learning Disorder, Motor Disorders, Developmental Coordination Disorder, Stereotypic Movement Disorder, Tic Disorders, Tourette’s Disorder, Persistent (Chronic) Motor or Vocal Tic Disorder, Provisional Tic Disorder, Other Specified Tic Disorder, Unspecified Tic Disorder, Other Neurodevelopmental Disorders, Other Specified Neurodevelopmental Disorder, Unspecified Neurodevelopmental Disorder, Schizophrenia Spectrum and OtherPsychotic Disorders, Schizotypal (Personality) Disorder, Delusional Disorder, Brief Psychotic Disorder, Schizophreniform Disorder, Schizophrenia, Schizoaffective Disorder, Substance / Medication-Induced Psychotic Disorder, Psychotic Disorder Due to Another Medical Condition, Catatonia, Catatonia Associated With Another Mental Disorder (Catatonia Specifier), Catatonic Disorder Due to Another Medical Condition, Unspecified Catatonia, Other Specified Schizophrenia Spectrum and Other Psychotic Disorder Unspecified Schizophrenia Spectrum and Other Psychotic Disorder, Bipolar and Related Disorders, Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, Substance / Medication-Induced Bipolar and Related Disorder, Bipolar and Related Disorder Due to Another Medical Condition, Other Specified Bipolar and Related Disorder, Unspecified Bipolar and Related Disorder, Depressive Disorders, Disruptive Mood Dysregulation Disorder, Major Depressive Disorder, Single and Recurrent Episodes, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance / Medication-Induced Depressive Disorder, Depressive Disorder Due to Another Medical Condition, Other Specified Depressive Disorder, Unspecified Depressive Disorder, Anxiety Disorders, Separation Anxiety Disorder, Selective Mutism, Specific Phobia, Social Anxiety Disorder (Social Phobia), Panic Disorder, Panic Attack (Specifier), Agoraphobia, Generalized Anxiety Disorder, Substance / Medication-Induced Anxiety Disorder, Anxiety Disorder Due to Another Medical Condition, Other Specified Anxiety Disorder, Unspecified Anxiety Disorder, Obsessive-Compulsive and Related Disorders, Obsessive-Compulsive Disorder, Body Dysmorphic Disorder, Hoarding Disorder, Trichotillomania (Hair-Pulling Disorder), Excoriation (Skin-Picking) Disorder, Substance / Medication-Induced Obsessive-Compulsive and Related Disorder, Obsessive- Compulsive and Related Disorder Due to Another Medical Condition, Other Specified Obsessive-Compulsive and Related Disorder, Unspecified Obsessive-Compulsive and Related Disorder, Trauma- and Stressor-Related Disorders, Reactive Attachment Disorder, Disinhibited Social Engagement Disorder, Posttraumatic Stress Disorder, Acute Stress Disorder, Adjustment Disorders, Other Specified Trauma- and Stressor-Related Disorder, Unspecified Trauma- and Stressor-Related Disorder, Dissociative Disorders, Dissociative Identity Disorder, Dissociative Amnesia, Depersonalization / Derealization Disorder, Other Specified Dissociative Disorder, Unspecified Dissociative Disorder, Somatic Symptom and Related Disorders, Somatic Symptom Disorder, Illness Anxiety Disorder, Conversion Disorder (Functional Neurological Symptom Disorder), Psychological Factors Affecting Other Medical Conditions, Factitious Disorder, Other Specified Somatic Symptom and Related Disorder, Unspecified Somatic Symptom and Related Disorder, Feeding and Eating Disorders, Pica,Rumination Disorder, Avoidant / Restrictive Food Intake Disorder, Anorexia Nervosa, Bulimia Nervosa, Binge-Eating Disorder, Other Specified Feeding or Eating Disorder, Unspecified Feeding or Eating Disorder, Elimination Disorders, Enuresis, Encopresis, Other Specified Elimination Disorder, Unspecified Elimination Disorder, Sleep-Wake Disorders, Insomnia Disorder, Hypersomnolence Disorder, Narcolepsy, Breathing-Related Sleep Disorders, Obstructive Sleep Apnea Hypopnea, Central Sleep Apnea, Sleep-Related Hypoventilation, Circadian Rhythm Sleep-Wake Disorders, Parasomnias, Non-Rapid Eye Movement Sleep Arousal Disorders, Sleepwalking, Sleep Terrors, Nightmare Disorder, Rapid Eye Movement Sleep Behavior Disorder, Restless Legs Syndrome, Substance / Medication-Induced Sleep Disorder, Other Specified Insomnia Disorder Unspecified Insomnia Disorder Other Specified Hypersomnolence Disorder Unspecified Hypersomnolence Disorder Other Specified Sleep- Wake Disorder Unspecified Sleep-Wake Disorder, Sexual Dysfunctions, Delayed Ejaculation, Erectile Disorder, Female Orgasmic Disorder, Female Sexual Interest / Arousal Disorder, Genito-Pelvic Pain / Penetration Disorder, Male Hypoactive Sexual Desire Disorder, Premature (Early) Ejaculation, Substance / Medication-Induced Sexual Dysfunction, Other Specified Sexual Dysfunction, Unspecified Sexual Dysfunction, Gender Dysphoria, Gender Dysphoria, Other Specified Gender Dysphoria, Unspecified Gender Dysphoria, Disruptive, Impulse- Control, and Conduct Disorders, Oppositional Defiant Disorder, Intermittent Explosive Disorder, Conduct Disorder, Antisocial Personality Disorder, Pyromania, Kleptomania, Other Specified Disruptive, Impulse-Control, and Conduct Disorder, Unspecified Disruptive, Impulse-Control, and Conduct Disorder, Substance-Related and Addictive Disorders, Substance-Related Disorders, Substance Use Disorders, Substance-Induced Disorders, Substance Intoxication and Withdrawal, Substance / Medication-Induced Mental Disorders, Alcohol-Related Disorders, Alcohol Use Disorder, Alcohol Intoxication, Alcohol Withdrawal, Other Alcohol-Induced Disorders, Unspecified Alcohol-Related Disorder, Caffeine-Related Disorders, Caffeine Intoxication, Caffeine Withdrawal, Other Caffeine-Induced Disorders, Unspecified Caffeine-Related Disorder, Cannabis-Related Disorders, Cannabis Use Disorder, Cannabis Intoxication, Cannabis Withdrawal, Other Cannabis-Induced Disorders, Unspecified Cannabis-Related Disorder, Hallucinogen-Related Disorders, Phencyclidine Use Disorder, Other Hallucinogen Use Disorder, Phencyclidine Intoxication, Other Hallucinogen Intoxication, Hallucinogen Persisting Perception Disorder, Other Phencyclidine-Induced Disorders, Other Hallucinogen-Induced Disorders, Unspecified Phencyclidine-Related Disorder, Unspecified Hallucinogen-Related Disorder, Inhalant-Related Disorders, Inhalant Use Disorder, Inhalant Intoxication, Other Inhalant-Induced Disorders, Unspecified Inhalant-Related Disorder, Opioid-Related Disorders, Opioid Use Disorder, Opioid Intoxication, Opioid Withdrawal, Other Opioid-Induced Disorders, Unspecified Opioid-Related Disorder, Sedative- , Hypnotic-, or Anxiolytic-Related Disorders, Sedative, Hypnotic, or Anxiolytic Use Disorder, Sedative, Hypnotic, or Anxiolytic Intoxication, Sedative, Hypnotic, or Anxiolytic Withdrawal, Other Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders, Unspecified Sedative-, Hypnotic-, or Anxiolytic-Related Disorder, Stimulant-Related Disorders, Stimulant Use Disorder, Stimulant Intoxication, Stimulant Withdrawal, Other Stimulant-Induced Disorders, Unspecified Stimulant-Related Disorder, Tobacco-Related Disorders, Tobacco Use Disorder, Tobacco Withdrawal, Other Tobacco-Induced Disorders, Unspecified Tobacco-Related Disorder, Other (or Unknown) Substance-Related Disorders, Other (or Unknown) Substance Use Disorder, Other (or Unknown) Substance Intoxication, Other (or Unknown) Substance Withdrawal, Other (or Unknown) Substance-Induced Disorders, Unspecified Other (or Unknown) Substance-Related Disorder, Non-Substance-Related Disorders, Gambling Disorder, Neurocognitive Disorders, Delirium, Other Specified Delirium, Unspecified Delirium, Major and Mild Neurocognitive Disorders, Major Neurocognitive Disorder, Mild Neurocognitive Disorder, Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease, Major or Mild Frontotemporal Neurocognitive Disorder, Major or Mild Neurocognitive Disorder With Lewy Bodies, Major or Mild Vascular Neurocognitive Disorder, Major or Mild Neurocognitive Disorder Due to Traumatic Brain Injury, Sub stance / Medi cation-induced Maj or or Mild Neurocognitive Disorder, Major or Mild Neurocognitive Disorder Due to HIV Infection, Major or Mild Neurocognitive Disorder Due to Prion Disease, Major or Mild Neurocognitive Disorder Due to Parkinson’s Disease, Major or Mild Neurocognitive Disorder Due to Huntington’s Disease, Major or Mild Neurocognitive Disorder Due to Another Medical Condition, Major or Mild Neurocognitive Disorder Due to Multiple Etiologies, Unspecified Neurocognitive Disorder, Personality Disorders, General Personality Disorder, Cluster A Personality Disorders, Paranoid Personality Disorder, Schizoid Personality Disorder, Schizotypal Personality Disorder, Cluster B Personality Disorders, Antisocial Personality Disorder, Borderline Personality Disorder, Histrionic Personality Disorder, Narcissistic Personality Disorder, Cluster C Personality Disorders, Avoidant Personality Disorder, Dependent Personality Disorder, Obsessive-Compulsive Personality Disorder, Other Personality Disorders, Personality Change Due to Another Medical Condition, Other Specified Personality Disorder, Unspecified Personality Disorder, Paraphilic Disorders, Voyeuristic Disorder, Exhibitionistic Disorder, Frotteuristic Disorder, Sexual Masochism Disorder, Sexual Sadism Disorder, Pedophilic Disorder, Fetishistic Disorder, Transvestic Disorder, OtherSpecified Paraphilic Disorder, Unspecified Paraphilic Disorder, Other Mental Disorders, Other Specified Mental Disorder Due to Another Medical Condition, Unspecified Mental Disorder Due to Another Medical Condition, Other Specified Mental Disorder, Unspecified Mental Disorder, Attenuated Psychosis Syndrome, Depressive Episodes With Short-Duration Hypomania, Persistent Complex Bereavement Disorder, Caffeine Use Disorder, Internet Gaming Disorder, Neurob ehavi oral Disorder Associated With Prenatal Alcohol Exposure, Suicidal Behavior Disorder, Nonsuicidal Self-Injury, or combinations thereof.

