Dimethoxyphenylalkylamine activators of serotonin receptors.

Abstract

Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and n are as defined herein. Also provided herein is a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a method of using a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for example, in the treatment of a mental health disease or disorder. [Formula 1] JPEG2024520832000121.jpg2858

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 208,391, filed June 8, 2021, and U.S. Provisional Patent Application No. 63 / 241,662, filed September 8, 2021, which are incorporated by reference herein in their entireties. [Background technology]

[0002] Hallucinogens can be divided into three main classes: indolamines, phenylalkylamines, and ergolines. The first class, indolamines, includes N,N-dimethyltryptamine (DMT), 5-methoxy-DMT (5-MeO-DMT), psilocybin, and 4-hydroxy-DMT. The second class, phenylalkylamines, includes mescaline and synthetic mescaline analogs such as 2,5-dimethoxy-4-iodoamphetamine (DOI) and 2,5-dimethoxy-4-bromoamphetamine (DOB). The third class is the ergolines, such as LSD. Phenylalkylamines are selective agonists of the 5-HT2 receptors, including the 5-HT2A, 5-HT2B, and 5-HT2C receptors. Indolamines and ergolines act as partial agonists of the 5-HT1, 5-HT2, 5-HT6, and 5-HT7 receptors. LSD and other ergolines also act on D1 and D2 dopamine receptors and adrenergic receptors.

[0003] Activation of 5-HT2A receptors, located in cortical and subcortical structures of the brain, is believed to mediate the subjective, behavioral, and psychological effects of hallucinogens in both animals and humans. Serotonergic hallucinogens have shown potential to treat a range of mental health diseases or disorders.

[0004] There remains a need for compounds that act as agonists of serotonin receptors, such as the 5-HT2A receptor, as well as compositions and methods of use thereof. Summary of the Invention

[0005] In one aspect, the disclosure provides compounds that act as agonists of serotonin receptors, such as the 5-HT2A receptor, and compositions and methods of use thereof, for example, for the treatment of mental health diseases or disorders.

[0006] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R1 is, independently at each occurrence, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2 and R3 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen; R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, O(C=O)(R 12 ), or NH(C=O)(R 12 ) and R 12 is C1-C6 alkyl, n is an integer from 0 to 3.

[0007] In some embodiments, the present disclosure provides a compound of formula (IA): [ka] or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, and R6 are defined herein.

[0008] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R1 is, independently at each occurrence, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2, R3, and R7 are independently hydrogen, heterocycle, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, S(O)(=NH)R1, S(O)2R1, S(O)R1, or SR1, and at least one of R2 and R3 is hydrogen; R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, (C=O)(R 14 ), O(C=O)(R 14 ), NO2, or NH(C=O)(R 14 ) and R 14 is C1-C6 alkyl, OH, or OC1-C6 alkyl, R8 and R9 are independently selected from hydrogen, C1-C6 alkyl, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C 10 cycloalkyl, CHOH, or CHO-C1-C4 alkyl; R 10 and R 11 are independently hydrogen, halogen, C1-C6 alkyl, OH, C1-C4 alkyl, C3-C6 cycloalkyl, or CH2O-C1-C4 alkyl; R 12 is hydrogen, CH2OH, CH2O-C1-C9 alkyl, C3-C 10 cycloalkyl, CHOH, or CHO-C1-C4 alkyl; R 13 is hydrogen, C1-C9 alkyl, C3-C 10 Cycloalkyl, or CH2OH, CH2O-C1-C4 alkyl.

[0009] In some embodiments, the present disclosure provides a compound of formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R3, R4, and R5 are defined herein.

[0010] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0011] In some embodiments, the disclosure provides a method of treating a mental health disease or disorder in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0012] [Figure 1] EC50 profiles of compounds 1-1, 1-2, and 2-1 comparing 5-HT2A Gq and β-arrestin biased signaling are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of a conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0014] definition For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0015] The term "about" when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, unless the context of this disclosure indicates otherwise or is inconsistent with such an interpretation, "about 50" can mean 45 to 55, and "about 25,000" can mean 22,500 to 27,500. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range that extends less than half the interval between the preceding value and the succeeding value, e.g., from more than 49.5 to less than 50.5. Furthermore, the phrases "less than about (value)" or "more than about (value)" should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of numerical values ​​or a range of values ​​(e.g., about 10, 20, 30", or "about 10 to 30") refers to every value in the series, or to the end of the range, respectively.

[0016] The terms "administer", "administering" or "administration" as used herein refer to administering to a patient a compound or a pharma- ceutically acceptable salt of a compound, or a composition or formulation including a compound or a pharma- ceutically acceptable salt of a compound.

[0017] The term "treating" as used herein with respect to a patient or subject refers to improving at least one symptom of a disorder in a patient or subject. In some embodiments, treating can be improving or at least partially ameliorating a disorder or one or more symptoms of a disorder.

[0018] The term "therapeutically effective" as applied to a dose or amount refers to that amount of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit following administration to a patient or subject in need thereof.

[0019] The term "pharmaceutically acceptable salts" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include salts obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are non-toxic acid addition salts, i.e., acids that form salts containing pharmaceutically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, acetate, tartrate, oleate, fumarate, formate, benzoate, glutamate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate. Base addition salts include, but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine dicyclohexylamine, and the like. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, and the like.Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0020] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" means C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C5 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be encompassed.

[0021] "Alkyl" or "alkyl group" refers to a fully saturated straight or branched hydrocarbon chain having from 1 to 12 carbon atoms and attached to the remainder of the molecule by a single bond. Alkyl containing any number of carbon atoms from 1 to 12 is included. Alkyl containing up to 12 carbon atoms is any group that is C1-C 12 Alkyl, containing up to 10 carbon atoms, is C1-C 10 An alkyl having up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl having up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes all of the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9, and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C12 Includes alkyl. C1~C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0022] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon, consisting only of carbon and hydrogen atoms, which may include fused, bridged, or spirocyclic ring systems having from 3 to 20 carbon atoms (e.g., having from 3 to 10 carbon atoms), and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated in the specification, cycloalkyl groups can be optionally substituted.

[0023] "Haloalkyl" refers to an alkyl as defined above substituted with one or more halo radicals, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise in the specification, a haloalkyl group can be optionally substituted.

[0024] "Heterocyclyl", "heterocyclic ring", or "heterocycle" refers to a stable saturated, unsaturated, or aromatic 3-20 membered ring consisting of 2-19 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, attached to the remainder of the molecule by a single bond. Heterocyclyl or heterocycle includes heteroaryl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless stated otherwise in the specification, a heterocyclyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, bridged, or spirocyclic ring systems, the nitrogen, carbon, or sulfur atoms in a heterocyclyl can be optionally oxidized, the nitrogen atom can be optionally quaternized, and the heterocyclyl can be partially or fully saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, heterocyclyl groups may be optionally substituted.

[0025] The term "substituted" as used herein means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, including, but not limited to, halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., a double bond or a triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" means that one or more hydrogen atoms are replaced by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g Rh "Substituted" also refers to any of the above groups being replaced with one or more hydrogen atoms, such as -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

[0026] compound In one aspect, the present disclosure provides a compound that acts as an agonist of 5-HT2A receptor.In some embodiments, the compound is a full agonist of 5-HT2A receptor.In some embodiments, the compound is a partial agonist of 5-HT2A receptor.In some embodiments, the compound shows selectivity for 5-HT2A receptor.

[0027] Activation of 5-HT2A receptors located in cortical and subcortical structures of the brain is believed to mediate the subjective, behavioral, and psychological effects of hallucinogens in both animals and humans. In rodents, hallucinogens have been shown to cause a "head twitch response" that has been demonstrated to be a direct and selective result of 5-HT2A activation compared to other similar serotonin receptors, including both 5-HT2C and 5-HT2B (Halberstadt, AL, Behav. Brain Res. 277, 99-120 (2015); Winter et al., Pharmacol. Biochem. Behav. 87, 472-480 (2007); Benneyworth et al., Psychopharmacology 179, 854-862 (2005); Titeler et al, Psychopharmacology, 94, 213-216 (1988)). Similar observations have been made in humans, where administration of the 5-HT2A receptor antagonist ketanserin blocked most of the subjective effects induced by DMT, psilocybin, and LSD (Preller, Curr. Biol. 27, 451-457 (2017); Preller, J. Neurosci. 38, 3603-3611 (2018); Kraehenmann, Front. Pharmacol. 8, 814 (2017); Kraehenmann, Psychopharmacology 234, 2031-2046 (2017); Vollenweider, Neuroreport 9, 3897-3902 (1998); Preller, Acad. Sci. USA 11, 3, 5119-5124 (2016); Valle, Eur. Neuropsychopharm 26, 1161-1175 (2016).) In addition, the hallucinogenic effects induced by psilocybin correlate with 5-HT2A receptor occupancy measured by positron emission tomography in the prefrontal cortex (PFC) and other cortical regions in humans (Madsen, Neuropsychopharmacology 44, 1328-1334 (2019).).Although 5-HT2A is the primary driver of hallucinatory effects in humans, other serotonin receptors such as 5-HT1A likely also contribute to the overall hallucinatory experience, including both visual and attention-disrupting effects in humans (Pokorny et al., Eur. Neuropsychopharmacol. 26, 756-766 (2016). Carter et al., Neuropsychopharmacology 30, 1154-1162 (2005).).

[0028] The consequences of biased signaling of 5-HT2A activation by various agonists strongly influence whether a compound is hallucinogenic or non-hallucinogenic. For example, LSD and lisuride both activate the 5-HT2A receptor, albeit in slightly different ways that result in the activation of different intracellular signaling cascades. Although LSD and lisuride have been shown to activate canonical Gq-based signaling downstream of 5-HT2A, only LSD stimulated the expression of early growth response proteins (EGR1 and EGR2) by activating Gi / o subunits and SRC protein kinases (Gonzalez-Maeso et al, Neuron 53, 439-452 (2007)). Differential functional selectivity has been shown for several phenylalkylamine hallucinogens that were found to be biased 5-HT2A agonists (Pottie et al, Biochemical pharmacology, 182, 114251, 2020). Compounds including 25H-NBF, 25H-NBMD, 25H-NBOH, and 25H-NBOMe showed a statistically significant preference towards recruiting β-arrestin2 over miniGαq compared to the reference hallucinogen LSD.

[0029] The differential biased agonism elicited across multiple classes of hallucinogens warrants further investigation to identify whether this functional selectivity may provide compounds with greater selectivity, fewer side effects, greater neuroplasticity effects, and improved therapeutic benefits.

[0030] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R1 is, independently at each occurrence, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2 and R3 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen; R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, O(C=O)(R 12 ), or NH(C=O)(R 12 ) and R 12 is C1-C6 alkyl, n is an integer from 0 to 3.

[0031] In some embodiments, the compound of formula (I) is a compound of formula (IA): [ka] or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, and R6 are defined herein.

[0032] In some embodiments of the compound of Formula (I) or (IA), R1 is, independently at each position, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0033] In some embodiments of the compound of Formula (I) or (IA), R1 is, independently at each position, hydrogen or C1-C6 alkyl.

[0034] In some embodiments of the compound of Formula (I) or (IA), R1 is, independently at each position, C1-C6 alkyl.

[0035] In some embodiments of the compound of formula (I) or (IA), R1 is, independently at each position, C1-C6 haloalkyl. In some embodiments, R1 is, independently at each position, C1-C3 haloalkyl. In some embodiments, R1 is, independently at each position, CF3.

[0036] In some embodiments of the compound of Formula (I) or (IA), R1 is, independently at each position, C1-C3 alkyl.

[0037] In some embodiments of the compound of Formula (I) or (IA), R 1 is, independently at each position, methyl, ethyl, propyl, or isopropyl.

[0038] In some embodiments of the compounds of Formula (I) or (IA), R 1 is methyl.

[0039] In some embodiments of the compound of formula (I) or (IA), R2 and R3 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen.

[0040] In some embodiments of the compound of formula (I) or (IA), R2 and R3 are independently hydrogen, C1-C6 alkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen.

[0041] In some embodiments of the compound of formula (I) or (IA), R2 and R3 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and at least one of R2 and R3 is hydrogen.

[0042] In some embodiments of the compound of formula (I) or (IA), R2 and R3 are independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and at least one of R2 and R3 is hydrogen.

[0043] In some embodiments of the compound of formula (I) or (IA), R2 and R3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, and at least one of R2 and R3 is hydrogen.

[0044] In some embodiments of the compound of formula (I) or (IA), R2 and R3 are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl, and at least one of R2 and R3 is hydrogen.

[0045] In some embodiments of the compound of Formula (I) or (IA), R2 and R3 are independently hydrogen or C1-C6 alkyl, and at least one of R2 and R3 is hydrogen.

[0046] In some embodiments of the compound of Formula (I) or (IA), R2 and R3 are independently hydrogen or C1-C3 alkyl, and at least one of R2 and R3 is hydrogen.

[0047] In some embodiments of the compound of Formula (I) or (IA), R2 and R3 are independently hydrogen, -CF3, methyl, or ethyl, and at least one of R2 and R3 is hydrogen.

[0048] In some embodiments of the compound of Formula (I) or (IA), R2 and R3 are independently hydrogen, methyl, or ethyl, and at least one of R2 and R3 is hydrogen.

[0049] In some embodiments of the compound of Formula (I) or (IA), R2 and R3 are independently hydrogen or methyl, and at least one of R2 and R3 is hydrogen.

[0050] In some embodiments of the compound of Formula (I) or (IA), R2 is hydrogen, -CF3, methyl, or ethyl, and R3 is hydrogen.

[0051] In some embodiments of the compounds of Formula (I) or (IA), R2 is hydrogen, methyl, or ethyl and R3 is hydrogen.

[0052] In some embodiments of the compounds of Formula (I) or (IA), R3 is hydrogen.

[0053] In some embodiments of the compounds of Formula (I) or (IA), R2 is hydrogen.

[0054] In some embodiments of the compound of Formula (I) or (IA), R2 is hydrogen and R3 is hydrogen, -CF3, methyl, or ethyl.

[0055] In some embodiments of the compounds of Formula (I) or (IA), R2 is hydrogen and R3 is hydrogen, methyl, or ethyl.

[0056] In some embodiments of the compounds of Formula (I) or (IA), R2 and R3 are hydrogen.

[0057] In some embodiments of the compounds of Formula (I) or (IA), R2 is halogen and R3 is hydrogen.

[0058] In some embodiments of the compounds of Formula (I) or (IA), R2 is iodo and R3 is hydrogen.

