Compounds for serotonin receptor activation and pharmaceutical compositions and methods of using the same

Abstract

The present disclosure provides compounds, pharmaceutical compositions, and methods for treating a mental disorder in a subject, which may include administering to the subject a pharmaceutical composition including a therapeutically effective amount of a non-hallucinogenic 5-HT2A receptor agonist or a pharmaceutically acceptable salt thereof, thereby treating the mental health disorder in the subject.

Description

COMPOUNDS FOR SEROTONIN RECEPTOR ACTIVATION AND PHARMACEUTICAL COMPOSITIONS AND METHODS OF USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No. 63 / 607,491, filed December 7, 2023, which is hereby incorporated by reference in its entirety.FIELD

[0002] This disclosure relates generally to small molecule activators of 5-HT2A serotonin receptors for the purpose of treating mental health 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 disorder, and eating disorders, and the like using psychedelics has received recent attention. Known psychedelics consist of three main molecular classes. The first class are indoleammes, including N,N-dimethyltryptaniine (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-iodoamphetarnine (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-HT1, 5-HT2, 5-HT6 and 5-HT7 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 and selective consequence of 5-HT2A activation over other similar serotonin receptors including both 5-HT2B and 5-HT2C. 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 bypositron 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, otherserotonin receptors, like 5-HT1 A, are likely contributing to the overall psychedelic experience including both visual and attention-disrupting effects in humans.

[0004] Biased signaling consequences of 5-HT2A activation by various agonists strongly impact whether or not a compound will be hallucinogenic or non-hallucinogenic. For example, LSD and lisuride both activate the 5-HT2A receptor, but in slightly different ways which result in the activation of different intracellular signaling cascades. LSD and lisuride have been shown to active canonical Gq-based signaling downstream of 5-HT2A, but only LSD stimulated the expression of early growth response proteins (EGR1 and EGR2) by activating Gi / o subunits and the SRC protein kinase. Differential functional selectivity has been shown for several phenalkylamine pyschedelics which were found to be biased 5-HT2 A agonists. The compounds, including 25H-NBF, 25H-NBMD, 25H-NBOH and 25H-NB()Me showed a statistically significant preference towards the recruitment of p-arrestm 2 over miniGaq, as compared to the reference psychedelic substance LSD. Differential biased agonism elicited across multiple classes of psychedelics warrants further investigation to identify whether this functional selectivity may provide compounds with greater selectivity, fewer side effects, greater neuroplastic effects and improved therapeutic benefit.

[0005] As a consequence of this body of research, compounds that are 1 ) activators of 5HT2A, 2) activators of 5HT1A, and 3) biased serotonergic receptor agonists would be of significant interest as psychedelic drags with more selective pharmacology and improved overall therapeutic benefit. Research in the discovery and pharmacological investigation of 1 ,2,4- substituted aminoethyl benzene exists, but research into the exact mechanism of how these molecules function and the structural-chemical-relationship important to that function are limited.

[0006] 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.SUMMARY

[0007] In aspects, this disclosure provides a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof;wherein:W, X, Y, and Z are independently N or CR10;R1is CHRl lR12, CDR11R12. C1-C6alkyl. C1-C6deuteroalkyk C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C(O)NR13R14, C(O)OR13, C(S)NR13R]4, or C(S)OR13;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R5and R6are independently F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR15;R7and R8are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R9is H, D, OR16, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H, D, F, NO2, CHR11OH, C(O)NR13R14, COOR13, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R1 land R12are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyk Ci- C,6 fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R13, R14, R15and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6, heterocycle. [0008 In aspects, this disclosure provides a compound having a structure of Formula (la):(la), or a pharmaceutically acceptable salt thereof;wherein:X, Y, and Z are independently N or CR7;R1is CHR8R9, CDR8R9, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C(O)NR10R11, C(O)OR10, C(S)NR10R11, or C(S)OR10;R is H. D, F, NO2CHR8OH, C(O)NR10R11, COOR12, SO2Me, SO2CF3. CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3is F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR12;R4and R!are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R6is H, D, OR12, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R7is H, D, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R8and R9are independently H, D, OH, C1-C6, alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R10, R11, and R12are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

[0009] In aspects, the compound is selected from :

[0010] In aspects, the compound has antidepressant and anxiolytic effects.

[0011] In aspects, this disclosure provides a compound of Formula (II):(II), or a pharmaceutically acceptable salt thereof;wherein:X, Y, and Z are independently N or CR11;R1is H, OH, D, CH2OH, CD2OH, C(Me)D OH, C(Me)HOH, CHR12R13, CDR12R13, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO2Me, SO2CH2F, SO2CH F2. SO2CF3, C(O)NR14R15, C(O)OR14, C(S)NR14R15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R4, R5R6, and R7are independently F, Cl, Br, I, C1-C6alkyl, CF3, CHF2, CH2F, or OR16; R8and R9are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R10is H, D, OR17, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11is H, D, F, NO2, CH2OH, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R12and R13are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, Ci- C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R14, R13, R16, and R17are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10and, or C3-C6heterocycle.

[0012] In aspects, this disclosure provides a compound having a structure of Formula (Ila):(Ila), or a pharmaceutically acceptable salt thereof; wherein:X, Y, and Z are independently N or CR6;R1is H, OH, D, CH2OH, CD2OH, C( Me)DOH, C(Me)HOH, CHR7R8, CDR7R8, C1-C6alkyl, C1-C6, deuteroalky], C1-C6, hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(O)NR9R . C(O)OR9, C(S)NR9R10, or C(S)OR9;R2is F, Cl, Br, I, C1-C6alkyl, CF3, CHF2, CH2F, or OR11;R3and R4are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl: R1is H, D, OR12, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R6is H, D, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl;R7and R8are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; each R9, R10, R11, and R12are independently H, D, C1-C.5 alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

[0013] In aspects, the compound is selected from:

[0014] In aspects, the compound has antidepressant and anxiolytic effects.

[0015] In aspects, this disclosure provides a pharmaceutical composition, including:

[0016] a therapeutically effective amount of a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof;wherein :W, X, Y, and Z are independently N or CR10;R1is CHR11R12, CDR11R12, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C(O)NR13R14, C(O)OR13,C(S)NR13R14, or C(S)OR13;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R5, and R6are independently F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR15;R7and R8are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R9is H, D, OR16, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H, D, F, NO2, CHR11OH, C(O)NR13R14, COOR13, SOrMe, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11and R12are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R13, R14, R13, and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle,

[0017] and one or more pharmaceutically acceptable excipients.

[0018] In aspects, the pharmaceutical composition further includes a second active agent.

[0019] In aspects, the one or more pharmaceutically acceptable excipients comprise a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a mold release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adj usting agent, or combinations thereof.

[0020] In aspects, the pharmaceutical composition is in an oral dosage form,

[0021] In aspects, the pharmaceutical composition includes a therapeutically effective amount of a compound selected from:0022] In aspects, this disclosure provides a pharmaceutical composition, including: a therapeutically effective amount of a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:X, Y, and Z are independently N or CR11;R1is H, OH, D, CIbOH, CD2OH, C(Me)DOH, C(Me)HOH, CH R12R13, CDR12R13, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO -Me. SO2CH2F, SO2CHF2, SO2CF3C(O)NR14R15, C(O)OR14, C(S)NR14R15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R4, R5, R6, and R7are independently F, Cl, Br, I, C1-C6alkyl.-l iCF3, CHF2, CH2F, or OR16;R8and R9are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R10is H, D, OR17, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is H, D, F, NO2, CH2OH, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12and R13are independently H, D, OH, Ci-Cb alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3- C6heterocycie; and each R14, R15, R16, and R17are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle, and one or more pharmaceutically acceptable excipients.

[0023] In aspects, the pharmaceutical composition further includes a second active agent.

[0024] In aspects, the one or more pharmaceutically acceptable excipients include a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a mold release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof.

[0025] In aspects, the pharmaceutical composition is in an oral dosage form.

[0026] In aspects, the compound is selected from:

[0027] In aspects, this disclosure provides a method of treating a mental health disorder in a subject in need thereof, including:

[0028] administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I):pharmaceutically acceptable salt thereof; wherein:W, X, Y, and Z are independently N or CR10;R1is CHR11R12, CDR11R12, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C(O)NR13R14, C(O)OR13, C(S)NR13R14, or C(S)OR13;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R5, and R6are independently F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR13;R7and R8are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or Ci-Cs fluoroalkyl;R9is H , D, OR16, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H, D, F, NO2, CHR11OH, C(O)NR13R14, COOR13, SO2Me , SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11and R12are independently H, D, OH, C1-C6alkyl, C1-C.5 deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R13, R14, R15. and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle,

[0029] and one or more pharmaceutically acceptable excipients.

[0030] In aspects, the method includes administering a therapeutically effective amount of a

[0031] In aspects, the administering includes intracutaneous, subcutaneous, intravenous. intraarterial, intradermal, transdermal, orai, sublingual buccal, or nasal route of administration.

[0032] In aspects, the mental health disorder is selected from major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, anxiety disorders, stress disorders, rumination disorder, and eating disorders.

[0033] In aspects, 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.

[0034] In aspects, the compound has antidepressant and anxiolytic effects.

[0035] In aspects, the method includes administering the pharmaceutical composition as a single dose.

[0036] In aspects, the method includes administering the pharmaceutical composition m repeated doses.

[0037] In aspects, this disclosure provides a method of treating a mental health disorder in a subject in need thereof, comprising:

[0038] administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (II) :(II), or a pharmaceutically acceptable salt thereof, wherein:X, Y, and Z are independently X or CR11;R1is H, OH, D, CIbOH , CD?.OH, C(Me)DOH, C(Me)H0H, CHR12R13, CDR12R13, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(O)NR14R15, C(O)OR14, C(S)NR14R15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or Ci- C6fluoroalkyl ;R4, R5, R6, and R7are independently F, Cl, Br, I, C1-C6alkyl, CF3, CHF2,CH2F, or OR16;R8and R9are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or Ci- Ce fluoroalkyl;R10is H , D, OR17, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11is H, D, F, NO2, CH2OH, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, Ci- Ce deuteroalkyl, or C1-C6fluoroalkyl;R12and R13are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R14, R15’, R16, and R17are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle, and one or more pharmaceutically acceptable excipients.

[0040] In aspects, the administering includes intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual buccal, or nasal route of administration.

[0041] In aspects, the mental health disorder is selected from major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, anxiety disorders, stress disorders, rumination disorder, and eating disorders.

[0042] 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.