[0149] In embodiments, the mental health disorder is selected from personality disorders, mood disorders, addictive disorder, eating disorders, obsessive-compulsive disorders, sleep disorders, autism spectrum disorder, chronic pain conditions, and combinations thereof.

[0150] In embodiments, the mental health disorder is selected from borderline personality disorder, depression, anxiety, substance use disorder, Opioid use disorder, Alcohol use disorder, gambling, anorexia nervosa, bulimia, obsessive compulsive disorder, body dysmorphic disorder, narcolepsy, headaches, and combinations thereof.

[0151] In embodiments, treating the disorder in the subject includes reducing symptom of the disorder, preventing a symptom of the disorder, or a combination thereof. In embodiments, treating the disorder includes an improvement in one or more health parameters of the subject, as determined by a healthcare professional or appropriate evaluation method.

[0152] In embodiments, the pharmaceutical composition includes one or more pharmaceutically acceptable excipients. In embodiments, the pharmaceutical composition includes a second active agent.

[0153] In embodiments, administering the pharmaceutical composition includes intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual buccal, or nasal routes of administration. In embodiments, the pharmaceutical composition is administered as a single dose, and in other embodiments, the pharmaceutical composition may be administered in repeated doses.

[0154] In embodiments, the non-hallucinogenic 5-HT2A receptor agonist has antidepressant and anxiolytic effects. The presence of such effects may be evaluated by method or test familiar to those skilled in the art.EXAMPLESGeneral synthetic experimental details

[0155] Unless otherwise noted, all materials / reagents were obtained from commercial suppliers and used without further purification. Reactions were monitored by LCMS and / or thin layer chromatography (TLC) on silica gel 60 F254 (0.2mm) pre-coated aluminum foil or glass-backed and visualized using UV light. 1HNMR (400 MHz) spectra was recorded on Broker spectrometers at RT with TMS or the residual solvent peak as the internal standard. The line positions or multiples are given in (5), and the coupling constants (J) are given as absolute values in Hertz (Hz). The multiplicities in 1HNMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad (broadened). Preparative HPLC purifications were performed on Shimadzu LC-6AD. All purification work was completed using a Shim-pack PREP-DDS(H)KIT Column Preparative TLC was performed on Whatman LK6F Silica Gel 60 A size 20x20 cm plates with a thickness of 1000 pm or equivalent. LCMS was performed on Shimadzu LCMS-2020 equipped with LC-20AD or 30AD pumps, SPD-M20APDA and Alltech 3300 ELSD. Mobile Phase A: water (0.1% formic acid); Mobile Phase B: acetonitrilthe (ACN); Duration: 5 minutes; Column: Sepax BR-C18 4.6*50mm, 3 pm; Flow Rate: 1.0 mL / min; Oven Temperature: 40°C.EXAMPLE 1

[0156] Synthesis of N-(3-chloro-5-methylbenzyl)-3-(2,5-dimethoxyphenyl)propenamide(1-3)

[0157] N-(3-chloro-5-methylbenzyl)-3-(2,5-dimethoxyphenyl)propenamide

[0158] To a suspension of 3-(2,5-dimethoxyphenyl)propanoic acid (1.0 g, 4.75 mmol, 1.0 eq), (3-chloro-5-methylphenyl)- methenamine (0.86 g, 4.51 mmol, 0.95 eq) and TEA (1.44 g, 14.2 mmol, 3.0 eq) in DCM (25 mL) was added in three equal portions TBTU (1.6 g, 5.22 mmol, 1.1 eq). The resulting mixture was stirred overnight at RT. The reaction mixture was diluted with water (40 mL) and extracted with DCM (20 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography (petroleum ether / EA = 4 / 1) to afford the title compound (200 mg, 13% yield) as a solid. LCMS: (ES+): m / z 348 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm7.96 (s, 1H), 6.96 (s, 1H), 6.72-6.75 (m, 3H), 5.83 (s, 1H), 4.32-4.34 (m, 2H), 3.73 (s, 3H),3.72 (s, 3H), 2.92-2.96 (m, 2H), 2.52-2.55 (m, 2H), 2.29 (s, 3H).EXAMPLE 2

[0159] Synthesis of N-(3-chloro-5-methylbenzyl)-5,8-dimethoxy-N-methyl-l,2,3,4- tetrahydronaphthalen-2-amine (1-4)

[0160] N-(3-chloro-5-methylbenzyl)-5,8-dimethoxy-N-methyl-l,2,3,4- tetrahydronaphthalen-2-amine

[0161] The free amine was converted to its HC1 salt (36 mg, 21%) as a solid after treatment with HC1 in dioxane. LCMS: (ES+): m / z 360[M+H] +. 1H NMR (400 MHz, solvent: CDCh) ppm 7.16 (s, 1H), 7.04-7.02 (d, J = 8 Hz, 2H), 6.6 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.60 (s, 2H), 3.05-2.98 (m, 2H), 2.85-2.83 (m, 1H), 2.56-2.49 (m, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.13- 2.09 (m, 1H), 1.62-1.58 (m, 2H).EXAMPLE 3

[0162] Synthesis of N-(3-chloro-5-methylbenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan- 1 -amine hydrochloride (1-6)

[0163] N-(3-chloro-5-methylbenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan-l -amine hydrochloride

[0164] A suspension of 2-HC1 (170 mg, 0.47 mmol, 1.0 eq), IC1 (103 mg, 0.61 mmol, 1.3 eq) in AcOH (3 mL) and stirred RT overnight. The reaction mixture was quenched with sodium thiosulfate solution (0.5g in 10 mL H2O) and extracted with EA (10 mL x 3). The combinedorganic extracts were dried over Na2SO4 and concentrated to give a crude product which was purified by silicas gel chromatography (DCM / methanol = 30 / 1) to afford the title compound as an oil. The free amine was converted to its HC1 salt (30 mg, yield 10%) as a solid after treatment with HC1 in dioxane. LCMS: (ES+): m / z 446 [M+H] +. 1HNMR (400 MHz, DMSO- d6) ppm 9.84 (s, 2H), 7.20 (s, 1H), 7.16 (s, 1H), 7.07 (s, 1H), 6.87 (s, 1H), 6.59 (s, 1H), 3.85 (s, 2H), 3.82 (s, 3H), 3.74 (s, 3H), 2.99-3.00 (m, 2H), 2.55-2.59 (m, 2H), 2.17 (s, 3H).EXAMPLE 4