[0059] In some embodiments of the compounds of Formula (I) or (IA), R2 is hydrogen and R3 is halogen.

[0060] In some embodiments of the compounds of Formula (I) or (IA), R2 is hydrogen and R3 is iodo.

[0061] In some embodiments of the compound of formula (I) or (IA), R4, R5, and R6 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, O(C=O)(R 12), or NH(C=O)(R 12 ) and R 12 is C1-C6 alkyl.

[0062] In some embodiments of the compound of formula (I) or (IA), R4, R5, and R6 are independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, OR1, SR1, O(C=O)(R 12 ), or NH(C=O)(R 12 ) and R 12 is C1-C6 alkyl.

[0063] In some embodiments of the compound of Formula (I) or (IA), R4 is C1-C6 alkyl or C1-C6 haloalkyl.

[0064] In some embodiments of the compound of Formula (I) or (IA), R4 is C1-C6 alkyl.

[0065] In some embodiments of the compounds of Formula (I) or (IA), R4 is -CF3 or methyl.

[0066] In some embodiments of the compounds of Formula (I) or (IA), R4 is methyl.

[0067] In some embodiments of the compounds of Formula (I) or (IA), R5 is halogen.

[0068] In some embodiments of the compounds of Formula (I) or (IA), R5 is chloro.

[0069] In some embodiments of the compounds of Formula (I) or (IA), R6 is hydrogen.

[0070] In some embodiments of a compound of Formula (I), n is an integer from 0 to 3 (i.e., 0, 1, 2, or 3). In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0071] In one embodiment, the compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R1 is, independently at each occurrence, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2, R3, and R7 are independently hydrogen, heterocycle, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, S(O)(=NH)R1, S(O)2R1, S(O)R1, or SR1, and at least one of R2 and R3 is hydrogen; R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, (C=O)(R 14 ), O(C=O)(R 14 ), NO2, or NH(C=O)(R 14 ) and R 14 is C1-C6 alkyl, OH, or OC1-C6 alkyl, R8 and R9 are independently selected from hydrogen, C1-C6 alkyl, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C 10 cycloalkyl, CHOH, or CHO-C1-C4 alkyl; R 10 and R 11 are independently hydrogen, halogen, C1-C6 alkyl, OH, C1-C4 alkyl, C3-C6 cycloalkyl, or CH2O-C1-C4 alkyl; R 12 is hydrogen, CH2OH, CH2O-C1-C9 alkyl, C3-C 10cycloalkyl, CHOH, or CHO-C1-C4 alkyl; R 13 is hydrogen, C1-C9 alkyl, C3-C 10 Cycloalkyl, or CH2OH, CH2O-C1-C4 alkyl.

[0072] In some embodiments, the compound of formula (II) is [ka] or a pharma- ceutically acceptable salt thereof, wherein: R1 is, independently at each occurrence, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2, R3, and R7 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen; R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, O(C=O)(R 14 ), or NH(C=O)(R 14 ) and R 14 is C1-C6 alkyl, R8 and R9 are independently hydrogen or C1-C6 alkyl; R 10 and R 11 are independently hydrogen, halogen, or C1-C6 alkyl; R 12 is hydrogen, CH2OH, CH2O-C1-C9 alkyl, C3-C 10 cycloalkyl, CHOH, CHO-C1-C4 alkyl; R 13 is hydrogen, C1-C9 alkyl, C3-C 10 Cycloalkyl, CH2OH, CH2O-C1-C4 alkyl.

[0073] In some embodiments, the compound of formula (II) is a compound of formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, R1 is, independently at each occurrence, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2, R3, and R7 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen; R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, O(C=O)(R 12 ), or NH(C=O)(R 12 ) and R 12 is C1-C6 alkyl, R8 and R9 are independently hydrogen or C1-C6 alkyl; R 10 and R 11 is independently hydrogen, halogen, or C1 to C6 alkyl.

[0074] In some embodiments, the compound of formula (II) is a compound of formula (II-B): [ka] or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R3, R4, and R5 are defined herein.

[0075] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R1 is, independently at each position, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0076] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R1 is, independently at each position, hydrogen or C1-C6 alkyl.

[0077] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R1 is, independently at each position, C1-C6 alkyl.

[0078] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R1 is, independently at each position, C1-C3 alkyl.

[0079] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R 1 is, independently at each position, methyl, ethyl, propyl, or isopropyl.

[0080] In some embodiments of the compound of formula (II), (II-A), or (II-B), R1 is, independently at each position, C1-C6 haloalkyl. In some embodiments, R1 is, independently at each position, C1-C3 haloalkyl. In some embodiments, R1 is, independently at each position, CF3.

[0081] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R 1 is methyl.

[0082] In some embodiments of the compound of formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen.

[0083] In some embodiments of the compound of formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen, C1-C6 alkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen.

[0084] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and at least one of R2 and R3 is hydrogen.

[0085] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and at least one of R2 and R3 is hydrogen.

[0086] In some embodiments of the compound of formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, and at least one of R2 and R3 is hydrogen.

[0087] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl, and at least one of R2 and R3 is hydrogen.

[0088] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen or C1-C6 alkyl, and at least one of R2 and R3 is hydrogen.

[0089] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen or C1-C3 alkyl, and at least one of R2 and R3 is hydrogen.

[0090] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen, -CF3, methyl, or ethyl, and at least one of R2 and R3 is hydrogen.

[0091] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen, methyl, or ethyl, and at least one of R2 and R3 is hydrogen.

[0092] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 and R3 are independently hydrogen or methyl, and at least one of R2 and R3 is hydrogen.

[0093] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 is hydrogen, -CF3, methyl, or ethyl, and R3 is hydrogen.

[0094] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 is hydrogen, methyl, or ethyl and R3 is hydrogen.

[0095] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R3 is hydrogen.

[0096] In some embodiments of the compounds of Formula (II), (II-A), or (II-B), R2 is hydrogen.

[0097] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 is hydrogen and R3 is hydrogen, -CF3, methyl, or ethyl.

[0098] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 is hydrogen and R3 is hydrogen, methyl, or ethyl.

[0099] In some embodiments of the compounds of Formula (II), (II-A), or (II-B), R2 and R3 are hydrogen.

[0100] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 is halogen and R3 is hydrogen.

[0101] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R2 is hydrogen and R3 is halogen.

[0102] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R4, R5, and R6 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, O(C=O)(R 12 ), or NH(C=O)(R 12 ) and R 12 is C1-C6 alkyl.

[0103] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R4 and R5 are independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, OR1, SR1, O(C=O)(R 12 ), or NH(C=O)(R 12 ) and R 12 is C1-C6 alkyl.

[0104] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R4 is C1-C6 alkyl or C1-C6 haloalkyl.

[0105] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R4 is C1-C6 alkyl.

[0106] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R4 is -CF3 or methyl.

[0107] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R4 is methyl.

[0108] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R5 is halogen.

[0109] In some embodiments of the compound of Formula (II), (II-A), or (II-B), R5 is chloro.

[0110] In some embodiments of the compound of Formula (II) or (II-A), R6 is hydrogen.

[0111] In some embodiments of the compound of Formula (II) or (II-A), R7 is hydrogen.

[0112] In some embodiments of the compound of Formula (II) or (II-A), R8 and R9 are hydrogen.

[0113] In some embodiments of the compound of Formula (II) or (II-A), R 10 and R 11 is hydrogen.

[0114] In some embodiments of the compound of Formula (II) or (II-A), R 10 and R 11 is fluoro.

[0115] In some embodiments of the compound of Formula (II), R 11 and R 12 is hydrogen.

[0116] In some embodiments, provided herein is one or more compounds selected from Table 1.

[0117] In some embodiments, provided herein is one or more pharma- ceutically acceptable salts of a compound selected from Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0118] In some embodiments, provided herein are the following compounds: [ka]

[0119] In some embodiments, provided herein is one or more compounds selected from Table 2.

[0120] In some embodiments, provided herein is one or more pharma- ceutically acceptable salts of a compound selected from Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0121] composition In some embodiments of the present disclosure, pharmaceutical compositions are provided that include a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (II), (II-A), (II-B), Table 1, or Table 2), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0122] Pharmaceutically acceptable excipients and adjuvants are added to compositions or formulations for various purposes. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein or pharma- ceutically acceptable salts thereof further comprises a pharma- ceutically acceptable carrier. In some embodiments, the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitable pharma- ceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents, and sterile aqueous or organic solutions. In some embodiments, suitable pharma- ceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0123] For the purposes of this disclosure, the compounds of this disclosure can be formulated for administration by various means, including oral, parenteral, by inhalation spray, topical, or rectal, in a formulation containing pharma- ceutically acceptable carriers, adjuvants, and vehicles.The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intraarterial injections using various injection techniques.Intraarterial and intravenous injections as used herein include administration through a catheter.

[0124] Treatment method The compounds of the present disclosure are used, for example, in methods for modulating serotonin receptors, for example, 5-HT2A receptors. Thus, in some embodiments, the present disclosure provides the use of any one of the compounds of the present disclosure (e.g., compounds of formula (I), (IA), (II), (II-A), (II-B), Table 1, or Table 2), or a pharma- ceutically acceptable salt thereof, for modulating serotonin receptor activity. Modulating serotonin (e.g., 5-HT2A) receptor activity can be for the treatment of any of the conditions or diseases described in a subject in need thereof (e.g., a mammalian subject, such as a human). In some embodiments, modulating is activating or agonizing a serotonin receptor, for example, a 5-HT2A receptor. In some embodiments, the subject is a human.

[0125] In some embodiments, the present disclosure provides a method for treating a disease or disorder treatable by administration of a serotonin receptor agonist, such as a 5-HT2A receptor agonist. In some embodiments, the agonist is a partial agonist of the 5-HT2A receptor. In some embodiments, the agonist is a full agonist of the 5-HT2A receptor.

[0126] In some embodiments, compounds of the present disclosure are used to treat a mental health disease or disorder in a subject in need of treatment, and the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of, for example, Formula (I), (IA), (II), (II-A), (II-B), Table 1 or Table 2, or a pharma- ceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of, for example, Formula (I), (IA), (II), (II-A), (II-B), Table 1 or Table 2, or a pharma- ceutically acceptable salt thereof) and a pharma- ceutically acceptable excipient.

[0127] In some embodiments, the mental health disease or disorder is selected from the group consisting of depression, substance use disorders (SUD), and eating disorders.

[0128] In some embodiments, the mental health disease or disorder is an eating disorder, including disorders such as anorexia nervosa, bulimia nervosa, and other disorders related to eating (e.g., binge eating).

[0129] In some embodiments, the mental health disease or disorder is a mood disorder, including, for example, a depressive disorder, such as major depressive disorder or treatment-resistant depression.

[0130] In some embodiments, the mental health disorder is a substance abuse disorder. In some embodiments, the substance use-related disorder is a disorder of maladaptive patterns of substance use, including criteria such as recurrent substance use-related problems, tolerance to the substance, withdrawal symptoms upon cessation, inability to reduce or control substance use, and abandonment of important social, occupational, or recreational activities due to substance use. See, for example, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In some embodiments, the substance use-related disorder is a disorder resulting from the use of alcohol, caffeine, cannabis, hallucinogens (such as phencyclidine or similarly acting arylcyclohexylamines, and other hallucinogens such as LSD), inhalants, opioids, sedatives, hypnotics, or anxiolytics, stimulants (including amphetamine-type substances, cocaine, and other stimulants), tobacco, and other substances. EXAMPLES

[0131] 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 (0.2 mm) pre-coated with aluminum foil or backed with glass and visualized using UV light. 1 H NMR (400 MHz) spectra were recorded on a Braker spectrometer at room temperature using TMS or residual solvent peak as internal standard. Chemical shifts are given in (δ) and coupling constants (J) are given as absolute values ​​in Hertz (Hz). 1Multiplicities in HNMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad. Preparative HPLC purification was performed on a Shimadzu LC-6AD. All purification work was completed using a Shim-pack PREP-DDS(H)KIT column. The mobile phase was water (containing 0.1% HCO2H) and acetonitrile, and all reagents used were HPLC grade. The flow rate was 10 ml / min. LC-MS analysis was performed on a 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 min run; column: Sepax BR-C18 4.6×50 mm, 3 um; flow rate: 1.0 ml / min; oven temperature: 40° C.; gradient: 20% B in 0.2 min, increasing to 70% B within 1.8 min, 70% B in 2.8 min, back to 20% B within 0.2 min, 20% B in 2 min). Preparative TLC was performed on Whatman LK6F Silica Gel 60A 20×20 cm size plates with a thickness of 1000 μm or equivalent.

[0132] Example 1: Synthesis of N-(3-chloro-5-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (1-1·HCl) [ka] To a solution of 5,8-dimethoxy-3,4-dihydronaphthalen-2(1H)-one (400 mg, 1.94 mmol, 1.0 equiv.) and (3-chloro-5-methylphenyl)methanamine hydrochloride (380 mg, 1.94 mmol, 1.0 equiv.) in CHCl (10 ml), NaBH(OAc) (600 mg, 2.83 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous sodium bicarbonate, extracted with DCM (2×10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified through a silica gel flash chromatography column (eluted with 1% methanol in dichloromethane containing 1% ammonium hydroxide) to give compound 1-1 as the free amine. The amine was converted to its HCl salt as a pale solid (400 mg, 60% yield) after treatment with hydrochloric acid in 1,4-dioxane. Formula:C 20 H 24 ClNO2; MW: 345.15. LCMS: (ES + ): m / z 347.0 [M+H] + t R =2.1 minutes. 1 HNMR(400MHz,DMSO-d6):δ9.37-9.51(br,2H),7.55(s,1H),7.40(s,1H),7.33(s,1H),6.76(s,2H),4.23-2.24(br,2H),3.74(s ,3H),3.72(s,3H),3.19-3.25(m,1H),2.87-2.92(m,1H),2.50-2.68(m,1H),2.43-2.48(m,1H),2.33(s,4H),1.71-1.75(m,1H).