[0043] In aspects, the compound has antidepressant and anxiolytic effects.

[0044] In aspects, the method includes administering the pharmaceutical composition as a single dose.

[0045] In aspects, the method includes administering the pharmaceutical composition in repeated doses.DETAILED DESCRIPTION

[0046] 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 52.5.

[0047] The terms “administration of’ and or “administering” should be understood to mean providing a pharmaceutical composition in a therapeutically effective amount to the subject in need of treatment. 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, buccally, epidurally, rectally, intravesically, and vaginally, among others.

[0048] The term "animal" or “subject” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, experimental, domestic, and farm animals, and pets. As used herein, the terms "subject," "individual," and "patient," are used interchangeably and refer to any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, non-human primates, humans, and the like.

[0049] As used herein, unless specifically indicated, the term “active ingredient” refers to a compound of any of the formulae as described herein.

[0050] 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. In embodiments, a pharmaceutically acceptable excipient may include a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a mold release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof.

[0051] 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.

[0052] The term “deuteroalkyl” refers to the definition of alkyl as used herein, wherein one or more hydrogens have been replaced with a deuterium.

[0053] Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, iso-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.

[0054] The terms “amido” and “carbamoyl,” as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term “C-amido” as used herein, alone or in combination, refers to a- C(O)N(RR’) group with R and R’ as defined herein or as defined by the specifically enumerated “R” groups designated. The term “N-amido” as used herein, alone or in combination, refers to a RC(O)NH(R’)- group, with R and R’ as defined herein or as defined by the specifically enumerated “R” groups designated. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(O)NH-).

[0055] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon ring atoms and at least one aromatic ring. For purposes of this disclosure, the and radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems. Aryl radicals include, but are not limited to, aiyl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted.

[0056] The term “cyano,” as used herein, alone or in combination, refers to -CN.

[0057] The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[0058] The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalky 1 , dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH- ), difluoromethylene (-CF2-), chloromethylene (-CHC1-) and the like.

[0059] The term “perhaloalkyl” as used herein, alone or in combination, refers to an haloalkyl group where all of the hydrogen atoms are replaced by halogen atoms, such as perfluoroalkyl.

[0060] The terms “heterocycloalkyl” and, interchangeably, '‘heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and sulfur. In certain embodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3- benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnohnyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyk benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidmyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

[0061] The term “hydroxy,” as used herein, alone or in combination, refers to -OH.

[0062] The term “hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[0063] The term “lower,” as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms (i.e., C1-C6 alkyl).

[0064] The term “lower aryl,” as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as provided.

[0065] lire term “lower heteroaryl,” as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms chosen from N, O, and S, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms chosen from N , O, and S.

[0066] The term “lower cycloalkyl,” as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members (i.e., C3-C6 cycloalkyl). Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0067] The term “lower heterocycloalkyl,” as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms chosen from N, O, and S (i.e., C3-C6 heterocycloalkyl). Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidmyl, pyrazolidmyl, piperidinyl, piperazinyl, and morpholmyl. Lower heterocycloalkyls may be unsaturated.

[0068] The term “thiol,” as used herein, alone or in combination, refers to an -SH group.

[0069] Any definition herein may be used m combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the team alkoxyalkyl would represent an alkoxy group atached to the parent molecule through an alkyl group.

[0070] The term “optionally substituted” means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an “optionally substituted” group mayinclude, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyi, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aiyloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, aiylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2 CH3, C02H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Where structurally feasible, two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,’’ the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.”

[0071] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a pharmaceutically acceptable salt thereof, that, when administered to a patient, is capable of performing the intended result . For example, an effective amount of an ibogaine is that amount that is required to reduce at least one symptom of OUD in a patient, e.g. opioid cravings in a patient.[0072} The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0073] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitablepharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3- hydroxybutyric, galactaric and galacturonic acid.

[0074] The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and / or the composition. For example, the method for treating opioid use disorder provides a therapeutic effect when the method improves at least one symptom of OUD, e.g., a reduction in opioid cravings, in a patient.

[0075] 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.COMPOUNDS

[0076] 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 aspects, the compounds may be full agonists of the 5- HT2.A receptor. In one embodiment, the compounds are partial agonists of the 5-HT2A receptor. In one embodiment, the compounds display selectivity for 5-HT2A receptor.

[0077] 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 and selective consequence of 5- HT2A activation over other similar serotonin receptors including both 5-HT2C and 5-HT2B. Similar observations have been made in humans where the administration of ketanserin, a 5- HT2.A receptor antagonist, blocked the majority of subjective effects induced by dimethyl tryptamine (DMT), psilocybin and lysergic acid diethylamide (LSD). In addition, psychedelic effects elicited by psilocybin have correlated with 5-HT2A receptor occupancy asmeasured 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-HT1A, are likely contributing to the overall psychedelic experience including both visual and attention-disrupting effects in humans. A screening program was initiated, based on structure guided drug design to identify novel chemical matter that maintained an overall selectivity profile similar to that of psilocin. Structure activity relationship studies done to date have demonstrated molecules with a range of potencies and target selectivity. Most scaffolds discovered to be potent were similar to the phenethylamine class of psychedelics. Continued structure activity relationship work generated a molecular class that was found to be selective, full-agonists of the 5-HT2A receptor. During the course of this work a series of 1 ,2,4-substituted aminoethyl benzene were prepared as synthetic intermediates and were tested independently. Embodiments of the series of 1,2,4-substituted aminoethyl benzene were found to maintain an overall 5HT2A selectivity profile and minimal 5-HT2B agonism to minimize the potential for 5-HT2B-induced cardiac vulvopathy with chronic use. Tire compounds described herein may contribute to both potency and serotonin receptor selectivity that are important for efficacy and improved safety.

[0078] In embodiments, there is provided a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein:W, X, Y, and Z are independently N or CR10;R1is CHR11R12, CDR11R12, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, Ci-Cr, fluoroalkyl, C(O)NR13R14, C(O)OR13, C(S)NR13R14, or C(S)OR13;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R3, and R6are independently F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR1 5.R' and R8are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R9is H, D, OR16, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H, D, F, NO2, CHR11OH, C(O)NR13R14, COOR13, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11and R12are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, Ci- Ce fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R13, R14, R13, and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C.i-Ce heterocycle.

[0079] In embodiments, R10is H , D, F, NO2, CH2OH, COOH, CHR1 !OH, C(O)NR13R14, COOR13, S()?.Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;

[0080] In embodiments, there is provided a compound having a structure of Formula (la):or a pharmaceutically acceptable salt thereof; wherein:X, Y, and Z are independently N or CR7;R1is CHR8R9, CDR8R9, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C(O)NR10R11, C(O)OR10, C(S)NR10R11, or C(S)OR10;R is H , D, F, NO2, CHR8OH, C(O)NR10R11, COOR12, SO2Me, SO2CF3. CN,OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3is F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6. fluoroalkyl, or OR12;R4and R5are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R6is H, D, OR12, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R7is H, D, F, C1-C6, alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R8and R9are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R10, R11, and R12are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

[0081] In embodiments, R2is CH2OH, COOH, CHR8OH, C(())NR10R11, or COOR12.

[0082] In embodiments, the compound of the present disclosure, such as the compound of Formula (I) or (Ia), may be selected from:

[0083] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0084] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0085] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0086] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof

[0087] In embodiments, the compound is:, or a pharmacally acceptable salt thereof.

[0088] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0089] In embodiments, the compound is:or a pharmaceutically acceptable salt thereof.

[0090] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0091] In embodiments, the compound is: , or a pharmaceutically acceptable salt thereof.

[0092] In embodiments, the compound is:or a pharmaceutically acceptable salt thereof.

[0093] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof

[0094] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0095] In embodiments, the compound is:or a pharmaceutically acceptable salt thereof.

[0096] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0097] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof

[0098] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0099] In embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0100] In embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0101] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0102] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0103] In embodiments, the compound is:, or a pharmaceutically acceptable salt thereof.

[0104] In embodiments, there is provided a compound of Formula (II):(II), or a pharmaceutically acceptable salt thereof; wherein:X, Y, and Z are independently N or CR11;R1is H , OH, D, CH2OH, CD2OH, C(Me)DOH, C(Me)H0H, CHR12R13, CDR12R1J, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2., SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(O)NR14R15, C(O)OR14, C(S)NR14R15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R4, R5R6, and R7are independently F, Cl, Br, I, C1-C6alkyl, CF3, CHF2, CH2F, or OR16; R8and R9are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R10is H, D, OR17, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11is H, D, F, NO2, CH2OH, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R12and R13are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, Ci-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R14, R13, R16, and R17are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

[0105] In embodiments, there is provided a compound having a structure of Formula (Ila):(Ila), or a pharmaceutically acceptable salt thereof; wherein:X, Y, and Z are independently N or CR6;R1is H, OH, D, CH2OH, CD2OH, C(Me)DOH, C(Me)HOH, CHR7R8, CDR7R8, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(O)NR9R10, C(O)OR9, C(S)NR9R10, or C(S)OR9;R2is F, Cl, Br, I, C1-C6alkyl, CF3, CHF2, CH2F, or OR11;R3and R4are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R" is H, D, OR12, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R6is H, D, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R7and R8are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; each R9, R10, R11, and R12are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

[0106] In embodiments, the compound of the present disclosure, such as the compound of Formula (II) or (Ila), may be selected from:

[0107] In embodiments, the compound is:pharmaceutically acceptable salt thereof.

[0108] In embodiments, the compound is:pharmaceutically acceptable salt thereof.

[0109] In embodiments, the compound is:, pharmaceutically acceptable salt thereof.

[0110] In embodiments, the compound is:, pharmaceutically acceptable salt thereof.

[0111] In embodiments, the compound is:, pharmaceutically acceptable salt thereof.[Oil 2] In embodiments, the compound is:pharmaceutically acceptable salt thereof.

[0113] In embodiments, the compound is:, pharmaceutically acceptable salt thereof.[Oil 4] In embodiments, the compound is:pharmaceutically acceptable salt thereof.PHARMACEUTICAL COMPOSITIONS

[0115] 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. Mixtures of different pharmaceutically acceptable salts, or mixtures of pharmaceutically acceptable salts and free base, are also contemplated.