[0165] Preparation of N-(3-chloro-5-methylbenzyl)-3-(2,5-dimethoxyphenyl)propan-l- amine (1-8)

[0166] Step 1 : N-(3-chloro-5-methylbenzyl)-3-oxo-3-(2,5-dimethoxyphenyl)propan-l- amine

[0167] To a solution of 3-(2,5-dimethoxyphenyl)propan-l-carboxylic acid (1 g, 4.76 mmol, 1 eq) and (3-chloro-5-methylphenyl)methenamine (909 mg, 4.76 mmol, 1 eq) in CH2CI2 (10 ml) was added EtiN (1.44 g, 14.28 mmol, 3 eq) at 25°C, followed by the addition of TBTU (1.68 g, 5.24 mmol, 1.1 eq). The reaction mixture was stirred at RT for 10 h. The mixture was quenched with aq. NH4Q solution and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue which was purified by flash chromatography (DCM / MeOH, 20%) to afford the title compound (1 ,47g, 89%) as a solid. LCMS: (ES+): m / z 349.2 [M+H] +. 1HNMR (400 MHz, solvent: CDCh) ppm 7.06 (s, 1H), 6.96 (s, 1H), 6.87 (s, 1H), 6.75-6.72 (m, 3H), 5.83 (s, 1H), 4.34-4.33 (m, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 2.96-2.93 (m, 2H), 2.56-2.52 (m, 2H), 2.29 (s, 3H).

[0168] Step 2: N-(3-chloro-5-methylbenzyl)-3-(2,5-dimethoxyphenyl)propan-l-amine

[0169] To a solution of N-(3-chloro-5-methylbenzyl)-3-oxo-3-(2,5- dimethoxyphenyl)propan-l-amine(1.47 g, 4.23 mmol) in 15 mL of dry THF, NaBT (322 mg, 8.47 mmol, 2eq) was slowly added at 0°C under nitrogen. BF3.OEt2 in 50 mL of dry THF was slowly added at 0°C, The reaction mixture was stirred at RT for 8 h. The reaction mixture was poured into water, acidified by the addition of dilute hydrochloric acid and stirred for 2h. The mixture was made basic by the addition of potassium hydroxide solution and extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (DCM / MeOH, 15%) to afford the title compound (706 mg, 51%) as an oil, which was converted to the HC1 salt (642 mg, 82%) as a solid. LCMS: (ES+): m / z 334.3 [M+H] +. 1H NMR (400 MHz, solvent: CDCh) ppm 8.62 (s, 2H), 7.24 (s, 2H), 7.17 (s, 1H), 6.76-6.74 (m, 2H), 6.70-6.67 (m, 2H), 4.05 (s, 2H), 3.73-3.72 (m, 6H), 2.81 (s, 2H), 2.68-2.65 (m, 2H), 2.332 (s, 3H), 2.16-2.08 (m, 2H).EXAMPLE 5EXPERIMENTAL METHODS

[0170] In Vitro Human Receptor Functional Activity and Radioligand Binding Assays

[0171] Control ligand (5-HT or al tanserin) and novel compounds were tested in agonist or antagonist mode using human 5-HT2A, 5-HT2C, 5-HT2B, 5-HTIA, 5-HTIB, 5-HTIF, 5-HTSA and 5-HT7D GPCR Biosensor Assays. Control ligand (haloperidol) and novel compounds also were tested in a human sigmal receptor radioligand binding assay. Data were normalized to the maximal and minimal response observed in the presence of control ligand and vehicle.

[0172] Euro fins DiscoverX 5-HT2A, 5-HT 2c and 5-HT2B Receptor Calcium MobilizationAssays

[0173] The Calcium No-WashPLUSassay monitors the activation of a GPCR via Gq secondary messenger signaling in a live cell, non- imaging assay format. Calcium mobilization in PathHunter® cell lines or other cell lines stably expressing Gq-coupled GPCRs is monitored using a calcium-sensitive dye that is loaded into cells. GPCR activation by a compound results in the release of calcium from intracellular stores and an increase in dye fluorescence that is measured in real-time.

[0174] Cell Handling

[0175] 1. Cell lines were expanded from freezer stocks according to standard procedures.Human 5-HT2A, 5-HT2B or 5-HT2C receptor-mediated calcium mobilization was evaluated in stably transfected human-derived U2OS (5-HT2A or 5-HT2B) or HEK (5-HT2B) cells.

[0176] 2 Cells were seeded in a total volume of 20 pL into black-walled, clear-bottom,Poly-D-lysine coated 384-well microplates and incubated at 37°C overnight prior to testing.

[0177] Dye Loading

[0178] 1. Assays were performed in 1 x Dye Loading Buffer consisting of lx Dye, lxAdditive A and 2.5 mM Probenecid in HBSS / 20 mM Hepes. Probenicid was prepared fresh.

[0179] 2 Cells were loaded with dye prior to testing. Media was aspirated from cells and replaced with 20 pL Dye Loading Buffer.

[0180] 3. Cells were incubated for 45 minutes at 37°C followed by 15 minutes at room temperature.

[0181] Agonist Format

[0182] 1. For agonist determination, cells were incubated with sample to induce response.

[0183] 2. After dye loading, cells were removed from the incubator and 10 pL HBSS / 20 mM Hepes was added. 3x vehicle was included in the buffer when performing agonist dose curves to define the EC80 for subsequent antagonist assays. Cells were incubated for 30 minutes at room temperature in the dark to equilibrate plate temperature.

[0184] 3 Intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer.

[0185] 4. Compound agonist activity was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and 5 pL 4X sample in HBSS / 20 mM Hepes was added to the cells 5 seconds into the assay.

[0186] Antagonist Format

[0187] 1. For antagonist determination, cells were pre-incubated with sample followed by agonist challenge at the EC80 concentration.

[0188] 2. Intermediate dilution of sample stocks was performed to generate 3X sample in assay buffer.

[0189] 3. After dye loading, cells were removed from the incubator and 10 pL 3X sample was added. Cells were incubated for 30 minutes at room temperature in the dark to equilibrate plate temperature. Vehicle concentration was 1%.

[0190] 4. Compound antagonist activity was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and 10 pL EC80 agonist in HBSS / 20 mM Hepes was added to the cells 5 seconds into the assay.

[0191] Data Analysis

[0192] 1. Compound activity was analyzed using CBIS data analysis suite(Chemlnnovation, CA).

[0193] 2 For agonist mode assays, percentage activity is calculated using the following formula:

[0194] % Activity =100% x (mean RFU of test sample - mean RFU of vehicle control) / (mean MAX RFU control ligand - mean RFU of vehicle control). In these studies, the MAX RFU was generated by using 0.1 pM serotonin for the calcium mobilization assay.

[0195] 3. For antagonist mode assays, percentage inhibition is calculated using the following formula:

[0196] % Inhibition =100% x (1 - (mean RFU of test sample - mean RFU of vehicle control) / (mean RFU of EC80 control - mean RFU of vehicle control)).

[0197] Eurofms Discover X 5-HT2A GPCR Arrestin Assay

[0198] The PathHunter® P-Arrestin assay monitors the activation of a GPCR in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) with P-galactosidase (P-Gal) as the functional reporter. The enzyme is split into two inactive complementary portions (EA for Enzyme Acceptor and PK for ProLink) expressed as fusion proteins in the cell. EA is fused to P-Arrestin and PK is fused to the GPCR of interest. When the GPCR is activated and P-Arrestin is recruited to the receptor, ED and EA complementation occurs, restoring P-Gal activity which is measured using chemiluminescent PathHunter® Detection Reagents.

[0199] Cell Handling1. PathHunter® cell lines were expanded from freezer stocks according to standard procedures. Human 5-HT2A receptor-mediated GPCR b-arrestin activity was evaluated in stably transfectedhuman-derived U2OS cells.2. Cells were seeded in a total volume of 20 pL into white walled, 384-well microplates and incubated at 37°C overnight prior to testing.