[0133] Example 2: Synthesis of N-(3-chloro-5-methylbenzyl)-6-iodo-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-2A) and N-(3-chloro-5-methylbenzyl)-7-iodo-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-2B) [ka] A solution of 1-1 (300 mg, 0.78 mmol, 1.0 equiv) and N-iodosuccinimide (350 mg, 1.5 mmol, 2.0 equiv) in AcOH (6 ml) was stirred at 70° C. for 48 h. The reaction was quenched with aqueous sodium bicarbonate, extracted with CHCl (2×10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified via preparative HPLC to give 1-2 as a mixture of 6 / 7 iodoisomers 1-2A and 1-2B (1:1 ratio, 5.0 mg, brown solid, 2% yield). Formula: C 20 H 23 ClINO2; MW: 471.76, LCMS: (ES + ): m / z 372.2[M+H] + t R =2.3 minutes. 1 HNMR(400MHz,DMSO-d6):δ7.42(s,1H),7.35(s,1H),7.32(s,1H),7.19(s,1 H),4.33-4.34(s,2H),3.81-3.83(s,3H),3.74-3.76(s,3H),3.52-3.58(m, 1H),3.43-3.48(m,1H),3.13-3.19(m,1H),3.52-3.58(m,1H),2.98-3.04(m ,1H),2.76-2.83(m,1H),2.56-2.67(m,1H),2.41(s,3H),1.74-1.84(m,1H).

[0134] Example 3: N-(3-fluoro-5-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-3) [ka] To a solution of 5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (141 mg, 0.58 mmol, 1 equiv) in DCM (5 mL) was added 3-fluoro-5-methylbenzaldehyde (80 mg, 0.58 mmol, 1 equiv), TEA (110 mg, 1.16 mmol, 1.5 equiv), and NaBH(OAc)3 (369 mg, 1.74 mmol, 3 equiv) at room temperature. The resulting mixture was stirred overnight. The reaction was quenched with aqueous NaHCO3 and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:1) to give the title compound as a colorless oil (162 mg, 84%). LCMS: 2.325 min, m / z 330.40[M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.74-7.62(m,2H),7.57-7.43(m,1H),6.79(s,2H),4.52(s,2H),3.81(s,3H),3.80(s,3H),3.72 -3.57(m,1H),3.48-3.39(m,1H),3.14-3.03(m,1H),2.77-2.60(m,2H),2.51-2.38(m,1H),1.84(qd,J=11.7,5.6Hz,1H).

[0135] Example 4: N-(3-bromo-5-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-4) [ka] The same procedure used to prepare 1-3 was applied to give the title compound as a colorless oil (111 mg, 71%). LCMS: 2.510 min, m / z 391.65 [M+H] + . 1H NMR (400MHz, methanol-d4) δ7.58(s,1H),7.51(s,1H),7.37(s,1H),6.78(s,2H),4.33(s,2H),3.81(s,3H),3.79(s,3H),3.5 9-3.46(m,1H),3.44-3.35(m,1H),3.13-3.02(m,1H),2.74-2.54(m,2H),2.48-2.33(m,4H),1.79(qd,J=12.0,5.5Hz,1H).

[0136] Example 5: N-(3-iodo-5-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-5) [ka] The same procedure used to prepare 1-3 was applied to give the title compound as a colorless oil (125 mg, 84%). LCMS: 2.440 min, m / z 438.50 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.77(s,1H),7.71(s,1H),7.39(s,1H),6.78(s,2H),4.29(s,2H),3.81(s,3H),3.79(s,3H),3.5 9-3.47(m,1H),3.43-3.35(m,1H),3.12-2.99(m,1H),2.72-2.55(m,2H),2.46-2.34(m,4H),1.78(qd,J=12.0,5.5Hz,1H).

[0137] Example 6: N-(2-chloro-5-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-6) [ka] The same procedure used to prepare 1-3 was applied to give the title compound as a colorless oil (130 mg, 72%). LCMS: 2.463 min, m / z 346.15 [M+H] + . 1H NMR (400MHz, methanol-d4) δ7.57(d,J=2.1Hz,1H),7.45-7.30(m,2H),6.79(s,2H),4.40(s,2H),3.82(s,3H),3.80(s,3H),3. 71-3.55(m,1H),3.49-3.38(m,1H),3.18-2.99(m,1H),2.77-2.58(m,2H),2.52-2.37(m,4H),1.82(qd,J=11.9,5.5Hz,1H).

[0138] Example 7: N-(4-chloro-3-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-7) [ka] The same procedure used for the preparation of 1-3 was applied to give the title compound, which was converted to the HCl salt EGX-13-6-HCl (35 mg, 30%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 345.9 [M+H] + . 1 H NMR(400MHz,CD3OD)7.53(d,J=1.7Hz,1H),7.48(d,J=8.2Hz,1H),7.39(dd,J=8. 2,2.0Hz,1H),6.77(s,2H),4.33(s,2H),3.81(s,3H),3.79(s,3H),3.60-3.47(m, 1H),3.39(dd,J=17.2,4.7Hz,1H),3.06(ddd,J=17.7,5.3,3.0Hz,1H),2.72-2.5 7(m,2H),2.44(s,3H),2.41(dd,J=6.2,3.5Hz,1H),1.81(qd,J=11.9,5.6Hz,1H).

[0139] Example 8: N-(3-chloro-4-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-8) [ka] The same procedure used to prepare 1-3 was applied to give the title compound (35 mg, 30%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 346 [M+H] + . 1 H NMR (400MHz, solvent: CD3OD) ppm 7.63(s,1H),7.43(d,J=7.1Hz,2H),6.77(s,2H),4.34(s,2H),3.81(s,3H),3.79(s,3H),3.53(tdd,J=11.3,5.4,2.9Hz,1H),3.44-3.35 (m,1H),3.06(ddd,J=17.7,5.4,3.1Hz,1H),2.72-2.57(m,2H),2.42(s,3H),2.40(dd,J=5.6,2.6Hz,1H),1.80(qd,J=11.8,5.6Hz,1H).

[0140] Example 9: N-(3-chloro-2-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-9) [ka] The same procedure used to prepare 3-1 was applied to give the title compound (20 mg, 20%) as a white solid after treatment with HCl in dioxane. LCMS: (ES + ): m / z 346.3[M+H] + . 1 H NMR(400MHz,MeOD)δ7.50(d,J=7.9Hz,1H),7.46(d,J=7.5Hz,1H),7.30(t,J=7. 8Hz,1H),6.76(s,2H),4.45(s,2H),3.79(s,3H),3.78(s,3H),3.64(d,J=11.4H z,1H),3.43(dd,J=16.4,4.4Hz,1H),3.07(d,J=18.1Hz,1H),2.66(dd,J=15.8, 10.3Hz, 2H), 2.52 (s, 3H), 2.45 (d, J = 12.7Hz, 1H), 1.81 (qd, J = 11.6, 5.4Hz, 1H).

[0141] Example 10: N-(2-chloro-3-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-10) [ka] The same procedure used for the preparation of 3-1 was applied to give the title compound (50 mg, 42%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 346 [M+H] + . 1 H NMR (400MHz, solvent: CD3OD)7.54-7.44(m,2H),7.36(t,J=7.6Hz,1H),6.78(s,2 H),4.54(s,2H),3.82(s,3H),3.80(s,3H),3.69-3.58(m,1H),3.43(dd,J=1 7.2,4.7Hz,1H),3.09(ddd,J=17.8,5.6,3.2Hz,1H),2.68(ddd,J=17.0,10. 8,4.5Hz,2H),2.48(s,3H),2.47-2.42(m,1H),1.84(qd,J=11.9,5.5Hz,1H).

[0142] Example 11: N-(4-chloro-2-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-11) [ka] The same procedure used to prepare 3-1 was applied to give the title compound (40 mg, 36%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 346 [M+H] + . 1 H NMR (400MHz, solvent: CD3OD)7.51(d,J=8.2Hz,1H),7.39(d,J=1.5Hz, 1H),7.34(dd,J=8.2,2.0Hz,1H),6.78(s,2H),4.39(s,2H),3.81(s,3H),3.80(s,3H),3.68-3.57(m,1H),3.44(dd,J=16.7,4.4 Hz,1H),3.09(ddd,J=17.8,5.4,3.0Hz,1H),2.75-2.61(m,2H),2.49(s,3H),2.48-2.42(m,1H),1.83(qd,J=11.9,5.6Hz,1H).

[0143] Example 12: N-(2-chloro-4-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine 3-12 [ka] The same procedure used to prepare 3-1 was applied to give the title compound (35 mg, 30% yield) as a white solid after treatment with HCl in dioxane. LCMS: m / z 346 [M+H] + . 1 H NMR (400MHz, solvent: CD3OD) 7.53(d,J=7.8Hz,1H),7.44(s,1H),7.29(d,J=7.7Hz,1H),6.78(s,2H),4.48(s,2H),3.81(s,3H),3.80(s,3H),3.67-3.55(m ,1H),3.47-3.36(m,1H),3.08(ddd,J=17.8,5.6,3.3Hz,1H),2.74-2.61(m ,2H),2.48-2.42(m,1H),2.41(s,3H),1.83(ddd,J=23.9,11.7,5.6Hz,1H).

[0144] Example 13: N-(2-chloro-5-methylbenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-13) [ka] The same procedure used to prepare 3-1 was applied to give the title compound E (26 mg, 30% yield) as a white solid after treatment with HCl in dioxane. LCMS: (ES+ ): m / z 347.1 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.50(d,J=1.7Hz,1H),7.46(d,J=8.2Hz,1H),7.32(dd,J=8.2,1.7Hz,1H),6.78(s,2H),4.49(s,2H),3.81(s,3H),3.80(s,3H),3. 66-3.58(m,1H),3.43(dd,J=16.5,4.0Hz,1H),3.08(ddd,J=17.8,5.5,3.0H z,1H),2.74-2.63(m,2H),2.50-2.39(m,4H),1.84(qd,J=11.9,5.6Hz,1H).

[0145] Example 14: N-(2,4-dichlorobenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-14) [ka] The same procedure used to prepare 3-1 was applied to give the title compound as a colorless oil (148 mg, 88%). LCMS: 2.465 min, m / z 368.00 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.73-7.64(m,2H),7.55-7.49(m,1H),6.79(s,2H),4.52(s,2H),3.81(s,3H),3.80(s,3H),3.70 -3.58(m,1H),3.47-3.38(m,1H),3.14-3.03(m,1H),2.77-2.61(m,2H),2.50-2.38(m,1H),1.85(tt,J=11.8,5.9Hz,1H).

[0146] Example 15: N-(3,5-dichlorobenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-15) [ka] The same procedure used to prepare 3-1 was applied to give the title compound as a colorless oil (138 mg, 82%). LCMS: 2.458 min, m / z 366.15 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.61 (s, 3H), 6.78 (s, 2H), 4.39 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.62-3.52 (m, 1H), 3.44-3.36 (m, 1H), 3.12-3.02 (m, 1H), 2.72-2.59 (m, 2H), 2.46-2.36 (m, 1H), 1.80 (qd, J = 11.9, 5.5 Hz, 1H).

[0147] Example 16: N-(3,4-dichlorobenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-16) [ka] The same procedure used to prepare 3-1 was applied to give the title compound (20 mg, 20%) as a white solid after treatment with HCl in dioxane. LCMS: (ES + ): m / z 367.3[M+H] + . 1 H NMR(400MHz,MeOD)δ7.79(d,J=1.9Hz,1H),7.66(d,J=8.3Hz,1H),7.50(dd,J=8.3,2.0Hz,1H),6.76(s,2H),4.37(s,2H),3.79(s,3H),3.78(s ,3H),3.61-3.50(m,1H),3.37(dd,J=16.7,4.4Hz,1H),3.10-3.00(m,1 H),2.71-2.58(m,2H),2.44-2.35(m,1H),1.79(qd,J=11.8,5.6Hz,1H).

[0148] Example 17: N-(2,3-dichlorobenzyl)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-17) [ka] The same procedure used to prepare 3-1 was applied to give the title compound as a colorless oil (111 mg, 66%). LCMS: m / z 367.65 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.71(dd,J=8.1,1.5Hz,1H),7.64(dd,J=7.7,1.5Hz,1H),7.47(t,J=7.9Hz,1H),6.79(s,2H),3.82(s,3H),3.8 0(s,3H),3.73-3.57(m,1H),3.49-3.37(m,1H),3.15-3.03(m,1H),2.77-2.60(m,2H),2.53-2.40(m,1H),1.85(qd,J=11.9,5.5Hz,1H).

[0149] Example 18: N-benzyl-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-amine (1-18) [ka] The same procedure used to prepare 3-1 was applied to give the title compound as a colorless oil (3.93 g, 90%). LCMS: (ES-): m / z 298.6 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.62-7.54(m,2H),7.55-7.45(m,3H),6.78(s,2H),4.37(s,2H),3.81(s,3H),3.79(s,3H),3.59 -3.48(m,1H),3.44-3.36(m,1H),3.11-3.03(m,1H),2.76-2.56(m,1H),2.45-2.38(m,1H),1.80(qd,J=11.8,5.6Hz,1H).

[0150] Example 19: N-(3-chloro-5-methylbenzyl)-5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydro-naphthalen-2-amine hydrochloride (1-19) [ka] Step 1: [2-hydroxy-5-methoxy-3-methylbenzaldehyde] 4-Methoxy-2-methylphenol (4.6 g, 33 mmol, 1.0 equiv), MgCl2 (5.0 g, 50.0 mmol, 1.5 equiv), (CHO) in ACN (25 mL) n A solution of (3.3 g, 110.0 mmol, 3.2 equiv) and TEA (5.0 g, 50.0 mmol, 1.5 equiv) was stirred at 85 °C for 2-3 h. The reaction mixture was cooled to room temperature and poured into ice water (200 mL). The resulting mixture was adjusted to pH = 3 with hydrochloric acid (4 N) and extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether:EA = 95:5) to give the title compound (5.0 g, 80%) as a yellow solid. 1 H NMR (400 MHz, solvent: CDCl3) ppm 10.94 (s, 1H), 9.84 (s, 1H), 7.02-7.03 (d, J=3.2 Hz, 1H), 6.83-6.84 (d, J=3.2, 1H), 3.80 (s, 3H), 2.26 (s, 3H).

[0151] Step 2: EGX-9-1-2 [2,5-dimethoxy-3-methylbenzaldehyde] A solution of 2-hydroxy-5-methoxy-3-methylbenzaldehyde (5.0 g, 30.0 mmol, 1.0 equiv), CHI (8.5 g, 60.0 mmol, 2.0 equiv), and KCO (10.0 g) in DMF (20 mL) was stirred at room temperature overnight. TLC was monitored until the starting material was consumed. The reaction mixture was poured into water (30 mL) and extracted with MTBE (50 mL×3). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over NaSO, and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether:EA=95:5) to give the title compound (5.2 g, 90%) as a yellow solid. 1H NMR (400MHz, solvent: CDCl3)ppm 10.35(s,1H),7.14-7.15(d,J=3.2Hz,1H),7.01-7.02(d,J=3.2,1H),3.84(s,3H),3.80(s,3H),2.31(s,3H).