[0116] In embodiments, there is provided a pharmaceutical composition, including: a therapeutically effective amount of a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof; wherein:W, X, Y, and Z are independently N or CR10;R1is CHR11R12, CDR11R12, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl. C1-C6fluoroalkyl, C(O)NR13R14, C(O)OR13, C(S)NR13R14, or C(S)OR11;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R5, and R6are independently F, Cl, Br, I, C1-C6. alkyl, C1-C6. deuteroalkyl, C1-C6fluoroalkyl, or OR15;R7and R8are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R9is H , D, OR16, F, Ci-CR alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H, D, F, NO2, CHR11OH, C(O)NR13R14, COOR13, SO.Alc. SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalky], or C1-C6fluoroalkyl; R11and R12are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, Ci- Ct, fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R1 3. R14, R15, and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and one or more pharmaceutically acceptable excipients.

[0117] In embodiments, there is provided a pharmaceutical composition, including: a therapeutically effective amount of a compound of Formula (II):(II), or a pharmaceutically acceptable salt thereof, wherein:X, Y, and Z are independently N or CR11;R1is H, OH, I), CH2OH, CD2OH, C(Me)DOH, C(Me)HOH, CHR12R13, CDR12R13, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10arvi. C3-C6heterocycle, CN, NO2., SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(O)NR14R15, C(O)OR14, C(S)NR14R15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R4, R5, R6, and R7are independently F, Cl, Br, I, C1-C6alkyl, CF3, CHF2., CH2F, or OR86;R8and R9are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R1C' is H, D, OR17, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is H, D, F, NO2, CH2OH, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R12and R13are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R14, R15, R16, and R17are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and one or more pharmaceutically acceptable excipients.

[0118] In embodiments, the pharmaceutical composition further includes a second active agent. The second active agent, if included, is not particularly limited and may include an active agent for the treatment of a condition such as major depressive disorder (MDD), treatmentresistant depression (TRD), substance use disorder (SUD), compulsive disorders, anxiety disorders, stress disorders, rumination disorder, and eating disorders, or the second active agent may include a pain reducer, an anti-anxiety medication, the like, or combinations thereof.[Oil 9] In embodiments, the one or more pharmaceutically acceptable excipients can include a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a mold release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof,

[0120] In embodiments, the pharmaceutical composition is in an oral dosage form. Suitable compositions for oral administration include solid formulations such as tablets, lozenges andcapsules, which can contain liquids, gels, or powders. Compositions for oral administration may be formulated as immediate or modified release, including delayed or sustained release, optionally with enteric coating.

[0121] 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 maybe 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.

[0122] Liquid formulations can include solutions, syrups, and suspensions, which can be used in soft or hard capsules. Such formulations may include a pharmaceutically acceptable carrier, for example, water, ethanol, polyethylene glycol, cellulose, or an oil. The formulation may also include one or more emulsifying agents and / or suspending agents.

[0123] In a tablet dosage fonn, the amount of drag present may be from about 0.05% to about 95% by weight, such as from about 2% to about 50% by- weight of the dosage form.

[0124] In addition, tablets may contain a disintegrant, comprising from about 0.5% to about 35% by weight, more typically from about 2% to about 25% of the dosage form. Examples of disintegrants include methyl cellulose, sodium or calcium carboxymethyl cellulose,croscarmellose sodium, polyvinylpyrrolidone, hydroxypropyl cellulose, starch, and the like.Suitable lubricants for use in a tablet may be present in amounts from about 0.1% to about 5% by weight, and include calcium, zinc or magnesium stearate, sodium stearyl fumarate and the like.

[0125] Suitable binders for use in a tablet include gelatin, polyethylene glycol, sugars, gums, starch, hydroxy propy l cellulose, and the like. Suitable diluents for use in a tablet include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch.

[0126] Suitable surface active agents and glidants, for use in a tablet, may be present in amounts from about 0.1 % to about 3% by weight, and include polysorbate 80, sodium dodecyl sulfate, talc and silicon dioxide. Other excipients familiar to those skilled in the art may also be included in the presently disclosed pharmaceutical compositions.

[0127] In embodiments, the pharmaceutical composition includes a therapeutically effective amount of a compound, such as the compound of Formula (I) or Formula (II), selected from:

[0128] Combinations of the presently disclosed compounds, or pharmaceutically acceptabL salts thereof, are also contemplated in embodiments of the present disclosure.

[0129] In embodiments, the compound has antidepressant and anxiolytic effects.TREATMENT

[0130] 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 comprising a therapeutically effective amount of: a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:W, X, Y, and Z are independently N or CR10;R1is CHR^R12, CDRUR12, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, Ci-Ci, fluoroalkyl, C(O)NR13R14, C(O)OR13, C(S)NR13R14, or C(S)OR13;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R5, and R6are independently F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR15;R7and R8are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R9is H, D, OR16, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H , D, F, NO2, CHR11OH, C(O)NR13R14, COOR’13, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11and R12are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalky], C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R13, R14, R13, and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; thereby treating the mental health disorder in the subject.

[0131] In embodiments, the disclosure is directed to the administration of the compound of Formula I and a therapeutic agent for the treatment of a mental health disorder, such as major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, anxiety disorders, stress disorders, rumination disorder, and eating disorders, the like, or combinations thereof. In embodiments, the therapeutic agent is administered simultaneously with, prior to or following administration of the compound of Formula I.

[0132] 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 comprising a therapeutically effective amount of: a compound of Formula (II):or a pharmaceutically acceptable salt thereof, whereinX, Y, and Z are independently N or CR11;R1is H, OH. D, CH2OH, CD2OH, C(Me)DOH, C(Me)HOH, CHR12R13, CDR12R13, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(())NR14R15, C(O)OR14, C(S)NR14R15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalky], or C1-C6fluoroalkyl;R4, R5, R6, and R7are independently F, Cl, Br, I, C1-C6alkyl, CF3, CHF2, CH2F, or OR16;R8and R9are independently H, D, C1-C6alkyl, C1-C6deuteroalky], or C1-C6fluoroalkyl;R10is H, D, OR17, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is H, D, F, NO2, CH2OH, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R12and R13are independently H, D, OH, C1-C6alkyl, C1-C6, deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R14, R15’, R16, and R17' are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; thereby treating the mental health disorder in the subject.

[0133] Certain embodiments are directed to the administration of the compound of Formula II and a therapeutic agent for the treatment of a mental health disorder, such as major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SLID), compulsive disorders, anxiety disorders, stress disorders, rumination disorder, and eating disorders, the like, or combinations thereof. In embodiments, the therapeutic agent isadministered simultaneously with, prior to or following administration of the compound ofFormula II.

[0134] In embodiments, the pharmaceutical composition is administered by 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 an embodiment, the methods include administering the compound in repeated doses.

[0135] In embodiments, the method includes administering to the subject a pharmaceutical composition including a therapeutically effective amount of a compound selected from:

[0136] In embodiments, the mental health disorder is selected from major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, anxiety disorders, stress disorders, rumination disorder, and eating disorders.

[0137] In embodiments, the subject has a disorder selected from Neurodev elopmental 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, Atention-Deficit / Hyperactivity Disorder, Attention-Deficit / Hyperactivity Disorder, Other Specified Attention-DeficitZHyperactivity Disorder, Unspecified Attention-Deficit / Hyperactivity Disorder, Specific Learning Disorder, Specific Learning Disorder, Motor Disorders, Developmental Coordination Disorder, Stereotypic Movement Disorder, Tic Disorders, Tourete’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 Other Psychotic 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 DisorderUnspecified Schizophrenia Spectrum and Other Psychotic Disorder, Bipolar and Related Disorders, Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, Substance / Medi cation -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 UseDisorder, 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 Mikl 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 Mikl Neurocognitive Disorder Due to Traumatic Brain Injury , Substance / Medication-Induced Major 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, Other Specified 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, InternetGaming Disorder, Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure, Suicidal Behavior Disorder, Nonsuicidal Self-Injury, or combinations thereof.

[0138] 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.

[0139] In embodiments, treating the mental health 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.

[0140] In embodiments, the subject is a human. The subject may be a human of any age, race, sex, gender identity, or demographic. The subject may be taking other medications including but not limited hormonal contraceptives.EXAMPLES

[0141] The following example was carried out according to embodiments of the present disclosure.

[0142] Unless otherwise noted, all materials / reagents were obtained from commercial suppliers and used without further purification. Reactions were monitored by LC-MS 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 room temperature (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). Th e 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. The mobile phases were water (with 0. 1 % HCO2H) and acetonitrile; all reagents used were of HPLC grade. The flow rate was 10ml / min. LC-MS analyses were performed on Shimadzu LCMS-2020 equipped with LC-20AD or 30AD pumps, SPD-M20A PDA and Alltech 3300 ELSD; Mobile Phase: A: Water (0.1 % Formic acid), B: ACN; 5 minute run; Column: Sepax BR-C18 4.6*50mm,3um; Flow Rate: 1 .Oml / min; Oven Temperature: 40oC; Gradient: 20% B for 0.2 min, increase to70% B within 1.8 min,70% B for 2.8 mm, back to 20% B within 0.2 min, 20%B tor 2 min). Preparative TLC was performed on Whatman LK6F Silica Gel 60A size 20x20 cm plates with a thickness of 1000 pm or equivalent.

[0143] Example 1 - Synthesis

[0144] The compounds in TABLE 1 were prepared as described herein.

[0145] TABLE 1

[0146] Scheme 1 :

[0147] Synthesis of 1.2, methyl 3 -form yl-4-hydroxy benzoate 1.2

[0148] A solution of 3-formyl-4-hydroxybenzoic acid, 1.1 (10 g, 0.060 mol) in DCM under nitrogen was treated with K2CO3(12.46 g, 0.090 mol) and iodomethane (9.34 g, 0.066 mol) and stirred for 3 h at RT. The resulting mixture was filtered: the filter cake was washed with CH2CI2(3 x 500 mL). The filtrate was concentrated under reduced pressure affording 10 g of methyl 3-formyl-4-hydroxybenzoate. MS m / z [M+H]+(ESI): 181.16. This compound was used directly for the next reaction.

[0149] Synthesis of 1.3, methyl 3-formyl-4~methoxybenzoate 1.3

[0150] A solution of 1.2 (10 g, 0.055 mol) in DMF (100 mL) was treated with sodium hydride (4.99 g, 0.082 mol, 60% in oil) and iodomethane (8.61 g, 0.060 mol) for 3 h at 0°C under nitrogen atmosphere, the resulting mixture was stirred at RT. The resulting mixture was filtered and the filter cake was washed with CH2CI2 (3 x 500 mL). The filtrate was concentrated under reduced pressure affording 8.0 g of 1.3. methyl 3-formyl-4-methoxybenzoate MS m / z [M+Hj!(ESl): 195. 19 which was used in the next strep without additional purification.