[0200] Agonist Format

[0201] 1. For agonist determination, cells were incubated with sample to induce response.

[0202] 2. Intermediate dilution of sample stocks was performed to generate 5X sample in assay buffer.

[0203] 3. 5 pL of 5X sample was added to cells and incubated at 37°C for 120 minutes.Vehicle concentration was 1%.

[0204] Signal Detection

[0205] 1. Assay signal was generated through a single addition of 15 pL (50% v / v) ofPathHunter Detection reagent cocktail, followed by a one hour incubation at room temperature.

[0206] 2. Microplates were read following signal generation with a PerkinElmerEnvisionTM instrument for chemiluminescent signal detection.

[0207] Data Analysis

[0208] 1. Compound activity was analyzed using CBIS data analysis suite(Chemlnnovation, CA).

[0209] 2. For agonist mode assays, percentage activity was calculated using the following formula:

[0210] % Activity =100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control). In these studies, the MAX control ligand response was generated using 10 pM serotonin.

[0211] Eurofins DiscoverX 5-HTIA, 5-HTIB, 5-HTIF, 5-HTSA and 5-HT7D GPCR CAMP Modulation Assays

[0212] DiscoverX has developed a panel of cell lines stably expressing non-tagged GPCRs that signal through cAMP. Hit Hunter® cAMP assays monitor the activation of a GPCR via Gi and Gs secondary messenger signaling in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) with P-galactosidase (P-Gal) as the functional reporter. The enzyme is split into two complementary portions: EA for Enzyme Acceptor and ED for Enzyme Donor. ED is fused to cAMP and inthe assay competes with cAMP generated by cells for binding to a cAMP-specific antibody. Active P-Gal is formed by complementation of exogenous EA to any unbound EDcAMP. Active enzyme can then convert a chemiluminescent substrate, generating an output signal detectable on a standard microplate reader

[0213] Cell Handling

[0214] 1. cAMP Hunter cell lines were expanded from freezer stocks according to standard procedures. Human 5-HTIA receptor-mediated cAMP signaling was evaluated in stably transfected hamster-derived CHO cells.

[0215] 2. Cells were seeded in a total volume of 20 pL into white walled, 384-well microplates and incubated at 37°C overnight.

[0216] 3 cAMP modulation was determined using the DiscoverX HitHunter® cAMP XS+ assay.

[0217] Gi Agoni st F ormat

[0218] 1. For agonist determination, cells were incubated with sample in the presence ofEC80 (15 pM) forskolin to induce response.

[0219] 2. Media was aspirated from cells and replaced with 10 pL HBSS / lOmM Hepes.

[0220] 3. Intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer containing 4x EC80 forskolin.

[0221] 4. 5 pL of 4x sample was added to cells and incubated at 37°C for 30 minutes. Final assay vehicle concentration was 1%.

[0222] Gs Agonist Format

[0223] 1. For agonist determination, cells were incubated with sample to induce response.

[0224] 2. Media was aspirated from cells and replaced with 15 pL 2: 1 HBSS / lOmM Hepes: cAMP XS+ Ab reagent .

[0225] 3. Intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer.

[0226] 4. 5 pL of 4x sample was added to cells and incubated at 37°C or room temperature for 30 or 60 minutes. Vehicle concentration was 1%.

[0227] Signal Detection

[0228] 1. After compound incubation, assay signal was generated through incubation with20 pL cAMP XS+ ED / CL lysis cocktail for one hour followed by incubation with 20 pL cAMP XS+ EA reagent for three hours at room temperature.

[0229] 2. Microplates were read following signal generation with a PerkinElmerEnvisionTM instrument for chemiluminescent signal detection.

[0230] Data Analysis

[0231] 1. Compound activity was analyzed using CBIS data analysis suite(Chemlnnovation, CA).

[0232] 2. For Gi agonist mode assays, percentage activity is calculated using the following formula:

[0233] % Activity = 100% x (1 - (mean RLU of test sample - mean RLU of MAX control) / (mean RLU of vehicle control - mean RLU of MAX control)). In these studies, the MAX RLU was generated by using 0.1 pM serotonin.

[0234] 3. For Gs agonist mode assays, percentage activity is calculated using the following formula:

[0235] % Activity =100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX control - mean RLU of vehicle control).

[0236] Eurofms Panlab Sigma 1 Receptor Radioligand Binding Assay

[0237] Methods employed in this study were adapted from Ganapathy et al., 1999, to maximize reliability and reproducibility. Human Jurkat cells expressing sigma si receptors were incubated for 2 hours at 37°C in incubation buffer containing 50 mM Tris-HCl, pH 8.0. [3H]-Pentazocine (15 nM) was the radioligand and haloperidol (lOpM) was used to determine non-specific binding. Vehicle concentration was 1% dimethyl sulfoxide (DMSO). Significance was set at >50% of maximal inhibition of radioligand binding.

[0238] EuroscreenFast 5-HT2A, 5-HT2B Receptor IPOne Assays

[0239] IPOne assays were conducted with recombinant cell lines. Receptors, accession numbers, cellular background and reference compounds are shown in Table 3.Table 3. Cell lines

[0240] Compounds were tested for agonist activity at the human 5-HT2A (FAST-05051) and 5-HT2B (FAST-05061) receptors at the following nanomolar concentrations in duplicate: 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000 and 10000. On each day of experimentation, reference compounds were tested at several concentrations in duplicate (n=2) to obtain a concentrationresponse curve and an estimated EC50 value. Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session. Values are indicated in Table 4.Table 4. Historical values

[0241] For replicate determinations, the maximum variability tolerated in the test was of + / -20% around the average of the replicates. Compounds identification codes and test concentrations, data output measurements, percentages of activity relative to the reference compound, ECso and Hill coefficients were reported. Concentration-response data from test compounds were analyzed with XLfit (IDBS) software using nonlinear regression applied to a sigmoidal concentration-response model and the following equation:XL Fit fit Model 203 : 4 Parameter Logistic ModelA : BottomB : TOPC : LogECsoD : Hill fit = (A+((B-A) / (l+(((10AC) / x)AD)))) inv = ((10AC) / ((((B-A) / (y-A))- 1)A( 1 / D))) res = (y-fit)

[0242] Agonist activity of test compounds was expressed as a percentage of the activity of the reference agonist at its EC 100 concentration.