[0152] Step 3: (E)-4-(2,5-dimethoxy-3-methylphenyl)but-3-enoic acid To a solution of 2,5-dimethoxy-3-methylbenzaldehyde (2.4 g, 13.3 mmol) in THF (40 mL) was added (2-carboxyethyl)triphenylphosphonium (8.3 g, 20 mmol, 1.5 equiv.) and t-BuOK solution in THF (40 mL, 40 mmol, 3 equiv.) at 0° C. The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with water, basified with sodium hydroxide, and extracted with EtOAc (50 mL). The aqueous phase was adjusted to pH=2 with hydrochloric acid solution and extracted with DCM (30 mL×3). The combined organic layers were washed with water (25 mL), then with brine (25 mL), dried over Na2SO4, filtered, and concentrated to give the crude product (4.48 g), which was used in the next step without further purification.

[0153] Step 4: 4-(2,5-dimethoxy-3-methylphenyl)butanoic acid To a solution of (E)-4-(2,5-dimethoxy-3-methylphenyl)but-3-enoic acid (4.48 g, 13.2 mmol) in MeOH (20 mL) was added Pd / C (250 mg) at room temperature. The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the filtrate was concentrated to give the crude product, which was used in the next step without further purification (3.88 g, 100%).

[0154] Step 5: 5,8-Dimethoxy-6-methyl-3,4-dihydronaphthalen-1(2H)-one To a solution of 4-(2,5-dimethoxy-3-methylphenyl)butanoic acid (3.88 g, 13.3 mmol) in TFA (10 mL) was added TFAA (8.5 mL, 66.6 mmol, 5 equiv.) at room temperature and the reaction mixture was stirred overnight. The reaction was diluted with EtOAc, washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (petroleum ether: EtOAc = 5: 1) to give the title compound (1.2 g, 56%) as a colorless oil.

[0155] Step 6: (E)-2-(hydroxyimino)-5,8-dimethoxy-6-methyl-3,4-dihydronaphthalen-1(2H)-one To a solution of 5,8-dimethoxy-6-methyl-3,4-dihydronaphthalen-1(2H)-one (1.2 g, 5.45 mmol) in t-BuOH / Et2O (10 mL / 10 mL) was added t-BuOK (911 mg, 8.12 mmol, 1.5 equiv.) and tert-butyl nitrite (842.7 mg, 8.12 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred overnight. The reaction was quenched with water (25 mL), adjusted to pH=2 with hydrochloric acid solution, and extracted with DCM (30 mL×3). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (DCM:MeOH=100:1) to give the title compound as a yellow solid (700 mg, 51%).

[0156] Step 7: N-(5,8-dimethoxy-6-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide To a solution of (E)-2-(hydroxyimino)-5,8-dimethoxy-6-methyl-3,4-dihydronaphthalen-1(2H)-one (500 mg, 2.27 mmol, 1.3 equiv.) in AcOH (6 mL) was added Zn (445 mg, 6.81 mmol, 3 equiv.) and Ac2O (4 mL) at room temperature under N2. The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the filtrate was diluted with water, adjusted to pH=8 with sodium hydroxide (4M in water) and extracted with EtOAc. The extract was washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:1) to give the title compound as a colorless oil (180 mg, 40%).

[0157] Step 8: N-(1-hydroxy-5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide To a solution of N-(5,8-dimethoxy-6-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (184 mg, 0.664 mmol) in MeOH (10 mL) was added NaBH4 (75.6 g, 2.0 mmol, 3 equiv.) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc, washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was used in the next step without further purification (203 mg, 100%).

[0158] Step 9: 2-Amino-5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-1-ol To a solution of N-(1-hydroxy-5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (158 mg, 0.565 mmol) in H2O (5 mL) was added concentrated hydrochloric acid (12 M in water) (0.8 mL) at room temperature. The reaction mixture was stirred at reflux for 2 h, cooled to room temperature, and adjusted to pH = 8 with sodium hydroxide (4 M in water). The reaction mixture was extracted with EtOAc. The organic layer was washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was used in the next step without further purification (143 mg, 56%). 1 H NMR (400 MHz, methanol-d4) δ 6.74 (s, 1H), 5.03 (dd, J = 3.7, 1.3 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 3.38-3.34 (m, 1H), 3.16-3.10 (m, 1H), 2.76-2.67 (m, 1H), 2.30 (s, 3H), 2.14-2.04 (m, 1H), 1.99-1.92 (m, 1H).

[0159] Step 10: 5,8-Dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-2-amine To a solution of 2-amino-5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (80 mg, 0.33 mmol) in TFA (6 mL) was added Et3SiH (206 mg, 1.65 mmol, 5 equiv.) at room temperature and the reaction mixture was stirred. The reaction was diluted with water (25 mL) and adjusted to pH=10 with sodium hydroxide (4 M in water). The reaction mixture was extracted with EtOAc. The organic layer was washed with water, then with brine (25 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:1) to give the title compound as a colorless oil (64 mg, 86%). 1H NMR (400MHz, methanol-d4) δ6.65(s,1H),3.80(s,3H),3.69(s,3H),3.50(m,1H),3.19(dd,J=17.2Hz,6.0Hz,1H),3.06(d t,J=17.5,4.8Hz,1H),2.81(m,1H),2.53(dd,J=16.8,9.8Hz,1H),2.28(s,3H),2.25-2.14(m,1H),1.90-1.65(m,1H).

[0160] Step 11: N-(3-chloro-5-methylbenzyl)-5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-2-amine To a solution of 3-chloro-5-methylbenzaldehyde (33.5 mg, 0.217 mmol, 1.2 equiv) in DCM (5 mL) were added 5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-2-amine (38 mg, 0.18 mmol) and NaBH(OAc)3 (137.8 mg, 0.65 mmol, 3 equiv) at room temperature and the reaction mixture was stirred overnight. The reaction was quenched with aqueous NaHCO3 and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100 / 1) to give the title compound as a colorless oil (41 mg, 67%). LCMS: (ES-): m / z 360.4 [M+H] + .

[0161] Step 12: N-(3-chloro-5-methylbenzyl)-5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride To a solution of N-(3-chloro-5-methylbenzyl)-5,8-dimethoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-2-amine (41 mg, 0.1 mmol) in MTBE (5 mL) was added 4M HCl in dioxane (0.1 mL, 0.4 mmol, 4 equiv.) at room temperature. The mixture was stirred at room temperature for 2 h. The suspension was filtered to give the title compound as a white solid (39 mg, 86%). LCMS: (ES-): m / z 360.4 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.43(s,1H),7.34(d,J=7.9Hz,2H),6.67(s,1H),4.33(s,2H),3.82(s,3H),3.69(s,3H),3.62-3.46(m,1H),3.37-3. 34(m,1H),3.17-3.10(m,1H),2.82-2.70(m,1H),2.60(dd,J=16.6,10. 4Hz, 1H), 2.46-2.40 (m, 1H), 2.28 (s, 3H), 1.78 (qd, J=12.0, 5.3Hz, 1H).

[0162] Example 20: N-(3-chloro-5-methylbenzyl)-4,7-dimethoxy-2,3-dihydro-1H-inden-2-amine hydrochloride (1-20) [ka] The same procedure as for the preparation of 1-19 was applied to give the title compound as a white solid (153 mg, 81%). LCMS: (ES-): m / z 332.3 [M+H] + . 1 H NMR (400MHz, solvent: CD3OD) ppm 7.40(s,1H),7.34(s,1H),7.30(s,1H),6.80(s,2H),4.27(s,2H),4.19-4.15(m,1H),3. 81(s,6H),3.47-3.41(m,2H),3.10(d,J=6.0Hz,1H),3.06(d,J=6.0Hz,1H),2.41(s,3H).

[0163] Example 21: N-(3-chloro-5-methylbenzyl)-4,7-dimethoxy-2,3-dihydro-1H-inden-1-amine (1-21) [ka] The same procedure as for the preparation of 1-19 was applied to give the title compound as a colorless oil (174 mg, 78%). LCMS: (ES-): m / z 332.3 [M+H] + . 1 H NMR (400MHz, solvent: CDCl3) ppm 7.17(s,1H),7.04(d,J=4.8Hz,2H),6.65(dd,J=15.6Hz,8.8Hz,2H),4.50(dd,J=7.6Hz,4.4Hz,1H),3.78(d,J=5.2Hz,6H),3.7 1(dd,J=20.8Hz,13.2Hz,2H),3.05-2.97(m,1H),2.57-2.50(m,1H),2.82-2.74(m,1H),2.33-2.24(m,4H),2.05-1.97(m,1H).

[0164] Example 22: Synthesis of N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-1) [ka] Step 1: Preparation of 2-(2,5-dimethoxyphenyl)ethan-1-amine hydrochloride A mixture of 2-(2,5-dimethoxyphenyl)acetonitrile (2.0 g, 11 mmol, 1.0 equiv) and NaBH4 (1.24 g, 33 mmol, 3.0 equiv) in THF (30 ml) was stirred at 0° C. for 0.5 h, followed by the addition of boron fluoride / ethyl ether (5.4 g, 38.5 mmol, 3.5 equiv) and the resulting mixture was warmed to 50° C. and stirred overnight. TLC was monitored until the starting material was consumed. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 5% MeOH in DCM gradient) to give 2-(2,5-dimethoxyphenyl)ethan-1-amine hydrochloride (1.7 g, 85% yield) as a colorless oil. The free amine was converted to the HCl salt EGX-4-14-HCl (2.0 g, 90% yield) as a white solid after treatment with HCl in dioxane (4.0 M). LCMS: (ES+): m / z 182 [M+H] + . 1 H NMR (400MHz, DMSO-d6)ppm 8.10(s,2H),6.90-6.92(d,1H),6.79-9.61(m,2H),3.74(s,3H),3.70(s,3H),2.93-2.97(m,2H),2.81-2.85(m,2H).

[0165] Step 2: [N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine] A suspension of 2-(2,5-dimethoxyphenyl)ethan-1-amine hydrochloride (510 mg, 2.3 mmol, 1 equiv.), 3-chloro-5-methylbenzaldehyde (350 mg, 2.3 mmol, 1 equiv.), NaBH(OAc)3 (2.44 g, 11.5 mmol, 5 equiv.), and TEA (0.35 g, 3.4 mmol, 1.5 equiv.) in DCM (5 ml) was stirred at room temperature overnight. The reaction was monitored by TLC until completion. The resulting mixture was poured into water (15 ml), followed by the addition of aqueous Na2CO3 and adjusting the pH to 9. The reaction mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 2% MeOH in DCM gradient) to give compound 2-1, which was converted to the HCl salt (200 mg, 27% yield) as a white solid after treatment with HCl in dioxane (4.0 M). LMS: (ES+): m / z 320 [M+H] + . 1 H NMR (400MHz, solvent: CDCl3)ppm 9.26(s,2H),7.47(s,1H),7.33-7.31(d,2H),6.91-6.94(d,1H),6.79-6.82(m,2H),4.1 4(s,2H),3.74(s,3H),3.71(s,3H),3.051-3.07(m,2H),2.93-2.95(m,2H),2.34(s,3H).

[0166] Example 23: Synthesis of 2-(2,5-dimethoxyphenyl)-N-(3-fluoro-5-methylbenzyl)ethan-1-amine (2-2) [ka] Step 1: 2-(2,5-dimethoxyphenyl)-N-(3-fluoro-5-methylbenzyl)ethan-1-amine To a solution of 3-fluoro-5-methylbenzaldehyde (80 mg, 0.58 mmol) in DCM (5 mL) was added 2-(2,5-dimethoxyphenyl)ethan-1-amine hydrochloride (105 mg, 0.58 mmol, 1.0 equiv), Et3N (110 mg), and NaBH(OAc)3 (368.9 mg, 1.74 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NaHCO3 and then extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100 / 1) to give the title compound as a colorless oil (94 mg, 54%). LCMS: (ES-): m / z 304.6 [M+H]+. tR=2.190 minutes.

[0167] Step 2: 2-(2,5-dimethoxyphenyl)-N-(3-fluoro-5-methylbenzyl)ethan-1-amine hydrochloride To a solution of 2-(2,5-dimethoxyphenyl)-N-(3-fluoro-5-methylbenzyl)ethan-1-amine (94 mg, 0.31 mmol) in MTBE (5 mL) was added 4M HCl in dioxane (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The suspension was filtered and dried to give the title compound as a white solid (93 mg, 89%). 1H NMR (400MHz, methanol-d4) δ7.16(s,1H),7.07(t,J=9.6Hz,2H),6.94(d,J=8.6Hz,1H),6.89-6.79(m ,2H),4.21(s,2H),3.81(s,3H),3.77(s,3H),3.29-3.19(m,2H),3.05-3.00(m,2H),2.42(s,3H).

[0168] Example 24: Synthesis of N-(2-chloro-4-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine 2-3) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound EGX-2-3, which was converted to the HCl salt (60 mg, 42%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 321 [M+H]+. 1H NMR (400MHz, solvent: DMSO) δ9.38(d,J=1.2Hz,2H),7.62(d,J=7.9Hz,1H),7.40(s,1H),7.26(d,J=7.8Hz,1H),6.96-6.88(m,1H) ,6.84-6.77(m,2H),4.25(s,2H),3.73(s,3H),3.70(s,3H),3.13(d,J=3.7Hz,2H),2.97(dd,J=9.8,6.3Hz,2H),2.33(s,3H).

[0169] Example 25: Synthesis of N-(2-chloro-5-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-4) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound EGX-12-11, which was converted to HCl (54 mg, 37% yield) as a white solid after treatment with HCl in dioxane. LCMS: m / z 320 [M+H]+. 1H NMR (400MHz, solvent: DMSO)9.40(s,2H),7.58(d,J=1.5Hz,1H),7.44(d,J=8.2Hz,1H),7.28(dd,J=8.2,1.6Hz,1H),6.93(d,J=9.7Hz,1H), 6.82(dd,J=5.9,2.9Hz,2H),4.25(s,2H),3.74(s,3H),3.71(s,3H),3.14(d,J=8.7Hz,2H),2.98(dd,J=9.8,6.3Hz,2H),2.33(s,3H).