[0151] Synthesis of methyl (E)-4-methoxy-3-(2 -methoxy vinypbenzoate 1.4

[0152] A solution of (methoxymethyl)triphenylphosphonium chloride (16.92 g, 0.058 mol) in dry THF (100 mL) stirring at 0°C was added potassium tert-butoxide, portion-wise (5.54 g, 0.049 mol). The reaction mixture was allowed to warm to 0°C over 20 min, after which 1.3 (8 g, 0.041 mol) was added. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with CH2CI2 (400 ml.,), washed with saturated aqueous ammonium chloride (2 x 300 mL) and brine (100 mL), dried over anhydrous MgSCL, filtered, and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (petroleum ether: ethyl acetate = 4: 1) followed by distillation at reduced pressure to provide 6.0 g of methyl (E)-4-methoxy-3-(2-methoxyvinyl)benzoate (1.4). MS m / z [M+H]+(ESI): 223.09.

[0153] Synthesis of methyl 4-methoxy-3-(2-oxoethyl)benzoate 1.5

[0154] A solution of 1.4 (6 g, 0.29 mol) and HC1: H2O =1: 1 (5 mL) in acetone (60 mL) under nitrogen atmosphere at 0°C, the resulting mixture was stirred for 30 min at RT The aqueous layer was extracted with ethyl acetate (3 x 300 mL) and the resulting mixture was washed with brine (3 x 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The oil obtained was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to afford methyl 4-methoxy-3-(2-oxoethyl)benzoate (1.5) 3.0 g. MS m / z [M+H]+(ESI): 209.21.

[0155] Synthesis of methyl 3-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-4-methoxy- benzoate (1.0)

[0156] A solution of 1.5 (3.0 g, 0.014 mol) in methanol was treated wdth 3-chloro-5-methyl benzylamine (1 .78 g, 0.01 1 mol) for 30 min at 0°C under nitrogen followed by the addition of NaBH3CN (2.27 g, 0.035 mol) and the reaction mixture was stirred overnight at RT. The reaction was cooled to 0°C and quenched by the slow addition of water. The aqueous layer was extracted with CH2CI2 (3x300 mL). The combined extracts were washed with brine (100 mL) and the concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography, C 18 silica gel column; mobile phase, acetonitrile in water (0.1% HCl), 10% to 50% gradient in 10 min; detector, UV 220 nm, which afforded in 1.5 g of methyl 3-(2-((3- chloro-5-methylbenzyl)amino)ethyl)-4-methoxybenzoate (1.0), MS m / z [M+H]+(ESI): 348.84.

[0157] Synthesis of 2, 3-(2-((3-chloro-5-methylbenzy1)amino)ethyl)-4-methoxybenzoic acid 2.0

[0158] A solution of 1.0 (100 mg, 0.288 mmol) and NaOH (35 mg, 0.864 mmol) in tetrahydrofuran: H2O = 5: 1 (2.0 ml) was stirred for 3 h at RT under nitrogen. The aqueous layer was extracted with ethyl acetate (3x30 mL). The combined extracts were concentrated in vacuo and the residue was purified by reversed-phase flash chromatography with the following conditions: column, 08 silica gel; mobile phase, acetonitrile in water (0.1% HC1), 10% to 100% gradient in 20 min; detector, UV 254 nm.to afford 45 rng of 2, 3-(2-((3-chloro-5- methylbenzyl)amino)ethyl)-4-methoxybenzoic acid (2.0). MS m / z [M+H]+(ESI): 333.95.1H NMR (300 MHz, DMSO-d6) 5 12.94-12.34(m, 1H), 9.40-9.21 (m, 1H), 7.95-7.85 (m, 1H) ,7.81-7.75 (m, 1H), 7.52-7.43 (rn, 1H), 7.37-7.22 (m, 1H), 7.11 (rn, 1H), 4.19 (s, 2H), 3.89 (s, 3H), 3.17-3.08 (m, 2H), 3.08-2.97 (m, 2.H), 2.31 (s, 3H).

[0159] Scheme 2:

[0160] Synthesis of (3-(2-((3~chloro-5-methylbenzyl)amino)ethyl)-4-methoxyphenyl) methanol 5.0

[0161] A solution of 2.0 (100 mg, 0.300 mmol) and LiAlH* (14 mg, 0.360 mmol) in THF (1 mL) was stirred for 3 h at RT under nitrogen. Tire reaction was cooled to 0° C and quenched by the slow addition of water. The aqueous layer was extracted with CH2CI2 (3x100 mL) and the combined layers were washed with brine (20 mL). The residue was purified by reversed- phase chromatography, C18 silica gel column; mobile phase, Acetonitrile in Water (0.1% HC1), 10% to 50% gradient in 10 min; detector, UV 254 nm affording 26 mg of (3-(2-((3-chloro-5- methylbenzyl)ammo)ethyl)-4-methoxyphenyl)methanol (5.0).1H NMR (300 MHz, Methanoi- d4) d 7.36-7.30 (m, 2H), 7.33-7.26 (m, 2H), 7.21 (d, .7 = 2.1 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 4.53 (s, 2H), 4.18 (s, 2H), 3.84 (s, 3H), 3.35-3.23 (m, 2H), 3.14-3.03 (m, 2H), 2.38 (s, 3H). MS m / z [M+H]+(ESI): 320.10.

[0162] 3.0 was prepared analogously to 1.0. MS m / z [M+H]+(ESI):332.39

[0163] 4.0 was prepared analogously to 2.0. MS m / z [M+H]4(ESI):318.20

[0164] 6.0 was prepared analogously to 3.0 MS m / z [M+H]+(ESI):304.15

[0165] Scheme 3:

[0166] Synthesis of 7, 3-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-4-methoxybenzamide7.0

[0167] To a solution of 2.0 (2.0 g, 6.0 mmol) in N,N~Dimethylformamide (20 mL) was added ammonium chloride (1.27 g, 24.0 mmol), HATU (4.56 g, 12.0 mmol) and N,N- Diisopropylethylamine (2.32 g, 18.0 mmol) under nitrogen and the solution was stirred tor 5 h at RT. The reaction was diluted with ethyl acetate (200 mL), washed with water (2x200 mL) and saturated aqueous sodium chloride (2x200 mL) respectively. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography, C18 silica gel column; mobile phase, acetonitrile in water (0.05% HQ), 10% to 100% gradient in 20 min; detector, L!V 254 nm affording 3-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-4-methoxybenzaniide (7.0) 488 mg.1H NMR(400 MHz, Methanol-d4) δ 7.85-7.83 (m, 1H), 7.77 (m, 1H), 7.36-7.30 (m, 2H), 7.25 (s, 1H), 7.07 (m, 1H), 4.19 (s, 2H), 3.92 (s, 3H), 3.31-3.24 (m, 2H), 3.09-3.05 (m, 2H), 2.38 (s, 3H). MS m / z [M+H]+(ESI): 323.05.

[0168] 8.0 was prepared analogously to 7.0. MS m / z [M+H]+(ESI): 317.20.

[0169] Synthesis of 9.0

[0170] A solution of 13.0 (200 mg, 0.62 mmol) in water 3 mL was added Potassium permanganate (247 mg, 1 .56 mmol) at 0°C. The resulting solution was stirred for overnight at room temperature. The resulting mixture was extracted with ethyl acetate (3x100 mL), The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography: column, C18 silica gel; mobile phase, acetonitrile in water (5M ammonium bicarbonate), 10% to 100% gradient in 15 mm; detector, UV 210 nm. to afford 9.1 (100 mg, 48%) as a yellow oil. MS m / z [M+H]+(ESI): 335.8.

[0171] Synthesis of 9.0

[0172] To a solution of 9.1 (100 mg, 0.30 mmol) in 0.5 mL of N, N-dimethylformamide was added ammonium chloride (48 mg, 0.90 mmol), BOP (265 mg, 0.60 mmol) and N, N~ diisopropylethylamine (116 mg, 0.90 mmol, 3.0) at RT under nitrogen and the mixture was stirred for 5 h at RT. The reacting solution was diluted with ethyl acetate (10 mL), washed with water (2x10 mL) and saturated aqueous sodium chloride (2. x 10 mL) respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by reverse phase chromatography: Column, C18 silica gel; mobile phase, water (with 0.05% HQ) and acetonitrile, 10% to 100% gradient in 20 mm; detector, UV 254 nm. 27 mg (27%) of 9.0 was obtained as a solid. MS m / z [M+ H]+(ESI): 334.05.1H NMR (400 MHz, Methanol-A) 5 8.33 (m, 1H), 8.05 (s, 1H), 7.30 (s, 1H), 7.21-7.14 (m, 2H), 4.15 (m, 2H), 4.00 (s, 3H), 3.31-3.25 (m, 2H), 3.15-3.04 (m, 2H), 2.29 (s, 3H).

[0173] Scheme 4

[0174] Synthesis of 13.0

[0175] Synthesis of 13.2

[0176] A solution of potassium hydroxide (280 g, 5.04 mol) was added 6-methyIpyridin-3-ol, 13.1 (100 g, 1.0 mol) in DMSO (1680 mL). The mixture was stirred at RT for 1 hour then was cooled at 0°C. lodomethane (69.5 mL, 1.1 mol) was added dropwise then the reaction was stirred at RT for 4 hours. Water (1.25 L) was added slowly to the aqueous phase was extracted with ethyl acetate (3 x 400 mL). The aqueous phase was saturated with sodium chloride then extracted again with ethyl acetate (3 x 200 mL). Organic phases were combined, dried over sodium sulfate, filtered and concentrated under vacuum. The resulting oil was purified bycolumn chromatography (petroleum ether: ethyl acetate 1:1) to give 13.2 (88 g, 70 %) as a yellow oil. MS m / z [ M + H] + (ESI): 124.15.

[0177] Synthesis of 13.3

[0178] A solution of 13.2 (88g, 0. 65 mol) in dichloromethane (900 mL) was added 3- chloroperoxybenzoic acid (134.51 g, 0.78 mol). The mixture was stirred for 20 hours at RT. The reacting solution was diluted with 1 L of dichloromethane, washed with 2 x 2L water and 2 x 1 L saturated aqueous sodium chloride solution respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate 1 : 1) to give 13.3 (80 g, 72%) as asolid. MS m / z [M +H]+(ESI):+139.06.