[0243] Primary Rat Cortical Neurite Outgrowth Assay

[0244] Multiple experiments were conducted to evaluate the effects of novel and reference compounds. Female Wistar rats of 17 days gestation were killed by cervical dislocation and the fetuses (typically 6 to 8 in number) were removed from the uterus. Fetal brains were placed in ice-cold medium of Leibovitz (L15, Gibco, France). Cortex was dissected and meninges were carefully removed. The cortical neurons were dissociated by trypsinization (trypsin- EDTA, Gibco) in the presence of DNAse I (Roche, France). The reaction was stopped by addition of Dulbecco’s Modified Eagle Medium (DMEM; Gibco) with 10% of fetal bovine serum (FBS; Gibco). The suspension was triturated with a 10-ml pipette and a 21-gauge needle syringe and centrifuged. The pellet of dissociated cells was resuspended in a medium consisting of Neurobasal (Gibco) supplemented with 2% B27 supplement (Gibco), 0.5mM L-Glutamine (Gibco), and an antibiotic-antimycotic mixture. Viable cells were counted in a Neubauer cytometer and cells were seeded in 96-well plates (Costar) precoated with poly-L-lysine at 10,000cells / well. Compounds, including negative control (vehicle), positive control (Donepezil 250nM), and test article(s) at one or more concentrations, were added to the cultures on the plating day (DayO). Stock solutions were prepared in 100% DMSO or sterile water between l-30mM and stored at -20°C until use. Further dilution was performed in culture in the medium on the day of the treatment. Depending on the vehicle used in an individual experiment, 0.1% DMSO or sterile water was present in all tested conditions. Testing of 7 novel compounds was conducted in two experiments. Compound stock solutions were prepared in 100% DMSO and compounds were tested at 0.1 and 10 pM. Each experimental protocol was performed in 1 culture (i.e., from 1 pregnant rat). Reference compounds were tested in separate experiments that each were performed using 2 independent cultures (i.e., from 2 different pregnant rats). The 5-HT2A receptor agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI, Ambinter, Amb8628869) stock solution was prepared in sterile water and tested at 8 concentrations (0.000001, 0.00001, 0.0001, 0.001, 0.01, 0.1, 1 and lOpM). The 5-HT2A receptor antagonist M100,907 (Sigma-Aldrich, M3324) stock solution was prepared in 100% DMSO and tested at 4 concentrations (0.001, 0.01, 0.1 and IpM). The Sigmal receptor antagonist NE-100 (Tocris Bioscience, 3133) was prepared in sterile water and tested at 4 concentrations (0.001, 0.01, 0.1 and IpM). For all experiments, each condition was tested in sextuplet (6 wells per condition per culture). Each plate contained 3 types of experimental conditions: the negative control condition treated with vehicle (0.1% DMSO or sterile water), the positive control condition treated with Donepezil (250nM) and test article conditions. After three days of plating and compound treatment (Day3), cultures were fixed with paraformaldehyde in phosphate buffered saline at 4°C (PBS, 4%, Sigma). Then, all subsequentsteps were performed at room temperature. Cells were successively permeabilized for 30 minutes using 0.1% triton, saturated with PBS containing 3% bovine serum albumin (BSA) and incubated for 1 hour with anti -beta III tubulin antibody (T5168, Sigma). Cells were first washed 3 times and then were incubated for 1 hour with goat anti-mouse secondary antibody coupled with Alexa Fluor 488 (AF488, Invitrogen Al 1001). Finally, nuclei were stained with 4’-6-diamidino-2-phenylindole (DAPI). After rinsing the cells with PBS, the plate was imaged and neurite networks were examined and analyzed using a High-Content Screening platform (Celllnsight CX5, Thermo Scientific) with integrated Photometries high-resolution fluorescent camera, Olympus objective (lOx) and HCS Studio Cell Analysis Software. Approximately 2,000 neurons per well were analyzed using a validated cortex neuron outgrowth algorithm that utilizes parameters optimized for analysis of embryonic rat cortical neuron cultures. The HCS Studio Cell Analysis Software output included average values for neurite total count (#), neurite total length (mm) and total number of branch points (#) for each well per treatment condition. Each data point also was transformed to percent (%) of the average vehicle control value. Results were expressed as treatment group means (± s.e.m.) of the transformed (% of vehicle control) data. Statistical analysis of the transformed test article data was performed using one-way analysis of variance (ANOVA, GraphPad Prism 9.3.1). Where applicable, Dunnett’s post hoc test was used for multiple pairwise comparisons to the negative control (vehicle) condition. The donepezil positive control condition was compared to the negative control (vehicle) condition using an unpaired t test. The level of significance was set at p-value less than or equal to 0.05.EXAMPLE 6EXPERIMENTAL RESULTS

[0245] In Vitro Human Receptor Functional and Binding Activity

[0246] As shown in Table 5, under the conditions tested, all novel compounds, except Compound 1-3 and Compound 1-4, exhibited potent (sub micromolar ECso) functional agonist activity at human 5-HT2A receptors. Testing of Compound 1-3 and Compound 1-4 for 5-HT2A receptor antagonism identified Compound 1-4 as a moderate potency antagonist (IC50 ~lpM). 5-HT2A agonist compounds also displayed agonist potencies <10pM at 5-HT2C receptors and >10pM at 5-HT2B receptors in the Gq Ca++ assay. Compound 1-2 and Compound 1-6 exhibited nanomolar potency at both 5-HT2A and 5-HT2B receptors in the Gq IPOne assay, with higher selectivity for 5-HT2A. Compound 1-1 also exhibited selectivity for 5-HT2A receptors, withnanomolar potency at 5-HT2A receptors and inactivity up to lOuM at 5-HT2B receptors in the IPOne assay (Table 4). Compound 1-8 exhibited potent (sub micromolar ECso) agonist activity at 5-HTIA receptors, and Compound 1-4 and Compound 1-6 displayed potent 5-HTIB receptor agonism. Only Compound 1-1, Compound 1-2, Compound 1-3 and Compound 1-4 were tested at 5-HTIF, 5-HTSA and 5-HT?D receptors, and all four compounds displayed agonist potencies <10pM at 5-HTSA receptors. Only Compound 1-2, Compound 1-3 and Compound 1-8 were screened for binding to sigma 1 receptors at 10pM, and Compound 1-2 and Compound 1-8 displaced the radioligand >100% at this concentration.Table 5: Summary of In Vitro 5-HT Receptor Functional Agonist ActivityTable 6

[0247] Primary Rat Cortical Neurite Outgrowth - Novel Compound Testing

[0248] Figure 1 shows the results from two independent experiments evaluating the effects of 7 novel compounds on neurite outgrowth measures in rat embryonic cortical neuron cultures at 0.1 and 10pM. Under the conditions tested, Compound 1-3, a compound lacking in vitro 5- HT2A receptor agonist or antagonist activity, significantly increased the neurite outgrowth parameter of number of branches in primary rat cortical neurons at 10pM compared to the 0.1% DMSO vehicle. Compound 1-4, a compound exhibiting moderate potency 5-HT2A receptor antagonist activity, showed a nonsignificant trend to increase the three neurite outgrowth parameters in a concentration-dependent manner (note: Compound 1-4 effect on number of branches was significant when a less stringent statistical post hoc test, i.e., Fisher’s Least Significant Difference, was used). Compound 1-1, Compound 1-2, Compound 1-5, Compound 1-6, and Compound 1-8, compounds exhibiting potent in vitro 5-HT2A receptor agonist activity, did not significantly increase any of the three neurite outgrowth parameters measured at 0.1 or 10pM. In contrast, Compound 1-2, Compound 1-5, Compound 1-6, and Compound 1-8 exhibited significant decreases in neurite parameters. Each of these four compounds showed significant reductions at 10pM compared to vehicle for average number of neurites and average total neurite length. In addition, Compound 1-5 and Compound 1-8 significantly reduced the average number of branchpoints per neuron. Compound 1-1 did not significantly alter any of the neurite parameters at the tested concentrations. The positive control donepezil (250nM, black bars) significantly increased the average number of neurites, total neurite length andnumber of branches per neuron compared to vehicle in both experiments. Asterisks (*) and octothorpes (#) in the figures indicate significant differences compared to the Vehicle condition (p<0.05) by 1-way ANOVA followed by Dunnett' s test, and unpaired t test, respectively.

[0249] Reference Compound Testing

[0250] Figure 2 shows the results from an experiment evaluating the effects of 8 concentrations of the reference 5-HT2A receptor agonist, DOI, on neurite outgrowth measures in rat embryonic cortical neuron cultures. Under the conditions tested, DOI significantly increased each of the three neurite outgrowth parameters measured in primary rat cortical neurons at 1 and / or 10pM compared to the 0.1% sterile water vehicle. The positive control donepezil (250nM, black bars) significantly increased the average number of neurites, total neurite length and number of branches per neuron compared to vehicle control.

[0251] Figure 3 shows the results from an experiment evaluating the effects of 4 concentrations of the reference 5-HT2A receptor antagonist M100907 and sigmal receptor antagonist NE-100. Under the conditions tested, M100907 (yellow / green bars) significantly increased each of the three neurite outgrowth parameters measured in primary rat cortical neurons at 0.01, 0.1 and / or IpM compared to the 0.1% sterile water vehicle. NE-100 (blue / purple bars) significantly increased each of the three neurite outgrowth parameters measured in primary rat cortical neurons at IpM compared to the 0.1% sterile water vehicle. The positive control donepezil (250nM, black bars) significantly increased the average number of neurites, total neurite length and number of branches per neuron compared to vehicle control.