[0170] Example 26: N-(2,4-dichlorobenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-5) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound EGX-12-12, which was converted to the HCl salt (180 mg, 58%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 341 [M+H] + . 1 H NMR (400MHz, solvent: DMSO)9.42(s,2H),7.80-7.75(m,2H),7.58(dd,J=8.3,2.2Hz,1H),6.96-6.90(m,1H),6.82( dd,J=7.3,2.7Hz,2H),4.29(s,2H),3.74(s,3H),3.70(s,3H),3.21-3.12(m,2H),2.96(dd,J=9.6,6.5Hz,2H).

[0171] Example 27: N-(3,5-dichlorobenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-6) [ka] 3.18(m,2H), 3.05-2.93(m,2H).

[0172] Example 28: N-(3,4-dichlorobenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-7) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt (50 mg, 32%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 341 [M+H] + . 1 H NMR (400MHz, solvent: DMSO)9.49(s,2H),7.91(d,J=1.9Hz,1H),7.72(d,J=8.3Hz,1H),7.58(dd,J=8.3,2.0Hz,1H),6.92(d,J =8.5Hz,1H),6.81(dd,J=11.8,3.1Hz,2H),4.19(s,2H),3.73(s,3H),3.70(s,3H),3.12-3.02(m,2H),2.99-2.90(m,2H).

[0173] Example 29: N-(2,3-dichlorobenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-8) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt (185 mg, 64%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 341 [M+H] + . 1 H NMR (400MHz, solvent: DMSO)9.61(s,2H),7.80-7.69(m,2H),7.48(t,J=7.9Hz,1H),6.97-6.90(m,1H),6.81(dd,J=7. 2,2.6Hz,2H),4.35(s,2H),3.74(s,3H),3.70(s,3H),3.18(dd,J=9.7,6.4Hz,2H),2.99(dd,J=9.7,6.4Hz,2H).

[0174] Example 30: 2-(2,5-dimethoxyphenyl)-N-(3-methyl-5-nitrobenzyl)ethan-1-amine (2-9) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt (50 mg, 33%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 331 [M+H]+. 1H NMR (400 MHz, solvent: DMSO) 9.40 (d, J = 0.7 Hz, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.86-6.75 (m, 2H), 4.29 (d, J = 4.3 Hz, 2H), 3.73 (s, 3H), 3.70 (s, 3H), 3.10 (d, J = 3.8 Hz, 2H), 2.99-2.90 (m, 2H), 2.47 (s, 3H).

[0175] Example 31: N-(3-bromo-5-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-10) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound as a colorless oil (45 mg, 31%) LCMS: (ES-): m / z 365.9 [M+H]+. tR=2.432 min; (40 mg, 80%). 1H NMR (400 MHz, methanol-d4) δ 7.50 (s, 2H), 7.29 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.89-6.79 (m, 2H), 4.19 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.29-3.21 (m, 2H), 3.06-2.99 (m, 2H), 2.40 (s, 3H).

[0176] Example 32: 2-(2,5-dimethoxyphenyl)-N-(3-iodo-5-methylbenzyl)ethan-1-amine (2-11) [ka] The same procedure used to prepare 2-2 was applied to give the title compound as a white solid hydrochloride salt (40 mg, 80%). LCMS: (ES-): m / z 412.35 [M+H] + t R =2.419 minutes; 1 H NMR (400MHz, methanol-d4) δ7.70(s,2H),7.32(s,1H),6.94(d,J=8.8Hz,1H),6.88-6.80(m,2H), 4.15(s,2H),3.82(s,3H),3.77(s,3H),3.28-3.21(m,2H),3.01(d,J=8.3Hz,2H),2.37(s,3H).

[0177] Example 33 N-(5-chloro-2-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-12 [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt (80 mg, 62%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 321 [M+H] + . 1 H NMR (400MHz, solvent: DMSO) δ9.39(d,J=0.5Hz,2H),7.66(d,J=2.2Hz,1H),7.37(dd,J=8.2,2.2Hz,1H),7.29(d,J=8.3Hz,1H),6.97-6.90 (m,1H),6.86-6.78(m,2H),4.16(s,2H),3.75(s,3H),3.71(s,3H),3.17(d,J=4.8Hz,2H),3.00(dd,J=10.0,6.3Hz,2H),2.37(s,3H).

[0178] Example 34: N-(3-chloro-4-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-13) [ka] The same procedure was used to prepare 2-2, which was converted to the HCl salt (80 mg, 61%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 321 [M+H] + . 1 H NMR (400MHz, solvent: DMSO)9.46(s,2H),7.67(d,J=1.1Hz,1H),7.48-7.38(m,2H),6.91(d,J=8.7Hz,1H),6.80(dt,J=8.9, 3.0Hz,2H),4.13(s,2H),3.72(s,3H),3.70(s,3H),3.05(d,J=19.6Hz,2H),2.94(dd,J=9.6,5.2Hz,2H),2.34(s,3H).

[0179] Example 35: N-(4-chloro-3-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-14) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt EGX-12-6-HCl (80 mg, 61%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 321 [M+H]+. 1H NMR (400MHz, solvent: d6-DMSO)9.37(s,1H),7.54(d,J=1.4Hz,1H),7.49(d,J=8.2Hz,1H),7.41(dd,J=8.2,1.8Hz,1H),6.92(d,J=8.8Hz,1H),6. 80(dt,J=7.1,3.0Hz,2H),4.12(t,J=4.6Hz,2H),3.72(s,3H),3.70(s,3H),3.12-3.00(m,2H),2.93(dd,J=9.8Hz,5.9Hz,2H),2.34(s,3H).

[0180] Example 36: N-(3-chloro-2-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-15) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt (82 mg, 62%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 321 [M+H] + . 1 H NMR (400MHz, solvent: DMSO) δ9.35(d,J=29.0Hz,2H),7.51(t,J=7.7Hz,2H),7.30(t,J=7.9Hz,1H),6.93(d,J=9.7Hz,1H),6.82(dd,J=6 .6,3.0Hz,2H),4.25(d,J=5.1Hz,2H),3.75(s,3H),3.71(s,3H),3.17(d,J=4.9Hz,2H),2.98(dd,J=9.8,6.4Hz,2H),2.43(s,3H).

[0181] Example 37: N-(2-chloro-3-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-16) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt (80 mg, 61%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 321 [M+H] + . 1 H NMR (400MHz, solvent: DMSO) δ9.43(s,1H),7.58(d,J=7.5Hz,1H),7.44(d,J=6.8Hz,1H),7.34(t,J=7.6Hz,1H),6.96-6.89(m,1H) ),6.84-6.78(m,2H),4.31(s,2H),3.74(s,3H),3.70(s,3H),3.21-3.11(m,2H),2.98(dd,J=9.9,6.3Hz,2H),2.38(s,3H).

[0182] Example 38: N-(4-chloro-2-methylbenzyl)-2-(2,5-dimethoxyphenyl)ethan-1-amine (2-17) [ka] The same procedure used for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt (80 mg, 61%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 321 [M+H] + . 1 H NMR (400MHz, solvent: DMSO) δ9.31(d,J=0.7Hz,2H),7.56(d,J=8.2Hz,1H),7.37(s,1H),7.37-7.33(m,1H),6.96-6.90(m,1H),6.82(dd ,J=6.3,3.0Hz,2H),4.15(s,2H),3.74(s,3H),3.70(s,3H),3.15(dd,J=1.6,0.8Hz,2H),2.98(dd,J=9.8,6.3Hz,2H),2.40(s,3H).

[0183] Example 39: N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-methylphenyl)ethan-1-amine (2-18) [ka] Step 1: 1,4-Dimethoxy-2-methyl-5-(2-nitrovinyl)benzene A suspension of 2,5-dimethoxy-4-methylbenzaldehyde (300 mg, 1.66 mmol, 2.5 equiv) and ammonium acetate (51.3 mg, 0.67 mmol, 1 equiv) in nitromethane (10 mL) was stirred at room temperature overnight. After the reaction was completed as confirmed by TLC, some yellow solid appeared. Water and 5 mL of EtOH were added and the mixture was stirred at room temperature for 30 min. The resulting yellow solid was filtered, washed with water (10 mL x 3) and dried at 50 °C to give the title compound (400 mg, 100% yield) as a yellow solid. LCMS: 3.143 min, m / z 224.00 [M+H] +

[0184] Step 2: 2-(2,5-dimethoxy-4-methylphenyl)ethan-1-amine A suspension of LAH (190 mg, 5.01 mmol, 3 equiv.) in 5 mL of THF was cooled to 0° C. under the protection of nitrogen, and then 1,4-dimethoxy-2-methyl-5-(2-nitrovinyl)benzene (400 mg, 1.66 mmol, 1 equiv.) dissolved in 5 mL of THF was added. The resulting mixture was heated to reflux. After the reaction was completed as confirmed by TLC, 2 mL of water was added to quench the LAH. Na2CO3 was added to adjust the pH to 11. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (DCM / CH3OH=20:) to give the title compound (352 mg, 100%) as a colorless oil. LCMS: 1.872 min, m / z 196.30 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 6.83 (s, 1H), 6.77 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.14 (t, J = 7.4 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 2.20 (s, 3H).

[0185] Step 3: EGX-15-2 N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-methylphenyl)ethan-1-amine (2-28) To a stirred solution of 2-(2,5-dimethoxy-4-methylphenyl)ethan-1-amine (150 mg, 0.77 mmol, 1.0 equiv.) and 3-chloro-5-methylbenzaldehyde (119 mg, 0.77 mmol, 1.0 equiv.) in dichloromethane (5 mL) was added NaBH(OAc)3 (488 mg, 2.3 mmol, 3.0 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by flash chromatography (eluted with petroleum ether / EA=1:1) to give the title compound which was converted to the HCl salt EGX-15-1-HCl (100 mg, 35%) as a white solid after treatment with HCl in dioxane. LCMS: 2.637 min, m / z 333.95[M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.34(s,2H),7.25(s,1H),6.83(s,1H),6.79(s,1H),4.19(s,2H), 3.80(s,3H),3.80(s,3H),3.29-3.19(m,2H),3.04-2.96(m,2H),2.40(s,3H),2.20(s,3H).

[0186] Example 40: N-(3-chloro-5-methylbenzyl)-2-(4-ethyl-2,5-dimethoxyphenyl)ethan-1-amine (2-19) [ka] The same procedure used for the preparation of 2-18 was applied to give the title compound, which was converted to the HCl salt EGX-15-2-HCl (90 mg, 32% yield) as a white solid after treatment with HCl in dioxane. LCMS: 2.730 min, m / z 348.25 [M+H] + . 1H NMR (400MHz, methanol-d4) δ7.41-7.32(m,2H),7.25(s,1H),6.82(d,J=7.9Hz,2H),4.19(s,2H),3.82(s,3H),3.80(s,3H) ),3.24(dd,J=9.0,6.4Hz,2H),3.01(dd,J=9.0,6.4Hz,2H),2.63(q,J=7.5Hz,2H),2.40(s,3H),1.18(t,J=7.5Hz,3H).

[0187] Example 41: N-(3-chloro-5-methylbenzyl)-2-(4-fluoro-2,5-dimethoxyphenyl)ethan-1-amine (2-20) [ka] Step 1: 4-Fluoro-2,5-dimethoxybenzaldehyde To a solution of 2-fluoro-1,4-dimethoxybenzene (1 g, 6.41 mmol, 1 equiv) in DCM (5 mL) was added dichloro(methoxy)methane (0.80 g, 7 mmol, 1.1 equiv), followed by SnCl4 (3.34 g, 12.82 mmol, 2 equiv) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and then extracted with EA (50 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (eluted with petroleum ether / EA=1:1) to give the title compound as a colorless oil (1.36 g, 100%). LCMS: 2.602 min, m / z 185.10 [M+H]+.

[0188] Step 2: 1-Fluoro-2,5-dimethoxy-4-(2-nitrovinyl)benzene The same procedure used for the preparation of 2-18 was applied to give the title compound EGX-15-5-2 (858 mg, 51%) as a yellow solid. LCMS: 2.963 min, m / z 491.20 [M+H]+

[0189] Step 3: 2-(4-fluoro-2,5-dimethoxyphenyl)ethan-1-amine hydrochloride The same procedure used for the preparation of 2-18 was applied to give the title compound, which was converted to the HCl salt (328 mg, 79%) as a white solid after treatment with HCl in dioxane. LCMS: 1.435 min, m / z 200.30 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.00 (d, J = 9.4 Hz, 1H), 6.88 (d, J = 13.0 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.17-3.12 (m, 2H), 2.94 (t, J = 7.4 Hz, 2H).

[0190] Step 4: N-(3-chloro-5-methylbenzyl)-2-(4-fluoro-2,5-dimethoxyphenyl)ethan-1-amine (2-20) The same procedure used for the preparation of 2-18 was applied to give the title compound, which was converted to the HCl salt (136 mg, 57%) as a white solid after treatment with HCl in dioxane. LCMS: 2.417 min, m / z 338.35 [M+H]+.

[0191] Example 42: 2-(4-chloro-2,5-dimethoxyphenyl)-N-(3-chloro-5-methylbenzyl)ethan-1-amine (2-21) [ka] The same procedure for the preparation of 2-20 was applied to give the title compound, which was converted to the HCl salt (86 mg, 36%) as a white solid after treatment with HCl in dioxane. LCMS: 2.470 min, m / z 354.45 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.36 (s, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 4.21 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.30-3.22 (m, 2H), 3.07-2.99 (m, 2H), 2.42-2.36 (s, 3H).

[0192] Example 43: 2-(4-bromo-2,5-dimethoxyphenyl)-N-(3-chloro-5-methylbenzyl)ethan-1-amine (2-22) [ka] The same procedure for the preparation of 2-18 was applied to give the title compound, which was converted to the HCl salt (40 mg, 35%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 399.04 [M+H] + . 1 H NMR (400MHz, solvent: DMSO) δ9.33(s,2H),7.48(s,1H),7.33(s,2H),7.21(s,1H),7.02(s,1H), 4.13(s,2H),3.80(s,3H),3.76(s,3H),3.14-3.02(m,2H),3.01-2.92(m,2H),2.33(s,3H).

[0193] Example 44 4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile (2-23) [ka] Step 1: 2-(4-iodo-2,5-dimethoxyphenethyl)isoindoline-1,3-dione A suspension of 2-(4-iodo-2,5-dimethoxyphenyl)ethan-1-amine (1 g, 3.25 mmol, 1 equiv.) and phthalic anhydride (0.53 g, 3.58 mmol, 1.1 equiv.) in 3 mL of DMF was heated to reflux overnight. After the reaction was complete as confirmed by TLC, 30 mL of water was added and a white solid was formed. The solid was filtered and washed with EtOH (5 mL x 3) and petroleum ether (5 mL x 3) to give the title compound (1 g, 64%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.83 (d, J = 1.2 Hz, 5H), 7.19 (s, 1H), 6.77 (s, 1H), 3.81 (t, 2H), 3.61 (s, 3H), 3.54 (s, 3H), 2.87 (t, 2H).