[0179] Synthesis 13.4

[0180] A solution of 13.3 (80 g, 58 mol) in dichloromethane (2.4 L) was treated with silica gel (533 g) for 30 min at RT under nitrogen followed by the addition of bromine (138 g, 0.86 mol) dropwise at RT and the resulting mixture was stirred for 18 hours at RT. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (3 x 500 mL). The filtrate was diluted with dichloromethane (1 L), washed with water (2. x 1 L) and saturated aqueous sodium chloride solution (2 x 1 L) respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Tire resulting oil was purified by column chromatography (ethyl acetate: Methanol 8: 1) to give 13.4 (60 g, 36%) as a solid. MS m / z [M+H]+(ESI): 218.05.

[0181] Synthesis 13.5

[0182] A solution of 13.4 (60 g, 0.32 mol) in acetic anhydride (600 mL) was stirred for 18 hours at 60 °C. Tire reacting solution was diluted with 500 mL of ethyl acetate, washed with water (2 x 500 mL) and saturated aqueous sodium chloride (2 x 500 mL) respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography (petroleum ether: ethyl acetate 1 : 1) to give 13.5 (50 g, 61%) as a solid. MS m / z [M+H]+(ESI): 260.08.

[0183] Synthesis of 13.6

[0184] A solution of 13.5 (50 g, 174 mmol) in tetrahydrofuran / water (500 mL) was added sodium hydroxide (20.42 g, 564 mmol) at RT and the resulting mixture was stirred for 20 h.The solution was neutralized with a 1 M aqueous HC1 solution to pH=7. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3 x 500 mL). The filtrate was diluted with 500 mL of dichloromethane, washed with water (2 x 500 mL) and saturated aqueous sodium chloride (2 x 500 mL) respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: Methanol 8: 1) to give compound 13.6 (48 g, 90%) as a solid. MS m / z [M+H]+(ESI): 218.05,

[0185] Synthesis of 13.7

[0186] A solution of 13.6 (48 g, 10 mmol) in dichloromethane (500 mL) was added pyridinium p-toluenesulfonate (6 g, 23 mmol, 0.2) and 3,4-Dihydro-2H-pyran (28.92 g, 344 mmol) with stirring at RT and the resulting solution was stirred for 20 h at RT. The reacting solution was diluted with 500 mL, of dichloromethane, washed with water (2 x 500 ml.,) and saturated aqueous sodium chloride (2 x 500 mL) respectively. Tire organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The oil obtained was purified by column chromatography (petroleum ether: ethyl acetate 2: 1) to give compound 13.7 (40 g, 54%) as an oil. MS m / z [M+H]+(ESI): 302.16.

[0187] Synthesis of 13.8

[0188] A solution of 13.7 (40 g, 132 mmol) in diethyl ether (400 mL) was added n-bulyllithium (78 mL) dropwise at -78 °C under nitrogen and the resulting mixture was stirred for and additional 30 min at -78°C. To a solution of N, N-Dimethylformamide (12.58 g, 198 mmol) dropwised at -78°C. The resulting mixture was stirred for 1 hours at RT. The reaction was diluted with of ethyl acetate (300 mL), washed with water (2 x 300 mL) and saturated aqueous sodium chloride (2 x 300 mL) respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate 1 : 1) to give compound 13.8 (20 g, 40%) as an oil. MS m / z [M+H]+(ESI): 252.12.

[0189] Synthesis of 13.9

[0190] A solution of 13.8 (20 g, 80 mmol, 1) in methanol (300mL) was added nitromethane (4.89 g, 79.6 mmol) and 2.M Sodium hydroxide (5.1 g, 82 mmol, 1.05) with stirring at 0°C. The resulting solution was stirred for 5 hours at 0°C. The reaction was diluted with dichloromethane (500 mL), washed with water (2 x 500 mL) and saturated aqueous sodium chloride (2 x 500mL ) respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residure was purified by column chromatography(petroleum ether: ethyl acetate 1: 1) to give compound 13.9 (16 g, 30%) as an oil. MS m / z [M+H]+(ESI): 313.13.

[0191] Synthesis of 13.10

[0192] A solution of 13.9 (16 g, 48 mmol) in dichloromethane (200mL) was added 4- dimethylaininopyridine (1.17 g, 9.6 mmol) and acetic anhydride (4.90 g, 48.0 mmol) with stirring at RT and the resulting solution was stirred for 2 hours. The reaction was diluted with dichloromethane (300 mL), washed with water (2 x 300 ml) and saturated aqueous sodium chloride (2 x 300 ml) respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Tire oil obtained was purified by column chromatography (petroleum ether: ethyl acetate 1: 1) to give compound 13.10 (14 g, 60%) as an oil. MS m / z [M+H]+(ESI): 295.12.

[0193] Synthesis of 13.11

[0194] A solution of 13.10 (14 g, 68 mmol) and lithium aluminum hydride (10.32 g, 272 mmol) in diethyl ether (300 mL) was stirred at 0°C. The resulting solution was stirred for 2 hours at 40°C, cooled to 0°C and the reaction was quenched with water. The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography: C18 silica gel; mobile phase, acetonitrile in 5M aq. ammonium bicarbonate, 10% to 50% gradient over 10 min; detector, UV 210 nm. to afford 13.11 (9 g, 46%) as an oil. MS m / z [M+H]+(ESI): 267.32.

[0195] Synthesis of 13.12

[0196] A solution of 13.11 (500 mg, 1.88 mmol) in methanol (5mL) was added 3-chloro-5- methylbenzaldehyde (232 mg, 1 .50 mmol) and sodium triacetoxyborohydridein (1.19 g, 5,63 mmol), acetic acid (1 Img, 0. 188 mmol) was stirred overnight at RT. Tire resulting mixture was quenched with water and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine (100 mL) dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue purified by reversed-phase chromatography: column. Cl 8 silica gel; mobile phase, acetonitrile in water (5M ammoniumbicarbonate), 10% to 100% gradient over 15 min; detector, UV 210 nm. to afford 13.12 (320 mg, 43%) as an oil. MS m / z [MM 1]!(ESI): 405.19.

[0197] Synthesis of 13.0

[0198] A solution of 13.12 (30 mg, 0.074 mmol) in 4 M hydrochloric acid in 1.4-dioxane (0.5 mL) was stirred for 4 hours at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography: Column: Atlantis Prep T3 OBD Column, 19*250 mm 10 pm: Mobile Phase A: water (0.05% HC1), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 8% B to 19% B over 12 min; UV 254 nm / 220 nm; RTl (min): 1 1.5. to afford 13.0 (6 mg, 23%) as a white solid. MS m / z [M+H]+(ESI): 321.13. ‘H NMR (400 MHz, Methanol-^) 5 8.37-8.31 (s, IH), 7.91-7.84 (s, IH), 7.42-7.37 (m, IH), 7.32-7.28 (m, 2H), 4.99-4.94 (m, 2H), 4.28-4.24 (s, 2H), 4.10 (s, 3H), 3.44-3.47 (m, 2H), 3.35-3.33 (m, 2H), 2.39 (s, 3H).

[0199] Synthesis of 14.0

[0200] 14.0 was prepared analoguesly to 13.0

[0201] Scheme 5:

[0202] Synthesis of 15.2

[0203] A solution of [4-(hydroxymethyl)~2,5~dimethoxyphenyl]methanol (15.1) , (10 g, 0.051 mol) in CH2.CI2 (100 mL) was treated with l,2-Dichloro-4,5-Dicyanobenzoquinone (12.03 g, 0.054 mol) for 30 min at 0°C under nitrogen and the resulting mixture was stirred at RT. Theresulting mixture was filtered, and the filter cake was washed with CH2CI2 (3x500 mL). The combined filtrates were concentrated under reduced pressure affording compound 15.2 (7.0 g) which was used without additional purification.

[0204] Synthesis of (E)-(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)methanol (15.3)

[0205] A solution of 15.1 (7 g, 0.036 mol) and NH4OAc(8.26 g, 0,107 mol) in AcOH under nitrogen atmosphere was treated with CH3NO2(10.99 g, 0.18 mol) under nitrogen at room RT. The mixture solution was stirred for 5 h at 95 °C and the aqueous layer was extracted with EtOAc (3x100 mL). The combined extracts were washed with brine (3x20 mL) and the residue was purified by reversed-phase chromatography: C18 silica gel column; mobile phase, acetonitrile in water (10 mrnol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm affording (E)-(2,5-dimetlioxy-4-(2-nitrovinyl)phenyl)metlianol 15.3 (5.0 g), which was used directly for the next step without additional purification.

[0206] Synthesis of 15.4

[0207] To a solution of 15.4 (5.0 g, 0.021 mol) in THF (50 mL) was added LiAIH4(3.18 g, 0.084 mol) under nitrogen RT. Tire mixture solution was stirred for 2 h at 65 °C. The reaction was cooled to 0 °C and quenched by slow addition of water. The aqueous layer was extracted with EtOAc(3x 200 ml.,) and the resulting mixture was w-ashed with brine (50 ml.,). Solvent was removed in vacuo and the residue was purified by reversed-phase chromatography: column, Cl 8 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 2.5 g of 15.4, (4-(2-aminoethyl)- 2,5 -dimetb oxyphenyl)methan ol .

[0208] Synthesis of (4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl) methanol (15.0)

[0209] A solution of 15.4 (100 mg, 0.473 mmol) in methanol (2 mL) was treated with 3-chloro- 5-methylbenzaldehyde (58 mg, 0.378 mmol) for 30 min at 0 °C under nitrogen atmosphere followed by the addition of NaBH3CN (74 mg, 1 .182 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. The resulting mixture was cooled to 0 °C and quenched by slow addition of water. The aqueous layer was extracted with CH2CI2 (30 mL) and the extract washed with brine (10 mL) and concentrated in vacuo. The residue was purified by reversed-phase chromatography: C18 silica gel column; mobile phase, acetonitrile in water (0.1% HC1), 10% to 50% gradient in 10 mm; detector, UV 220 nm. (4-(2-((3-chloro-5- methylbenzyl)amino)etliyl)"2,5~dimethoxyphenyl)methanol (15.0).1H N MR (300 MHz,Methanol-dr) δ 7.33 (m, 2H), 7.23 (m, 1H), 7.07 (s, 1H), 6.82-6.80 (s, 1H), 4.63-4.58 (m, 2H), 4.18-4.16 (m, 2H), 3.83-3.75 (m, 7H), 3.29-3.20 (m, 21 1). 3.05-2.95 (rn, 2H), 2.39 (s, 3H). MS m / z [M+H]+(ESI): 350.15.