[0252] In summary, the data with DOI and M100907 indicate that both 5-HT2A receptor agonists and antagonists can promote neurite outgrowth in the current rat embryonic cortical neuron assay. In addition, the assay appears to be sensitive to both sigmal receptor agonists and antagonists, based on the pharmacological validation data reported with agonists PRE-084 and 4-IBP by the service provider of the assay and current data with NE-100, respectively. The novel compound that exhibited a statistically significant increase in the number of branches, Compound 1-3, did not exhibit in vitro 5-HT2A receptor agonist or antagonist activity when tested at 30pM or higher concentrations, and it did not display in vitro binding to sigmal receptors when tested at 10pM. Compound 1-4, the compound that demonstrated a nonsignificant trend to increase the three neurite outgrowth parameters in a concentrationdependent manner displayed moderate potency 5-HT2A receptor antagonist activity.EXAMPLE 7Mouse Head Twitch Response (HTR)

[0253] Mouse Head Twitch Response (HTR)

[0254] Male C57BL / 6J mice at 6-8 weeks of age were purchased and housed four per cage in a climate and humidity-controlled room in a vivarium. The room operated on a reverse light cycle (lights on at 1900 h, off at 0700 h) with food and water available ad libitum, except during testing. All testing was performed during 1000 h and 1800 h. After a minimum of 1 week acclimation to the housing facility, mice were anesthetized using a mixture of ketamine (100 mg / kg IP) and xylazine (10 mg / kg IP). Under deep anesthesia, an incision was made in the scalp and a small neodymium magnet (4.57 mm x 4.57 mm x 2.03 mm) was attached to the cranium using cyanoacrylate and dental cement. After at least a 2-week recovery period, head twitch response (HTR) testing was initiated. The mouse was removed from the home cage and injected intraperitoneally with the test article or vehicle. Immediately after injection, the mouse was placed individually in a glass cylinder surrounded by a magnetometer coil and the HTR was assessed for 30 minutes. The output of the coil was recorded using a Powerlab / 8SP with LabChart v.7.3.2 (ADInstruments). Coil voltage was amplified, low-pass filtered (2-10 kHz cut-off frequency) to remove interference, digitized and sampled at 20 kHz. Head twitches were identified using a validated technique based on artificial intelligence. Events in the recordings were transformed into a visual representation in the time-frequency domain and deep features were extracted using the pretrained convolutional neural network ResNet-50, and the images were subsequently classified using a Support Vector Machine algorithm. Data output was the number of HTR detected per minute for each animal.

[0255] Compounds 1-2 and 1-5 were dissolved in 40% HPBCD in water, compound 1-6 was dissolved in 40% HPBCD, 15% DMSO, 10% Tween-80 in water, and compound 1-1 was dissolved in 20% DMA, 40% PEG400, 40% Captisol in water at a volume of 5 mL / kg. Each dose was calculated based on the free base form of the compounds.

[0256] For each treatment condition, six groups of mice (n=5-6 mice / group) were treated with vehicle or the test compound (0.3 - 60 mg / kg) and HTR assessed for 30 or 40 minutes immediately following injections. Individual mice were injected with vehicle or test article and assessed for HTR on multiple test occasions. To avoid compound carryover effects, each test was performed at least 7 days apart. Data were plotted as the average (± standard error of the mean (sem)) number of HTR recorded during the 30 or 40 minute test for each treatment group.HTR data were analyzed using a 1-way Analysis of Variance (ANOVA; GraphPad Prism). If there was a significant overall effect of treatment at the p<0.05 level, then a Dunnett’s post hoc test was performed to compare each treatment group to the vehicle condition.

[0257] Results

[0258] Compound 1-2 significantly increased HTR compared to the vehicle treatment at 3 and 10 mg / kg i.p. (1-way ANOVA followed by Dunnett’s test, **p<0.01, ***p<0.001 vs. vehicle) (Figure 4). This data indicates that compound 1-2 produced behavioral effects in the intact mouse that is consistent with in vivo 5-HT2A receptor activation-mediated activity. None of the other compounds significantly increased HTR compared to the vehicle condition at the doses tested.EXAMPLE 8Rat Forced Swim Test

[0259] Rat Forced Swim Test (FST)Method #1

[0260] Male adult Sprague Dawley rats weighing 200-250g were used for Forced Swim Test (FST) experiments. Animals were grouped 3 / cage and housed in a room operated on a light cycle (1900h off; 0700h on) with food and water available ad libitum, except during testing. The housing room was maintained between 20 and 23 °C with a relative humidity maintained between 30% - 70%. Rats were weighed and handled daily for a minimum of 3 days prior to testing. Animals were randomly assigned across treatment groups, n=10 per group. All experiments were carried out at ambient temperatures (20 and 23°C) under artificial lighting during the lights-on part of the light / dark cycle. Each Forced Swim chamber was made of clear acrylic material with a height of 40 cm and diameter of 20.3 cm. Only one rat was placed in the swim chamber at a time for each swim test. The water was changed, and the chamber cleaned between each animal. The water depth was 16 cm in the first swim session and 30 cm in the second swim session. The water was maintained at 23 ± 1° C for all swim sessions. The first swim session (pre-swim) lasted for 15 minutes, the second swim session occurred 24 hours later and lasted for 5 min. All rats were exposed to a pre-swim session on day 1 and the swim session on day 2. At the end of each swim test rats were dried with paper towels. Once dried, rats were administered vehicle (40% 2HPBCD in water), ketamine (10 mg / kg), and compound 1-2 (3, 10, 30 mg / kg). All compounds were administered intraperitoneally at a dose volume of 1 ml / kg. Dose calculation was based on free base of the compound. Eight hours following the pre-swim, rats received a second administration ofcompound 1-2 or vehicle (vehicle and ketamine treatment groups). A final administration of compound 1-2 along with the respective vehicle (vehicle and ketamine treatment groups) was given 30 min prior to the 5 min FST on Day 2. All animals were carefully monitored to ensure their safety in the swim test and any animal unable to maintain a posture with its nose above water was immediately removed from the water and not used further in the study. The second swim test was video recorded for scoring. Data were plotted as the average (± standard error of the mean (sem)) frequency of behaviors that included immobility, swimming, and climbing during the 5 minute FST test for each treatment group. Data were analyzed using a 1-way Analysis of Variance (ANOVA; GraphPad Prism). If there was a significant overall effect of treatment at the p<0.05 level, then a Dunnett’s post hoc test was performed to compare each treatment group to the vehicle condition.

[0261] Rat Forced Swim Test (FST) Method #2

[0262] Male adult Sprague Dawley rats weighing 200-250g were used for Forced Swim Test (FST) experiments. Animals were grouped 3-4 / cage and housed in a room operated on a light cycle (1900h off; 0700h on) with food and water available ad libitum, except during testing. The housing room was maintained between 20 and 24°C with a relative humidity maintained between 30% - 70%. Rats were weighed and handled daily for a minimum of 3 days prior to testing. Animals were randomly assigned across treatment groups, n=10 per group. All experiments were carried out at ambient temperatures (20 and 23°C) under artificial lighting during the lights-on part of the light / dark cycle. Each Forced Swim chamber was made of clear acrylic material with a height of 45 cm and diameter of 21.5 cm. Only one rat was placed in the swim chamber at a time for each swim test. The water was changed, and the chamber cleaned between each animal. The water depth was 30 cm and maintained at 24 ± 0.5° C for all swim sessions. The first swim session (pre-swim) lasts for 15 min, the second swim session occurs 24 hours later and lasts for 5 min. All rats were exposed to a pre-swim session on day 1 and the swim session on day 2. At the end of each swim test rats were toweled-dried and placed in a heated chamber at approximately 30°C for 15 min. Once dried, rats were administered vehicle (40% 2HPBCD, 15% DMSO, 10% Tween-80 in water), imipramine (30 mg / kg), and compound 1-6 (3, 10, 30 mg / kg). All compounds were administered intraperitoneally at a dose volume of 5 ml / kg. Dose calculation was based on free base of the compound. Eight hours following the pre-swim, rats received a second administration of vehicle, imipramine or compound 1-6. A final administration of vehicle, imipramine or compound 1-6 was given 30 min prior to the 5 min FST on Day 2. All animals were carefullymonitored to ensure their safety in the swim test and any animal unable to maintain a posture with its nose above water was immediately removed from the water and not used further in the study. The second swim test was video recorded for scoring. Data were plotted as the average (± standard error of the mean (sem)) duration of immobility, swimming, and climbing during the 5 minute FST test for each treatment group. Data were analyzed using a 1-way Analysis of Variance (ANOVA; GraphPad Prism). If there was a significant overall effect of treatment at the p<0.05 level, then a Dunnett’ s post hoc test was performed to compare each treatment group to the vehicle condition.

[0263] FST Results (T est Method #1)

[0264] Compound 1-2 significantly decreased the frequency of immobility compared to the vehicle treatment at 3 and 30 mg / kg i.p., while an increased frequency of swimming was observed at 3 mg / kg i.p. compared to vehicle (1-way ANOVA followed by Dunnett’s test, *p<0.05 vs. vehicle) (Figure 5). The novel antidepressant, ketamine (10 mg / kg), was included as the positive control condition in the study. Ketamine significantly decreased the frequency of immobility and increased the frequency of swimming compared to vehicle (1-way ANOVA followed by Dunnett’ s test, **p<0.01 vs. vehicle). No significant differences were observed in climbing behaviors among the treatment groups.