[0194] Step 2: 4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2,5-dimethoxybenzonitrile A suspension of 2-(4-iodo-2,5-dimethoxyphenethyl)isoindoline-1,3-dione (600 mg, 1.37 mmol, 1 equiv.) and copper cyanide (135 mg, 1.5 mmol, 1.1 equiv.) in 1.5 mL of DMF was heated to reflux overnight. A solid formed as the reaction was cooled to room temperature. The solid was filtered and washed with petroleum ether (10 mL×3) to give the title compound (550 mg, 89%) as a white solid. LCMS: m / z 337.05. 1 H NMR (400MHz, DMSO) δ7.83(s,5H),7.21(s,1H),7.05(s,1H),3.91-3.80(t,2H),3.72(s,3H),3.56(s,3H),2.96(t,J=6.5Hz,2H).

[0195] Step 3: 4-(2-aminoethyl)-2,5-dimethoxybenzonitrile A suspension of 4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2,5-dimethoxybenzonitrile (200 mg, 0.59 mmol, 1 equiv.) and hydrazine hydrate (59 mg, 1.48 mmol, 2.5 equiv.) in 5 mL of EtOH was heated to reflux for 20 min. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (eluted with DCM / CH3OH=20:1) to give the title compound (35 mg, 28%). LCMS: m / z 207.24 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 6.82 (s, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 2.94 (s, 2H), 2.80 (t, J=6.9 Hz, 2H).

[0196] Step 4: 4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile (2-23) The same procedure for the preparation of 2-18 was applied to give the title compound, which was converted to the HCl salt EGX-15-8-HCl (20 mg, 34%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 346.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ7.17(s,1H),7.07(s,1H),6.96(s,1H),6.87(s,1H),6.76(s,1H),3.8 8(s,3H),3.86(s,2H),3.78(s,3H),3.03(d,J=8.3Hz,2H),2.74-2.59(m,2H),2.18(s,3H).

[0197] Example 45: N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-(methylthio)phenyl)ethan-1-amine (2-24) [ka] Step 1: 2,5-Dimethoxy-4-(methylthio)benzaldehyde The same procedure used to prepare 2-20 was applied to give the title compound as a colorless oil (1.45 g, 100%). LCMS: 2.717 min, m / z 213.30 [M+H] + .

[0198] Step 2: EGX-15-10-2 (2,5-dimethoxy-4-(2-nitrovinyl)phenyl)(methyl)sulfane The same procedure used to prepare 2-20 was applied to give the title compound (385 mg, 22%) as a yellow solid. LCMS: 1.818 min, m / z 228.40 [M+H] + .

[0199] Step 3: 2-(2,5-dimethoxy-4-(methylthio)phenyl)ethan-1-amine hydrochloride The same procedure used for the preparation of 2-20 was applied to give the title compound, which was converted to the HCl salt (332 mg, 83%) as a white solid after treatment with HCl in dioxane. LCMS: m / z 212 [M+H]+ . 1 NMR (400MHz, CDCl3) δ6.74(s,1H),6.52(s,1H),3.88(s,3H),3.83(s,3H),3.80(s,3H),3.00(s,2H),2.80(s,2H).

[0200] Step 4: N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-(methylthio)phenyl)ethan-1-amine The same procedure used for the preparation of 2-20 was applied to give the title compound, which was converted to the HCl salt (86 mg, 36%) as a white solid after treatment with HCl in dioxane. LCMS: 2.483 min, m / z 366.35 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.40-7.31(m,2H),7.25(s,1H),6.84(d,J=5.6Hz,2H),4.20(s,2H) ,3.86(s,3H),3.84(s,3H),3.29-3.21(m,2H),3.05-2.97(m,2H),2.44(s,3H),2.41(s,3H).

[0201] Example 46: N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-(methylsulfinyl)phenyl)-ethan-1-amine (2-25) [ka] To a stirred solution of N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-(methylthio)phenyl)ethan-1-amine (2-24 (50 mg, 0.14 mmol, 1.0 equiv.) in dichloromethane (5 mL) was added m-CPBA (28 mg, 0.14 mmol, 1.0 equiv.) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous NaSO and extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography (eluted with petroleum ether / EA=1:1) to give the title compound, which was converted to the HCl salt (40 mg, 42%) as a white solid after treatment with HCl in dioxane. LCMS: 2.192 min, m / z 382.25 [M+H]+. 1H NMR (400MHz, methanol-d4) δ7.38-7.33(m,3H),7.29-7.23(m,1H),7.05(s,1H),4.22(s,2H), 3.92(s,3H),3.90(s,3H),3.32-3.26(m,2H),3.14-3.07(m,2H),2.81(s,3H),2.41(s,3H).

[0202] Example 47: (3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-(methylsulfonyl)phenyl)ethan-1-amine (2-26) [ka] Step 1: (2,5-Dimethoxy-4-(2-nitroethyl)phenyl)(methyl)sulfane To a stirred solution of (2,5-dimethoxy-4-(2-nitrovinyl)phenyl)(methyl)sulfane (349 mg, 1.37 mmol, 1.0 equiv) in MeOH / THF (1:2, 10 mL) was added NaBH4 (152 mg, 4.1 mmol, 3.0 equiv) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by flash chromatography (eluted with petroleum ether / EA=1:1) to give the title compound (216 mg, 62%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 6.74 (s, 1H), 6.66 (s, 1H), 4.59 (t, J = 7.2 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H).

[0203] Step 2 1,4-Dimethoxy-2-(methylsulfonyl)-5-(2-nitroethyl)benzene To a stirred solution of (2,5-dimethoxy-4-(2-nitroethyl)phenyl)(methyl)sulfane (100 mg, 0.39 mmol, 1.0 equiv) in AcOH (2 mL) was added HO (132 mg, 1.17 mmol, 3.0 equiv) and HSO (1 drop) at 0° C. The resulting mixture was stirred at 75° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by flash chromatography (eluted with petroleum ether / EA=1:1) to give the title compound (110 mg, 98%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.47 (s, 1H), 6.90 (s, 1H), 4.64 (t, J = 6.9 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.34 (t, J = 6.9 Hz, 2H), 3.22 (s, 3H).

[0204] Step 3: 2-(2,5-dimethoxy-4-(methylsulfonyl)phenyl)ethan-1-amine To a stirred solution of 1,4-dimethoxy-2-(methylsulfonyl)-5-(2-nitroethyl)benzene (110 mg, 0.39 mmol, 1.0 equiv) in EtOH / HO (2.5 / 1 mL) was added Fe (65 mg, 1.17 mmol, 3.0 equiv) and NH4Cl (65 mg, 1.17 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at reflux overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude residue which was purified by flash chromatography (eluted with MeOH / DCM=1:100) to give the title compound (104 mg, 100%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.43 (s, 1H), 6.89 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.22 (s, 3H), 2.95 (t, J = 6.9 Hz, 2H), 2.81 (t, J = 6.9 Hz, 2H).

[0205] Step 4: (3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-(methylsulfonyl)phenyl)ethan-1-amine The same procedure for the preparation of 2-2 was applied to give the title compound, which was converted to the HCl salt (35 mg, 20%) as a white solid after treatment with HCl in dioxane. LCMS: 2.112 min, m / z 398.35 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.46(s,1H),7.35(s,1H),7.32(s,1H),7.26(s,1H),7.19(s,1H),4.20( s,2H),3.97(s,3H),3.88(s,3H),3.30-3.26(m,2H),3.22(s,3H),3.17-3.05(m,2H),2.39(s,3H).

[0206] Example 48 N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-methylphenyl)propan-1-amine (2-27) [ka] Step 1: 1,4-Dimethoxy-2-methyl-5-(2-nitroprop-1-en-1-yl)benzene A suspension of 2,5-dimethoxy-4-methylbenzaldehyde (3 g, 17 mmol, 1 equiv), nitroethane (3.12 g, 42 mmol, 2.5 equiv), and NHOAc (6.4 g, 83 mmol, 5 equiv) in 30 mL of AcOH was stirred at 80° C. overnight. The reaction was monitored by TLC until completion. The resulting mixture was poured into water (20 mL). A yellow solid was formed, which was filtered and recrystallized from EtOH to give the title compound (0.84 g, 21%) as a yellow solid. 1 HNMR (400MHz, CDCl3): ppm 8.28 (s, 1H), 6.76 (s, 1H), 6.75 (s, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H).

[0207] Step 2: 1-(2,5-dimethoxy-4-methylphenyl)propan-2-amine 1,4-Dimethoxy-2-methyl-5-(2-nitroprop-1-en-1-yl)benzene (300 mg, 1 equiv.) dissolved in THF (5 mL) was added dropwise to a suspension of LiAlH4 (192 mg, 4 equiv.) in THF (4 mL) at 0° C. The reaction was stirred at 0° C. for another 30 min. Water (1 mL) was added to quench the reaction, followed by NaOH / H2O (3 mL). The resulting mixture was extracted with DCM (5 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with DCM / MeOH=10:1) to give the title compound (94 mg, 34%) as a brown oil. LC_MS: (ES+): m / z 210 [M+H] + . 1 H NMR (400 MHz, solvent: CDCl3) ppm 6.68 (s, 1H), 6.64 (s, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.27-3.22 (m, 1H), 2.75-2.71 (m, 1H), 2.60-2.54 (m, 1H), 1.15 (d, J = 8.0 Hz, 3H).

[0208] Step 3: N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-methylphenyl)propan-2-amine The same procedure as for the preparation of 2-2 was applied to give the title compound as a colorless oil. The free amine was converted to its HCl salt (30 mg, 64%) as a white solid after treatment with HCl in dioxane. LCMS: (ES+): m / z 348 [M+H] + . 1 H NMR (400MHz, solvent: CDCl3) ppm 7.35(s,1H),7.33(s,1H),7.25(s,1H),6.84(s,1H),6.77(s,1H),4.29-4.21(m,2H),3.80(s,3H),3.79(s,3H) ),3.62-3.57(m,1H),3.22-3.18(m,1H),2.83-2.77(m,1H),2.40(s,3H),2.21(s,1H),1.31(d,J=8.0Hz,3H).

[0209] Example 49: N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-3-methylphenyl)propan-2-amine 2-28 [ka] The same procedure as for the preparation of 2-27 was applied to give the title compound as a colorless oil. The free amine was converted to its HCl salt (20 mg, 44%) as a white solid after treatment with HCl in dioxane. LCMS: (ES+): m / z 348 [M+H] + . 1 H NMR (400MHz, solvent: CDCl3) ppm 7.38(s,1H),7.35(s,1H),7.12(s,1H),6.62(s,1H),6.54(s,1H),4.06-3.93(m,2H),3.75(s,3H),3 .60(s,3H),3.45-3.37(m,2H),2.83-2.77(m,1H),2.32(s,3H),2.24(s,3H),1.34(d,J=8.0Hz,3H).

[0210] Example 50: 2-((3-chloro-5-methylbenzyl)amino)-3-(2,5-dimethoxyphenyl)propan-1-ol (2-29) [ka] Step 1: 2-Amino-3-(2,5-dimethoxyphenyl)propan-1-ol To a solution of 2-amino-3-(2,5-dimethoxyphenyl)propanoic acid (500 mg, 2.22 mmol, 1 equiv) in THF (20 mL) was added LAH (337 mg, 9 mmol, 4 equiv). The resulting mixture was stirred for 16 h. LCMS showed the reaction was complete. The reaction was quenched with water and NaOH. The resulting mixture was filtered and washed with EA. The organic phase was collected and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography to give the title compound as an oil (190 mg, 40%).

[0211] Step 2: 2-Amino-3-(2,5-dimethoxyphenyl)propan-1-ol hydrochloride To a solution of 2-amino-3-(2,5-dimethoxyphenyl)propan-1-ol (190 mg, 1 equiv.) in MTBE (10 mL) was added 4M HCl in dioxane (2 mL, >10 equiv.). The resulting white solid was filtered and washed with MTBE to give the title compound (180 mg, 90%).

[0212] Step 3: 2-((3-chloro-5-methylbenzyl)amino)-3-(2,5-dimethoxyphenyl)propan-1-ol To a solution of 3-chloro-5-methylbenzaldehyde (112 mg, 0.72 mmol, 1 equiv) in DCM (5 mL) were added 2-amino-3-(2,5-dimethoxyphenyl)propan-1-ol hydrochloride (180 mg, 0.72 mmol, 1 equiv), TEA (218 mg, 2.16 mmol, 3 equiv), and NaBH(OAc)3 (440 mg, 2.16 mmol, 3 equiv), and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NaHCO3 and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100 / 1) to give the title compound as a colorless oil (98 mg, 44%). LCMS: m / z 351.00 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.08(s,1H),7.04(s,1H),6.94(s,1H),6.87(d,J=8.8Hz,1H),6.78(dd,J=8.8,3.0Hz,1H),6.73(d,J=3.0Hz,1H),3.74(m,8H),3. 53(dd,J=11.1,4.7Hz,1H),3.45(dd,J=11.1,6.5Hz,1H),2.93-2.86(m,1H ),2.79(dd,J=13.1,6.7Hz,1H),2.65(dd,J=13.1,6.9Hz,1H),2.31(s,3H).

[0213] Example 51 2-((3-chloro-5-methylbenzyl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol (2-30) [ka] The same procedure for the preparation of 2-29 was applied to give the target, which was treated with 4M HCl in dioxane to give the title compound as a white solid (57 mg, 73%). 1H NMR(400MHz,MeOD)δ7.38(s,1H),7.34(s,1H),7.27(s,1H),7.15(d,J=3.0Hz,1H),6.93(d,J=8.9Hz,1H),6.87(dd,J=8.9,3.0Hz,1H),5 .28(dd,J=9.5,2.9Hz,1H),4.24(s,2H),3.79(d,J=1.7Hz,6H),3.28(dd,J=12.5,2.9Hz,1H),2.98(dd,J=12.5,9.6Hz,1H),2.41(s,3H). LCMS:m / z 336.95[M+H] +

[0214] Example 52: N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-morpholinophenyl)ethan-1-amine (2-31). [ka] Step 1: 4-(2,5-dimethoxyphenyl)morpholine To a solution of 2-fluoro-1,4-dimethoxybenzene (733 mg, 4.7 mmol, 1 equiv) in THF at 0° C. was added 1M n-BuLi in THF (5 mL, 5 mmol, 1.05 equiv) and the reaction was stirred at 0° C. for 15 min. Morpholine (435 mg, 5 mmol, 1.05 equiv) was added and the resulting mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction was quenched with water and extracted with DCM. The organic phase was concentrated under reduced pressure to give a residue which was purified by flash chromatography to give the title compound (232 mg, 20%).