[0210] Scheme 6:

[0211] Synthesis of (4-(2-((3-fluoro-5-methylbenzyl)amino)ethy1)-2,5-dimethoxyphenyl) methanol (16.0)

[0212] To a solution of 15.4 (100 mg, 0.473 mmol) m methanol (2mL) was added 3-fluoro-5- methylbenzaldehyde (52 mg, 0.378 mmol) and sodium triacetoxyborohydride (201 mg, 0.946 mmol), acetic acid (20 mg, 0.046 mmol). The mixture was stirred for 1 hour at RT and the solution was diluted with ethyl acetate (15 mL), washed with water (2 x 15 mL) and saturated aqueous sodium chloride (2 x 50 mL) respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Tire residue was purified by reverse-phase chromatography: C18 silica gel column; mobile phase, water (containing 0.1% HC1) and acetonitrile (10% acetonitrile up to 100% in 20 min; Detector, UV 254 nm). Affording (4-(2-((3-fluoro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)methanol (16.0) 25 mg.1H NMR (400 MHz, Methanol-d4) 5 7.12 (s, 1H), 7.08-7.00 (rn, 3H), 6.82 (s, 1H), 4.61 (m, 2H), 4.19 (m, 2H), 3.83-3.74 (m, 6H), 3.26 - 3.19 (m, 2H), 3.02-2.94 (m, 2H), 2.40 (s, 3H). MS m / z [M+H]+(ESI): 334.40.

[0213] Synthesis of 18, 4-(2-((3-chIoro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxybenzoic acid (18.0)

[0214] Scheme 7:

[0215] A solution of 15.0 (100 mg, 0.286 mmol) and Jones reagent (226 mg, 1.144 mmol) in acetone under nitrogen atmosphere at 0 °C, the resulting mixture was stirred for 3 h at room temperature. The aqueous layer was extracted with EtOAc (3x100 mL). The resulting mixture was washed with brine (3x20 mL). The residue was purified by reversed-phase chromatography: column, C 18 silica gel; mobile phase, Acetonitrile in Water (0, 1 % HC1), 10% to 50% gradient in 10 min; detector, UV 220 nm. Uris resulted in 28 mg of 18.0, 4-(2-((3- chloro~5“methyibenzyl)amino)ethyl)-2,5-dimethoxybenzoic acid. MS m / z [M+H]+(ESI):364.10.1H NMR (400 MHz, DMSO-ric,) d 12.65 (m, 1H), 9.24 (m, 2H), 7.47 (m, 1H), 7.36-7.30 (m, 2H), 7.26-7.23 (s, 1H), 7.01 (s, 1H), 4.18-4.14 (m, 2H), 3.85-3.70 (m, 6H), 3.13- 3.06 (m, 2H), 3.04-2.93 (m, 2H), 2.34-2.30 (s, 3H).

[0216] Scheme 8

[0217] Synthesis of methyl 4-(2-((3-chloro-5-methylbenzyl)amino)ethyi)-2,5- dimethoxy benzoate (17.0)

[0218] To a solution of 18.0 (100 mg, 0.275 mmol) in methanol (1 mL) was treated with H2SO4(135 mg, 1.3 mmol). The mixture was stirred for 2 h at 60 °C under nitrogen. The aqueous layer was extracted with CH2CI2 (3x100 mL). The combined extracts were washed with brine (3x20 mL) and concentrated in vacuo. The residue was purified by reversed-phase chromatography: column. Cl 8 silica gel; mobile phase, Acetonitrile in Water (0.1% HC1), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3 mg of methyl 4-(2-((3- chloro~.5-met.hylbenzyl)amino)ethyl)-2,5-dimet.hoxybenzoate (17.0). MS m / z [M+H]+(ESI):378.20.1H NMR (300 MHz, Methanol- A) δ 7.39-7.31 (m, 3H), 7.25 (s, 1H), 7.03 (s,IH), 4.23-4.16 (m, 2H), 3.88-3.81 (m, 9H), 3.27-3.21 (m, 2H), 3.1 1-3.02 (m, 2H) 17.0, 2.38 (s, 3H).

[0219] Scheme 9

[0220] To a solution of 16.0 (100 m g, 0.270 mmol, 1 equiv) in acetone (2 niL) was added jones reagent (214,21 mg, 1.080 mmol, 4 equiv). The mixture was stirred for 1.5 hours at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash with the following conditions: Column, C18 silica gel; mobile phase, water (containing 0.1% HCl) and acetonitrile (10% acetonitrile up to 100% in 20 min; Detector, UV 220 nm). This resulted in 29 mg of 4-(2-((3-fluoro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxybenzoic acid (19.0) MS m / z [ M + H]+(ESI): 348.30.1H NMR (400 MHz. Methanol-d4) 8 7.45 (s, 1H), 7.14 (s, 1H), 7.07-7.00 (m, 3H), 4.21 (m, 2H), 3.91-3.79 (m, 6H), 3.27-3.20 (m, 2H), 3.10-3.12. (m, 2H), 2.38 (s, 3H).

[0221] Scheme 10

[0222] Synthesis of methyl 4-(2-((3~fluoro-5-methylbenzyl)ammo)ethyl)~2,5~ dimethoxybenzoate (20.0)

[0223] To a solution of 19 (100 mg, 0,270 mmol) m methanol (ImL) was added sulfuric acid (24 mg, 0.054 mmol). The mixture was stirred for 2 hours at RT and the resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash: Column, C18 silica gel; mobile phase, water (containing 0.1% HCl) and acetonitrile (10% acetonitrile up to 100% in 20 min; Detector, UV 220nm). This resulted in 32 mg of methyl 4-(2-((3-fluoro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxybenzoate (20.0). MS m / z [M+H]+(ESI): 362.17.1H NMR (400 MHz, Methanol-d4) δ 7.36 (m, 1H), 7.15 (m, 1H), 7.11-7.00 (m, 3H), 4.23-4.18 (m,2H), 3.90-3.79 (m, 9H), 3.27-3.20 (m, 2H), 3.12-3.02 (m, 2H), 2.40 (s, 3H).

[0224] Scheme 11

[0225] Synthesis of 21.2

[0226] To a solution of methyl 2-(2-methoxyphenyl)acetate 21.1 (5 g, 30 mmol) and acetic anhydride (4.61 g, 45 mmol) in DCM (50 mL) was added AiCh (8.02 g, 60.1 mmol) in portions at 0°C . The resulting mixture was stirred for 2 h at RT. The reaction was quenched with water (100 mL) at 0°C. and the resulting mixture was extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography, eluted with petroleum ether / EA (2: 1) to afford 21.2 (4.8 g, 72%) as a solid. MS m / z [M+H]+(ESI):223.09.

[0227] Synthesis of 21.3

[0228] To a solution of 21.2 (500 mg, 2.25 mmol) andNaBH4(102 mg, 2.70 mmol) in MeOH (5 mL) was stirred for 2 h at RT under nitrogen. The reaction was diluted with DCM (50 mL), washed with water (25 mL), brine (25 mL), dried over Na2SO4. The residue was purified byreversed-phase chromatography: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% NH3-H2O), 10% to 50% gradient in 10 mm; detector, UV 254 nm affording 21.3 (450 mg. 89%) as an oil . MS m / z [M+H]+(ESI):225.10.

[0229] Synthesis of 21.4

[0230] To a solution of 21.3 (300 mg, 1 ,34 mmol) and diisobutylaluminum hydride (228 mg, 1.61 mmol) in toluene (6 mL) was stirred for 2 h at -78°C under nitrogen. Tire reaction mixture was diluted with DCM (30 mL). The organic mixture was washed with water, brine (25 mL each) and dried over Na2SO4The residue was purified by silica gel chromatography, eluted with petroleum ether / EA (1 : 1) to afford 21.4 (150 mg, 58%) as an oil. MS m / z [M+H]+(ESI): 195.09

[0231] Synthesis of 21 .0

[0232] To a solution of 21.4 (100 mg, 0.515 mmol) and 3 -chloro-5 -methyl benzylamine (88.14 mg, 0.57 mmol) in MeOH (2 mL) was added NaBHsCN (65 mg, 1.03 mmol) 0°C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched by addition of water 0,5 mL. The aqueous layer was extracted with ethyl acetate (20 mL) and organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. The residue was purified by reverse phase chromatography: column, C l 8 silica gel; mobile phase, MeCN in Water (0.1% HC1), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 21.0 (30 mg, 16%) as a solid. MS m / z [Mt-H];(ESI):334.05.1H NMR (300 MHz. Methanol-d4) 8 7.19 - 7.10 (m, 2H), 7.08 (s, 2H). 6.99 (s, 1H), 6,91 (d, J= 8.3 Hz, 1H), 3.83 (s, 3H), 3.76 - 3.67 (m, 3H), 3.58 - 3.46 (m, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2,31 (s, 3H), L37 (d, .7 = 6.7 Hz, 3H).

[0233] Scheme 12

[0234] Synthesis of 23.1

[0235] To a solution of 21.2 (1 g, 4.50 mmol) in THF (20 mL) at -78°C under nitrogen was added 1 M bromo(methyl)magnesium in THF (14 mL, 13.5 mmol) dropwise at -78°C. The resulting mixture was stirred for 1 h at -30°C. The reaction was quenched with sat.NHrCl (10 mL) at 0°C and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with petroleum ether / EA (1: 1) to afford 23.1 (500 mg, 47%) as an oil. MS m / z [M- H | (ESI): 239.10

[0236] Synthesis of 2.3.2

[0237] A solution of 23.1 (2.0 g, 8.4 mmol) in THF (10 mL) and water (10 mL) was treated with NaOH (1.68 g, 42.0 mmol) at RT. The resulting mixture was stirred for 3 h at 65°C. The reaction mixture was cooled to RT and then acidified to pH = 2 with 6 M HC1 (aq.). The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic extracts were washed with brine (30 mL) and dried over anhydrous NasSCfi. After filtration, the filtrate was concentrated under reduced pressure to afford 23.2 (1.5 g, 80%) as an oil. MS m / z [M-H]+(ESI):223.10

[0238] Synthesis of 23.3

[0239] To a stirred mixture 23.2 (700 rag, 3.12 mmol) and EDCI (718 mg, 3.74 mmol) in pyridine (10 mL) was added 3-chIoro-5-methyl benzylamine (534 mg, 3.43 mmol) at RT. Tire resulting mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo to give a residue which was purified by reversed-phase chromatography: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, U V 254 nm. to afford 23.3 (600 mg, 53%) as an oil. MS m / z [M+H]+(ESI):362.20

[0240] Synthesis of 23.0

[0241] A solution of 23.3 (100 mg, 0.27 mmol) in THF (2 mL) at 0°C under nitrogen was added LiAlHr (21 mg, 0.55 mmol) at 0°C. lire resulting mixture was stirred overnight at 0°. The reaction was quenched with water (0.1 mL) at 0°C. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography: Column: XBridge Prep C18 OBD Column 30* 150 mm, 5 um; Mobile Phase A: Water / 10mmol / L NH4HCO3+0.1%NH3-H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 37% B to 55% B in 9 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.03 to afforf (2.9 mg, 30%) as an semi-solid. MS m / z [M+H]+(ESI):348.15.1HNMR (400 MHz, MeOD) 6 7.33 - 7.20 (m, 2H), 7.11 (d, J= 11.3 Hz, 2H), 7.04 (s, IH), 6.87 (d, .7= 8.5 Hz, 1H), 3.76 (d, J ----- 16.1 Hz, 5H), 2.82 (dq. J= 13.2, 7.2 Hz, 4H), 2.31 (s, 3H ). 1.49 (s, 6H).