[0265] FST Results (T est Method #2)

[0266] Compound 1-6 at 3, 10 and 30 mg / kg i.p. did not significantly affect duration of immobility, swimming or climbing in the FST compared to vehicle (p>0.05) (Figure 6). The tricyclic antidepressant, imipramine (30 mg / kg), was included as the positive control condition in the study. Imipramine significantly decreased the duration of immobility and increased the duration of climbing compared to vehicle (1-way ANOVA followed by Dunnett’s test, *p<0.05, ***p<0.001 vs. vehicle).EXAMPLE 9Other Experiments

[0267] In vitro binding and functional activity profiles across multiple human and rodent receptor targets may be performed to further characterize the novel compounds in order to identify potential pharmacological bases for the differential effects of the compounds on neuronal structural plasticity.

[0268] Concentration-response curves will be generated to understand the maximal effect and potency of the compounds to stimulate neurite outgrowth in primary rat cortical cultures. Studies also may investigate the effects of these compounds in combination with other compounds that have demonstrated promotion of neurite outgrowth, in order to evaluate the potential for these compounds to enhance the effects of the other agent at efficacious and / or sub-efficacious concentrations. Agents for combination treatments may include SSRIs (e.g., citalopram, fluoxetine, sertraline, etc.), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, etc.), N-methyl-D-aspartate (NMDA) receptor modulators (e.g., ketamine, D-cycloserine, memantine, etc.), histone deacetylase inhibitors (e.g., valproic acid, b-hydroxybutyrate, etc.), serotonin 2A receptor agonists (e.g., N,N-dimethyltryptamine, lysergic acid diethylamide, psilocybin, etc.), entactogens (e.g., 3,4- methylenedi oxymethamphetamine, 3,4-methylenedioxyamphetamine, etc.), lithium chloride, neurotrophic factors (e.g., BDNF, insulin-like growth factor 1, nerve growth factor, glial- derived growth factor, etc.), acetylcholine receptor modulators (e.g., donepezil, scopolamine, etc.) and others. Such experiments would involve characterization of the concentrationresponse function of the agent to be combined with these compounds, alone, on measures of neurite outgrowth in neuron cultures, prior to the experiment exploring the effect of the combination on neurite outgrowth. In addition, pharmacological antagonism studies may be conducted to clarify the mechanisms involved in the observed compound- or combination- induced effects (e.g., BDNF TrkB receptor antagonism, downstream intracellular signaling mTOR inhibition, 5-HT receptor antagonism, cannabinoid receptor antagonism, glutamate receptor antagonism, etc.).

[0269] The compounds may be tested in in vivo screening assays relevant to stress-related disorders, such as the rat forced swim test (FST). The FST is based on aversion to water and the desire to escape when put in water. A rat is placed in a tall, inescapable cylinder containing sufficient water that requires the animal to swim. Duration of immobility, swimming and climbing behaviors are measured during the test. The assay is sensitive to effects of novel, rapidly-acting antidepressant drugs, such as ketamine. The potential finding of compound- induced reductions of immobility in rats would support an antidepressant-like effect of the compound in animals. Other novel compounds, such as Compound 1-1 and Compound 1-2, may be tested for comparison.

[0270] The compounds may be tested in Wistar-Kyoto (WKY) rats, a genetic model of treatment-resistant depression. WKY rats have been used as a stress-sensitive animal modelthat exhibits resistance to traditional antidepressant drugs, such as SSRIs. WKY rats demonstrate increased immobility in the forced swim test (FST), increased REM sleep and deficits in extinction learning following fear conditioning. Single administration of ketamine has been found to reduce FST immobility in WKY rats. In WKY rat electroencephalography (EEG) studies, single administration of ketamine or psilocybin normalized REM sleep, with differential effects on gamma power (Thomas et al., 2020). The FST is based on aversion to water and the desire to escape when put in water. A WKY rat is placed in a tall, inescapable cylinder containing sufficient water that requires the animal to swim. Duration of immobility, swimming and climbing behaviors are measured during the test. For EEG studies, WKY rats are surgically implanted with frontoparietal cortex EEG and electromyography (EMG) electrodes under anesthesia. Following surgical recovery, animals are placed in chambers for EEG recording of pre-dose baseline and post-dose treatment effects. Data are analyzed in terms of time spent in wake and sleep states, and absolute and relative EEG spectral power within each wake / sleep state. For the test of extinction learning, WKY rats initially are trained to associate a foot shock with sound cue (fear conditioning). On subsequent days, animals are placed in a new context with exposure to the sound cue in the absence of shock (extinction test). The time the animals spend freezing, indicating fear memory, is measured during the test. The potential finding of compound-induced normalization of behavioral and / or EEG effects in WKY rats would support an antistress-like effect of the compound in animals.

[0271] EEG provides a translational approach to explore the effects of the compounds on intact brain functional activity. In addition, most antidepressant drugs acutely suppress REM sleep, suggesting this effect may be an important but not absolute requirement for antidepressant activity of a compound. Rats will be surgically implanted with EEG and EMG electrodes under anesthesia. Following surgical recovery, animals are placed in chambers for EEG recording of pre-dose baseline and post-dose treatment effects. Data are analyzed in terms of time spent in wake and sleep states, and absolute and relative EEG spectral power within each wake or sleep state. The potential finding of compound effects on EEG spectral power and / or sleep measures in rats would support selection of clinical biomarkers related to target engagement and antidepressant-like activity.

[0272] The compounds may be tested in rat in vivo brain microdialysis experiments in order to understand the potential neurochemical basis underlying the pharmacological activity of these compounds.EXAMPLE 10

[0273] 5-HT2A Receptor Agonist Studies

[0274] Human 5-HT2A receptor agonism calcium (Ca++) flux assay: The Calcium No- WashPLUS assay monitors the activation of a GPCR via Gq secondary messenger signaling in a live cell, non-imaging assay format. Calcium mobilization in PathHunter® cell lines or other cell lines stably expressing Gq-coupled GPCRs is monitored using a calcium-sensitive dye that is loaded into cells. GPCR activation by a compound result in the release of calcium from intracellular stores and an increase in dye fluorescence that is measured in real-time. Cell lines expressing the GPCR of interest were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 pL into black-walled, clear-bottom, Poly- D-lysine coated 384-well microplates and incubated at 37 °C for the appropriate time prior to testing. Assays were performed in 1 x Dye Loading Buffer consisting of lx Dye, lx Additive A and 2.5 mM Probenecid in HBSS / 20 mM Hepes. Probenicid was prepared fresh. Cells were loaded with dye prior to testing. Media was aspirated from cells and replaced with 20 pL Dye Loading Buffer. Cells were incubated for 30-60 minutes at 37°C. For agonist determination, cells were incubated with sample to induce response. After dye loading, cells were removed from the incubator and 10 pL HBSS / 20 mM Hepes was added. 3x vehicle was included in the buffer when performing agonist dose curves to define the EC80 for subsequent antagonist assays. Cells were incubated for 30 minutes at room temperature in the dark to equilibrate plate temperature. Intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer. Compound agonist activity was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and 10 pL 4X sample in HBSS / 20 mM Hepes was added to the cells 5 seconds into the assay. Compound activity data was analyzed using CBIS data analysis suite. For agonist mode assays, percentage activity is calculated using the following formula:% Activity =100% x (mean RFU of test sample - mean RFU of vehicle control) / (mean MAX RFU control ligand - mean RFU of vehicle control).