[0215] Step 2: 2,5-Dimethoxy-4-morpholinobenzaldehyde To a solution of 4-(2,5-dimethoxyphenyl)morpholine (182 mg, 1 equiv.) in POCl3 (5 mL) was added DMF (0.5 mL). The resulting mixture was stirred at room temperature for 16 h. TLC showed the reaction was complete. The reaction was quenched with water and extracted with DCM. The organic phase was concentrated under reduced pressure to give a residue which was purified by flash chromatography to give the title compound (92 mg, 45%).

[0216] Step 3: (E)-4-(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)morpholine To a solution of 2,5-dimethoxy-4-morpholinobenzaldehyde (92 mg, 0.36 mmol, 1 equiv) in CH3NO2 (10 mL) was added NHOAc (11 mg, 0.15 mmol, 0.4 equiv) and the resulting mixture was stirred at 100° C. for 1 h. TLC showed the reaction was complete. The reaction was quenched by adding water. The yellow solid was filtered to give the title compound (87 mg, 82%).

[0217] Step 4: 2-(2,5-dimethoxy-4-morpholinophenyl)ethan-1-amine To a solution of (E)-4-(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)morpholine (87 mg, 0.27 mmol, 1 equiv.) in THF (5 mL) was added LAH (38 mg, 1 mmol, 4 equiv.). The resulting mixture was then stirred at room temperature for 2 h. TLC showed the reaction was complete. Water and NaOH were added to quench the reaction. The resulting mixture was filtered and washed with EA. The organic phase was concentrated under reduced pressure to give a residue which was purified by flash chromatography to give the title compound (25 mg, 30%).

[0218] Step 5: N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-morpholinophenyl)ethan-1-amine hydrochloride To a solution of 3-chloro-5-methylbenzaldehyde (14 mg, 0.094 mmol, 1 equiv) in DCM (2 mL) was added 2-(2,5-dimethoxy-4-morpholinophenyl)ethan-1-amine (25 mg, 0.094 mmol, 1 equiv) and NaBH(OAc)3 (59 mg, 0.282 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NaHCO3 and extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100 / 1) to give the product, which was treated with 4M HCl in dioxane to give the title compound as a white solid (12 mg, 29%). LCMS: m / z 406.45 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.40(s,1H),7.37(s,1H),7.35(s,1H),7.32(s,1H),7.29(s,1H),4.24(s,2H),4.14(t,J=4.7Hz, 4H), 4.04(s,3H),3.93(s,3H),3.78(s,4H),3.27(dd,J=18.7,10.0Hz,2H),3.12(dd,J=9.5,6.2Hz,2H),2.41(s,3H).

[0219] Example 53(a): (R)-2-((3-chloro-5-methylbenzyl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol (2-32) Example 53(b): (S)-2-((3-chloro-5-methylbenzyl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol (2-33) [ka] 2-((3-chloro-5-methylbenzyl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol, 2-30 (48 mg, 0.14 mmol) was purified by chiral chromatography to give (R)-2-((3-chloro-5-methylbenzyl)-amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol (18 mg) and (S)-2-((3-chloro-5-methylbenzyl)-amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol (16 mg). 1 H NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 7.07-7.03 (m, 2H), 7.01 (s, 1H), 6.80-6.73 (m, 2H), 5.03 (dd, J=8.4, 3.4 Hz, 1H), 3.83-3.71 (m, 8H), 2.96 (dd, J=12.1, 3.5 Hz, 1H), 2.72 (dd, J=12.1, 8.5 Hz, 1H), 2.32 (s, 3H). NMR is identical for both.

[0220] Example 54: (R)-(4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)-(imino)(methyl)-16-sulfanone (2-34) Example 55: (S)-(4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)-(imino)(methyl)-16-sulfanone (2-35) [ka] Step 1: (3-chloro-5-methylbenzyl)(2,5-dimethoxy-4-methylsulfinyl)phenethyl)-tert-butyl carbamate To a solution of N-(3-chloro-5-methylbenzyl)-2-(2,5-dimethoxy-4-(methylsulfinyl)phenyl)ethan-1-amine (283 mg, 0.74 mmol, 1 eq.) in DCM was added di-tert-butyl dicarbonate (324 mg, 1.48 mmol, 2 eq.), TEA (224 mg, 2.22 mmol, 3 eq.) and DMAP (9 mg, 0.074 mmol, 0.1 eq.). The resulting mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction was quenched with water and extracted with DCM. The combined organic phase was concentrated under reduced pressure to give the title compound (330 mg, 92%).

[0221] Step 2: tert-butyl (3-chloro-5-methylbenzyl)(2,5-dimethoxy-4-(S-methylsulfonimidoyl)-phenethyl)carbamate To tert-butyl (3-chloro-5-methylbenzyl)(2,5-dimethoxy-4-(methylsulfinyl)phenethyl)carbamate (180 mg, 0.37 mmol, 1 equiv.) in MeOH (5 mL) was added ammonium carbamate (58 mg, 0.74 mmol, 2 equiv.) and (diacetoxyiodo)benzene (238 mg, 0.74 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction was quenched with water and extracted with DCM. The organic phase was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography to give the title compound (100 mg, 52%).

[0222] Step 3: (4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)-(methyl)-16-sulfanone hydrochloride tert-Butyl (3-chloro-5-methylbenzyl)(2,5-dimethoxy-4-(S-methylsulfonimidoyl)phenethyl)-carbamate (100 mg, 0.20 mmol, 1 eq) in DCM (10 mL) was added to 4M HCl in dioxane (5 mL). The resulting mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction was concentrated, washed with petroleum ether (10 mL) and filtered to give the title compound as the HCl salt (96 mg, 90%). LCMS: m / z 398.15 [M+H] + . 1 H NMR(400MHz,CDCl3)δ7.46(s,1H),7.09(s,1H),7.05(s,1H),6.98(s,1H),6.89(s, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.76 (s, 2H), 3.28 (s, 3H), 2.87 (s, 4H), 2.31 (s, 3H).

[0223] Step 4: (R)-(4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-16-sulfanone (2-34) (S)-(4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-16-sulfanone (2-35) (4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-16-sulfanone hydrochloride (60 mg, 0.14 mmol) was purified by chiral chromatography to give (R)-(4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-16-sulfanone (18 mg) and (S)-(4-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-2,5-dimethoxyphenyl)(imino)(methyl)-16-sulfanone (16 mg). LCMS: m / z 398.15 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.46(s,1H), 7.09(s,1H), 7.05(s,1H), 6.98(s,1H), 6.89(s,1H), 3.93(s,3H), 3.83(s,3H), 3.75(s,2H), 3.28(s,3H), 2.87(s,4H), 2.31(s,3H). The spectra were identical for both enantiomers.

[0224] Example 56: 3-(((2,5-dimethoxyphenethyl)amino)methyl)-5-methylbenzonitrile (2-36) [ka] The same procedure as for the preparation of 2-2 was applied to give the product, which was treated with 4M HCl in dioxane to give the title compound as a white solid. (47 mg, 20%). LCMS: m / z 311.50 [M+H] + . 1 H NMR(400MHz,DMSO)δ9.37(s,2H),7.85(s,1H),7.74(s,1H),7.72(s,1H),6.93(d,J=8.8Hz,1H),6.81(dt,J=7.0,3 .0Hz,2H),4.19(t,J=5.5Hz,2H),3.74(s,3H),3.70(s,3H),3.07(d,J=5.2Hz,2H),2.99-2.85(m,2H),2.38(s,3H).

[0225] Example 57: 3-Chloro-5-(((2,5-dimethoxyphenethyl)amino)methyl)benzonitrile hydrochloride (2-37) [ka] The same procedure as for the preparation of 2-2 was applied to give the crude product, which was treated with 4M HCl in dioxane to give the title compound as a white solid (100 mg, 45%). LCMS: m / z 332.15 [M+H] + . 1H NMR(400MHz,MeOD)δ7.97-7.95(m,1H),7.91(t,J=1.5Hz,1H),7.85(s,1H),6.95(d,J=8.5Hz,1H),6.8 8-6.82(m,2H),4.32(s,2H),3.83(s,3H),3.77(s,3H),3.29(dd,J=8.9,6.7Hz,2H),3.06-2.99(m,2H).

[0226] Example 58: Methyl 3-chloro-5-(((2,5-dimethoxyphenethyl)amino)methyl)benzoate hydrochloride (2-38) [ka] The same procedure as for the preparation of 2-2 was applied to give the crude product, which was treated with 4M HCl in dioxane to give the title compound as a white solid (120 mg, 54%). LCMS: m / z 365.15 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.12(s,1H),8.09(t,J=1.6Hz,1H),7.82(t,J=1.7Hz,1H),6.94(d,J=8.6Hz,1H),6.88-6. 82(m,2H),4.31(s,2H),3.97(s,3H),3.82(s,3H),3.77(s,3H),3.28(dd,J=8.8,6.7Hz,2H),3.07-2.99(m,2H).

[0227] Example 59: 3-Chloro-5-(((2,5-dimethoxyphenethyl)amino)methyl)benzoic acid hydrochloride (2-39) [ka] A solution of methyl 3-chloro-5-(((2,5-dimethoxyphenethyl)amino)methyl)benzoate (100 mg, 0.27 mmol, 1 equiv.), lithium hydroxide (32 mg, 1.35 mmol, 5 equiv.) in THF / MeOH / water (1:1, 4 mL) was stirred at room temperature for 16 h. TLC showed the reaction was complete. The reaction mixture was washed with NaHCO3 (aqueous) and extracted with DCM. The organic phase was collected and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (eluted with DCM / MeOH=10 / 1) to give the crude product as an oil, which was treated with 4M HCl in dioxane to give the title compound as a white solid (45 mg, 47%). LCMS: m / z 350.45 [M+H] + . 1 H NMR(400MHz,CDCl3)δ9.63(s,2H),8.25(s,1H),8.09(s,1H),7.46(s,1H),6.64(d,J=2.8Hz,1H),6.61(d,J=8.9Hz,1 H),6.56(dd,J=8.9,2.8Hz,1H),4.19(s,2H),3.61(s,3H),3.60(s,3H),3.19(t,J=6.4Hz,2H),2.98(t,J=6.8Hz,2H).

[0228] Example 60: N-(3-chloro-5-methylbenzyl)-1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (2-40) [ka] Step 1: 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine A solution of 1-(2,5-dimethoxyphenyl)propan-2-amine hydrochloride from the preparation of 2-27 (190 mg, 0.82 mmol, 1 equiv), silver sulfate (586 mg, 1.89 mmol, 2.3 equiv), and iodine (483 mg, 1.89 mmol, 2.3 equiv) in MeOH (10 mL) was stirred at room temperature for 16 h. The reaction was washed with NaHCO3 (aqueous) and extracted with DCM. The organic phase was concentrated under reduced pressure to give a residue which was purified by flash chromatography (DCM / MeOH=10 / 1) to give the title compound (50 mg, 19%). LCMS: (ES+): m / z 322.15 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.38(s,1H),6.84(s,1H),3.84(s,3H),3.83(s,3H),3.56(dd,J=13.4,6 .7Hz,1H),2.93(dd,J=13.5,6.8Hz,1H),2.85(dd,J=13.5,7.0Hz,1H),1.28(d,J=6.6Hz,3H).

[0229] Step 2: N-(3-chloro-5-methylbenzyl)-1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine A solution of 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (50 mg, 0.16 mmol, 1 equiv.) and 3-chloro-5-methylbenzaldehyde (24 mg, 0.16 mmol, 1 equiv.) in DCM (5 mL) was stirred at room temperature for 1 h, followed by the addition of NaBH(OAc)3 (120 mg, 0.64 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 16 h. The reaction was washed with NaHCO3 (aqueous) and extracted with DCM. The organic phase was concentrated under reduced pressure to give a residue which was purified by flash chromatography (DCM / MeOH=10 / 1) to give the product which was purified by preparative HPLC to give the title compound as a TFA salt (50 mg, 54% yield). LCMS: (ES+): m / z 460.25 [M+H] + . 1H NMR(400MHz,MeOD)δ7.38(s,1H),7.35(s,2H),7.24(s,1H),6.84(s,1H),4.33-4.20(m,2H),3.84(s,3H),3.81(s,3H),3.6 1(dq,J=13.2,6.7Hz,1H),3.22(dd,J=13.1,4.9Hz,1H),2.80(dd,J=13.2,9.1Hz,1H),2.41(s,3H),1.31(d,J=6.6Hz,3H).

[0230] Example 61: (R)-1-(2,5-dimethoxyphenyl)-2-((3-fluoro-5-methylbenzyl)amino)ethan-1-ol hydrochloride (2-41) [ka] Example 62: (S)-1-(2,5-dimethoxyphenyl)-2-((3-fluoro-5-methylbenzyl)amino)ethan-1-ol hydrochloride (2-42) [ka] The same procedure for the preparation of 2-2 was applied to give a racemic mixture, which was resolved by chiral chromatography to give 2-41 and 2-42. LCMS: m / z 320.45 [M+H] + . 1 H NMR(400MHz,CDCl3)δ7.05(d,J=2.4Hz,1H),6.91(s,1H),6.85(d,J=9.2Hz,1H),6.77(m,3H),5.04(dd,J=8 .5,3.4Hz,1H),3.87-3.71(m,8H),2.97(dd,J=12.1,3.4Hz,1H),2.73(dd,J=12.1,8.6Hz,1H),2.33(s,3H).

[0231] Example 63: GPCR Arrestin Assay: Arrestin Pathway (Performed by DiscoverX Eurofins) The PathHunter® β-arrestin assay uses a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) using β-galactosidase (β-Gal) as a functional reporter to monitor GPCR activation in a homogenous, non-imaging assay format. The enzyme is split into two inactive complementation moieties (EA for enzyme acceptor and PK for ProLink) that are expressed as fusion proteins in cells. The EA is fused to β-arrestin and the PK is fused to the GPCR of interest. When the GPCR is activated and β-arrestin is recruited to the receptor, ED and EA complementation occurs, restoring β-Gal activity that is measured using chemiluminescent PathHunter® detection reagents.