[0242] Scheme 13

[0243] Synthesis of 22.0

[0244] To a stirred solution of 21.4 (100 mg, 0.52 mmol) in anhydrous MeOH (2 mL) was added 3 -fluoro-5 -methyl benzylamine (79 mg, 0.57 mmol) followed by NaBH3CN (65 mg, 1.03 mmol) at 0°C. The reaction mixture was stirred at RT for 2 h and the reaction mixture wasquenched by addition of water (0.5 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. The residue was purified by reverse phase chromatography: column, C18 silica gel; mobile phase, MeCN in Water (0.1% HO), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 22.0 (27 mg, 14%) as a solid. MS m / z i M H | (ESI): 179.05.:lH T4MR (300 MHz, Methanol-A) 8 7.39 - 7.23 (m, 2H), 7.14 - 6.89 (m, 4H), 4.42 - 4.30 (m, 1H), 4.06 (d, J= 13.2 Hz, 1H), 3.88 (d, J = 7.5 Hz, 4H), 3.76 (t, J = 6.8 Hz, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.37 (s, 3H), 1.69 (d, J = 6.9 Hz, 3H).

[0245] Scheme 14

[0246] Synthesis of 26.2

[0247] A solution of (2, 5 -dimethoxyphenyl (acetic acid (1 g, 5.09 mmol) in acetic acid (10 mL) was added 1.0 M HNOs in acetic acid (5.6 mL, 5,60 mmol). The reaction was stirred at RT for 10 min and diluted with 75 mL of water. The yellow- precipitate was collected and washed with water (3x 10 mL) and dried under high vacuum. Precipitation from 2 -propanol afforded 26.2 (800 mg, 65%) as a solid. MS m / z [M-t-Hp (ESI):242.05.

[0248] Synthesis of 26.3

[0249] To a solution of 26.2 (100 mg, 0.41 mmol) in acetonitrile (5 mL) was added l-(3-fluoro- 5-methylphenyl)methanamine (63 mg, 0.46 mmol), BOP (275 mg, 0.62 mmol) and DIEA (107 mg, 0.83 mmol). The mixture was stirred for 2 h at RT and concentrated in vacuo. The residue was purified by reverse phase chromatography: column, C18 silica gel; mobile phase, acetonitrile in water (0. 1% NH3.H2.CM-l Ommol / L NH4HCO3), 10% to 100% gradient in 15 min; detector, UV 254 nm to afford 26.3 (120 mg, 80%) as a solid. MS m / z [M+H]+(ESI):363.15.

[0250] Synthesis of 26.0

[0251] To a solution of 26.3 (50 mg, 0.14 mmol) in THF (0.5 mL) was added BHs in THF (1 mol / 'L, 0.41 mol, 0.41 mL) dropwise at 0°C. The mixture was stirred for 1 hour at 65°C and cooled to room temperature. NaOH aq. (1 mol / L, 0.02 mL) and ethanol (0.02 mL) was added to the solution. The mixture was stirred overnight at 65°C. The reaction mixture was cooled toRT and concentrated in vacuuo and the resulting residue was purified by reverse phase chromatography. Column: XBridge Prep Cl 8 OBD Column 30* 150 mm, 5pm; Mobile Phase A: Wate^10mmol / L NHiHCOs+O.l / oNHjHzO), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 45% B to 60% B in 9 min: Wave Length: 254nm / 22.0nm nm; RTl(mm): 7.35 affording 26.0 (15 mg, 30%) as a solid. MS m / z [M+H]+(ESI):349.1 . NMR (300 MHz,1HMethanol -c / 4) 8 7.41 (s, 1H), 7.10 (s, 1H), 6.93 (s, 1H), 6.91 -6.72 (m, 2H) 3.89 (s, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.95-2.73 (m, 4H), 2.32 (s, 3H).

[0252] Scheme 15

[0253] Synthesis of 27.1

[0254] To a stirred solution of 26.2 (50 mg, 0.21 mmol) and l-(3-chloro-5- methylphenyl)methanamine (35 mg, 0.23 mmol) in MeCN (2 mL) were added BOP (137 mg, 0.31 mmol) and DIEA (54 mg, 0.41 mmol) dropwise at RT under nitrogen. The resulting mixture was stirred for 8 h and concentrated in vacuo. The residue was purified by reverseph ase flash chromatography: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3H2O+10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 27.1 (30 mg, 38%) as a solid. MS m / z [M+H ]+(ESI):379.10

[0255] Synthesis of 27.0

[0256] To a solution of 27.1 (28 mg, 0.074 mmol) in THF (0.5 mL) was added 1 M BEb-THF (0.22 mL, 0.22 mmol) at 0°C. The mixture was stirred for 3 h at RT under nitrogen. The reaction was quenched by the addition of EtOH ( 1 mL) at 0°C. followed by NaOH aq. (0. 1 mL) dropwise at 0°C. The resulting mixture was stirred for additional 8 h at 65°C. and then concentrated in vacuum to give a residue. The crude product was purified by preparative HPLC [Column: YMC-Actus Triart C18 ExRS 30* 150mm, 5pm; Mobile Phase A: Water (10mmol / L NH4HCO3+0. 1 % NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 54% B to 71% B in 9 min; Wave Length: 254nm / 220nm nm; RTl(rnin): 8.5] to afford 27.0 (9 mg, 32%) as a solid. MS m / z [M+H]+(ESI):365.15.1H NMR (300 MHz, Methanol-Ai) 5 7.42 (s, 1H), 7.13 (s, 1H), 7.1 1 (s, 1H), 7.09 (s, 1H), 7.04 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.72 (s, 21 1). 2.93 - 2.85 (rn, 2H), 2.83 - 2.75 (m, 2H), 2.31 (d, J ----- 0.8 Hz, 3H).

[0257] Example 2 - GPCR Arrestin Assay Methods

[0258] Arrestin Pathway (Performed by DiscoverX Eurofins)

[0259] 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 β-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.

[0260] 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 chemiluminescentPathHunter® Detection Reagents.

[0261] PathHunter cell lines (DiscoveRx Eurofins) 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.

[0262] 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 μL. of 5X sample was added to cells and incubated at 37°C or room temperature for 90 to 180 minutes. Vehicle concentration was 1 %.

[0263] b-Arrestin assay signal was generated through a single addition of 12.5 or 15 gL (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.

[0264] 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).

[0265] In these studies, the MAX control ligand response was generated using 10 mM serotonin.

[0266] Calcium Mobilization Assay Method (Performed by DiscoveRx Eurofins)

[0267] lire Calcium No-WashPLUS assay monitors tire 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.

[0268] 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 blackwalled, clear-bottom, Poly-D-lysine coated 384-well microplates and incubated at 37°C for the appropriate time prior to testing.

[0269] 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. Cellswere 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.

[0270] 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 rnM 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.

[0271] 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.

[0272] Compound activity data was analyzed using CBIS data analysis suite (Chemlnnovation, CA). 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).

[0273] In these studies, the MAX RFU was generated by using 0.1 mM serotonin for the calcium mobilization assay.

[0274] Example 3 - Biological Experiments

[0275] Selected compounds were assessed for biological activity across a panel of 5-HT receptors including 5-HT2A, 5-HT2B, 5-HT2C and 5-HT1A. Biased signaling was assessed by monitoring both intracellular Gq-mediated calcium release, as well as beta-arrestin activation and recruitment to the GPCR. TABLE 2 is a summary of findings across selected compounds and the 5-HT receptors tested.

[0276] TABLE 2

[0277] 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):(I), or a pharmaceutically acceptable salt thereof; wherein:W, X, Y, and Z are independently N or CR10;R1is CHR11R12, CDR11R12, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C(O)NR13R14, C(O)OR13, C(S)NR13R14, or C(S)OR13;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R3, and R6are independently F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR15;R' and R8are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R9is H, D, OR16, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H, D, F, NO2, CHR11OH, C(O)NR13R14, COOR13, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11and R12are independently H, D, OH, C1-C6alkyl, C1-C6, deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R13, R14, R15, and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

2. The compound of claim 1, having a structure of Formula (la):(la), or a pharmaceutically acceptable salt thereof;wherein:X, Y, and Z are independently N or CR7;R1is CHR8R9, CDR8R9, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C(O)NR10R11, C(O)OR10, C(S)NR10R11, or C(S)OR10;R2is H, D, F, NO2. CHR8OH. C(O)NR10R11, COOR12, SO2Me. SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl;R3is F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR12;R4and R5are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R6is H, D, OR12, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R7is H, D, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl;R8and R9are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R10, R1 !, and R12are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

3. The compound of claim 1, wherein the compound is selected from :

4. The compound of claim 1 , wherein the compound is:

5. Tire compound of claim 1 , wherein the compound is:

6. The compound of claim 1, wherein the compound is:7, The compound of claim 1, wherein the compound is:

9. The compound of claim 1 , wherein the compound is:1 1. Tire compound of claim 1 , wherein the compound is:

12. The compound of claim 1, wherein the compound is:

13. The compound of claim 1, wherein the compound is:

14. The compound of claim 1, wherein the compound is:

15. The compound of claim 1, wherein the compound is:16 The compound of claim 1 wherein the compound is:

17. The compound of claim 1, wherein the compound is:

18. 'The compound of claim 1, wherein the compound is:

19. The compound of claim 1 , wherein the compound is:

20. The compound of claim 1, wherein the compound is:

21. The compound of claim 1, wherein the compound is:

22. The compound of claim 1, wherein the compound is:

3. The compound of claim 1, wherein the compound is:

24. The compound of claim 1, wherein the compound is:

25. The compound of claim I, wherein the compound has antidepressant and anxiolytic effects.

26. A compound of Formula (II):(II), or a pharmaceutically acceptable salt thereof;wherein:X, Y, and Z are independently N or CR11;R1is H , OH, D, CH2OH, CD2OH, C(Me)DOH, C(Me)HOH, CHR12R13, CDR12R13, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(O)NR14R15, C(O)OR’14, C(S)NR14R’15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl;R4, R5, R6, and R7are independently F, Cl, Br, I, C1-C6alkyl, CF3, CHF2, CH2F, or OR16; R8and R9are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl; R10is H, D, OR17, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11is H, D, F, NO2, CH2OH, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl;R12and R13are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R14, R15, R16, and R1?are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

27. The compound of claim 26. having a structure of Formula (Ila):(IIa), or a pharmaceutically acceptable salt thereof; wherein:X, Y, and Z are independently N or CR6;R1is H , OH, D, CH2OH , CD2OH, C(Me)DOH, C(Me)HOH, CHR7R8, CDR7R8, Ci- Cg alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO2Me. SO2CH2F SO2CHF2, SO2CF3, C(O)NR9R10, C(O)OR9. C(S)NR9R10, or C(S)OR9;R2is F, Cl, Br, I, C1-C6alkyl, CF3, CHF2., CH2F, or OR11;R3and R4are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R5is H, D, OR12, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R6is H, D, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R7and R8are independently H, D, OH, C1-C6alkyl, C1-C.5 deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; each R9, R10, R11, and R12are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle.

28. The compound of claim 26, wherein the compound is selected from:

29. The compound of claim 26, wherein the compound is:

30. Tire compound of claim 26, wherein the compound is:

31. The compound of claim 26, wherein the compound is:

32. The compound of claim 26. wherein the compound is:

33. The compound of claim 26, wherein the compound is:

34. The compound of claim 26, wherein the compound is:

35. The compound of claim 26, wherein the compound is:

36. Tire compound of claim 26, wherein the compound is:

37. The compound of any of claims 1-36, wherein the compound has antidepressant and anxiolytic effects.

38. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of Formula (I):wherein:W, X, Y, and Z are independently N or CR10;R1is CHR11R12, CDR11R12, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C(O)NR13R14, C(O)OR13, C(S)NR13R14, or C(S)OR13;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R5, and R6are independently F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR15;Rzand R8are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R9is H, D, OR16, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H , D, F, NO2, CHR11OH, C(O)NR13R14, COOR’13, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11and R12are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R13, R14, R15, and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle, and one or more pharmaceutically acceptable excipients.

39. The pharmaceutical composition of claim 38, further comprising a second active agent.

40. Tire pharmaceutical composition of claim 38 or claim 39, wherein the one or more pharmaceutically acceptable excipients comprise a diluent, a binder, a filler, a buffer, a lubricant, aglidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a mold release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof.41 . The pharmaceutical composition of any of claims 38-40, in an oral dosage form.

42. The pharmaceutical composition of any of claims 38-41, comprising a therapeutically effective amount of a compound selected from:

43. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

44. The pharmaceutical composition of any of claims 38-41 , wherein the compound is:

45. The pharmaceutical composition of any of ciaims 38-41, wherein the compound is:

46. The pharmaceutical composition of any of claims 38-41, wherein the compound is:47.T h e pharmaceutical composition of any of claims 38-41, wherein the compound is:

48. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

49. The pharmaceutical composition of any of ciaims 38-41, wherein the compound is:

50. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

51. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

52. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

53. Tire pharmaceutical composition of any of claims 38-41 , wherein the compound is:

54. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

55. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

56. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

57. The pharmaceutical composition of any of claims 38-41 , wherein the compound is:

58. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

59. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

60. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

61. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

62. Tire pharmaceutical composition of any of claims 38-41 , wherein the compound is:

63. The pharmaceutical composition of any of claims 38-41, wherein the compound is:

64. A pharmacal composition, comprising: a therapeutically effective amount of a compound of Formula (II):(II), or a pharmaceutically acceptable salt thereof. wherein:X, Y, and Z are independently N or CR11R1is H, OH, D, CH2OH, CD2OH, C(Me)DOH, C(Me)HOH, CHR12R13, CDR12R13, C1-C6, alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C6heterocycle, CN, NO2, SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(O)XR14R15, C(O)OR14, C(S)NR14R15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R4, R5, R°, and R' are independently F, Cl, Br, I, Ci-Cs alkyl, CFa, CHF?,, CFbF, or OR16;R8and R9are independently H, D, Cj-Ce alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H, D, OR1', F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11is H, D, F, NO2, Cl L OH SO2Me, SO OIC. CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R12and R13are independently H , D, OH, C1-C6alkyl, C1-C6deuteroalkyl, Ci- Ce fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R14, R1’, R16, and R17are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C.i-Cs heterocycle, and one or more pharmaceutically acceptable excipients.

65. The pharmaceutical composition of claim 64, further compri sing a second active agent,66. The pharmaceutical composition of claim 64 or claim 65, wherein the one or more pharmaceutically acceptable excipients comprise a diluent, a binder, a filler, a buffer, a lubricant, aglidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a mold release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof.

67. The pharmaceutical composition of any of claims 64-66, in an oral dosage form.

68. The pharmaceutical composition of any of claims 64-67, wherein the compound is selected from:69 The pharmaceutical composition of any of claims 64-67, wherein the compound is:

70. The pharmaceutical composition of any of claims 64-67, wherein the compound is:71 . The pharmaceutical composition of any of claims 64-67, wherein the compound is:

72. The pharmaceutical composition of any of claims 64-67, wherein the compound is:

73. The pharmaceutical composition of any of claims 64-67, wherein the compound is:

74. The pharmaceutical composition of any of claims 64-67, wherein the compound is:

75. The pharmaceutical composition of any of ciaims 64-67, wherein the compound is:

76. Th e pharmaceutical composition of any of claims 64-67, wherein the compound is:

77. A method of treating a mental health disorder in a subject in need thereof composing: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof;wherein:W, X, Y, and Z are independently N or CR10;R1is CHR11R12, CDR11R12, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, ( fluoroalkyl, C(O)NR13R14, C(O)OR13, C(S)NR13R14, or C(S)OR13;R2is H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R3, R4, R5, and R6are independently F, Cl, Br, I, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or OR15;R7and R8are independently H , D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R9is H, D, OR16, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R10is H , D, F, NO2, CHR11OH, C(O)NR13R14, COOR13, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11and R12are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R13, R14, R15, and R16are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle, and one or more pharmaceutically acceptable excipients.

78. The method of claim 77, comprising a therapeutically effective amount of a compound selected from:

79. The method of claim 77, wherein the compound is:

80. Tire method of claim 77, wherein the compound is:

81. The method of claim 77, wherein the compound is:

82. The method of claim 77, wherein the compound is:

83. The method of claim 77, wherein the compound is:

84. The method of claim 77, wherein the compound is:

86. The method of claim 77, wherein the compound is:

88. "Die method of claim 77, wherein the compound is:

89. The method of claim 77, wherein the compound is:

90. The method of claim 77, wherein the compound is:

91. "Die method of claim 77, wherein the compound is:

92. The method of claim 77, wherein the compound is:

93. The method of claim 77, wherein the compound is:

94. The method of claim 77, wherein the compound is:

95. The method of claim 77, wherein the compound is:

96. The method of claim 77, wherein the compound is:

97. The method of claim 77, wherein the compound is:

98. Tire method of claim 77, wherein the compound is:

99. The method of claim 77, wherein the compound is:

100. The method of any of claims 77-99, wherein the administering comprises intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual buccal, or nasal route of administration.

101. The method of any of claims 77-100, wherein the mental health disorder is selected from the group consisting of major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, anxiety disorders, stress disorders, rumination disorder, and eating disorders.

102. The method of any of claims 77-101, 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.

103. ITe method of any of claims 77-102, wherein tire compound has antidepressant and anxiolytic effects.

104. The method of any of claims 77-103, comprising administering the pharmaceutical composition as a single dose.

105. The method of any of claims 77-103, comprising administering the pharmaceutical composition in repeated doses.

106. A method of treating a mental health disorder in a subject in need thereof, comprising:administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (II):(II), or a pharmaceutically acceptable salt thereof.X, Y, and Z are independently N or CR1 l;R1is H, OH, D, CHzOH, CDzOH, C(Me)DOH, C(Me)HOH, CHR12R13, CDR12R13, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, C6-C10aryl, C3-C.5 heterocycle, ON, NO2, SO2Me, SO2CH2F, SO2CHF2, SO2CF3, C(O)NR14R15, C(O)OR’14, C(S)NR14R’15, or C(S)OR14;R2and R3are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl;R4, R5, R6, and R7are independently F, Cl, Br, I, C1-C6alkyl, CF3, CHF2, CH2F, or OR16; R8and R9are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl; R10is H, D, OR17, F, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;R11is H, D, F, NO2, CH2OH, SO2Me, SO2CF3, CN, OMe, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6, fluoroalkyl; R12and R13are independently H, D, OH, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle; and each R14, R1S, R1b, and R17are independently H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C6-C10aryl, or C3-C6heterocycle, and one or more pharmaceutically acceptable excipients.The method of claim 106, wherein the compound is selected from :

108. The method of claim 106, wherein the compound is:

109. The method of claim 106, wherein the compound is:

110. The method of claim 106, wherein the compound is:

111. The method of claim 106, wherein the compound is:

112. The method of claim 106, wherein the compound is:

113. The method of claim 106, wherein the compound is:

114. The method of claim 106, wherein the compound is:

115. The method of claim 106, wherein the compound is:

116. The method of any of claims 106-115, wherein the administering comprises intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual buccal, or nasal route of administration.

117. The method of any of claims 106-116, wherein the mental health disorder is selected from the group consisting of major depressive disorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, anxiety disorders, stress disorders, rumination disorder, and eating disorders.

118. The method of any of claims 106-117, 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.

119. lire method of any of claims 106-118, wherein the compound has antidepressant and anxiolytic effects.

120. The method of any of claims 106-119, comprising administering the pharmaceutical composition as a single dose.

121. The method of any of claims 106-119, comprising administering the pharmaceutical composition in repeated doses.

Images