[0275] In these studies, the MAX RFU was generated by using 0.1 pM serotonin for the calcium mobilization assay. Results are shown in Table 3

[0276] Human 5-HT2A receptor agonism P-arrestin2 recruitment assay: The PathHunter® P-Arrestin assay monitors the activation of a GPCR in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) with P-galactosidase (P-Gal) as the functional reporter. The enzymeis split into two inactive complementary portions (EA for Enzyme Acceptor and PK for ProLink) expressed as fusion proteins in the cell. EA is fused to P-Arrestin and PK is fused to the GPCR of interest. When the GPCR is activated and P-Arrestin is recruited to the receptor, ED and EA complementation occurs, restoring P-Gal activity which is measured using chemiluminescent PathHunter® Detection Reagents. PathHunter cell lines were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 pL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing. For agonist determination, cells were incubated with sample to induce response. Intermediate dilution of sample stocks was performed to generate 5X sample in assay buffer. 5 pL of 5X sample was added to cells and incubated at 37°C or room temperature for 90 to 180 minutes. Vehicle concentration was 1%. Assay signal was generated through a single addition of 12.5 or 15 pL (50% v / v) of PathHunter Detection reagent cocktail, followed by a one hour incubation at room temperature. Microplates were read following signal generation with a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection. Compound activity was analyzed using CBIS data analysis suite (Chemlnnovation, CA). For agonist mode assays, percentage activity was calculated using the following formula:% Activity =100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control). In these studies, the MAX RLU was generated by using 10 pM serotonin for the P-arrestin2 recruitment assay. Results are shown in TABLE 2

[0277] Human 5-HT2A receptor agonism myo-inositol 1 phosphate (IPOne) homogeneous time-resolved fluorescence (HTRF) assay: Recombinant human 5-HT2A receptors (accession number NP 000612.1) were expressed in the CHO-K1 cell line. Functional agonist activity was assessed using an IPOne accumulation assay with oc-Me-5-HT as a reference agonist. Compounds were tested for agonist activity in duplicate. On each day of experimentation, the reference compound was tested at several concentrations in duplicate (n=2) to obtain a concentration-response curve and an estimated EC50 value. Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session. For replicate determinations, the maximum variability tolerated in the test was + / -20% around the average of the replicates. Concentration-response data from test compounds were analyzed with XLfit (IDBS) software using nonlinear regression applied to a sigmoidal dose-response model and the following equation:XL Fit fit Model 203 : 4 Parameter Logistic ModelA : BottomB : TOPC : LogEC50D : Hill fit = (A+((B-A) / (l+(((10AC) / x)AD)))) inv = ((10AC) / ((((B-A) / (y-A))- 1)A( 1 / D))) res = (y-fit)Agonist activity of test compounds was expressed as a percentage of the activity of the reference agonist at its EC 100 concentration (top oc-Me-5-HT concentration = 1 pM). Results are shown in Table 7.TABLE 7TABLE 8TABLE 9

[0278] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

What is claimed is:

1. A compound of Formula I:wherein:R1is benzyl wherein the benzyl is optionally substituted with one or more of D, halogen, or Ci-Ce alkyl;R2is H or Ci-Ce alkyl;R3and R4are independently H, D, or Ci-Ce alkyl;R3and R4are independently H, D, or halogen; n is 0 or 1;A is CR7, C(R7R8)C(R9) or C(R7R8)C(R9R10)C(Rn); or when B is absent is CR7R8, C(R7R8)C(R9R10), or C(R7R8)C(R9R10)C(RnR12);B is CR7R8, C(R7R8)C(R9R10), or is absent; andR7, R8, R9, R10, R11, and R12are independently H, D, Ci-Ce alkyl, or halogen.

2. The compound of Claim 1, wherein the compound is:The compound of Claim 1, wherein the compound iThe compound of Claim 1, wherein the compound iThe compound of Claim 1, wherein the compoundThe compound of Claim 1, wherein the compound iThe compound of Claim 1, wherein the compound iThe compound of Claim 1, wherein the compound iThe compound of Claim 1, wherein the compound10. The compound of Claim 1, wherein the compound i11. The compound of Claim 1, wherein the compoundThe compound of Claim 1, wherein the compound13. The compound of Claim 1, wherein the compound i14. The compound of Claim 1, wherein the compound i15. A composition comprising: a compound of any of claims 1-14 or a combination thereof; and a pharmaceutically acceptable excipient.

16. A method of treating a stress-related disease or disorder, comprising administering a therapeutically effective amount of a compound of any of claims 1-14, or a combination thereof to a subject in need thereof.

17. The method of claim 16, wherein the stress-related disease or disorder is mood / depressive disorder, bipolar disorder, anxiety disorder, psychotic or delirium disorder, schizophrenia, schizoaffective disorder, personality disorder, abuse or neglect disorder, tic disorder, neurocognitive disorder, neurodevelopmental disorder, learning disorder, disruptive mood regulation disorder, intermittent explosive disorder, antisocial personality disorder, conduct disorder, behavioral and psychological symptoms of dementia, depression, anxiety, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, stress disorders, rumination, eating disorders, or a combination thereof.

18. The method of claim 17, wherein the stress-related disease or disorder is depression, anxiety or post-traumatic stress disorder.

19. A method for inducing neurite outgrowth, comprising administering a therapeutically effective amount of a compound of any of claims 1-14 or a combination thereof, to a patient in need thereof.

20. A method of treating neuronal atrophy, comprising administering a therapeutically effective amount of a compound of any of claims 1-14 or a combination thereof, to a patient in need thereof.

21. A method of inducing structural neuroplasticity, comprising administering a therapeutically effective amount of a compound of any of claims 1-14 or a combination thereof, to a patient in need thereof.

22. The method of any one of claims 19-21, wherein the subject has a stress-related disease or disorder.

23. The method of claim 22, wherein the stress-related disease or disorder is mood / depressive disorder, bipolar disorder, anxiety disorder, psychotic or delirium disorder, schizophrenia, schizoaffective disorder, personality disorder, abuse or neglect disorder, tic disorder, neurocognitive disorder, neurodevelopmental disorder, learning disorder, disruptive mood regulation disorder, intermittent explosive disorder, antisocial personality disorder, conduct disorder, behavioral and psychological symptoms of dementia, depression, anxiety, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, stress disorders, rumination, eating disorders, or a combination thereof.

24. The method of any one of claims 16-21, wherein the compound has antidepressant and anxiolytic effects.

25. The method of any one of claims 16-21, wherein the administering comprises intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual, buccal, or nasal route of administration.

26. The method of any one of claims 16-21, comprising administering the compound as a single dose.

27. The method of any one of claims 16-21, comprising administering the compound in repeated doses.

28. The method of any one of claims 16-21, wherein administration of the compound induces neurite outgrowth.

29. The method of any one of claims 16-21, further comprising administering a therapeutic agent.

30. The method of claim 29, wherein the compound of any of claims 1-14 or is administered prior to, simultaneously with or following administration of the therapeutic agent.

31. A method of treating a mental health disorder, comprising:administering a pharmaceutical composition comprising a therapeutically effective amount of a non-hallucinogenic 5-HT2A receptor agonist or a pharmaceutically acceptable salt thereof, to a subject in need hereof, thereby treating the mental health disorder in the subject.

32. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is selected from:or a pharmaceutically acceptable salt thereof or a combination thereof.

33. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is:or a pharmaceutically acceptable salt thereof.

34. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is:or a pharmaceutically acceptable salt thereof.

35. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is:or a pharmaceutically acceptable salt thereof.

36. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is:or a pharmaceutically acceptable salt thereof.

37. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is:or a pharmaceutically acceptable salt thereof.

38. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is :or a pharmaceutically acceptable salt thereof.

39. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is:or a pharmaceutically acceptable salt thereof.

40. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is:or a pharmaceutically acceptable salt thereof.

41. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist is:or a pharmaceutically acceptable salt thereof.

42. The method of claim 31, wherein administering the pharmaceutical composition comprises intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual, buccal, or nasal routes of administration.

43. The method of claim 31, wherein the mental health disorder is selected from the group consisting of personality disorders, mood disorders, addictive disorder, eating disorders, obsessive-compulsive disorders, sleep disorders, autism spectrum disorder, chronic pain conditions, and combinations thereof.

44. The method of claim 31, wherein the mental health disorder is selected from the group consisting of borderline personality disorder, depression, anxiety, mood disorder, substance use disorder, Opioid use disorder, Alcohol use disorder, gambling, anorexia nervosa, bulimia, obsessive compulsive disorder, body dysmorphic disorder, narcolepsy, headaches, and combinations thereof.

45. The method of claim 31 , wherein treating the mental health disorder comprises reducing a symptom of the mental health disorder, preventing a symptom of the mental health disorder, or a combination thereof.

46. The method of claim 31, wherein the non-hallucinogenic 5-HT2A receptor agonist has antidepressant and anxiolytic effects.

47. The method of claim 31, comprising administering the pharmaceutical composition as a single dose.

48. The method of claim 31, comprising administering the pharmaceutical composition in repeated doses.

Images