[0232] PathHunter cell lines (DiscoveRx Eurofins) were grown from freezer stocks following standard procedures. Cells were seeded into white-walled 384-well microplates in a total volume of 20 μL and incubated at 37°C for the appropriate time prior to testing. For agonist determinations, cells were incubated with samples to elicit a response. Intermediate dilutions of sample stocks were performed to generate 5X samples in assay buffer. 5 μL of 5X samples were added to cells and incubated at 37°C or room temperature for 90-180 minutes. Vehicle concentration was 1%. b-Arrestin assay signal was generated through a single addition of 12.5 or 15 μL (50% v / v) of PathHunter detection reagent cocktail, followed by 1 hour incubation at room temperature. Microplates were read after signal generation using a PerkinElmer Envision™ instrument for chemiluminescent signal detection. Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). For the agonist mode assay, percent activity was calculated using the following formula: % Activity=100%×(mean RLU of test sample−mean RLU of vehicle control) / (mean maximum control ligand−mean RLU of vehicle control).

[0233] In these studies, 10 μM serotonin was used to generate the maximal control ligand response.

[0234] Calcium Mobilization Assay (Performed by DiscoveRx Eurofins) Calcium No-Wash PLUS The assay monitors activation of GPCRs via Gq second messenger signaling in a live cell, non-imaging assay format. Calcium mobilization is monitored in PathHunter® cell lines, or other cell lines stably expressing Gq-coupled GPCRs, using a calcium-sensitive dye that is loaded into the cells. GPCR activation by compounds results in the release of calcium from intracellular stores and an increase in dye fluorescence that is measured in real time.

[0235] Cell lines expressing the GPCR of interest were grown from freezer stocks following standard procedures. Cells were seeded into black-walled and clear-bottom poly-D-lysine-coated 384-well microplates in a total volume of 20 μL and incubated at 37°C for the appropriate time prior to testing. Assays were performed in 1x dye loading buffer consisting of 1x dye, 1x additive A, and 2.5 mM probenecid in HBSS / 20 mM Hepes. Probenecid was freshly prepared. Cells were loaded with dye prior to testing. Media was aspirated from cells and replaced with 20 μL of dye loading buffer. Cells were incubated for 30-60 min at 37°C. For agonist determinations, cells were incubated with sample to elicit a response. After dye loading, cells were removed from the incubator and 10 μL HBSS / 20 mM Hepes was added. 3x vehicle was included in the buffer when performing agonist dose curves to define the EC80 for subsequent agonist assays. Cells were incubated at room temperature in the dark for 30 minutes to equilibrate plate temperature. Intermediate dilutions of sample stocks were performed to generate 4x samples in assay buffer. Compound agonist activity was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and 10 μL of 4x sample in HBSS / 20mM Hepes was added to cells 5 seconds into the assay. Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). For agonist mode assays, the percent activity was calculated using the following formula: % Activity=100%×(mean RFU of test sample−mean RFU of vehicle control) / (mean max RFU control ligand−mean RFU of vehicle control).

[0236] In these studies, maximum RFU was generated by using 0.1 μM serotonin in the calcium mobilization assay.

[0237] Biological Experiments Compounds 1-1 HCl, 1-2, and 2-1 were evaluated 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, and β-arrestin activation and recruitment to GPCRs. The results are shown in Table 3 below. [Table 3]

[0238] The compounds showed greater potency on the 5-HT2A receptor compared to the other 5-HT receptors studied. 5-HT2A activity is shown in Tables 4-5. Interestingly, all compounds showed selectivity for 5-HT2A, with approximately 560-fold selectivity for 5-HT2A compared to 5-HT2B. Such selectivity is surprising and unexpected considering the structural similarity between the 5-HT2A and 5-HT2B receptors. Furthermore, this selectivity would allow for a safety advantage over other non-selective hallucinogens by potentially reducing the risk of valvular heart disease typically associated with prolonged 5-HT2B activation and repeated dosing. Among other receptors, compound 1-2 showed approximately 7-10-fold greater potency for 5-HT1A and 5-HT2C than compound 1-1·HCl. All compounds are also potent activators of β-arrestin recruitment at 5-HT2A at slightly lower potency than Gq-mediated signaling, suggesting a slight Gq signaling bias. Compound 2-1 was found to be the most potent of all compounds studied at 5-HT2A and 5-HT2C, and showed the greatest selectivity for 5-HT2A over 5-HT2B by approximately 4400-fold. As with the other compounds, no significant activity was observed at 5-HT2B at concentrations below 10 uM.

[0239] EC of the compound 50The profiles demonstrated that all were agonists of 5-HT2A-mediated signaling. However, while compounds 1-1·HCl and 1-2 showed full agonism, compound 2-1 was observed to be a partial agonist (Figure 1). Both compounds 1-1·HCl and 1-2 showed maximal effect levels of approximately 100% compared to the maximum serotonin response to Gq signaling, whereas the maximal effect level for compound 2-1 was approximately 86%. Similar to the bias signaling potency findings above, all compounds showed less than 100% maximal response to β-arretin, suggesting a slight bias towards Gq-mediated signaling of the 5-HT2A receptor. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

[0240] Numbered embodiments of the present disclosure In addition to the above disclosure, the following examples, and the appended claims, the present disclosure describes the following numbered embodiments: 1. Compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R1 is, independently at each occurrence, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2 and R3 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, or SR1, and at least one of R2 and R3 is hydrogen; R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, O(C=O)(R 12 ), or NH(C=O)(R 12 ) and R 12 is C1-C6 alkyl, A compound wherein n is an integer of 0 to 3. 2. The compound of embodiment 1, wherein R1 is C1-C6 alkyl. 3. The compound according to embodiment 1, wherein R1 is methyl, ethyl, propyl, or isopropyl. 4. The compound according to embodiment 1, wherein R1 is methyl. 5. A compound according to any one of embodiments 1-4, wherein R2 is hydrogen, methyl, or ethyl, and R3 is hydrogen. 6. A compound according to any one of embodiments 1-4, wherein R2 is halogen and R3 is hydrogen. 7. A compound according to any one of embodiments 1-4, wherein R2 is hydrogen and R3 is halogen. 8. The compound according to any one of embodiments 1-7, wherein R4 is C1-C6 alkyl. 9. The compound according to any one of embodiments 1-8, wherein R4 is methyl. 10. A compound according to any one of embodiments 1-9, wherein R5 is halogen. 11. A compound according to any one of embodiments 1-10, wherein R5 is chloro. 12. A compound according to any one of the preceding embodiments, wherein R6 is hydrogen. 13. The compound according to any one of embodiments 1 to 12, wherein n is 1. 14. The compound according to any one of embodiments 1 to 12, wherein n is 2. 15. A compound: [Table 6-1] [Table 6-2] 16. Compound of formula (II): (II), [ka] or a pharma- ceutically acceptable salt thereof, wherein: R1 is, independently at each occurrence, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2, R3, and R7 are independently hydrogen, heterocycle, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, S(O)(=NH)R1, S(O)2R1, S(O)R1, or SR1, and at least one of R2 and R3 is hydrogen; R4, R5, and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, OR1, SR1, (C=O)(R 14 ), O(C=O)(R 14 ), NO2, or NH(C=O)(R 14 ) and R 14 is C1-C6 alkyl, OH, or OC1-C6 alkyl; R8 and R9 are independently hydrogen, C1-C6 alkyl, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C 10cycloalkyl, CHOH, or CHO-C1-C4 alkyl; R 10 and R 11 are independently hydrogen, halogen, C1-C6 alkyl, OH, C1-C4 alkyl, C3-C6 cycloalkyl, or CH2O-C1-C4 alkyl; R 12 is hydrogen, CH2OH, CH2O-C1-C9 alkyl, C3-C 10 cycloalkyl, CHOH, or CHO-C1-C4 alkyl; R 13 is hydrogen, C1-C9 alkyl, C3-C 10 cycloalkyl, or CHOH, CHO-C1-C4 alkyl; A compound wherein n is an integer of 0 to 3. 17. The compound according to embodiment 16, wherein R1 is C1-C6 alkyl. 18. The compound according to embodiment 17, wherein R1 is methyl, ethyl, propyl, or isopropyl. 19. The compound according to embodiment 18, wherein R1 is methyl. 20. A compound according to any one of embodiments 16-19, wherein R2 and R3 are hydrogen. 21. A compound according to any one of embodiments 16-19, wherein R2 is halogen and R3 is hydrogen. 22. A compound according to any one of embodiments 16-19, wherein R2 is hydrogen and R3 is halogen. 23. The compound according to any one of embodiments 16-22, wherein R4 is C1-C6 alkyl. 24. The compound according to embodiment 23, wherein R4 is methyl. 25. A compound according to any one of embodiments 16-24, wherein R5 is halogen. 26. The compound according to embodiment 25, wherein R5 is chloro. 27. A compound according to any one of embodiments 16-26, wherein R6 is hydrogen. 28. A compound according to any one of embodiments 16-27, wherein R7 is hydrogen. 29. A compound according to any one of embodiments 16-28, wherein R8 and R9 are hydrogen. 30.R 10 and R 11 The compound of any one of embodiments 16-29, wherein is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or CH2O-C1-C4 alkyl. 31.R 10 and R 11 The compound of any one of embodiments 16-29, wherein is fluoro. 32.R 12 CH2OH, CH2O-C1-C4 alkyl, C3-C 10 The compound according to any one of embodiments 16-31, which is cycloalkyl, CH2OH, or CH2O-C1-C4 alkyl. 33.R 13 The compound of any one of embodiments 16-32, wherein is C1-C4 alkyl or C3-C6 cycloalkyl. 34.R 12 and R 13 The compound of any one of embodiments 16-33, wherein is hydrogen. 35. A compound: [ka] or a pharma- ceutically acceptable salt thereof. 36. A compound: [ka] or a pharma- ceutically acceptable salt thereof. 37. A compound: [ka] or a pharma- ceutically acceptable salt thereof. 38. A compound: [ka] or a pharma- ceutically acceptable salt thereof. 39. A compound: [ka] or a pharma- ceutically acceptable salt thereof. 40. A compound is [ka] or a pharma- ceutically acceptable salt thereof. 41. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 40 and a pharma- ceutically acceptable excipient. 42. A method for treating a mental health disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40. 43. The method of embodiment 42, wherein the mental health disease or disorder is major depressive disorder, treatment-resistant depression, a substance use disorder, or an eating disorder. 44. A compound selected from one of the compounds in Table 1. 45. A compound selected from one of the compounds in Table 2. 46. ​​The compound of formula (I) is of formula (IA): [ka] or a pharma- ceutically acceptable salt thereof. 47. The compound of formula (II) is represented by the formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof.

Claims

1. A compound of formula (I): 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof, wherein in the formula, R １ is, independently at each position, hydrogen, C １ -C ６ alkyl, or C １ -C ６ haloalkyl, R ２ and R ３ are, independently, hydrogen, C １ -C ６ alkyl, C １ -C ６ haloalkyl, halogen, cyano, OR １ or SR １ wherein at least one of R ２ and R ３ is hydrogen, R ４ R ５ and R ６ are, independently, hydrogen, C １ -C ６ alkyl, C １ -C ６ haloalkyl, halogen, cyano, OR １ SR １ O(C=O)(R １２ ) or NH(C=O)(R １２ ) wherein R １２ is C １ -C ６ alkyl, and n is an integer from 0 to 3. A compound

2. The compound according to claim 1, selected from 【Table 1-1】 【Table 1-2】 or a pharmaceutically acceptable salt thereof

3. A compound of formula (II): (II), 【Chemical formula 2】 or a pharmaceutically acceptable salt thereof, R １ is, independently at each position, hydrogen, C １ ~ C ６ alkyl, or C １ ~ C ６ haloalkyl, R ２ , R ３ , and R ７ are, independently, hydrogen, a heterocyclic ring, C １ ~ C ６ alkyl, C １ ~ C ６ haloalkyl, halogen, cyano, OR １ , S(O)(=NH)R １ , S(O) ２ R １ , S(O)R １ , or SR １ , and at least one of R ２ and R ３ is hydrogen, R ４ , R ５ , and R ６ are, independently, hydrogen, C １ ~ C ６ alkyl, C １ ~ C ６ haloalkyl, halogen, cyano, OR １ , SR １ , (C=O)(R １４ ), O(C=O)(R １４ ), NO ２ , or NH(C=O)(R １４ ), and R １４ is C １ ~ C ６ alkyl, OH, or OC １ ~ C ６ alkyl, R ８ and R ９ are, independently, hydrogen, C １ ~ C ６ alkyl, C １ ~ C ４ alkyl, C ３ ~ C ６Cycloalkyl, C ３ ~C １０ Cycloalkyl, CH ２ OH, or CH ２ O-C １ ~C ４ alkyl, and R １０ and R １１ are independently hydrogen, halogen, C １ ~C ６ alkyl, OH, C １ ~C ４ alkyl, C ３ ~C ６ cycloalkyl, or CH ２ O-C １ ~C ４ alkyl, and R １２ is hydrogen, CH ２ OH, CH ２ O-C １ ~C ９ alkyl, C ３ ~C １０ cycloalkyl, CH ２ OH, or CH ２ O-C １ ~C ４ alkyl, and R １３ is hydrogen, C １ ~C ９ alkyl, C ３ ~C １０ cycloalkyl, or CH ２ OH, CH ２ O-C １ ~C ４ alkyl, a compound.

4. The compound is 【Chemical Formula 3】 Or a pharmaceutically acceptable salt thereof, the compound according to claim 3.

5. The compound is 【Chemical Formula 4】 Or a pharmaceutically acceptable salt thereof, the compound according to claim 3.

6. The compound is [Chemical Formula 5] or a pharmaceutically acceptable salt thereof, the compound according to claim 3.

7. The compound is [Chemical Formula 6] or a pharmaceutically acceptable salt thereof, the compound according to claim 3.

8. The compound is [Chemical Formula 7] or a pharmaceutically acceptable salt thereof, the compound according to claim 3.

9. The compound is [Chemical Formula 8] or a pharmaceutically acceptable salt thereof, the compound according to claim 3.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 and a pharmaceutically acceptable excipient.

11. Formula (I) is a compound of formula (I-A), [Chemical Formula 9] or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

12. Formula (II) is a compound of formula (II-A), [Chemical Formula 10] or a pharmaceutically acceptable salt thereof, the compound according to claim 3.

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